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 # Guanfacine: Package Insert / Prescribing Info **Package insert / product label** **Generic name:** guanfacine hydrochloride **Dosage form:** tablet **Drug class:** [Antiadrenergic agents, centrally acting](/drug-class/antiadrenergic-agents-centrally-acting.html) [Medically reviewed](/support/editorial-policy.html#editorial-staff) by Drugs.com. Last updated on May 13, 2026. ##### On This Page ## Guanfacine Description Guanfacine hydrochloride is a centrally acting antihypertensive with α2-adrenoceptor agonist properties in tablet form for oral administration. The chemical name of guanfacine hydrochloride is N-Amidino-2-(2,6-dichlorophenyl) acetamide monohydrochloride and its molecular weight is 282.55. Its structural formula is:  Guanfacine hydrochloride is a white to off-white powder; sparingly soluble in water and alcohol and slightly soluble in acetone. Each tablet, for oral administration, contains guanfacine hydrochloride equivalent to 1 mg or 2 mg guanfacine. The tablets contain the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, partially pregelatinized starch, magnesium stearate and talc. ## Guanfacine - Clinical Pharmacology Guanfacine hydrochloride is an orally active antihypertensive agent whose principal mechanism of action appears to be stimulation of central α2-adrenergic receptors. By stimulating these receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate. The dose-response relationship for blood pressure and adverse effects of guanfacine given once a day as monotherapy has been evaluated in patients with mild to moderate hypertension. In this study patients were randomized to placebo or to 0.5 mg, 1 mg, 2 mg, 3 mg, or 5 mg of guanfacine. Results are shown in the following table. A useful effect was not observed overall until doses of 2 mg were reached, although responses in white patients were seen at 1 mg; 24 hour effectiveness of 1 mg to 3 mg doses was documented using 24 hour ambulatory monitoring. While the 5 mg dose added an increment of effectiveness, it caused an unacceptable increase in adverse reactions. | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | | Mean Changes (mm Hg) from Baseline in Seated Systolic and Diastolic Blood Pressure for Patients Completing 4 to 8 Weeks of Treatment with Guanfacine Monotherapy | | | | | | | | | Mean Change S/D\* Seated | n= (range) | Placebo | 0.5 mg | 1 mg | 2 mg | 3 mg | 5 mg | | White Patients | 11-30 | -1/-5 | -6/-8 | -8/-9 | -12/-11 | -15/-12 | -18/-16 | | Black Patients | 8-28 | -3/-5 | 0/-2 | -3/-5 | -7/-7 | -8/-9 | -19/-15 | | \*S/D=Systolic/diastolic blood pressure | | | | | | | | Mean Changes (mm Hg) from Baseline in Seated Systolic and Diastolic Blood Pressure for Patients Completing 4 to 8 Weeks of Treatment with Guanfacine Monotherapy Mean Change S/D\* Seated n= (range) Placebo 0.5 mg 1 mg 2 mg 3 mg 5 mg White Patients 11-30 -1/-5 -6/-8 -8/-9 -12/-11 -15/-12 -18/-16 Black Patients 8-28 -3/-5 0/-2 -3/-5 -7/-7 -8/-9 -19/-15 \*S/D=Systolic/diastolic blood pressure Controlled clinical trials in patients with mild to moderate hypertension who were receiving a thiazide-type diuretic have defined the dose-response relationship for blood pressure response and adverse reactions of guanfacine given at bedtime and have shown that the blood pressure response to guanfacine can persist for 24 hours after a single dose. In the 12-week placebo-controlled dose-response study, patients were randomized to placebo or to doses of 0.5, 1, 2, and 3 mg of guanfacine, in addition to 25 mg chlorthalidone, each given at bedtime. The observed mean changes from baseline, tabulated below, indicate the similarity of response for placebo and the 0.5 mg dose. Doses of 1, 2, and 3 mg resulted in decreased blood pressure in the sitting position with no real differences among the three doses. In the standing position there was some increase in response with dose. | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | | Mean Decreases (mm Hg) in Seated and Standing Blood Pressure for Patients Treated with Guanfacine in Combination with Chlorthalidone | | | | | | | | Mean Change | n= | Placebo 63 | 0.5 mg 63 | 1 mg 64 | 2 mg 58 | 3 mg 59 | | S/D\* Seated | | -5/-7 | -5/-6 | -14/-13 | -12/-13 | -16/-13 | | S/D\* Standing | | -3/-5 | -5/-4 | -11/-9 | -9/-10 | -15/-12 | | \*S/D = Systolic/diastolic blood pressure | | | | | | | Mean Decreases (mm Hg) in Seated and Standing Blood Pressure for Patients Treated with Guanfacine in Combination with Chlorthalidone Mean Change n= Placebo 63 0.5 mg 63 1 mg 64 2 mg 58 3 mg 59 S/D\* Seated -5/-7 -5/-6 -14/-13 -12/-13 -16/-13 S/D\* Standing -3/-5 -5/-4 -11/-9 -9/-10 -15/-12 \*S/D = Systolic/diastolic blood pressure While most of the effectiveness of guanfacine in combination (and as monotherapy in white patients) was present at 1 mg, adverse reactions at this dose were not clearly distinguishable from those associated with placebo. Adverse reactions were clearly present at 2 and 3 mg (see [ADVERSE REACTIONS](#i4i_adverse_effects_id_325f020a-44e8-484d-933c-93b08f0b2614)). In a second 12-week placebo-controlled study 1, 2, or 3 mg of guanfacine hydrochloride administered with 25 mg chlorthalidone once daily, a significant decrease in blood pressure was maintained for a full 24 hours after dosing. While there was no significant difference between the 12 and 24 hour blood pressure readings, the fall in blood pressure at 24 hours was numerically smaller, suggesting possible escape of blood pressure in some patients and the need for individualization of therapy. In a double-blind, randomized trial, either guanfacine or clonidine was given at recommended doses with 25 mg chlorthalidone for 24 weeks and then abruptly discontinued. Results showed equal degrees of blood pressure reduction with the two drugs and there was no tendency for blood pressures to increase despite maintenance of the same daily dose of the two drugs. Signs and symptoms of rebound phenomena were infrequent upon discontinuation of either drug. Abrupt withdrawal of clonidine produced a rapid return of diastolic and especially, systolic blood pressure to approximately pretreatment levels, with occasional values significantly greater than baseline, whereas guanfacine withdrawal produced a more gradual increase to pretreatment levels, but also with occasional values significantly greater than baseline. ### Pharmacodynamics Hemodynamic studies in man showed that the decrease in blood pressure observed after single-dose or long-term oral treatment with guanfacine was accompanied by a significant decrease in peripheral resistance and a slight reduction in heart rate (5 beats/min). Cardiac output under conditions of rest or exercise was not altered by guanfacine. Guanfacine lowered elevated plasma renin activity and plasma catecholamine levels in hypertensive patients, but this does not correlate with individual blood-pressure responses. Growth hormone secretion was stimulated with single oral doses of 2 and 4 mg of guanfacine. Long-term use of guanfacine had no effect on growth hormone levels. Guanfacine had no effect on plasma aldosterone. A slight but insignificant decrease in plasma volume occurred after one month of guanfacine therapy. There were no changes in mean body weight or electrolytes. ### Pharmacokinetics Relative to an intravenous dose of 3 mg, the absolute oral bioavailability of guanfacine is about 80%. Peak plasma concentrations occur from 1 to 4 hours with an average of 2.6 hours after single oral doses or at steady state. The area under the concentration-time curve (AUC) increases linearly with the dose. In individuals with normal renal function, the average elimination half-life is approximately 17 hr (range 10-30 hr). Younger patients tend to have shorter elimination half-lives (13-14 hr) while older patients tend to have half-lives at the upper end of the range. Steady state blood levels were attained within 4 days in most subjects. In individuals with normal renal function, guanfacine and its metabolites are excreted primarily in the urine. Approximately 50% (40-75%) of the dose is eliminated in the urine as unchanged drug; the remainder is eliminated mostly as conjugates of metabolites produced by oxidative metabolism of the aromatic ring. The guanfacine-to-creatinine clearance ratio is greater than 1, which would suggest that tubular secretion of drug occurs. The drug is approximately 70% bound to plasma proteins, independent of drug concentration. The whole body volume of distribution is high (a mean of 6.3 L/kg), which suggests a high distribution of drug to the tissues. The clearance of guanfacine in patients with varying degrees of renal insufficiency is reduced, but plasma levels of drug are only slightly increased compared to patients with normal renal function. When prescribing for patients with renal impairment, the low end of the dosing range should be used. Patients on dialysis also can be given usual doses of guanfacine hydrochloride as the drug is poorly dialyzed. ## Indications and Usage for Guanfacine Guanfacine hydrochloride tablets are indicated in the management of hypertension. Guanfacine may be given alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. ## Contraindications Guanfacine hydrochloride tablets are contraindicated in patients with known hypersensitivity to guanfacine hydrochloride. ## Precautions ### General Like other antihypertensive agents, guanfacine should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease or chronic renal or hepatic failure. #### Sedation Guanfacine, like other orally active central α2 adrenergic agonists, causes sedation or drowsiness, especially when beginning therapy. These symptoms are dose-related (see [ADVERSE REACTIONS](#i4i_adverse_effects_id_325f020a-44e8-484d-933c-93b08f0b2614)). When guanfacine is used with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), the potential for additive sedative effects should be considered. #### Rebound Abrupt cessation of therapy with orally active central α2 adrenergic agonists may be associated with increases (from depressed on-therapy levels) in plasma and urinary catecholamines, symptoms of “nervousness and anxiety” and, less commonly, increases in blood pressure to levels significantly greater than those prior to therapy. ### Information for Patients Patients who receive guanfacine should be advised to exercise caution when operating dangerous machinery or driving motor vehicles until it is determined that they do not become drowsy or dizzy from the medication. Patients should be warned that their tolerance for alcohol and other CNS depressants may be diminished. Patients should be advised not to discontinue therapy abruptly. ### Laboratory Tests In clinical trials, no clinically relevant laboratory test abnormalities were identified as causally related to drug during short-term treatment with guanfacine. ### Drug Interactions The potential for increased sedation when guanfacine is given with other CNS-depressant drugs should be appreciated. The administration of guanfacine concomitantly with a known microsomal enzyme inducer (phenobarbital or phenytoin) to two patients with renal impairment reportedly resulted in significant reductions in elimination half-life and plasma concentration. In such cases, therefore, more frequent dosing may be required to achieve or maintain the desired hypotensive response. Further, if guanfacine is to be discontinued in such patients, careful tapering of the dosage may be necessary in order to avoid rebound phenomena (see [Rebound](#i4i_section_id_dc3278e3-4e31-46e7-a89c-ab64bbc9a130) above). #### Anticoagulants Ten patients who were stabilized on oral anticoagulants were given guanfacine, 1-2 mg/day, for 4 weeks. No changes were observed in the degree of anticoagulation. In several well-controlled studies, guanfacine was administered together with diuretics with no drug interactions reported. In the long-term safety studies, guanfacine was given concomitantly with many drugs without evidence of any interactions. The principal drugs given (number of patients in parentheses) were: cardiac glycosides (115), sedatives and hypnotics (103), coronary vasodilators (52), oral hypoglycemics (45), cough and cold preparations (45), NSAIDs (38), antihyperlipidemics (29), antigout drugs (24), oral contraceptives (18), bronchodilators (13), insulin (10), and beta blockers (10). #### Drug/Laboratory Test Interactions No laboratory test abnormalities related to the use of guanfacine have been identified. ### Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenic effect was observed in studies of 78 weeks in mice at doses more than 150 times the maximum recommended human dose and 102 weeks in rats at doses more than 100 times the maximum recommended human dose. In a variety of test models, guanfacine was not mutagenic. No adverse effects were observed in fertility studies in male and female rats. ### Pregnancy Category B Administration of guanfacine to rats at 70 times the maximum recommended human dose and to rabbits at 20 times the maximum recommended human dose resulted in no evidence of harm to the fetus. Higher doses (100 and 200 times the maximum recommended human dose in rabbits and rats respectively) were associated with reduced fetal survival and maternal toxicity. Rat experiments have shown that guanfacine crosses the placenta. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. ### Labor and Delivery Guanfacine is not recommended in the treatment of acute hypertension associated with toxemia of pregnancy. There is no information available on the effects of guanfacine on the course of labor and delivery. ### Nursing Mothers It is not known whether guanfacine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when guanfacine hydrochloride is administered to a nursing woman. Experiments with rats have shown that guanfacine is excreted in the milk. ### Pediatric Use Safety and effectiveness in pediatric patients under 12 years of age have not been demonstrated. Therefore, the use of guanfacine in this age group is not recommended. There have been spontaneous postmarketing reports of mania and aggressive behavioral changes in pediatric patients with attention-deficit hyperactivity disorder (ADHD) receiving guanfacine. The reported cases were from a single center. All patients had medical or family risk factors for bipolar disorder. All patients recovered upon discontinuation of guanfacine HCl. Hallunications have been reported in pediatric patients receiving guanfacine for treatment of attention-deficit hyperactivity disorder. ### Geriatric Use Clinical studies of guanfacine did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy (see [CLINICAL PHARMACOLOGY](#i4i_clinical_pharmacology_id_1402f258-7479-4300-9405-cde0a5fe4e22), [Pharmacokinetics](#i4i_pharmacokinetics_id_4cd77603-229b-4975-a267-58fbadd6640c)). ## Adverse Reactions/Side Effects Adverse reactions noted with guanfacine are similar to those of other drugs of the central α2 adrenoreceptor agonist class: dry mouth, sedation (somnolence), weakness (asthenia), dizziness, constipation, and impotence. While the reactions are common, most are mild and tend to disappear on continued dosing. Skin rash with exfoliation has been reported in a few cases; although clear cause and effect relationships to guanfacine could not be established, should a rash occur, guanfacine should be discontinued and the patient monitored appropriately. In the dose-response monotherapy study described under [CLINICAL PHARMACOLOGY](#i4i_clinical_pharmacology_id_1402f258-7479-4300-9405-cde0a5fe4e22), the frequency of the most commonly observed adverse reactions showed a dose relationship from 0.5 to 3 mg as follows: | | | | | | | | --- | --- | --- | --- | --- | --- | | Adverse Reaction | Placebo n=59 | 0.5 mg n=60 | 1 mg n=61 | 2 mg n=60 | 3 mg n=59 | | Dry Mouth | 0% | 10% | 10% | 42% | 54% | | Somnolence | 8% | 5% | 10% | 13% | 39% | | Asthenia | 0% | 2% | 3% | 7% | 3% | | Dizziness | 8% | 12% | 2% | 8% | 15% | | Headache | 8% | 13% | 7% | 5% | 3% | | Impotence | 0% | 0% | 0% | 7% | 3% | | Constipation | 0% | 2% | 0% | 5% | 15% | | Fatigue | 2% | 2% | 5% | 8% | 10% | Adverse Reaction Placebo n=59 0.5 mg n=60 1 mg n=61 2 mg n=60 3 mg n=59 Dry Mouth 0% 10% 10% 42% 54% Somnolence 8% 5% 10% 13% 39% Asthenia 0% 2% 3% 7% 3% Dizziness 8% 12% 2% 8% 15% Headache 8% 13% 7% 5% 3% Impotence 0% 0% 0% 7% 3% Constipation 0% 2% 0% 5% 15% Fatigue 2% 2% 5% 8% 10% The percent of patients who dropped out because of adverse reactions are shown below for each dosage group. | | | | | | | | --- | --- | --- | --- | --- | --- | | | Placebo | 0.5 mg | 1 mg | 2 mg | 3 mg | | Percent dropouts | 0% | 2% | 5% | 13% | 32% | Placebo 0.5 mg 1 mg 2 mg 3 mg Percent dropouts 0% 2% 5% 13% 32% The most common reasons for dropouts among patients who received guanfacine were dry mouth, somnolence, dizziness, fatigue, weakness, and constipation. In the 12-week placebo-controlled, dose-response study of guanfacine administered with 25 mg chlorthalidone at bedtime, the frequency of the most commonly observed adverse reactions showed a clear dose relationship from 0.5 to 3 mg as follows: | | | | | | | | --- | --- | --- | --- | --- | --- | | Adverse Reaction | Placebo n = 73 | 0.5 mg n = 72 | 1 mg n = 72 | 2 mg n = 72 | 3 mg n = 72 | | Dry mouth | 5 (7%) | 4 (5%) | 6 (8%) | 8 (11%) | 20 (28%) | | Somnolence | 1 (1%) | 3 (4%) | 0 (0%) | 1 (1%) | 10 (14%) | | Asthenia | 0 (0%) | 2 (3%) | 0 (0%) | 2 (2%) | 7 (10%) | | Dizziness | 2 (2%) | 1 (1%) | 3 (4%) | 6 (8%) | 3 (4%) | | Headache | 3 (4%) | 4 (3%) | 3 (4%) | 1 (1%) | 2 (2%) | | Impotence | 1 (1%) | 1 (0%) | 0 (0%) | 1 (1%) | 3 (4%) | | Constipation | 0 (0%) | 0 (0%) | 0 (0%) | 1 (1%) | 1 (1%) | | Fatigue | 3 (3%) | 2 (3%) | 2 (3%) | 5 (6%) | 3 (4%) | Adverse Reaction Placebo n = 73 0.5 mg n = 72 1 mg n = 72 2 mg n = 72 3 mg n = 72 Dry mouth 5 (7%) 4 (5%) 6 (8%) 8 (11%) 20 (28%) Somnolence 1 (1%) 3 (4%) 0 (0%) 1 (1%) 10 (14%) Asthenia 0 (0%) 2 (3%) 0 (0%) 2 (2%) 7 (10%) Dizziness 2 (2%) 1 (1%) 3 (4%) 6 (8%) 3 (4%) Headache 3 (4%) 4 (3%) 3 (4%) 1 (1%) 2 (2%) Impotence 1 (1%) 1 (0%) 0 (0%) 1 (1%) 3 (4%) Constipation 0 (0%) 0 (0%) 0 (0%) 1 (1%) 1 (1%) Fatigue 3 (3%) 2 (3%) 2 (3%) 5 (6%) 3 (4%) There were 41 premature terminations because of adverse reactions in this study. The percent of patients who dropped out and the dose at which the dropout occurred were as follows: | | | | | | | | --- | --- | --- | --- | --- | --- | | Dose: | Placebo | 0.5 mg | 1 mg | 2 mg | 3 mg | | Percent dropouts | 6.9% | 4.2% | 3.2% | 6.9% | 8.3% | Dose: Placebo 0.5 mg 1 mg 2 mg 3 mg Percent dropouts 6.9% 4.2% 3.2% 6.9% 8.3% Reasons for dropouts among patients who received guanfacine were: somnolence, headache, weakness, dry mouth, dizziness, impotence, insomnia, constipation, syncope, urinary incontinence, conjunctivitis, paresthesia, and dermatitis. In a second 12-week placebo-controlled combination therapy study in which the dose could be adjusted upward to 3 mg per day in 1-mg increments at 3-week intervals, i.e., a setting more similar to ordinary clinical use, the most commonly recorded reactions were: dry mouth, 47%; constipation, 16%; fatigue, 12%; somnolence, 10%; asthenia, 6%; dizziness, 6%; headache, 4%; and insomnia, 4%. Reasons for dropouts among patients who received guanfacine were: somnolence, dry mouth, dizziness, impotence, constipation, confusion, depression, and palpitations. In the clonidine/guanfacine comparison described in [CLINICAL PHARMACOLOGY](#i4i_clinical_pharmacology_id_1402f258-7479-4300-9405-cde0a5fe4e22), the most common adverse reactions noted were as follows: | | | | | --- | --- | --- | | Adverse Reactions | Guanfacine (n=279) | Clonidine (n=278) | | Dry Mouth | 30% | 37% | | Somnolence | 21% | 35% | | Dizziness | 11% | 8% | | Constipation | 10% | 5% | | Fatigue | 9% | 8% | | Headache | 4% | 4% | | Insomnia | 4% | 3% | Adverse Reactions Guanfacine (n=279) Clonidine (n=278) Dry Mouth 30% 37% Somnolence 21% 35% Dizziness 11% 8% Constipation 10% 5% Fatigue 9% 8% Headache 4% 4% Insomnia 4% 3% Adverse reactions occurring in 3% or less of patients in the three controlled trials of guanfacine with a diuretic were: Cardiovascular - bradycardia, palpitations, substernal pain Gastrointestinal - abdominal pain, diarrhea, dyspepsia, dysphagia, nausea CNS - amnesia, confusion, depression, insomnia, libido decrease ENT disorders - rhinitis, taste perversion, tinnitus Eye disorders - conjunctivitis, iritis, vision disturbance Musculoskeletal - leg cramps, hypokinesia Respiratory - dyspnea Dermatologic - dermatitis, pruritus, purpura, sweating Urogenital - testicular disorder, urinary incontinence Other - malaise, paresthesia, paresis Adverse reaction reports tend to decrease over time. In an open-label trial of one year’s duration, 580 hypertensive subjects were given guanfacine, titrated to achieve goal blood pressure, alone (51%), with diuretic (38%), with beta blocker (3%), with diuretic plus beta blocker (6%), or with diuretic plus vasodilator (2%). The mean daily dose of guanfacine reached was 4.7 mg. | | | | | --- | --- | --- | | Adverse Reaction | Incidence of adverse reactions at any time during the study n=580 | Incidence of adverse reactions at end of one year n=580 | | Dry Mouth | 60% | 15% | | Drowsiness | 33% | 6% | | Dizziness | 15% | 1% | | Constipation | 14% | 3% | | Weakness | 5% | 1% | | Headache | 4% | 0.2% | | Insomnia | 5% | 0% | Adverse Reaction Incidence of adverse reactions at any time during the study n=580 Incidence of adverse reactions at end of one year n=580 Dry Mouth 60% 15% Drowsiness 33% 6% Dizziness 15% 1% Constipation 14% 3% Weakness 5% 1% Headache 4% 0.2% Insomnia 5% 0% There were 52 (8.9%) dropouts due to adverse effects in this 1-year trial. The causes were: dry mouth (n=20), weakness (n=12), constipation (n=7), somnolence (n=3), nausea (n=3), orthostatic hypotension (n=2), insomnia (n=1), rash (n=1), nightmares (n=1), headache (n=1), and depression (n=1). ### Postmarketing Experience An open-label postmarketing study involving 21,718 patients was conducted to assess the safety of guanfacine (as the hydrochloride) 1 mg/day given at bedtime for 28 days. Guanfacine was administered with or without other antihypertensive agents. Adverse events reported in the postmarketing study at an incidence greater than 1% included dry mouth, dizziness, somnolence, fatigue, headache, and nausea. The most commonly reported adverse events in this study were the same as those observed in controlled clinical trials. Less frequent, possibly guanfacine-related events observed in the postmarketing study and/or reported spontaneously include: BODY AS A WHOLE: asthenia, chest pain, edema, malaise, tremor CARDIOVASCULAR: bradycardia, palpitations, syncope, tachycardia CENTRAL NERVOUS SYSTEM: paresthesias, vertigo EYE DISORDERS: blurred vision GASTROINTESTINAL SYSTEM: abdominal pain, constipation, diarrhea, dyspepsia LIVER AND BILIARY SYSTEM: abnormal liver function tests MUSCULOSKELETAL SYSTEM: arthralgia, leg cramps, leg pain, myalgia PSYCHIATRIC: agitation, anxiety, confusion, depression, insomnia, nervousness REPRODUCTIVE SYSTEM, MALE: impotence RESPIRATORY SYSTEM: dyspnea SKIN AND APPENDAGES: alopecia, dermatitis, exfoliative dermatitis, pruritus, rash SPECIAL SENSES: alterations in taste URINARY SYSTEM: nocturia, urinary frequency Rare, serious disorders with no definitive cause and effect relationship to guanfacine have been reported spontaneously and/or in the postmarketing study. These events include acute renal failure, cardiac fibrillation, cerebrovascular accident, congestive heart failure, heart block, and myocardial infarction. ## Related/similar drugs ### [Adderall](/pro/adderall.html) Adderall (amphetamine and dextroamphetamine) is used to treat narcolepsy and ADHD. Includes side ... ### [Vyvanse](/pro/vyvanse.html) Vyvanse is a prescription stimulant used to treat ADHD in children and adults, and binge eating ... ### [Skyrizi](/pro/skyrizi.html) Skyrizi (risankizumab) is an injection used to treat plaque psoriasis, psoriatic arthritis ... ### [Strattera](/pro/strattera.html) Strattera (atomoxetine) is used to treat attention deficit hyperactivity disorder. 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A 25-year-old female intentionally ingested 60 mg. She presented with severe drowsiness and bradycardia of 45 beats/minute. Gastric lavage was performed and an infusion of isoproterenol (0.8 mg in 12 hours) was administered. She recovered quickly and without sequelae. A 28-year-old female who ingested 30-40 mg developed only lethargy, was treated with activated charcoal and a cathartic, was monitored for 24 hours, and was discharged in good health. A 2-year-old male weighing 12 kg, who ingested up to 4 mg of guanfacine, developed lethargy. Gastric lavage (followed by activated charcoal and sorbitol slurry via NG tube) removed some tablet fragments within 2 hours after ingestion, and vital signs were normal. During 24-hour observation in ICU, systolic pressure was 58 and heart rate 70 at 16 hours post-ingestion. No intervention was required, and child was discharged fully recovered the next day. #### Treatment of Overdosage: Gastric lavage and supportive therapy as appropriate. Guanfacine is not dialyzable in clinically significant amounts (2.4%). ## Guanfacine Dosage and Administration The recommended initial dose of guanfacine (as the hydrochloride) when given alone or in combination with another antihypertensive drug is 1 mg daily given at bedtime to minimize somnolence. If after 3 to 4 weeks of therapy, 1 mg does not give a satisfactory result, a dose of 2 mg may be given, although most of the effect of guanfacine is seen at 1 mg (see [CLINICAL PHARMACOLOGY](#i4i_clinical_pharmacology_id_1402f258-7479-4300-9405-cde0a5fe4e22)). Higher daily doses have been used, but adverse reactions increase significantly with doses above 3 mg/day. The frequency of rebound hypertension is low, but it can occur. When rebound occurs, it does so after 2-4 days, which is delayed compared with clonidine hydrochloride. This is consistent with the longer half-life of guanfacine. In most cases, after abrupt withdrawal of guanfacine, blood pressure returns to pretreatment levels slowly (within 2-4 days) without ill effects. ## How is Guanfacine supplied Guanfacine Tablets USP, 1 mg are available as white, round, flat-faced beveled-edge tablets, debossed “Є48” on one side and plain on the other side. Supplied Cartons of 30 tablets (10 tablets each blister pack x 3), NDC 0904-7140-04 WARNING: This Unit Dose package is not child resistant and is Intended for Institutional Use Only. Keep this and all drugs out of the reach of children. Store at 20°-25°C (68°-77°F). [See USP controlled room temperature.] Dispense in a tight, light-resistant container. Manufactured by: Epic Pharma, LLC Laurelton, NY 11413 Packaged and Distributed by: MAJOR® PHARMACEUTICALS Indianapolis, IN 46268 USA Refer to package label for Distributor's NDC Number Revised 06-2023-00 MF048REV06/23 OE1126 ## Package/Label Display Panel MAJOR® NDC 0904-7140-04 Unit Dose Guanfacine Tablets, USP 1 mg\* 30 TABLETS (3 x 10) Rx only  | | | --- | | **GUANFACINE** guanfacine tablet | | | | | | | | --- | --- | --- | --- | | Product Information | | | | | Product Type | HUMAN PRESCRIPTION DRUG | Item Code (Source) | NDC:0904-7140(NDC:42806-048) | | Route of Administration | ORAL | | | | | | | | --- | --- | --- | | Active Ingredient/Active Moiety | | | | Ingredient Name | Basis of Strength | Strength | | **GUANFACINE HYDROCHLORIDE** (UNII: PML56A160O) (GUANFACINE - UNII:30OMY4G3MK) | GUANFACINE | 1 mg | | | | | | | --- | --- | | Inactive Ingredients | | | Ingredient Name | Strength | | **ANHYDROUS LACTOSE** (UNII: 3SY5LH9PMK) | | | **MICROCRYSTALLINE CELLULOSE** (UNII: OP1R32D61U) | | | **STARCH, CORN** (UNII: O8232NY3SJ) | | | **MAGNESIUM STEARATE** (UNII: 70097M6I30) | | | **TALC** (UNII: 7SEV7J4R1U) | | | | | | | | | | --- | --- | --- | --- | | Product Characteristics | | | | | Color | WHITE, WHITE | Score | no score | | Shape | ROUND | Size | 7mm | | Flavor | | Imprint Code | E48 | | Contains | | | | | | | | | | | --- | --- | --- | --- | --- | | Packaging | | | | | | # | Item Code | Package Description | Marketing Start Date | Marketing End Date | | 1 | NDC:0904-7140-04 | 30 in 1 CARTON | 12/02/2013 | | | 1 | | 1 in 1 BLISTER PACK; Type 0: Not a Combination Product | | | | | | | | | | | | | --- | --- | --- | --- | | Marketing Information | | | | | Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date | | ANDA | ANDA074673 | 12/02/2013 | | | | | | | | | --- | --- | --- | --- | | Product Information | | | | | Product Type | HUMAN PRESCRIPTION DRUG | Item Code (Source) | NDC:0904-7140(NDC:42806-048) | | Route of Administration | ORAL | | | | | | --- | --- | --- | | Active Ingredient/Active Moiety | | | | Ingredient Name | Basis of Strength | Strength | | **GUANFACINE HYDROCHLORIDE** (UNII: PML56A160O) (GUANFACINE - UNII:30OMY4G3MK) | GUANFACINE | 1 mg | | | | | --- | --- | | Inactive Ingredients | | | Ingredient Name | Strength | | **ANHYDROUS LACTOSE** (UNII: 3SY5LH9PMK) | | | **MICROCRYSTALLINE CELLULOSE** (UNII: OP1R32D61U) | | | **STARCH, CORN** (UNII: O8232NY3SJ) | | | **MAGNESIUM STEARATE** (UNII: 70097M6I30) | | | **TALC** (UNII: 7SEV7J4R1U) | | | | | | | | --- | --- | --- | --- | | Product Characteristics | | | | | Color | WHITE, WHITE | Score | no score | | Shape | ROUND | Size | 7mm | | Flavor | | Imprint Code | E48 | | Contains | | | | | | | | | --- | --- | --- | --- | --- | | Packaging | | | | | | # | Item Code | Package Description | Marketing Start Date | Marketing End Date | | 1 | NDC:0904-7140-04 | 30 in 1 CARTON | 12/02/2013 | | | 1 | | 1 in 1 BLISTER PACK; Type 0: Not a Combination Product | | | | | | | | | --- | --- | --- | --- | | Marketing Information | | | | | Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date | | ANDA | ANDA074673 | 12/02/2013 | | | | | | | | --- | --- | --- | --- | | Labeler - Major Pharmaceuticals (191427277) | | | | ## More about guanfacine ### Patient resources ### Professional resources #### Other brands [Intuniv](/pro/intuniv.html), [Tenex](/pro/tenex.html) ### Related treatment guides [Medical Disclaimer](/support/disclaimer-pro.html) Loading... 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Package leaflet: Information for the user Guanfacine 1 mg prolonged-release tablets Guanfacine 2 mg prolonged-release tablets Guanfacine 3 mg prolonged-release tablets Guanfacine 4 mg prolonged-release tablets Guanfacine 5 mg prolonged-release tablets Guanfacine 6 mg prolonged-release tablets Guanfacine 7 mg prolonged-release tablets Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. • Keep this leaflet. You may need to read it again. • If you have any further questions, ask your doctor, pharmacist or nurse. • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. • If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. • This leaflet has been written as though the person taking the medicine is reading it. If you are giving this medicine to your child, please replace “you” with “your child” throughout. What is in this leaflet: 1. What Guanfacine is and what it is used for 2. What you need to know before you take Guanfacine 3. How to take Guanfacine 4. Possible side effects 5. How to store Guanfacine 6. Contents of the pack and other information 1. What Guanfacine is and what it is used for What Guanfacine is Guanfacine contains the active substance guanfacine. This medicine belongs to a group of medicines which affects brain activity. This medicine can help improve your attention, concentration and make you less impulsive and hyperactive. What Guanfacine is used for This medicine is used to treat ‘attention deficit hyperactivity disorder’ (ADHD) in children and adolescents 6-17 years old for whom current stimulant medication is not appropriate and/or current medication does not adequately control ADHD symptoms. The medicine is given as part of a treatment programme, which usually includes the following: • psychological therapy • educational therapy • social therapy About ADHD People with ADHD find it hard to: • sit still • concentrate. ADHD can cause problems with everyday life. Children and young people with ADHD may have difficulty learning and doing homework. They can find it hard to behave well at home, at school or in other places. 2. What you need to know before you take Guanfacine Do not take Guanfacine if: • you are allergic to guanfacine or any of the other ingredients of this medicine (listed in section 6). Warnings and precautions Talk to your doctor or pharmacist before taking this medicine if: • you have low or high blood pressure, heart problems or have a family history of heart problems • you have fainted recently • you have thoughts or feelings of suicide • you suffer from any other psychiatric conditions Talk to your doctor or pharmacist if you are taking this medicine and: • experience aggressive feelings or behaviour, or • have suicidal thoughts or feelings Guanfacine may affect your weight and height if taking for long periods, your doctor will therefore monitor your growth. Do not stop taking Guanfacine without talking to your doctor. If you suddenly stop taking Guanfacine, you may develop withdrawal symptoms of increased heart rate and high blood pressure (see section 4). If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking this medicine. This is because this medicine can make these problems worse. Your doctor will routinely monitor you to see how this medicine affects you. Children (under 6 years old) and adults (18 years and over) This medicine should not be used in children under 6 years of age and adults 18 years and over because it is not known if it works or is safe. Checks your doctor will do when you take Guanfacine Before you start taking this medicine your doctor will check to make sure this medicine is safe for you and that it will help you. While you are taking this medicine your doctor will repeat these checks weekly during initial dosing, after dose adjustments, at least every 3 months for the first year and then at least twice a year. These checks may include: • your blood pressure and heart rate and other checks on your heart if appropriate • your response to treatment, in particular if it makes you sleepy or drowsy • your height and weight You should talk to your doctor if you do not feel better or if you feel worse and very sleepy or drowsy after taking this medicine for around 6 weeks. Your doctor may want to review your treatment. Other medicines and Guanfacine Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is because Guanfacine and some other medicines can affect each other. In particular, tell your doctor or pharmacist if you are taking any of the following types of medicines: • medicines that lower your blood pressure (antihypertensives) • medicines for epilepsy such as valproic acid • medicines that make you sleepy (sedatives) • medicines for mental health problems (benzodiazepines, barbiturates and antipsychotics) • medicines that can affect the way Guanfacine is eliminated by the liver (please see table below) Medicines Used to treat Aprepitant Nausea and vertigo. Atazanavir, efavirenz, etravirine, fosamprenavir, indinavir, nevirapine, ritonavir, saquinavir HIV infection. Ciprofloxacin, chloramphenicol, clarithromycin, erythromycin, rifabutin, rifampicin, telithromycin Bacterial infections. Fluconazole, itraconazole, posaconazole, ketoconazole Fungal infections. Crizotinib, imatinib Cancer. Diltiazem, verapamil Cardiovascular conditions. Boceprevir, telaprevir Viral hepatitis. Suboxone Substance dependence. Bosentan Cardiovascular conditions (e.g. constriction of blood vessels in the lung). Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone Used to control epilepsy. Modafinil Is a medicine that promotes alertness and is used to treat sleep disorders. St. John’s Wort Is a herbal preparation that is used to treat depression. If any of the above apply to you or you are not sure, talk to your doctor or pharmacist before taking this medicine. Guanfacine with food, drinks and alcohol • Do not take this medicine with fatty foods (e.g., high fat breakfast), as it may affect the way this medicine works. • Do not take grapefruit juice with this medicine as it can have an effect on the way this medicine works. • Do not drink alcohol when taking this medicine as it may make you sleepy or drowsy. Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. • Do not take this medicine if you are pregnant or you are not using contraception. It is not known if Guanfacine will affect your unborn baby. • Do not breast-feed while taking Guanfacine unless told to do so by your doctor. Driving and using machines You may feel dizzy and drowsy when taking this medicine, especially at the start of treatment and this may last for 2 to 3 weeks possibly longer. If this happens, do not drive, cycle, use any tools or machines or participate in activities that could cause injury until you know how this medicine affects you. Fainting has also been reported but is not a common effect. Guanfacine contains lactose Lactose is a type of sugar. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. Guanfacine contains sodium This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’. 3. How to take Guanfacine Your treatment will start under the supervision of an appropriate specialist in childhood and/or adolescent behavioural disorders. Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. As part of your treatment your doctor will closely monitor how Guanfacine is affecting you during initial dosing and/or dose adjustments. How much to take • Your doctor will start you on 1 mg per day. Your doctor may increase your dose based on your body weight and how Guanfacine is working for you but not by more than 1 mg per week. Depending on how you respond to treatment your doctor may increase your dose more slowly. The recommended maintenance dose is between 0.05 up to 0.12 mg per kg of bodyweight per day. • You may not notice an immediate effect upon starting treatment, some patients may notice an improvement after the first week but it could take longer. • Your daily dose will be between 1 and 7 mg depending on your age and how you respond to Guanfacine, but not more that 7 mg. How to take Guanfacine • This medicine should be taken once a day either in the morning or evening. • It can be taken with or without food, but do not take it with fatty foods (e.g., high fat breakfast). • Swallow the tablet whole with a drink of water or other liquid (but not grapefruit juice). • Do not break, crush or chew the tablet; this will affect how the tablet works. Tell your doctor if you cannot swallow the tablet whole. Duration of treatment If you need to take Guanfacine for more than a year your doctor will monitor your response to treatment and your doctor may stop the medicine for a short time; this may happen during a school holiday. This will show if you still need to take the medicine. If you take more Guanfacine than you should If you take more Guanfacine than you should, talk to a doctor or go to a hospital straight away. Take the medicine pack with you and tell them how much you have taken. The following effects may happen: low or high blood pressure, slow heart rate, slow breathing rate, feeling tired or exhausted. If you forget to take Guanfacine If you forget a dose, wait until the next day and take your usual dose. • If you have missed two or more doses talk to your doctor as you may need to restart Guanfacine with a lower dose. • Do not take a double dose to make up for a forgotten dose. If you stop taking Guanfacine Do not stop taking this medicine without first talking to your doctor. • If you stop taking this medicine your blood pressure and heart rate may increase (see section 4 below). • To stop the medicine, your doctor will slowly reduce your Guanfacine dose to minimise any side effects. If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. If you are worried, speak to your doctor. If you feel unwell in any way while you are taking your medicine please tell an adult straight away. Serious side effects The following serious side effects have been reported: feeling drowsy (sedation), feeling dizzy (hypotension), slow heart beat (bradycardia), feeling faint or loss of conciousness (syncope), a serious withdrawal side effect of high blood pressure after suddenly stopping Guanfacine; symptoms may include headaches, feeling confused, nervousness, agitation, and tremors (hypertensive encephalopathy). Some of these side effects are more likely to occur at the start of treatment and may disappear as you continue with your treatment, if you experience any of these side effects contact your doctor straight away. Other side effects The following side effects have been reported. Very common (may affect more than 1 in 10 people) • feeling sleepy (somnolence) • feeling tired (fatigue) • headache • tummy pain (abdominal pain). Common (may affect up to 1 in 10 people) • low heart rate • blood pressure decreased • feeling restless or irritable • trouble sleeping (insomnia) or broken sleep (middle insomnia) or nightmares • feeling depressed, worried (anxiety) or having mood swings (affect lability) • lack of energy (lethargy) • weight gain • loss of appetite • have a dry mouth • wetting yourself (enuresis) • feeling (nausea) or being sick (vomiting) • diarrhoea, abdominal discomfort or constipation • low blood pressure when standing up (orthostatic hypotension) • rash. Uncommon (may affect up to 1 in 100 people) • allergic reaction (hypersensitivity) • chest pain • indigestion (dyspepsia) • trouble breathing (asthma) • feeling weak (asthenia) • pale skin colour (pallor) • fits or convulsions • need to urinate frequently (pollakiuria) • feeling agitated • aggression • changes in liver blood test results (increased alanine aminotransferase) • increase in blood pressure • unusual heart rhythm (sinus arrhythmia and first-degree arterioventricular block) • fast heart beat (tachycardia) • reduced heart rate • feeling dizzy when standing up (postural dizziness) • itchy skin (pruritus) • seeing or hearing things that are not there (hallucination). Rare (may affect up to 1 in 1,000 people) • sleeping more than normal (hypersomnia) • high blood pressure (hypertension) • feeling unwell (malaise). Very rare (may affect up to 1 in 10,000 people) • a serious withdrawal side effect of high blood pressure after suddenly stopping Guanfacine; symptoms may include headaches, feeling confused, nervousness, agitation, and tremors (hypertensive encephalopathy). Not known (frequency cannot be estimated from the available data) • difficulty to get or keep an erection (erectile dysfunction). Reporting of side effects If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Guanfacine Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and blister pack after EXP. The expiry date refers to the last day of that month. This medicinal product does not require any special storage conditions. Do not use this medicine if the tablets or blister pack look damaged. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Guanfacine contains • Each 1 mg tablet contains guanfacine hydrochloride equivalent to 1 mg of guanfacine • Each 2 mg tablet contains guanfacine hydrochloride equivalent to 2 mg of guanfacine • Each 3 mg tablet contains guanfacine hydrochloride equivalent to 3 mg of guanfacine • Each 4 mg tablet contains guanfacine hydrochloride equivalent to 4 mg of guanfacine • Each 5 mg tablet contains guanfacine hydrochloride equivalent to 5 mg of guanfacine • Each 6 mg tablet contains guanfacine hydrochloride equivalent to 6 mg of guanfacine • Each 7 mg tablet contains guanfacine hydrochloride equivalent to 7 mg of guanfacine The other ingredients are Hypromellose (2208), methacrylic acid-ethyl acrylate copolymer (Type A), lactose monohydrate, povidone K-30, crospovidone (Type A), microcrystalline cellulose, silica colloidal anhydrous, sodium laurilsulfate, polysorbate 80, fumaric acid, glycerol dibehenate. What Guanfacine looks like and contents of the pack Guanfacine is a prolonged-release tablet which means that the active substance is released from the tablet over a period of time. The tablets come in pack sizes of 28. • The 1 mg prolonged-release tablets are white, 8 mm diameter round, biconvex tablets with the inscription “I” on one side. • The 2 mg prolonged-release tablets are white, 14 x 6 mm oblong, biconvex tablets with the inscription “II” on one side. • The 3 mg prolonged-release tablets are white, 6 mm diameter round, biconvex tablets with the inscription “3” on one side. • The 4 mg prolonged-release tablets are white, 7 mm diameter round, biconvex tablets with the inscription “IV” on one side. • The 5 mg prolonged-release tablets are white, 8 mm diameter round, biconvex tablets with the inscription “V” on one side. • The 6 mg prolonged-release tablets are white, 9 mm diameter round, biconvex tablets with the inscription “VI” on one side. • The 7 mg prolonged-release tablets are white, 12.5 x 6.5 mm oblong, biconvex tablets with the inscription “7” on one side. Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder Neuraxpharm UK Limited Suite 2, Arlington Flex, Third Floor Building 1420, Arlington Business Park Theale, Reading Berkshire, RG7 4SA United Kingdom Manufacturer Neuraxpharm Pharmaceuticals, S.L. Avda. Barcelona 69 08970 Sant Joan Despí Barcelona – Spain or Neuraxpharm Arzneimittel GmbH Elisabeth-Selbert-Strasse 23, Richrath Langenfeld (Rheinland) 40764, Germany or Wasdell Packaging Limited Units 1,2,3,5,6,7 & 8 Euro Way Industrial Estate Blagrove Swindon SN5 8YW, United Kingdom This leaflet was last revised in August 2025

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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use INTUNIV® safely and effectively. See full prescribing information for INTUNIV®. INTUNIV® (guanfacine) extended-release tablets, for oral use Initial U.S. Approval: 1986 ----------------------------INDICATIONS AND USAGE ---------------------------­ INTUNIV® is a central alpha2A-adrenergic receptor agonist indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications (1, 14). ----------------------- DOSAGE AND ADMINISTRATION ----------------------­ • Recommended dose: 1 mg to 7 mg (0.05-0.12 mg/kg target weight based dose range) once daily in the morning or evening based on clinical response and tolerability (2.2). • Begin at a dose of 1 mg once daily and adjust in increments of no more than 1 mg/week (2.2). • Do not crush, chew or break tablets before swallowing (2.1). • Do not administer with high-fat meals, because of increased exposure (2.1). • Do not substitute for immediate-release guanfacine tablets on a mg-per-mg basis, because of differing pharmacokinetic profiles (2.3). • If switching from immediate-release guanfacine, discontinue that treatment and titrate with INTUNIV® as directed (2.3). • When discontinuing, taper the dose in decrements of no more than 1 mg every 3 to 7 days to avoid rebound hypertension (2.5). --------------------- DOSAGE FORMS AND STRENGTHS --------------------­ Extended-release tablets: 1 mg, 2 mg, 3 mg and 4 mg (3) -------------------------------CONTRAINDICATIONS------------------------------­ History of hypersensitivity to INTUNIV® , its inactive ingredients, or other products containing guanfacine (4). ----------------------- WARNINGS AND PRECAUTIONS-----------------------­ • Hypotension, bradycardia, syncope: Titrate slowly and monitor vital signs frequently in patients at risk for hypotension, heart block, bradycardia, syncope, cardiovascular disease, vascular disease, cerebrovascular disease or chronic renal failure. Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Avoid concomitant use of drugs with additive effects unless clinically indicated. Advise patients to avoid becoming dehydrated or overheated (5.1). • Sedation and somnolence: Occur commonly with INTUNIV® . Consider the potential for additive sedative effects with CNS depressant drugs. Caution patients against operating heavy equipment or driving until they know how they respond to INTUNIV® (5.2). • Cardiac Conduction Abnormalities: May worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. Titrate slowly and monitor vital signs frequently (5.3). • Rebound Hypertension: Abrupt discontinuation of INTUNIV® can lead to clinically significant and persistent rebound hypertension. Subsequent hypertensive encephalopathy was also reported. To minimize the risk of rebound hypertension upon discontinuation, the total daily dose of INTUNIV® should be tapered in decrements of no more than 1 mg every 3 to 7 days (5.4). ------------------------------ ADVERSE REACTIONS -----------------------------­ Most common adverse reactions (≥5% and at least twice placebo rate) in fixed-dose monotherapy ADHD trials in children and adolescents (6 to 17 years): hypotension, somnolence, fatigue, nausea, and lethargy (6.1) Flexible dose-optimization ADHD trials in children (6 to 12 years) and adolescents (13 to 17 years): somnolence, hypotension, abdominal pain, insomnia, fatigue, dizziness, dry mouth, irritability, nausea, vomiting, and bradycardia (6.1). Adjunctive treatment to psychostimulant ADHD trial in children and adolescents (6 to 17 years): somnolence, fatigue, insomnia, dizziness, and abdominal pain (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Shire US Inc. at 1-800-828-2088 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------DRUG INTERACTIONS------------------------------­ • Strong and moderate CYP3A4 inhibitors increase guanfacine exposure. Decrease INTUNIV® to 50% of target dosage when coadministered with strong and moderate CYP3A4 inhibitors (2.7). • Strong and moderate CYP3A4 inducers decrease guanfacine exposure. Based on patient response, consider titrating INTUNIV dosage up to double the target dosage over 1 to 2 weeks (2.7). See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 04/2019 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Instruction for Use 2.2 Dose Selection 2.3 Switching from Immediate-Release Guanfacine to INTUNIV® 2.4 Maintenance Treatment 2.5 Discontinuation of Treatment 2.6 Missed Doses 2.7 Dosage Adjustment with Concomitant Use of Strong and Moderate CYP3A4 Inhibitors or Inducers 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypotension, Bradycardia, and Syncope 5.2 Sedation and Somnolence 5.3 Cardiac Conduction Abnormalities 5.4 Rebound Hypertension 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE INTUNIV® is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications [see Clinical Studies (14)]. 2 DOSAGE AND ADMINISTRATION 2.1 General Instruction for Use Swallow tablets whole. Do not crush, chew, or break tablets because this will increase the rate of guanfacine release. Do not administer with high fat meals, due to increased exposure. 2.2 Dose Selection Take INTUNIV orally once daily, either in the morning or evening, at approximately the same time each day. Begin at a dose of 1 mg/day, and adjust in increments of no more than 1 mg/week. In monotherapy clinical trials, there was dose- and exposure-related clinical improvement as well as risks for several clinically significant adverse reactions (hypotension, bradycardia, sedative events). To balance the exposure-related potential benefits and risks, the recommended target dose range depending on clinical response and tolerability for INTUNIV® is 0.05-0.12 mg/kg/day (total daily dose between 1-7 mg) (See Table 1). Table 1: Recommended Target Dose Range for Therapy with INTUNIV® Weight Target dose range (0.05 - 0.12 mg/kg/day) 25-33.9 kg 2-3 mg/day 34-41.4 kg 2-4 mg/day 41.5-49.4 kg 3-5 mg/day 49.5-58.4 kg 3-6 mg/day 58.5-91 kg 4-7 mg/day >91 kg 5-7 mg/day Doses above 4 mg/day have not been evaluated in children (ages 6-12 years) and doses above 7 mg/day have not been evaluated in adolescents (ages 13-17 years) In the adjunctive trial which evaluated INTUNIV® treatment with psychostimulants, the majority of patients reached optimal doses in the 0.05-0.12 mg/kg/day range. Doses above 4 mg/day have not been studied in adjunctive trials. 2.3 Switching from Immediate-Release Guanfacine to INTUNIV® If switching from immediate-release guanfacine, discontinue that treatment, and titrate with INTUNIV® following above recommended schedule. Do not substitute for immediate-release guanfacine tablets on a milligram-per-milligram basis, because of differing pharmacokinetic profiles. INTUNIV® has significantly reduced Cmax (60% lower), bioavailability (43% lower), and a delayed Tmax (3 hours later) compared to those of the same dose of immediate-release guanfacine [see Clinical Pharmacology (12.3)]. 2 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2.4 Maintenance Treatment Pharmacological treatment of ADHD may be needed for extended periods. Healthcare providers should periodically re-evaluate the long-term use of INTUNIV®, and adjust weight-based dosage as needed. The majority of children and adolescents reach optimal doses in the 0.05-0.12 mg/kg/day range. Doses above 4 mg/day have not been evaluated in children (ages 6-12 years) and above 7 mg/day have not been evaluated in adolescents (ages 13-17 years) [see Clinical Studies (14)]. 2.5 Discontinuation of Treatment Following discontinuation of INTUNIV®, patients may experience increases in blood pressure and heart rate [see Warnings and Precautions (5.4) and Adverse Reactions (6)]. Patients/caregivers should be instructed not to discontinue INTUNIV® without consulting their health care provider. Monitor blood pressure and pulse when reducing the dose or discontinuing the drug. Taper the daily dose in decrements of no more than 1 mg every 3 to 7 days to minimize the risk of rebound hypertension. 2.6 Missed Doses When reinitiating patients to the previous maintenance dose after two or more missed consecutive doses, consider titration based on patient tolerability. 2.7 Dosage Adjustment with Concomitant Use of Strong and Moderate CYP3A4 Inhibitors or Inducers Dosage adjustments for INTUNIV® are recommended with concomitant use of strong and moderate CYP3A4 inhibitors (e.g., ketoconazole), or CYP3A4 inducers (e.g., carbamazepine) (Table 2) [see Drug Interactions (7)]. Table 2: INTUNIV® Dosage Adjustments for Patients Taking Concomitant CYP3A4 Inhibitors or Inducers Clinical Scenarios Starting INTUNIV® Continuing Continuing while currently on a INTUNIV® while INTUNIV® while CYP3A4 modulator adding a CYP3A4 modulator stopping a CYP3A4 modulator CYP3A4 Decrease INTUNIV® dosage to half the Decrease INTUNIV® dosage to half the Increase INTUNIV® dosage to Strong and recommended level. recommended level. recommended level. moderate (see Table 1) (see Table 1) (see Table 1) Inhibitors CYP3A4 Consider increasing INTUNIV® dosage up Consider increasing Decrease INTUNIV® dosage to Strong and to double the INTUNIV® dosage recommended level moderate recommended level. up to double the over 1 to 2 weeks. Inducers (see Table 1) recommended level over 1 to 2 weeks. (see Table 1) (see Table 1) 3 DOSAGE FORMS AND STRENGTHS 1 mg, 2 mg, 3 mg and 4 mg extended-release tablets 3 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 4 CONTRAINDICATIONS INTUNIV is contraindicated in patients with a history of a hypersensitivity reaction to INTUNIV or its inactive ingredients, or other products containing guanfacine. Rash and pruritus have been reported. 5 WARNINGS AND PRECAUTIONS 5.1 Hypotension, Bradycardia, and Syncope Treatment with INTUNIV® can cause dose-dependent decreases in blood pressure and heart rate. Decreases were less pronounced over time of treatment. Orthostatic hypotension and syncope have been reported [see Adverse Reactions (6.1)]. Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Titrate INTUNIV slowly in patients with a history of hypotension, and those with underlying conditions that may be worsened by hypotension and bradycardia; e.g., heart block, bradycardia, cardiovascular disease, vascular disease, cerebrovascular disease, or chronic renal failure. In patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration, advise patients to avoid becoming dehydrated or overheated. Monitor blood pressure and heart rate, and adjust dosages accordingly in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. 5.2 Sedation and Somnolence Somnolence and sedation were commonly reported adverse reactions in clinical studies [see Adverse Reactions (6.1)]. Before using INTUNIV® with other centrally active depressants, consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with INTUNIV®. Advise patients to avoid use with alcohol. 5.3 Cardiac Conduction Abnormalities The sympatholytic action of INTUNIV® may worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. Titrate INTUNIV slowly and monitor vital signs frequently in patients with cardiac conduction abnormalities or patients concomitantly treated with other sympatholytic drugs. 5.4 Rebound Hypertension In post marketing experience, abrupt discontinuation of INTUNIV® has resulted in clinically significant and persistent rebound hypertension above baseline levels and increases in heart rate. Hypertensive encephalopathy has also been reported in association with rebound hypertension with both INTUNIV® and immediate release guanfacine [see Adverse Reactions (6.2)]. In these cases, high-dosage guanfacine was discontinued; concomitant stimulant use was also reported, which may potentially increase hypertensive response upon abrupt discontinuation of guanfacine. Children commonly have gastrointestinal illnesses that lead to vomiting, and a resulting inability to take medications, so they may be especially at risk for rebound hypertension. To minimize the risk of rebound hypertension upon discontinuation, the total daily dose of INTUNIV® should be tapered in decrements of no more than 1 mg every 3 to 7 days [see Dosage and Administration (2.5)]. Blood pressure and heart rate should be monitored when reducing the dose or discontinuing INTUNIV®. If abrupt discontinuation occurs (especially with concomitant stimulant use), patients should be closely followed for rebound hypertension. 6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: 4 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • Hypotension, bradycardia, and syncope [see Warnings and Precautions (5.1)] • Sedation and somnolence [see Warnings and Precautions (5.2)] • Cardiac conduction abnormalities [see Warnings and Precautions (5.3)] • Rebound Hypertension [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect clinical trial exposure to INTUNIV® in 2,825 patients. This includes 2,330 patients from completed studies in children and adolescents, ages 6 to 17 years and 495 patients in completed studies in adult healthy volunteers. The mean duration of exposure of 446 patients that previously participated in two 2-year, open-label long-term studies was approximately 10 months. Fixed Dose Trials Table 3: Percentage of Patients Experiencing Most Common (≥5% and at least twice the rate for placebo) Adverse Reactions in Fixed Dose Studies 1 and 2 INTUNIV® (mg) Adverse Reaction Term Placebo (N=149) 1mg* (N=61) 2mg (N=150) 3mg (N=151) 4mg (N=151) All Doses of INTUNIV® (N=513) Somnolencea 11% 28% 30% 38% 51% 38% Fatigue 3% 10% 13% 17% 15% 14% Hypotensionb 3% 8% 5% 7% 8% 7% Dizziness 4% 5% 3% 7% 10% 6% Lethargy 3% 2% 3% 8% 7% 6% Nausea 2% 7% 5% 5% 6% 6% Dry mouth 1% 0% 1% 6% 7% 4% *The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. a: The somnolence term includes somnolence, sedation, and hypersomnia. b: The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). 5 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 4: Adverse Reactions Leading to Discontinuation (≥2% for all doses of INTUNIV and >rate than in placebo) in Fixed Dose Studies 1 and 2 INTUNIV® (mg) Adverse Reaction Term Placebo (N=149) 1mg* (N=61) 2mg (N=150) 3mg (N=151) 4mg (N=151) All Doses of INTUNIV® (N=513) n (%) n (%) n (%) n (%) n (%) n (%) Total patients 4 (3%) 2 (3%) 10 (7%) 15 (10%) 27 (18%) 54 (11%) Somnolencea 1 (1%) 2 (3%) 5 (3%) 6 (4%) 17 (11%) 30 (6%) Fatigue 0 (0%) 0 (0%) 2 (1%) 2 (1%) 4 (3%) 8 (2%) Adverse reactions leading to discontinuation in ≥2% in any dose group but did not meet this criteria in all doses combined: hypotension (hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased), headache, and dizziness. * The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. a: The somnolence term includes somnolence, sedation, and hypersomnia. Table 5: Other Common Adverse Reactions (≥2% for all doses of INTUNIV and >rate than in placebo) in Fixed Dose Studies 1 and 2 INTUNIV® (mg) Adverse Reaction Term Placebo (N=149) 1mg* (N=61) 2mg (N=150) 3mg (N=151) 4mg (N=151) All Doses of INTUNIV® (N=513) Headache 19% 26% 25% 16% 28% 23% Abdominal Paina 9% 10% 7% 11% 15% 11% Decreased Appetite 4% 5% 4% 9% 6% 6% Irritability 4% 5% 8% 3% 7% 6% Constipation 1% 2% 2% 3% 4% 3% Nightmareb 0% 0% 0% 3% 4% 2% Enuresisc 1% 0% 1% 3% 2% 2% Affect Labilityd 1% 2% 1% 3% 1% 2% Adverse reactions ≥2% for all doses of INTUNIV and >rate in placebo in any dose group but did not meet this criteria in all doses combined: insomnia (insomnia, initial insomnia, middle insomnia, terminal insomnia, sleep disorder), vomiting, diarrhea, abdominal/stomach discomfort (abdominal discomfort, epigastric discomfort, stomach discomfort), rash (rash, rash generalized, rash papular), dyspepsia, increased weight, bradycardia (bradycardia, sinus bradycardia), asthma (asthma, bronchospasm, wheezing), agitation, anxiety (anxiety, nervousness), sinus arrhythmia, blood pressure increased (blood pressure increased, blood pressure diastolic increased), and first degree atrioventricular block. * The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. a: The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. b: The nightmare term includes abnormal dreams, nightmare, and sleep terror. c: The enuresis term includes enuresis, nocturia, and urinary incontinence. d: The affect lability term includes affect lability and mood swings. 6 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Monotherapy Flexible Dose Trials Table 6: Percentage of Patients Experiencing Most Common (≥5% and at least twice the rate for placebo) Adverse Reactions in the Monotherapy Flexible Dose Study 4 INTUNIV® Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of INTUNIV® (N=221) Somnolencea 15% 57% 54% 56% Abdominal Painb 7% 8% 19% 14% Fatigue 3% 10% 11% 11% Irritability 3% 7% 7% 7% Nausea 1% 6% 5% 5% Dizziness 3% 6% 4% 5% Vomiting 2% 7% 4% 5% Hypotensionc 0% 6% 4% 5% Decreased Appetite 3% 6% 3% 4% Enuresisd 1% 2% 5% 4% a: The somnolence term includes somnolence, sedation, and hypersomnia. b: The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness c: The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). d: The enuresis term includes enuresis, nocturia, and urinary incontinence. Table 7: Adverse Reactions Leading to Discontinuation (≥2% for all doses of INTUNIV and >rate than in placebo) in Monotherapy Flexible Dose Study 4 INTUNIV® Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of INTUNIV® (N=221) n (%) n (%) n (%) n (%) Total patients 0 (0%) 8 (7%) 7 (6%) 15 (7%) Somnolencea 0 (0%) 4 (4%) 3 (3%) 7 (3%) Adverse reactions leading to discontinuation in ≥2% in any dose group but did not meet this criteria in all doses combined: fatigue a: The somnolence term includes somnolence, sedation, and hypersomnia. 7 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 8: Other Common Adverse Reactions (≥2% for all doses of INTUNIV and >rate than in placebo) in the Monotherapy Flexible Dose Study 4 INTUNIV® Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of INTUNIV® (N=221) Headache 11% 18% 16% 17% Insomniaa 6% 8% 6% 7% Diarrhea 4% 4% 6% 5% Lethargy 0% 4% 3% 3% Constipation 2% 2% 4% 3% Dry Mouth 1% 3% 3% 3% Adverse reactions ≥2% for all doses of INTUNIV and >rate in placebo in any dose group but did not meet this criteria in all doses combined: affect lability (affect lability, mood swings), increased weight, syncope/loss of consciousness (loss of consciousness, presyncope, syncope), dyspepsia, tachycardia (tachycardia, sinus tachycardia), and bradycardia (bradycardia, sinus bradycardia). a: The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. Table 9: Percentage of Patients Experiencing Most Common (≥ 5% and at least twice the rate for placebo) Adverse Reactions in the Monotherapy Flexible Dose Study 5 Adverse Reaction Term Placebo (N=155) All Doses of INTUNIV® (N=157) Somnolencea 23% 54% Insomniab 6% 13% Hypotensionc 3% 9% Dry Mouth 0% 8% Postural Dizziness 2% 5% Bradycardiad 0% 5% a: The somnolence term includes somnolence, sedation, and hypersomnia. b: The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. c: The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). d: The bradycardia term includes bradycardia and sinus bradycardia. There were no specific adverse reactions ≥2% in any treatment group that led to discontinuation in the monotherapy flexible dose study (Study 5). 8 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 10: Other Common Adverse Reactions (≥2% for all doses of INTUNIV and >rate than in placebo) in the Monotherapy Flexible Dose Study 5 INTUNIV® Adverse Reaction Term Placebo (N=155) All Doses of INTUNIV® (N=157) Headache 18% 27% Fatigue 12% 22% Dizziness 10% 16% Decreased Appetite 14% 15% Abdominal Paina 8% 12% Irritability 4% 7% Anxietyb 3% 5% Rashc 1% 3% Constipation 0% 3% Increased Weight 2% 3% Abdominal/Stomach Discomfortd 1% 2% Pruritus 1% 2% Adverse reactions ≥2% for all doses of INTUNIV and >rate in placebo in any dose group but did not meet this criteria in all doses combined: nausea, diarrhea, vomiting, and depression (depressed mood, depression, depressive symptom). a: The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. b: The anxiety term includes anxiety and nervousness. c: The rash term includes rash, rash generalized, and rash papular. d: The abdominal/stomach discomfort term includes abdominal discomfort, epigastric discomfort, and stomach discomfort. Adjunctive Trial Table 11: Percentage of Patients Experiencing Most Common (≥5% and at least twice the rate for placebo) Adverse Reactions in the Short-Term Adjunctive Study 3 INTUNIV® + stimulant Adverse Reaction Term Placebo+ stimulant (N=153) AM (N=150) PM (N=152) All Doses (N=302) Somnolencea 7% 18% 18% 18% Insomniab 6% 10% 14% 12% Abdominal Painc 3% 8% 12% 10% 9 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Fatigue 3% 12% 7% 10% Dizziness 4% 10% 5% 8% Decreased Appetite 4% 7% 8% 7% Nausea 3% 3% 7% 5% a: The somnolence term includes somnolence, sedation, and hypersomnia. b: The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. c: The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. There were no specific adverse reactions ≥2% in any treatment group that led to discontinuation in the short-term adjunctive study (Study 3). Table 12: Other Common Adverse Reactions (≥2% for all doses of INTUNIV and >rate than in placebo) in the Short-Term Adjunctive Study 3 INTUNIV® + stimulant Adverse Reaction Term Placebo (N=153) AM (N=150) PM (N=152) All Doses of INTUNIV® (N=302) Headache 13% 21% 21% 21% Diarrhea 1% 4% 3% 4% Hypotensiona 0% 4% 2% 3% Constipation 0% 2% 3% 2% Affect Labilityb 1% 3% 2% 2% Dry Mouth 0% 1% 3% 2% Bradycardiac 0% 1% 3% 2% Postural Dizziness 0% 1% 3% 2% Rashd 1% 1% 2% 2% Nightmaree 1% 2% 1% 2% Tachycardiaf 1% 2% 1% 2% Adverse reactions ≥2% for all doses of INTUNIV and >rate in placebo in any dose group but did not meet this criteria in all doses combined: irritability, vomiting, asthma (asthma, bronchospasm, wheezing), and enuresis (enuresis, nocturia, urinary incontinence). a: The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased. b: The affect lability term includes affect lability and mood swings. c: The bradycardia term includes bradycardia and sinus bradycardia. d: The rash term includes rash, rash generalized, and rash papular. e: The nightmare term includes abnormal dreams, nightmare, and sleep terror. f: The tachycardia term includes tachycardia and sinus tachycardia. Effects on Blood Pressure and Heart Rate In the monotherapy pediatric, short-term, controlled trials (Studies 1 and 2), the maximum mean changes from baseline in seated systolic blood pressure, diastolic blood pressure, and pulse were −5.4 mmHg, −3.4 mmHg, and −5.5 bpm, respectively, for all doses combined (generally one week after reaching target doses). For the respective fixed doses 1 mg/day, 2 mg/day, 3 mg/day or 4 mg/day the maximum mean changes in seated systolic blood pressure were -4.3 mmHg, -5.5 mmHg, -5.4 mmHg and -8.2 mmHg. For these respective fixed doses the maximum mean changes in seated diastolic blood pressure were 10 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda -3.4 mmHg, -3.3 mmHg, -4.4 mmHg and -5.4 mmHg. For these respective fixed doses the maximum mean changes in seated pulse were -4.8 bpm, -3.1 bpm, -6.5 bpm and -8.6 bpm. Decreases in blood pressure and heart rate were usually modest and asymptomatic; however, hypotension and bradycardia can occur. Hypotension was reported as an adverse reaction for 7% of the INTUNIV® group and 3% of the placebo group. This includes orthostatic hypotension, which was reported for 1% of the INTUNIV® group and none in the placebo group. These findings were generally similar in the monotherapy flexible dose trials (Studies 4 and 5). In the adjunctive trial, hypotension (3%) and bradycardia (2%) were observed in patients treated with INTUNIV® as compared to none in the placebo group. In long-term, open-label studies, (mean exposure of approximately 10 months), maximum decreases in systolic and diastolic blood pressure occurred in the first month of therapy. Decreases were less pronounced over time. Syncope occurred in 1% of pediatric patients in the clinical program. The majority of these cases occurred in the long-term, open-label studies. Discontinuation of Treatment Blood pressure and pulse may increase above baseline values following discontinuation of INTUNIV®. In five studies of children and adolescents [see Clinical Studies (14)], increases in mean systolic and diastolic blood pressure averaging approximately 3 mmHg and increases in heart rate averaging 5 beats per minute above original baseline were observed upon discontinuation with tapering of INTUNIV+. In a maintenance of efficacy study, increases in blood pressure and heart rate above baseline slowly diminished over the follow up period, which ranged between 3 and 26 weeks post final dose; the estimated average time to return to baseline was between six and twelve months. In this study, the increases in blood pressure and pulse were not considered serious or associated with adverse events. However, individuals may have larger increases than reflected by the mean changes. In postmarketing experience, following abrupt discontinuation of INTUNIV®, rebound hypertension and hypertensive encephalopathy have been reported [see Warnings and Precautions (5.4) and Adverse Reactions (6.2)]. Effects on Height, Weight, and Body Mass Index (BMI) Patients taking INTUNIV® demonstrated similar growth compared to normative data. Patients taking INTUNIV® had a mean increase in weight of 0.5 kg compared to those receiving placebo over a comparable treatment period. Patients receiving INTUNIV® for at least 12 months in open-label studies gained an average of 8 kg in weight and 8 cm (3 in) in height. The height, weight, and BMI percentile remained stable in patients at 12 months in the long-term studies compared to when they began receiving INTUNIV®. Other Adverse Reactions Observed in Clinical Studies Table 13 includes additional adverse reactions observed in short-term, placebo-controlled and long-term, open-label clinical studies not included elsewhere in section 6.1, listed by organ system. 11 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 13: Other adverse reactions observed in clinical studies Body System Adverse Reaction Cardiac Atrioventricular block General Asthenia, chest pain Immune System Disorders Hypersensitivity Investigations Increased alanine amino transferase Nervous system Convulsion Renal Increased urinary frequency Vascular Hypertension, pallor 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of guanfacine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Less frequent, possibly guanfacine-related events observed in the post-marketing study and/or reported spontaneously, not included in section 6.1, include: General: edema, malaise, tremor Cardiovascular: palpitations, tachycardia, rebound hypertension, hypertensive encephalopathy Central Nervous System: paresthesias, vertigo Eye Disorders: blurred vision Musculo-Skeletal System: arthralgia, leg cramps, leg pain, myalgia Psychiatric: confusion, hallucinations Reproductive System, Male: erectile dysfunction Respiratory System: dyspnea Skin and Appendages: alopecia, dermatitis, exfoliative dermatitis, pruritus, rash Special Senses: alterations in taste 7 DRUG INTERACTIONS Table 14 contains clinically important drug interactions with INTUNIV® [see Clinical Pharmacology (12.3)]. Table 14: Clinically Important Drug Interactions: Effect of other Drugs on INTUNIV® Concomitant Drug Name or Drug Class Clinical Rationale and Magnitude of Drug Interaction Clinical Recommendation Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure Consider dose reduction [see Dosage and administration (2.7)] 12 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure Consider dose increase [see Dosage and administration (2.7)] 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B Risk Summary There are no adequate and well-controlled studies of INTUNIV in pregnant women. No fetal harm was observed in rats and rabbits with administration of guanfacine at 4 and 2.7 times, respectively, the maximum recommended human dose. Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Animal data Reproduction studies conducted in rats have shown that guanfacine crosses the placenta. However, administration of guanfacine to rats and rabbits at 4 and 2.7 times, respectively, the maximum recommended human dose of 0.12 mg/kg/day on a mg/m2 basis resulted in no evidence of harm to the fetus. Higher doses (13.5 times the maximum recommended human dose in both rabbits and rats) were associated with reduced fetal survival and maternal toxicity. 8.3 Nursing Mothers It is not known whether guanfacine is excreted in human milk; however, guanfacine is excreted in rat milk. Because many drugs are excreted in human milk, caution should be exercised when INTUNIV® is administered to a nursing woman. Observe human milk-fed infants for sedation and somnolence. 8.4 Pediatric Use Safety and efficacy of INTUNIV® in pediatric patients less than 6 years of age have not been established. The efficacy of INTUNIV® was studied for the treatment of ADHD in five controlled monotherapy clinical trials (up to 15 weeks in duration), one randomized withdrawal study and one controlled adjunctive trial with psychostimulants (8 weeks in duration) in children and adolescents ages 6-17 who met DSM-IV® criteria for ADHD [see Adverse Reactions (6) and Clinical Studies (14)]. Animal Data In studies in juvenile rats, guanfacine alone produced a slight delay in sexual maturation in males and females at 2 to 3 times the maximum recommended human dose (MRHD). Guanfacine in combination with methylphenidate produced a slight delay in sexual maturation and decreased growth as measured by a decrease in bone length in males at a dose of guanfacine comparable to the MRHD and a dose of methylphenidate approximately 4 times the MRHD. In a study where juvenile rats were treated with guanfacine alone from 7 to 59 days of age, development was delayed as indicated by a slight delay in sexual maturation and decreased body weight gain in males at 2 mg/kg/day and in females at 3 mg/kg/day. The No Adverse Effect Level (NOAEL) for delayed sexual maturation was 1 mg/kg/day, which is equivalent to the MRHD of 4 mg/day, on a mg/m2 basis. The effects on fertility were not evaluated in this study. In a study where juvenile rats were treated with guanfacine in combination with methylphenidate from 7 to 59 days of age, a decrease in ulna bone length and a slight delay in sexual maturation were observed in males given 1 mg/kg/day of guanfacine in combination with 50 mg/kg/day of methylphenidate. The 13 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda NOAELs for these findings were 0.3 mg/kg of guanfacine in combination with 16 mg/kg/day of methylphenidate, which are equivalent to 0.3 and 1.4 times the MRHD of 4 mg/day and 54 mg/day for guanfacine and methylphenidate, respectively, on a mg/m2 basis. These findings were not observed with guanfacine alone at 1 mg/kg/day or methylphenidate alone at 50 mg/kg/day. 8.5 Geriatric Use The safety and efficacy of INTUNIV® in geriatric patients have not been established. 8.6 Renal Impairment It may be necessary to reduce the dosage in patients with significant impairment of renal function [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment It may be necessary to reduce the dosage in patients with significant impairment of hepatic function [see Clinical Pharmacology (12.3)]. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance INTUNIV® is not a controlled substance and has no known potential for abuse or dependence. 10 OVERDOSAGE Symptoms Postmarketing reports of guanfacine overdosage indicate that hypotension, drowsiness, lethargy, and bradycardia have been observed following overdose. Initial hypertension may develop early and may be followed by hypotension. Similar symptoms have been described in voluntary reports to the American Association of Poison Control Center’s National Poison Data System. Miosis of the pupils may be noted on examination. No fatal overdoses of guanfacine have been reported in published literature. Treatment Consult a Certified Poison Control Center by calling 1-800-222-1222 for up-to-date guidance and advice. Management of INTUNIV® overdose should include monitoring for and the treatment of initial hypertension, if that occurs, as well as hypotension, bradycardia, lethargy and respiratory depression. Children and adolescents who develop lethargy should be observed for the development of more serious toxicity including coma, bradycardia and hypotension for up to 24 hours, due to the possibility of delayed onset hypotension. 11 DESCRIPTION INTUNIV® is a once-daily, extended-release formulation of guanfacine hydrochloride (HCl) in a matrix tablet formulation for oral administration only. The chemical designation is N-amidino-2-(2,6­ dichlorophenyl) acetamide monohydrochloride. The molecular formula is C9H9Cl2 N3O·HCl corresponding to a molecular weight of 282.55. The chemical structure is: Cl Cl O H N NH2 HCl NH Guanfacine HCl is a white to off-white crystalline powder, sparingly soluble in water (approximately 1 mg/mL) and alcohol and slightly soluble in acetone. The only organic solvent in which it has relatively 14 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda high solubility is methanol (>30 mg/mL). Each tablet contains guanfacine HCl equivalent to 1 mg, 2 mg, 3 mg, or 4 mg of guanfacine base. The tablets also contain hypromellose, methacrylic acid copolymer, lactose, povidone, crospovidone, microcrystalline cellulose, fumaric acid, and glyceryl behenate. In addition, the 3-mg and 4-mg tablets also contain green pigment blend PB-1763. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Guanfacine is a central alpha2A-adrenergic receptor agonist. Guanfacine is not a central nervous system (CNS) stimulant. The mechanism of action of guanfacine in ADHD is not known. 12.2 Pharmacodynamics Guanfacine is a selective central alpha2A-adrenergic receptor agonist in that it has a 15-20 times higher affinity for this receptor subtype than for the alpha2B or alpha2C subtypes. Guanfacine is a known antihypertensive agent. By stimulating central alpha2A-adrenergic receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate. In a thorough QT study, the administration of two dose levels of immediate-release guanfacine (4 mg and 8 mg) produced concentrations approximately 2 to 4 times the concentrations observed with the maximum recommended dose of INTUNIV® of 0.12 mg/kg. Guanfacine was not shown to prolong the QTc interval to any clinically relevant extent. 12.3 Pharmacokinetics Absorption and Distribution Guanfacine is readily absorbed and approximately 70% bound to plasma proteins independent of drug concentration. After oral administration of INTUNIV® the time to peak plasma concentration is approximately 5 hours in children and adolescents with ADHD. Immediate-release guanfacine and INTUNIV® have different pharmacokinetic characteristics; dose substitution on a milligram per milligram basis will result in differences in exposure. A comparison across studies suggests that the Cmax is 60% lower and AUC0-∞ 43% lower, respectively, for INTUNIV® compared to immediate-release guanfacine. Therefore, the relative bioavailability of INTUNIV® to immediate-release guanfacine is 58%. The mean pharmacokinetic parameters in adults following the administration of INTUNIV® 1 mg once daily and immediate-release guanfacine 1mg once daily are summarized in Table 15. Table 15: Comparison Guanfacine in Adults of Pharmacokinetics: INTUNIV® vs. Immediate release Parameter INTUNIV® 1 mg once daily (n=52) Immediate-release guanfacine 1 mg once daily (n=12) Cmax (ng/mL) 1.0 ± 0.3 2.5 ± 0.6 AUC0-∞ (ng·h/mL) 32 ± 9 56 ± 15 tmax (h) 6.0 (4.0 – 8.0) 3.0 (1.5-4.0) t½ (h) 18 ± 4 16 ± 3 Note: Values are mean +/- SD, except for tmax which is median (range) 15 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 1: Comparison of Pharmacokinetics: INTUNIV® vs. Immediate-release guanfacine in Adults Exposure to guanfacine was higher in children (ages 6-12) compared to adolescents (ages 13-17) and adults. After oral administration of multiple doses of INTUNIV® 4 mg, the Cmax was 10 ng/mL compared to 7 ng/mL and the AUC was 162 ng·h/mL compared to 116 ng·h/mL in children (ages 6-12) and adolescents (ages 13-17), respectively. These differences are probably attributable to the lower body weight of children compared to adolescents and adults. The pharmacokinetics were affected by intake of food when a single dose of INTUNIV® 4 mg was administered with a high-fat breakfast. The mean exposure increased (Cmax ~75% and AUC ~40%) compared to dosing in a fasted state. Dose Proportionality Following administration of INTUNIV® in single doses of 1 mg, 2 mg, 3 mg, and 4 mg to adults, Cmax and AUC0-∞ of guanfacine were proportional to dose. Metabolism and Elimination In vitro studies with human liver microsomes and recombinant CYP’s demonstrated that guanfacine was primarily metabolized by CYP3A4. In pooled human hepatic microsomes, guanfacine did not inhibit the activities of the major cytochrome P450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5); guanfacine is also not an inducer of CYP3A, CYP1A2 and CYP2B6. Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5 inducers/inhibitors. Guanfacine inhibits MATE1 and OCT1, but does not inhibit BSEP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, or MATE2K. Guanfacine is a substrate of OCT1 and OCT2, but not BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, or MATE2. Concomitant administration of guanfacine with OCT1 substrates might potentially increase the exposure of these OCT1 substrates. 16 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Studies in Specific Populations Renal Impairment The impact of renal impairment on the pharmacokinetics of guanfacine in children was not assessed. In adult patients with impaired renal function, the cumulative urinary excretion of guanfacine and the renal clearance diminished as renal function decreased. In patients on hemodialysis, the dialysis clearance was about 15% of the total clearance. The low dialysis clearance suggests that the hepatic elimination (metabolism) increases as renal function decreases. Hepatic Impairment The impact of hepatic impairment on PK of guanfacine in children was not assessed. Guanfacine in adults is cleared both by the liver and the kidney, and approximately 50% of the clearance of guanfacine is hepatic [see Hepatic Impairment (8.7)]. Drug Interaction Studies Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be affected significantly by CYP3A4 inhibitors or inducers (Figure 2). Figure 2: Effect of Other Drugs on the Pharmacokinetics (PK) of INTUNIV® Guanfacine does not significantly affect exposures of methylphenidate and lisdexamfetamine when coadministered (Figure 3). Figure 3: Effect of INTUNIV® on the Pharmacokinetics (PK) of Other Drugs 17 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenic effect of guanfacine was observed in studies of 78 weeks in mice or 102 weeks in rats at doses up to 6.8 times the maximum recommended human dose of 0.12 mg/kg/day on a mg/m2 basis. Mutagenesis Guanfacine was not genotoxic in a variety of test models, including the Ames test and an in vitro chromosomal aberration test; however, a marginal increase in numerical aberrations (polyploidy) was observed in the latter study. Impairment of Fertility No adverse effects were observed in fertility studies in male and female rats at doses up to 22 times the maximum recommended human dose on a mg/m2 basis. 14 CLINICAL STUDIES Efficacy of INTUNIV® in the treatment of ADHD was established in children and adolescents (6 to 17 years) in: • Five short-term, placebo-controlled monotherapy trials (Studies 1, 2, 4, 5, and 6). • One short-term, placebo-controlled adjunctive trial with psychostimulants (Study 3). • One long-term, placebo-controlled monotherapy maintenance trial (Study 7). Studies 1 and 2: Fixed-dose INTUNIV® Monotherapy Study 1 (301 study) was a double-blind, placebo-controlled, parallel-group, fixed-dose study, in which efficacy of once daily dosing with INTUNIV® (2 mg, 3 mg and 4 mg) was evaluated for 5 weeks (n=345) in children and adolescents aged 6-17 years. Study 2 (304 study) was a double-blind, placebo-controlled, parallel-group, fixed-dose study, in which efficacy of once daily dosing with INTUNIV® (1 mg, 2 mg, 3 mg and 4 mg) was evaluated for 6 weeks (n=324) in children and adolescents aged 6-17 years. In both studies, randomized patients in 2 mg, 3 mg and 4 mg dose groups were titrated to their target fixed dose, 18 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda and continued on the same dose until a dose tapering phase started. The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. Patients who weighed less than 25 kg were not included in either study. Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week for which a valid score was obtained prior to dose tapering (up to Week 5 in Study 1 and up to Week 6 in Study 2). The mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV® compared to placebo for Studies 1 and 2. Placebo-adjusted changes from baseline were statistically significant for each of the 2 mg, 3 mg, and 4 mg INTUNIV® randomized treatment groups in both studies, as well as the 1 mg INTUNIV® treatment group that was included only in Study 2 (see Table 16). Dose-responsive efficacy was evident, particularly when data were examined on a weight-adjusted (mg/kg) basis. When evaluated over the dose range of 0.01-0.17 mg/kg/day, clinically relevant improvements were observed beginning at doses in the range 0.05-0.08 mg/kg/day. Doses up to 0.12 mg/kg/day were shown to provide additional benefit. In the monotherapy trials (Studies 1 and 2), subgroup analyses were performed to identify any differences in response based on gender or age (6-12 vs. 13-17). Analyses of the primary outcome did not suggest any differential responsiveness on the basis of gender. Analyses by age revealed a statistically significant treatment effect only in the 6-12 age subgroup. Due to the relatively small proportion of adolescent patients (ages 13-17) enrolled into these studies (approximately 25%), these data may not have been sufficient to demonstrate efficacy in the adolescent patients. In these studies, patients were randomized to a fixed dose of INTUNIV® rather than optimized by body weight. Therefore, some adolescent patients were randomized to a dose that might have resulted in relatively lower plasma guanfacine concentrations compared to the younger patients. Over half (55%) of the adolescent patients received doses of 0.01-0.04 mg/kg. In studies in which systematic pharmacokinetic data were obtained, there was a strong inverse correlation between body weight and plasma guanfacine concentrations. Table 16: Fixed dose Studies Study Treatment Group Primary Efficacy Measure: ADHD-RS-IV Total Score Number (Age Range) Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Differencea (95% CI) Study 1 (6—17 years) INTUNIV® 2 mg* INTUNIV® 3 mg* INTUNIV® 4 mg* Placebo 36.1 (9.99) 36.8 (8.72) 38.4 (9.21) 38.1 (9.34) -15.9 (1.37) -16.0 (1.38) -18.5 (1.39) -8.5 (1.42) -7.4 (-11.3, -3.5) -7.5 (-11.4, -3.6) -10.0 (-13.9, -6.1) -­ Study 2 (6—17 years) INTUNIV® 1 mg*^ INTUNIV® 2 mg* INTUNIV® 3 mg* INTUNIV® 4 mg* Placebo 41.7 (7.81) 39.9 (8.74) 39.1 (9.22) 40.6 (8.57) 39.3 (8.85) -19.4 (1.69) -18.1 (1.60) -20.0 (1.64) -20.6 (1.60) -12.7 (1.60) -6.8 (-11.3, -2.2) -5.4 (-9.9, -0.9) -7.3 (-11.8, -2.8) -7.9 (-12.3, -3.4) -­ SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. a Difference (drug minus placebo) in least-squares mean change from baseline. * Doses statistically significantly superior to placebo. ^ The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. 19 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Study 3: Flexible-dose INTUNIV® as Adjunctive Therapy to Psychostimulants Study 3 (313 study) was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily optimized dosing (morning or evening) with INTUNIV® (1 mg, 2 mg, 3 mg and 4 mg), when co-administered with psychostimulants, was evaluated for 8 weeks, in children and adolescents aged 6-17 years with a diagnosis of ADHD, with a sub-optimal response to stimulants (n=455). Patients were started at the 1 mg INTUNIV® dose level and were titrated weekly over a 5-week dose-optimization period to an optimal INTUNIV® dose not to exceed 4 mg/day based on tolerability and clinical response. The dose was then maintained for a 3-week dose maintenance period before entry to 1 week of dose tapering. Patients took INTUNIV® either in the morning or the evening while maintaining their current dose of psychostimulant treatment given each morning. Allowable psychostimulants in the study were ADDERALL XR®, VYVANSE®, CONCERTA®, FOCALIN XR®, RITALIN LA®, METADATE CD® or FDA-approved generic equivalents. Symptoms of ADHD were evaluated on a weekly basis by clinicians using the ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week prior to dose tapering for which a valid score was obtained (up to Week 8). Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV® given in combination with a psychostimulant compared to placebo given with a psychostimulant for Study 3, for both morning and evening INTUNIV® dosing (see Table 17). Nearly two-thirds (64.2%) of patients reached optimal doses in the 0.05-0.12 mg/kg/day range. Studies 4, 5 and 6: Flexible-dose INTUNIV® Monotherapy Study 4 (314 study) was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily dosing (morning or evening) with INTUNIV® (1 mg, 2 mg, 3 mg, and 4 mg) was evaluated for 8 weeks in children aged 6-12 years (n=340). Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline score at endpoint on the ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week for which a valid score was obtained prior to dose tapering (up to Week 8). Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV® compared to placebo in both AM and PM dosing groups of INTUNIV® (see Table 17). Study 5 (312 study) was a 15-week, double-blind, randomized, placebo-controlled, dose-optimization study conducted in adolescents aged 13-17 years (n=314) to evaluate the efficacy and safety of INTUNIV® (1-7 mg/day; optimized dose range of 0.05-0.12 mg/kg/day) in the treatment of ADHD as measured by the ADHD Rating Scale-IV (ADHD-RS-IV). Patients receiving INTUNIV® showed statistically significantly greater improvement on the ADHD-RS-IV total score compared with patients receiving placebo (see Table 17). Study 6 (316 study) was a 12-week (for children aged 6-12) or 15-week (for adolescents aged 13-17), randomized, double-blind, parallel-group, placebo-and active-reference, dose-optimization study conducted in pediatric patients (children and adolescents aged 6-17 years old inclusive) (n=337) to assess the efficacy and safety of once-daily dosing (children: 1-4 mg/day, adolescents: 1-7 mg/day; optimized dose range of 0.05 to 0.12 mg/kg/day) in the treatment of ADHD. INTUNIV® was statistically superior to placebo on symptoms of ADHD in patients 6-17 years as measured by change from baseline in ADHD-RS-IV total scores (see Table 17). 20 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 17: Flexible-Dose studies Study Number Treatment Group Primary Efficacy Measure: ADHD-RS-IV Total Score (Age Range) Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Differenceb (95% CI) Study 3a INTUNIV® 1—4 mg AM* 37.6 (8.13) -20.3 (0.97) -4.5 (-7.5, -1.4) (6—17 INTUNIV® 1—4 mg PM* 37.0 (7.65) -21.2 (0.97) -5.3 (-8.3, -2.3) years) Placebo 37.7 (7.75) -15.9 (0.96) -­ Study 4 INTUNIV® 1—4 mg AM* 41.7 (6.39) -20.0 (1.23) -9.4 (-12.8, -6.0) (6—12 INTUNIV® 1—4 mg PM* 41.6 (6.66) -20.4 (1.19) -9.8 (-13.1, -6.4) years) Placebo 42.9 (6.29) -10.6 (1.20) -­ Study 5 INTUNIV® 1—7 mg* 39.9 (5.57) -24.6 (1.06) -6.03 (-8.87, -3.19) (13—17 Placebo 40.0 (6.11) -18.5 (1.08) -­ years) Study 6 INTUNIV® 1—7 mg* 43.1 (5.47) -23.89 (1.15) -8.88 (-11.94, ­ (6—17 Placebo 43.2 (5.60) -15.01 (1.16) 5.81) years) -­ SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. a Treatment was given in combination with a psychostimulant. b Difference (drug minus placebo) in least-squares mean change from baseline. * Doses statistically significantly superior to placebo. Study 7: Long-Term Maintenance of INTUNIV® Efficacy Study 7 (315 study) was a double-blind, placebo-controlled, randomized withdrawal trial in pediatric patients aged 6 to 17 years with DSM-IV-TR diagnosis of ADHD. The study consisted of an open-label phase, including a 7-week dose optimization period to titrate patients to an optimal dose (maximum 4 mg/day for children and 7 mg/day for adolescents; optimized dose range: 0.05 to 0.12 mg/kg/day) and a 6-week dose maintenance period. There were 526 patients included in the open-label phase. Among those, 315 patients who met response criteria in the open-label phase were then randomized (1:1, INTUNIV:placebo) in a 26-week, double-blind, randomized withdrawal phase. The response criteria were defined by ≥30% reduction in ADHD-RS-IV total score and a Clinical Global Impression-Improvement (CGI-I) score of 1 or 2 during the open-label phase. A statistically significantly lower proportion of treatment failures occurred among INTUNIV patients compared to placebo at the end of the randomized withdrawal period (Figure 4). Treatment failure was defined as a ≥50% increase (worsening) in ADHD-RS-IV total score and a ≥2-point increase in Clinical Global Impression-Severity (CGI-S) score. Patients who met the treatment failure criteria on two consecutive visits or discontinued for any reason were classified as treatment failure. 21 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 4. Kaplan-Meier Estimation of Proportion of Patients with Treatment Failure for Children and Adolescents Ages 6-17 (Study 7) 16 HOW SUPPLIED/STORAGE AND HANDLING INTUNIV® is supplied in 1 mg, 2 mg, 3 mg, and 4 mg strength extended-release tablets in 100 count bottles. 1 mg 2 mg 3 mg 4 mg Color White/off-white White/off-white Green Green Shape Round Caplet Round Caplet Debossment (top/bottom) 503 / 1 mg 503 / 2 mg 503 / 3 mg 503 / 4 mg NDC number 54092-513-02 54092-515-02 54092-517-02 54092-519-02 Storage - Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). See USP Controlled Room Temperature. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Dosing and Administration Instruct patients to swallow INTUNIV® whole with water, milk or other liquid. Tablets should not be crushed, chewed or broken prior to administration because this may increase the rate of release of the active drug. Patients should not take INTUNIV® together with a high-fat meal, since this can raise blood levels of INTUNIV®. Instruct the parent or caregiver to supervise the child or adolescent taking INTUNIV® and to keep the bottle of tablets out of reach of children. Advise patients not to abruptly discontinue INTUNIV® as abrupt discontinuation can result in clinically significant rebound hypertension. Concomitant stimulant use and abrupt discontinuation of Intuniv may increase this hypertensive response. Instruct patients on how to properly taper the dose to minimize the risk of rebound hypertension [see Dosage and Administration (2.5) and Warnings and Precautions (5.4)]. 22 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Adverse Reactions Advise patients that sedation can occur, particularly early in treatment or with dose increases. Caution against operating heavy equipment or driving until they know how they respond to treatment with INTUNIV® [see Warnings and Precautions (5.2)]. Headache and abdominal pain can also occur. If any of these symptoms persist, or other symptoms occur, the patient should be advised to discuss the symptoms with the health care provider. Advise patients to avoid becoming dehydrated or overheated, which may potentially increase the risks of hypotension and syncope [see Warnings and Precautions (5.1)]. Advise patients to avoid use with alcohol. 23 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Patient Information INTUNIV® (in-TOO-niv) (guanfacine) Extended-Release Tablets Read the Patient Information that comes with INTUNIV® before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment. What is INTUNIV®? INTUNIV® is a prescription medicine used to treat the symptoms of attention deficit hyperactivity disorder (ADHD). INTUNIV may be used alone or with ADHD stimulant medicines. INTUNIV® is not a central nervous system (CNS) stimulant. It is not known if INTUNIV is safe and effective in children younger than 6 years of age. Who should not take INTUNIV®? Do not take INTUNIV if you are allergic to guanfacine or any of the ingredients in INTUNIV. See the end of this leaflet for a complete list of ingredients in INTUNIV. What should I tell my doctor before taking INTUNIV®? Before you take INTUNIV®, tell your doctor if you: • have heart problems or a low heart rate • have fainted • have low or high blood pressure • have liver or kidney problems • have any other medical conditions • are pregnant or plan to become pregnant. It is not known if INTUNIV® will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant. • are breastfeeding or plan to breastfeed. It is not known if INTUNIV® passes into your breast milk. Talk to your doctor about the best way to feed your baby while taking INTUNIV®. Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Tell your doctor about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. INTUNIV® may affect the way other medicines work, and other medicines may affect how INTUNIV® works. Especially tell your doctor if you take: • ketoconazole • medicines that can affect enzyme metabolism • high blood pressure medicine • sedatives • benzodiazepines • barbiturates • antipsychotics Ask your doctor or pharmacist for a list of these medicines, if you are not sure. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine. How should I take INTUNIV®? • Take INTUNIV® exactly as your doctor tells you. • Your doctor may change your dose. Do not change your dose of INTUNIV® without talking to your doctor. • Do not stop taking INTUNIV® without talking to your doctor. • Try not to miss your dose of INTUNIV®. If you miss a dose of INTUNIV®, take the next dose at your regular time. If you miss 2 or more doses, talk to your doctor, as you may need to restart INTUNIV® with a lower dose. • Do not take a double dose to make up for a missed dose. • INTUNIV® should be taken 1 time a day in the morning or in the evening, either alone or in combination with an ADHD stimulant medicine that your doctor may prescribe. Your doctor will tell you when to take INTUNIV® and when to take your ADHD stimulant medication. • INTUNIV® should be swallowed whole with a small amount of water, milk, or other liquid. • Do not crush, chew, or break INTUNIV®. Tell your doctor if you cannot swallow INTUNIV® whole. • Do not take INTUNIV® with a high-fat meal. • Your doctor will check your blood pressure and heart rate while you take INTUNIV®. 25 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • If you take too much INTUNIV®, call your local Poison Control Center at 1-800-222-1222 or go to the nearest emergency room right away. What should I avoid while taking INTUNIV®? • Do not drive, operate heavy machinery, or do other dangerous activities until you know how INTUNIV® affects you. INTUNIV® can slow your thinking and motor skills. • Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking INTUNIV® until you talk with your doctor. INTUNIV® taken with alcohol or medicines that cause sleepiness or dizziness may make your sleepiness or dizziness worse. • Do not become dehydrated or overheated. This may increase your chance of having low blood pressure or fainting while taking INTUNIV. • Do not suddenly stop INTUNIV. Tell your healthcare provider if you have been vomiting and cannot take INTUNIV, you may be at risk for rebound hypertension. What are the possible side effects of INTUNIV®? INTUNIV® may cause serious side effects including: • low blood pressure • low heart rate • fainting • sleepiness • increased blood pressure and heart rate after suddenly stopping INTUNIV (rebound hypertension). Suddenly stopping INTUNIV can cause increased blood pressure and heart rate and other withdrawal symptoms such as headache, confusion, nervousness, agitation, and tremors. If these symptoms continue to get worse and are left untreated, it could lead to a very serious condition including very high blood pressure, feeling very sleepy or tired, severe headache, vomiting, vision problems, seizures. Get medical help right away, if you have any of the symptoms listed above. The most common side effects of INTUNIV® include: • sleepiness • tiredness • trouble sleeping • low blood pressure • nausea • stomach pain • dizziness 26 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda • dry mouth • irritability • vomiting • slow heart rate Tell the doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of INTUNIV®. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store INTUNIV®? • Store INTUNIV® between 68°F to 77°F (20°C to 25°C) Keep INTUNIV® and all medicines out of the reach of children. General Information about the safe and effective use INTUNIV® Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use INTUNIV® for a condition for which it was not prescribed. Do not give INTUNIV® to other people, even if they have the same symptoms that you have. It may harm them. This leaflet summarizes the most important information about INTUNIV®. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about INTUNIV® that is written for health professionals. For more information, go to www.INTUNIV.com or call 1-800-828-2088. What are the ingredients in INTUNIV®? Active ingredient: guanfacine hydrochloride Inactive ingredients: hypromellose, methacrylic acid copolymer, lactose, povidone, crospovidone, microcrystalline cellulose, fumaric acid, and glycerol behenate. In addition, the 3 mg and 4 mg tablets also contain green pigment blend PB-1763. This Patient Information has been approved by the U.S. Food and Drug Administration. Manufactured for Shire US Inc., 300 Shire Way, Lexington, MA 02421. INTUNIV® is a registered trademark of Shire LLC. Revised: 11/2017 © 2017 Shire US Inc. This product is covered by US patents including 6,287,599; 6,811,794. 27 Reference ID: 4426258 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda

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NIH Websites Are Changing    # Label: INTUNIV- guanfacine tablet, extended release ## View Package Photos   ## [Drug Label Info](#drug-information) ## [Safety](#) ## [Related Resources](#) ## [More Info For This Drug](#) ## Drug Label Information Updated August 31, 2013 If you are a consumer or patient please visit [this version.](/dailymed/drugInfo.cfm?setid=1bb3fac5-11e8-4d1c-a5e4-2520abcdeb47&audience=consumer) # RECENT MAJOR CHANGES Dosage and Administration, Dose Selection ( ), 02/2013 [2.2](#LINK_84f3cb3f-ac5d-4e82-8d49-0618a832be3a) # INDICATIONS AND USAGE INTUNIV is a central alpha -adrenergic receptor agonist indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications ( ). ®2A[1](#LINK_58faaac3-eca4-47c0-853d-5e8b44d1020b) # DOSAGE AND ADMINISTRATION # DOSAGE FORMS AND STRENGTHS Extended-release tablets: 1 mg, 2 mg, 3 mg and 4 mg ( ) [3](#LINK_959ac67a-e3c8-49b9-8ac4-35cd476678f9) # CONTRAINDICATIONS History of hypersensitivity to INTUNIV , its inactive ingredients, or other products containing guanfacine ( ). ®[4](#LINK_54d24e00-8933-4f44-8e82-67666786a862) # WARNINGS AND PRECAUTIONS # ADVERSE REACTIONS Most common adverse reactions (≥5% and at least twice placebo rate) in the monotherapy trials: somnolence, fatigue, nausea, lethargy, and hypotension ( ). Most common adverse reactions (≥5% and at least twice placebo rate) in the adjunctive trial: somnolence, fatigue, insomnia, dizziness, and abdominal pain ( ). [6](#LINK_1eef5616-3c54-4176-9111-50817b6a895f)[6](#LINK_1eef5616-3c54-4176-9111-50817b6a895f) To report SUSPECTED ADVERSE REACTIONS, contact Shire US Inc. at 1-800-828-2088 or FDA at 1-800-FDA-1088 orwww.fda.gov/medwatch. # DRUG INTERACTIONS # USE IN SPECIFIC POPULATIONS Hepatic or Renal Impairment: dose reduction may be required in patients with clinically significant impairment of hepatic or renal function ( ). [8.6](#LINK_0609fd99-d0bd-479f-a154-827f40d4816c) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 10/2014 # FULL PRESCRIBING INFORMATION: CONTENTS[\*](#footnote-content) # [1 INDICATIONS AND USAGE](#section-1) # [2 DOSAGE AND ADMINISTRATION](#section-2) ## [2.1 General Instruction for Use](#section-2.1) ## [2.2 Dose Selection](#section-2.2) ## [2.3 Switching from Immediate-Release Guanfacine to INTUNIV](#section-2.3) ## [2.4 Maintenance Treatment](#section-2.4) ## [2.5 Discontinuation](#section-2.5) ## [2.6 Missed Doses](#section-2.6) ## [2.7 Dose Adjustment with Concomitant Use of Strong CYP3A4 Inhibitors or Inducers](#section-2.7) # [3 DOSAGE FORMS AND STRENGTHS](#section-3) # [4 CONTRAINDICATIONS](#section-4) # [5 WARNINGS AND PRECAUTIONS](#section-5) ## [5.1 Hypotension, Bradycardia, and Syncope](#section-5.1) ## [5.2 Sedation and Somnolence](#section-5.2) # [6 ADVERSE REACTIONS](#section-6) ## [6.1 Clinical Trials Experience](#section-6.1) ## [6.2 Post-marketing Experience](#section-6.2) # [7 DRUG INTERACTIONS](#section-7) # [8 USE IN SPECIFIC POPULATIONS](#section-8) ## [8.1 Pregnancy](#section-8.1) ## [8.3 Nursing Mothers](#section-8.2) ## [8.4 Pediatric Use](#section-8.3) ## [8.5 Geriatric Use](#section-8.4) ## [8.6 Use in Patients with Renal or Hepatic Impairment](#section-8.5) # [9 DRUG ABUSE AND DEPENDENCE](#section-9) ## [9.1 Controlled Substance](#section-9.1) # [10 OVERDOSAGE](#section-10) # [11 DESCRIPTION](#section-11) # [12 CLINICAL PHARMACOLOGY](#section-12) ## [12.1 Mechanism of Action](#section-12.1) ## [12.2 Pharmacodynamics](#section-12.2) ## [12.3 Pharmacokinetics](#section-12.3) # [13 NONCLINICAL TOXICOLOGY](#section-13) ## [13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility](#section-13.1) # [14 CLINICAL STUDIES](#section-14) ## [14.1 Safety and Efficacy Studies](#section-14.1) # [16 HOW SUPPLIED/STORAGE AND HANDLING](#section-15) # [17 PATIENT COUNSELING INFORMATION](#section-16) INTUNIV is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications. The efficacy of INTUNIV was studied for the treatment of ADHD in three controlled monotherapy clinical trials (up to 8 weeks in duration) and one controlled adjunctive trial with psychostimulants (8 weeks in duration) in children and adolescents ages 6-17 who met DSM-IV criteria for ADHD [ ]. The effectiveness of INTUNIV for longer-term use (more than 8 weeks) has not been systematically evaluated in controlled trials. ®®®[see Clinical Studies (14)](#LINK_6445dffa-b93e-4fef-bdc9-8d4008a1fa18)® ## 2.1 General Instruction for Use  Do not administer with high fat meals, due to increased exposure. Swallow tablets whole. Do not crush, chew, or break tablets because this will increase the rate of guanfacine release. ## 2.2 Dose Selection INTUNIV should be taken once daily, either in the morning or evening, at approximately same time each day. Begin at a dose of 1 mg/day, and adjust in increments of no more than 1 mg/week. Maintain the dose within the range of 1 mg to 4 mg once daily, depending on clinical response and tolerability, for both monotherapy and adjunctive therapy to a psychostimulant. Doses above 4 mg/day have not been systematically studied in controlled clinical studies . [ ] [see Clinical Studies (14.1)](#LINK_aa52c071-e91a-4619-901c-f05e2feee168) Clinically relevant improvements were observed beginning at doses in the range 0.05-0.08 mg/kg once daily in both mono- and adjunctive therapy. Efficacy increased with increasing weight-adjusted dose (mg/kg). If well tolerated, doses up to 0.12 mg/kg once daily may provide additional benefit. In clinical trials, there were dose-related and exposure-related risks for several clinically significant adverse reactions (hypotension, bradycardia, sedative events). Thus, consideration should be given to dosing INTUNIV on a mg/kg basis, in order to balance the exposure-related potential benefits and risks of treatment. ® ## 2.3 Switching from Immediate-Release Guanfacine to INTUNIV If switching from immediate-release guanfacine, discontinue that treatment, and titrate with INTUNIV following above recommended schedule. ® Do not substitute for immediate-release guanfacine tablets on a milligram-per-milligram basis, because of differing pharmacokinetic profiles. INTUNIV has a delayed T , reduced C and lower bioavailability compared to those of the same dose of immediate-release guanfacine . ®maxmax[ ] [see Clinical Pharmacology (12.3)](#LINK_bed1af78-5f58-4139-9898-9ec1710522a3) ## 2.4 Maintenance Treatment It is generally agreed that pharmacological treatment of ADHD may be needed for an extended period. The effectiveness of INTUNIV for longer-term use (more than 9 weeks) has not been systematically evaluated in controlled trials. Therefore the physician electing to use INTUNIV for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. ®® ## 2.5 Discontinuation Infrequent, transient elevations in blood pressure above original baseline (i.e., rebound) have been reported to occur upon abrupt discontinuation of guanfacine. To minimize these effects, the dose should generally be tapered in decrements of no more than 1 mg every 3 to 7 days. ## 2.6 Missed Doses When reinitiating patients to the previous maintenance dose after two or more missed consecutive doses, physicians should consider titration based on patient tolerability. ## 2.7 Dose Adjustment with Concomitant Use of Strong CYP3A4 Inhibitors or Inducers Dosage adjustments for INTUNIV are recommended with concomitant use of strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole), or CYP3A4 inducers (e.g., avasimibe, carbamazepine, phenytoin, rifampin, and St.John’s wort) (Table 1) . ®[] [see Drug Interactions (7)](#LINK_7d18bf19-e14f-47e9-88dc-4021f4805d3c) Table 1: Dose Adjustments in Patients Taking Concomitant CYP3A4 Inhibitors or Inducers | | | | | | --- | --- | --- | --- | | Comedications | Scenarios | | | | Initiate INTUNIV when taking comedications ® | Continue INTUNIV   when adding a comedication ® | Stop a comedication    when continuing INTUNIV   ® | | Strong CYP3A4 Inhibitors | INTUNIV dose should be limited to 2 mg/day ® | INTUNIV dose should be decreased by half. ® | INTUNIV dose should be doubled based on patient tolerability. The maximum dose should not exceed 4 mg/day ® | | Strong CYP3A4 Inducers | INTUNIV dose may be titrated up to 8 mg/day. Consider faster titration (e.g. in increments of 2 mg/week) ® | Consider increase INTUNIV dose gradually in 1-2 weeks to 2 fold of the original dose based on patient tolerability. ® | INTUNIV dose should be decreased by half in 1-2 weeks based on patient tolerability. The maximum dose should not exceed 4 mg/day ® | Initiate INTUNIV when taking comedications ® 1 mg, 2 mg, 3 mg and 4 mg extended-release tablets Patients with a history of hypersensitivity to INTUNIV , its inactive ingredients or other products containing guanfacine should not take INTUNIV . ®[ ] [see Description (11)](#LINK_362a81c0-6b1b-4173-982a-effbc61fba8f)® ## 5.1 Hypotension, Bradycardia, and Syncope Treatment with INTUNIV can cause dose-dependent decreases in blood pressure and heart rate. Decreases were less pronounced over time of treatment. Orthostatic hypotension and syncope have been reported . ®[] [see Adverse Reactions](#LINK_fc086e21-c9e8-452b-8a21-73f06ea6cda1)[(6.1)](#LINK_fc086e21-c9e8-452b-8a21-73f06ea6cda1) Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Use INTUNIV with caution in patients with a history of hypotension, heart block, bradycardia, cardiovascular disease, or who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Use INTUNIV with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. Advise patients to avoid becoming dehydrated or overheated. ®® ## 5.2 Sedation and Somnolence Somnolence and sedation were commonly reported adverse reactions in clinical studies [ . Before using INTUNIV with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects.  Caution patients against operating heavy equipment or driving until they know how they respond to treatment with INTUNIV Advise patients to avoid use with alcohol. ] [see Adverse Reactions (6.1)](#LINK_fc086e21-c9e8-452b-8a21-73f06ea6cda1)®®. The following serious adverse reactions are described elsewhere in the labelling:   ## 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A total of 2,028 subjects have been exposed to INTUNIV while participating in clinical trials. This includes 1,533 patients from completed studies in children and adolescents, and 495 subjects in completed studies in adult healthy volunteers. ® The mean duration of exposure of 446 patients that previously participated in two 2-year, open-label long-term studies was approximately 10 months. Monotherapy Trials The most commonly observed adverse reactions (incidence ≥ 5% and at least twice the rate for placebo) in the monotherapy trials (Studies 1 and 2) with INTUNIV were: somnolence, fatigue, nausea, lethargy, and hypotension. Most Common Adverse Reactions -® Twelve percent (12%) of patients receiving INTUNIV discontinued from the monotherapy clinical studies (Studies 1 and 2) due to adverse reactions, compared to 4% in the placebo group. The most common adverse reactions leading to discontinuation of INTUNIV -treated patients from the studies were somnolence/sedation (6%) and fatigue (2%). Less common adverse reactions leading to discontinuation (occurring in approximately 1% of patients) included: hypotension, headache, and dizziness. Adverse Reactions Leading to Discontinuation -®® Adjunctive Trial The most commonly observed adverse reactions (incidence ≥ 5% and at least twice the rate for placebo) in the adjunctive trial with INTUNIV were: somnolence, fatigue, insomnia, dizziness, and abdominal pain. Most Common Adverse Reactions -® In the adjunctive clinical study, 3% of patients receiving INTUNIV discontinued due to adverse reactions, compared to 1% in the placebo group.  Each adverse reaction leading to discontinuation occurred in less than 1% of INTUNIV -treated patients. Adverse Reactions Leading to Discontinuation –®® Short Term Monotherapy Clinical Studies - Two short-term, placebo-controlled, double-blind pivotal studies (Studies 1 and 2) were conducted in children and adolescents with ADHD, using fixed doses of INTUNIV (1 mg, 2 mg, 3 mg, and 4 mg/day).  The most commonly reported adverse reactions (occurring in ≥ 2% of patients) that were considered drug-related and reported in a greater percentage of patients taking INTUNIV compared to patients taking placebo are shown in Table 2. Adverse reactions that were dose-related include: somnolence/sedation, abdominal pain, dizziness, hypotension, dry mouth and constipation. Common Adverse Reactions®® | | | | | --- | --- | --- | | Table 2:  Percentage of Patients Experiencing Common (≥ 2%)    Adverse Reactions in Short-Term Monotherapy Studies 1 and 2 | | | | Adverse Reaction Term | All Doses of INTUNIV (N=513) ® | Placebo    (N=149) | | Somnolence a | 38% | 12% | | Headache | 24% | 19% | | Fatigue | 14% | 3% | | Abdominal pain b | 11% | 9% | | Hypotension c | 7% | 3% | | Nausea | 6% | 2% | | Lethargy | 6% | 3% | | Dizziness | 6% | 4% | | Irritability | 6% | 4% | | Decreased appetite | 5% | 3% | | Dry mouth | 4% | 1% | | Constipation | 3% | 1% | | a: The somnolence term includes somnolence, sedation, and hypersomnia. b: The abdominal pain term includes abdominal pain, abdominal pain upper, and abdominal pain lower. c: The hypotension term includes hypotension, orthostatic hypotension, and decreased blood pressure. | | |    Table 2:  Percentage of Patients Experiencing Common (≥ 2%)    Adverse Reactions in Short-Term Monotherapy Studies 1 and 2 In an 8-week, placebo-controlled study in children 6-12 years of age with ADHD in which INTUNIV was dosed once (1-4 mg/day) in the morning or evening (Study 4), the safety profile was consistent with the once daily morning dosing of INTUNIV . ®® Short Term Adjunctive Clinical Study - A 8-week, placebo-controlled, double-blind, dose-optimized pivotal study (Study 3) was conducted in children and adolescents aged 6-17 years with a diagnosis of ADHD who were identified as having a sub-optimal response to psychostimulants. Patients received INTUNIV (1 mg, 2 mg, 3 mg, and 4 mg/day) or placebo, dosed in the morning or in the evening, in combination with their morning dose of psychostimulant. The most commonly reported adverse reactions (occurring in ≥ 2% of patients in the overall INTUNIV group) that were reported in a greater percentage of patients taking INTUNIV compared to patients taking placebo are shown in Table 3. Common Adverse Reactions®®® | | | | | --- | --- | --- | | Table 3:  Percentage of Patients Experiencing Common (≥ 2%) Adverse Reactions in Short-Term Adjunctive Study 3 | | | | Adverse Reaction Term | All Doses of INTUNIV ® (N=302) a | Placebo   (N=153) | | Headache | 21% | 13% | | Somnolence b | 18% | 7% | | Insomnia c | 12% | 6% | | Fatigue | 10% | 3% | | Abdominal pain d | 10% | 3% | | Dizziness | 8% | 4% | | Decreased appetite | 7% | 4% | | Nausea | 5% | 3% | | Diarrhea | 4% | 1% | | Hypotension e | 3% | 0% | | Affect lability | 2% | 1% | | Bradycardia | 2% | 0% | | Constipation | 2% | 0% | | Dry mouth | 2% | 0% | | a: The morning and evening dose groups of INTUNIV are combined. b: The somnolence term includes somnolence, sedation, and hypersomnia. c: The insomnia term includes insomnia, initial insomnia, and middle insomnia. d: The abdominal pain term includes abdominal pain, abdominal pain upper, and abdominal pain lower. e: The hypotension term includes hypotension, orthostatic hypotension, and decreased blood pressure. ® | | | Effects on Blood Pressure and Heart Rate In the monotherapy pediatric, short-term, controlled trials (Studies 1 and 2), the maximum mean changes from baseline in systolic blood pressure, diastolic blood pressure, and pulse were −5 mmHg, −3 mmHg, and −6 bpm, respectively, for all dose groups combined (generally one week after reaching target doses of 1 mg/day, 2 mg/day, 3 mg/day or 4 mg/day). These changes were dose dependent. Decreases in blood pressure and heart rate were usually modest and asymptomatic; however, hypotension and bradycardia can occur. Hypotension was reported as an adverse reaction for 7% of the INTUNIV group and 3% of the placebo group. This includes orthostatic hypotension, which was reported for 1% of the INTUNIV group and none in the placebo group. In the adjunctive trial, hypotension (3%) and bradycardia (2%) were observed in patients treated with INTUNIV as compared to none in the placebo group.  In long-term, open label studies, (mean exposure of approximately 10 months), maximum decreases in systolic and diastolic blood pressure occurred in the first month of therapy. Decreases were less pronounced over time. Syncope occurred in 1% of pediatric subjects in the clinical program. The majority of these cases occurred in the long-term, open-label studies. ®®® Other Adverse Reactions Observed in Clinical Studies Table 4 includes additional adverse reactions observed in short-term, placebo-controlled and long-term, open-label clinical studies not included elsewhere in section 6.1, listed by organ system. | | | | --- | --- | | Table 4: Other adverse reactions observed in clinical studies | | | Body System | Adverse Reaction | | Cardiac | Atrioventricular block, sinus arrhythmia | | Gastrointestinal | Dyspepsia, stomach discomfort, vomiting | | General | Asthenia, chest pain | | Immune System            Disorders | Hypersensitivity | | Investigations | Increased alanine amino transferase, increased weight | | Nervous system | Convulsion | | Psychiatric | Agitation, anxiety, depression, nightmare | | Renal | Increased urinary frequency, enuresis | | Respiratory | Asthma | | Vascular | Hypertension, pallor | ## 6.2 Post-marketing Experience The following adverse reactions have been identified during post-approval use of guanfacine.  Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. An open-label post-marketing study involving 21,718 patients was conducted to assess the safety of guanfacine (as the hydrochloride) 1 mg/day given at bedtime for 28 days. Guanfacine was administered with or without other antihypertensive agents. Adverse events reported in the post-marketing study at an incidence greater than 1% included dry mouth, dizziness, somnolence, fatigue, headache and nausea. The most commonly reported adverse events in this study were the same as those observed in controlled clinical trials. Less frequent, possibly guanfacine-related events observed in the post-marketing study and/or reported spontaneously, not included in , include: [section 6.1](#LINK_fc086e21-c9e8-452b-8a21-73f06ea6cda1) edema, malaise, tremor General: palpitations, tachycardia Cardiovascular: paresthesias, vertigo Central Nervous System: blurred vision Eye Disorders: arthralgia, leg cramps, leg pain, myalgia Musculo-Skeletal System: confusion, hallucinations Psychiatric: impotence Reproductive System, Male: dyspnea Respiratory System: alopecia, dermatitis, exfoliative dermatitis, pruritus, rash Skin and Appendages: alterations in taste Special Senses: Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be affected significantly by CYP3A4 inhibitors or inducers (Figure 1). Dose adjustments are recommended . Guanfacine does not significantly affect exposures of methylphenidate and lisdexamfetamine when coadministered (Figure 2). Therefore, no dose adjustments in methylphenidate or lisdexamfetamine are necessary. [] [see Dosage and Administration (2.7)](#LINK_cb8d549f-5ffc-4dd4-ae9d-b096c38e0a32) Figure 1: Impact of Other Drugs on the Pharmacokinetics (PK) of Intuniv  Figure 2: Impact of Intuniv on the Pharmacokinetics (PK) of Other Drugs  ## 8.1 Pregnancy Pregnancy Category B Risk Summary There are no adequate and well-controlled studies of INTUNIV in pregnant women.  No fetal harm was observed in rats and rabbits with administration of guanfacine at 6 and 4 times, respectively, the maximum recommended human dose.  Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Animal data Reproduction studies conducted in rats have shown that guanfacine crosses the placenta. However, administration of guanfacine to rats and rabbits at 6 and 4 times, respectively, the maximum recommended human dose of 4 mg/day on a mg/m basis resulted in no evidence of harm to the fetus. Higher doses (20 times the maximum recommended human dose in both rabbits and rats) were associated with reduced fetal survival and maternal toxicity. 2 ## 8.3 Nursing Mothers It is not known whether guanfacine is excreted in human milk; however, guanfacine is excreted in rat milk. Because many drugs are excreted in human milk, caution should be exercised when INTUNIV is administered to a nursing woman. Observe human milk-fed infants for sedation and somnolence. ® ## 8.4 Pediatric Use Safety and efficacy of INTUNIV in pediatric patients less than 6 years of age have not been established.  ® Animal Data In studies in juvenile rats, guanfacine alone produced a slight delay in sexual maturation in males and females at 2-3 times the maximum recommended human dose (MRHD). Guanfacine in combination with methylphenidate produced a slight delay in sexual maturation and decreased growth as measured by a decrease in bone length in males at a dose of guanfacine comparable to the MRHD and a dose of methylphenidate approximately 4 times the MRHD. In a study where juvenile rats were treated with guanfacine alone from 7 to 59 days of age, development was delayed as indicated by a slight delay in sexual maturation and decreased body weight gain in males at 2 mg/kg/day and in females at 3 mg/kg/day.  The No Adverse Effect Level (NOAEL) for delayed sexual maturation was 1 mg/kg/day, which is equivalent to the MRHD of 4 mg/day, on a mg/m basis.  The effects on fertility were not evaluated in this study. 2 In a study where juvenile rats were treated with guanfacine in combination with methylphenidate from 7 to 59 days of age, a decrease in ulna bone length and a slight delay in sexual maturation were observed in males given 1 mg/kg/day of guanfacine in combination with 50 mg/kg/day of methylphenidate. The NOAELs for these findings were 0.3 mg/kg of guanfacine in combination with 16 mg/kg/day of methylphenidate, which are equivalent to 0.3 and 1.4 times the MRHD of 4 mg/day and 54 mg/day for guanfacine and methylphenidate, respectively, on a mg/m basis. These findings were not observed with guanfacine alone at 1 mg/kg/day or methylphenidate alone at 50 mg/kg/day. 2 ## 8.5 Geriatric Use The safety and efficacy of INTUNIV in geriatric patients have not been established. ® ## 8.6 Use in Patients with Renal or Hepatic Impairment Renal Impairment The impact of renal impairment on the pharmacokinetics of guanfacine in children was not assessed. In adult patients with impaired renal function, the cumulative urinary excretion of guanfacine and the renal clearance diminished as renal function decreased. In patients on hemodialysis, the dialysis clearance was about 15% of the total clearance. The low dialysis clearance suggests that the hepatic elimination (metabolism) increases as renal function decreases. It may be necessary to adjust the dose in patients with significant impairment of renal function. Hepatic Impairment The impact of hepatic impairment on PK of guanfacine in children was not assessed. Guanfacine in adults is cleared both by the liver and the kidney, and approximately 50% of the clearance of guanfacine is hepatic. It may be necessary to adjust the dose in patients with significant impairment of hepatic function. ## 9.1 Controlled Substance INTUNIV is not a controlled substance and has no known potential for abuse or dependence. ® Symptoms Post-marketing reports of guanfacine overdosage indicate that hypotension, drowsiness, lethargy, and bradycardia have been observed following overdose. Initial hypertension may develop early and may be followed by hypotension.  Similar symptoms have been described in voluntary reports to the American Association of Poison Control Center’s National Poison Data System. Miosis of the pupils may be noted on examination No fatal overdoses of guanfacine have been reported in published literature. . Treatment Consult a Certified Poison Control Center by calling 1-800-222-1222 for up to date guidance and advice. Management of INTUNIV overdose should include monitoring for and the treatment of initial hypertension, if that occurs, as well as hypotension, bradycardia, lethargy and respiratory depression. Children and adolescents who develop lethargy should be observed for the development of more serious toxicity including coma, bradycardia and hypotension for up to 24 hours, due to the possibility of delayed onset hypotension. ® INTUNIV is a once-daily, extended-release formulation of guanfacine hydrochloride (HCl) in a matrix tablet formulation for oral administration only. The chemical designation is N-amidino-2-(2,6-dichlorophenyl) acetamide monohydrochloride. The molecular formula is C H Cl N O·HCl corresponding to a molecular weight of 282.55. The chemical structure is: ®9923  Guanfacine HCl is a white to off-white crystalline powder, sparingly soluble in water (approximately 1 mg/mL) and alcohol and slightly soluble in acetone. The only organic solvent in which it has relatively high solubility is methanol (>30 mg/mL). Each tablet contains guanfacine HCl equivalent to 1 mg, 2 mg, 3 mg, or 4 mg of guanfacine base. The tablets also contain hypromellose, methacrylic acid copolymer, lactose, povidone, crospovidone, microcrystalline cellulose, fumaric acid, and glyceryl behenate. In addition, the 3mg and 4mg tablets also contain green pigment blend PB-1763. ## 12.1 Mechanism of Action Guanfacine is a central alpha -adrenergic receptor agonist. Guanfacine is not a central nervous system (CNS) stimulant. The mechanism of action of guanfacine in ADHD is not known. 2A ## 12.2 Pharmacodynamics Guanfacine is a selective central alpha -adrenergic receptor agonist in that it has a 15-20 times higher affinity for this receptor subtype than for the alpha or alpha subtypes. 2A2B2C Guanfacine is a known antihypertensive agent. By stimulating central alpha -adrenergic receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate. 2A Effects on Height, Weight, and Body Mass Index (BMI) Patients taking INTUNIV demonstrated similar growth compared to normative data. Patients taking INTUNIV had a mean increase in weight of 0.5 kg (1 lb) compared to those receiving placebo over a comparative treatment period. Patients receiving INTUNIV for at least 12 months in open-label studies gained an average of 8 kg (17 lbs) in weight and 8 cm (3 in) in height. The height, weight, and BMI percentile remained stable in patients at 12 months in the long-term studies compared to when they began receiving INTUNIV .  ®®®® Effect on ECG The effect of two dose levels of immediate-release guanfacine (4 mg and 8 mg) on the QT interval was evaluated in a double-blind, randomized, placebo- and active-controlled, cross-over study in healthy adults. A dose-dependent decrease in heart rate was observed during the first 12 hours, at time of maximal concentrations. The mean change in heart rate was -13 bpm at 4 mg and -22 bpm at 8 mg.  An apparent increase in mean QTc was observed for both doses. However, guanfacine does not appear to interfere with cardiac repolarization of the form associated with pro-arrhythmic drugs. This finding has no known clinical relevance. ## 12.3 Pharmacokinetics Absorption and Distribution Guanfacine is readily absorbed and approximately 70% bound to plasma proteins independent of drug concentration. After oral administration of INTUNIV the time to peak plasma concentration is approximately 5 hours in children and adolescents with ADHD. ® Immediate-release guanfacine and INTUNIV have different pharmacokinetic characteristics; dose substitution on a milligram for milligram basis will result in differences in exposure. ® A comparison across studies suggests that the C is 60% lower and AUC 43% lower, respectively, for INTUNIV compared to immediate-release guanfacine.  Therefore, the relative bioavailability of INTUNIV to immediate-release guanfacine is 58%. The mean pharmacokinetic parameters in adults following the administration of INTUNIV 1 mg once daily and immediate-release guanfacine 1mg once daily are summarized in Table 5. max0-∞®®® | | | | | --- | --- | --- | | Table 5: Pharmacokinetic Parameters in Adults | | | | Parameter | INTUNIV ®        1 mg once daily        (n=52) | Immediate-release      guanfacine 1 mg once daily (n=12) | | C (ng/mL)   max | 1.0 ± 0.3 | 2.5 ± 0.6 | | AUC (ng.h/mL)                  0-∞ | 32 ± 9 | 56 ± 15 | | t (h)   max | 6.0 (4.0 - 8.0) | 3.0 (1.5-4.0) | | t (h)   1/2 | 18 ± 4 | 16 ± 3 | Note: Values are mean +/- SD, except for t which is median (range)   max Exposure to guanfacine was higher in children (ages 6-12) compared to adolescents (ages 13-17) and adults. After oral administration of multiple doses of INTUNIV 4 mg, the C was 10 ng/mL compared to 7 ng/mL and the AUC was 162 ng h/mL compared to 116 ng h/mL in children (ages 6-12) and adolescents (ages 13-17), respectively. These differences are probably attributable to the lower body weight of children compared to adolescents and adults. ®max The pharmacokinetics were affected by intake of food when a single dose of INTUNIV 4 mg was administered with a high-fat breakfast. The mean exposure increased (C ~75% and AUC ~40%) compared to dosing in a fasted state. ®max Dose Proportionality Following administration of INTUNIV in single doses of 1 mg, 2 mg, 3 mg, and 4 mg to adults, C and AUC of guanfacine were proportional to dose. ®max0-∞ Metabolism and Elimination In vitro studies with human liver microsomes and recombinant CYP’s demonstrated that guanfacine was primarily metabolized by CYP3A4. In pooled human hepatic microsomes, guanfacine did not inhibit the activities of the major cytochrome P450 isoenzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5).  Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5 inducers/inhibitors. Renal and Hepatic Impairment The impact of renal impairment on PK of guanfacine in children was not assessed . [] [see Use in Specific Populations (8.6)](#LINK_0609fd99-d0bd-479f-a154-827f40d4816c) ## 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenic effect of guanfacine was observed in studies of 78 weeks in mice or 102 weeks in rats at doses up to 6-7 times the maximum recommended human dose of 4 mg/day on a mg/ m basis. 2 Mutagenesis Guanfacine was not genotoxic in a variety of test models, including the Ames test and an chromosomal aberration test; however, a marginal increase in numerical aberrations (polyploidy) was observed in the latter study. in vitro Impairment of Fertility No adverse effects were observed in fertility studies in male and female rats at doses up to 30 times the maximum recommended human dose on a mg/ m basis. 2 ## 14.1 Safety and Efficacy Studies The efficacy of INTUNIV in the treatment of ADHD was established in 3 placebo-controlled monotherapy trials (Studies 1, 2, and 4) and in 1 placebo-controlled adjunctive trial with psychostimulants (Study 3) in pediatric population. Studies 1, 2, and 3 were conducted in children and adolescents ages 6-17 and Study 4 was conducted in children ages 6-12 years. ® Studies 1 and 2: Fixed-dose INTUNIV Monotherapy ® Study 1 was a double-blind, placebo-controlled, parallel-group, fixed dose study, in which efficacy of once daily dosing with INTUNIV (2 mg, 3 mg and 4 mg) was evaluated for 5 weeks (n=345). Study 2 was a double-blind, placebo-controlled, parallel-group, fixed-dose study, in which efficacy of once daily dosing with INTUNIV (1 mg, 2 mg, 3 mg and 4 mg) was evaluated for 6 weeks (n=324). In both studies, randomized subjects in 2 mg, 3 mg and 4 mg dose groups were titrated to their target fixed dose, and continued on the same dose until a dose tapering phase started  The lowest dose of 1 mg used in Study 2 was assigned only to patients less than 50 kg (110 lbs).  Patients who weighed less than 25 kg (55 lbs) were not included in either study. ®® Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week for which a valid score was obtained prior to dose tapering (up to Week 5 in Study 1 and up to Week 6 in Study 2). The mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV compared to placebo for Studies 1 and 2. Placebo-adjusted changes from baseline were statistically significant for each of the 2 mg, 3 mg, and 4 mg INTUNIV randomized treatment groups in both studies, as well as the 1 mg INTUNIV treatment group (for patients 55-110 lbs) that was included only in Study 2 (see Table 6).  ®®® Dose-responsive efficacy was evident, particularly when data were examined on a weight-adjusted (mg/kg) basis. When evaluated over the dose range of 0.01-0.17 mg/kg/day, clinically relevant improvements were observed beginning at doses in the range 0.05-0.08 mg/kg/day. Doses up to 0.12 mg/kg/day were shown to provide additional benefit. Controlled, monotherapy long-term efficacy studies (>9 weeks) have not been conducted. In the monotherapy trials (Studies 1 and 2), subgroup analyses were performed to identify any differences in response based on gender or age (6-12 vs. 13-17).  Analyses of the primary outcome did not suggest any differential responsiveness on the basis of gender.  Analyses by age revealed a statistically significant treatment effect only in the 6-12 age subgroup. Due to the relatively small proportion of adolescent patients (ages 13-17) enrolled into these studies (approximately 25%), these data may not be sufficient to demonstrate efficacy in the adolescent patients. In these studies, patients were randomized to a fixed dose of INTUNIV rather than optimized by body weight. Therefore, some adolescent patients were randomized to a dose that might have resulted in relatively lower plasma guanfacine concentrations compared to the younger patients. Over half (55%) of the adolescent patients received doses of 0.01-0.04mg/kg. In studies in which systematic pharmacokinetic data were obtained, there was a strong inverse correlation between body weight and plasma guanfacine concentrations. ® Table 6: Fixed dose Studies | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | | Study                     (Age Range) | Primary Efficacy Measure | Treatment Group | | | | | | Placebo | Intuniv®           1mg | Intuniv®             2mg | Intuniv®              3mg | Intuniv®              4mg | | (6 – 17 years) 1 | Mean Baseline (SD) | 38.1 (9.34) | -- | 36.1   (9.99) | 36.8   (8.72) | 38.4  (9.21) | | LS Mean Change from Baseline (SE) | -8.5 (1.42) | -- | -15.9 (1.37) | -16.0 (1.38) | -18.5 (1.39) | | LS Mean Difference from Placebo (95% CI) | -- | -- | -7.4 (-11.3, -3.5)  a | -7.5 (-11.4, -3.6)  a | -10.0 (-13.9, -6.1)  a | | | | | | | | | | (6 – 17 years) 2 | Mean Baseline (SD) | 39.3  (8.85) | 41.7  (7.81) | 39.9   (8.74) | 39.1   (9.22) | 40.6   (8.57) | | LS Mean Change from Baseline (SE) | -12.7 (1.60) | -19.4 (1.69) | -18.1   (1.60) | -20.0 (1.64) | -20.6 (1.60) | | LS Mean Difference from Placebo (95% CI) | -- | -6.8 (-11.3, -2.2)  a | -5.4    (-9.9, -0.9)  a | -7.3 (-11.8, -2.8)  a | -7.9 (-12.3, -3.4)  a | | | | | | | | | Study                     (Age Range)   1 Mean Baseline (SD)   LS Mean Change from Baseline (SE)   2 Mean Baseline (SD)   LS Mean Change from Baseline (SE)   LS Mean: least-square mean; SD: standard deviation; SE: standard error; 95% CI (unadjusted) Doses were shown to be statistically significantly superior to placebo.    a Study 3: Flexible-dose INTUNIV as Adjunctive Therapy to Psychostimulants ® Study 3 was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily optimized dosing (morning or evening) with INTUNIV (1mg, 2mg, 3mg and 4mg), when co-administered with psychostimulants, was evaluated for 8 weeks, in children and adolescents aged 6-17 years with a diagnosis of ADHD, with a sub-optimal response to stimulants (n=455). Subjects were started at the 1 mg INTUNIV dose level and were titrated weekly over a 5-week dose-optimization period to an optimal INTUNIV dose not to exceed 4 mg/day based on tolerability and clinical response. The dose was then maintained for a 3-week dose maintenance period before entry to 1 week of dose tapering.  Subjects took INTUNIV either in the morning or the evening while maintaining their current dose of psychostimulant treatment given each morning.  Allowable psychostimulants in the study were ADDERALL XR , VYVANSE , CONCERTA , FOCALIN XR , RITALIN LA , METADATE CD or FDA-approved generic equivalents. ®®®®®®®®®® Symptoms of ADHD were evaluated on a weekly basis by clinicians using the ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week prior to dose tapering for which a valid score was obtained (up to Week 8). Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV given in combination with a psychostimulant compared to placebo given with a psychostimulant for Study 3, for both morning and evening INTUNIV dosing (see Table 7). Nearly two-thirds (64.2%) of subjects reached optimal doses in the 0.05-0.12 mg/kg/day range. ®® Study 4: Flexible-dose INTUNIV Monotherapy ® Study 4 was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily dosing (morning or evening) with INTUNIV (1mg, 2mg, 3mg, and 4mg) was evaluated for 8 weeks in children aged 6-12 years  (n=340). ® Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline score at endpoint on the ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week for which a valid score was obtained prior to dose tapering (up to Week 8). Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV compared to placebo in both AM and PM dosing groups of INTUNIV (see Table 7). ®® Table 7: Flexible-Dose studies | | | | | | | --- | --- | --- | --- | --- | | Study (Age Range) | | Treatment Group | | | | Placebo | Intuniv®1mg – 4mg | | | | | | AM | PM | | (6 – 17 years) 3   a | Mean Baseline (SD) | 37.7 (7.75) | 37.6 (8.13) | 37.0 (7.65) | | LS Mean Change from Baseline (SE) | -15.9 (0.96) | -20.3 (0.97) | -21.2 (0.97) | | LS Mean Difference from Placebo (95% CI) | -- | -4.5 (-7.5, -1.4) b | -5.3 (-8.3, -2.3) b | | | | | | | | (6 – 12 years) 4 | Mean Baseline (SD) | 42.9 (6.21) | 41.7 (6.39) | 41.6 (6.66) | | LS Mean Change from Baseline (SE) | -10.6 (1.20) | -20.0 (1.23) | -20.4 (1.19) | | LS Mean Difference from Placebo (95% CI) | -- | -9.4 (-12.8, -6.0) b | -9.8 (-13.1, -6.4) b | | | | | | | 3   a 4   LS Mean: least-square mean; SD: standard deviation; SE: standard error; 95% CI (unadjusted) Treatment was given in combination with a psychostimulant. Doses were shown to be statistically significantly superior to placebo. a b NDC:64725-0515-1 in a CONTAINER of 30 TABLET, EXTENDED RELEASES See FDA-approved patient labeling ([Patient Information](#LINK_b4d7d1d9-6678-4e5c-9e4f-095e7afa9f34)) Dosing and Administration Instruct patients to swallow INTUNIV whole with water, milk or other liquid. Patients should not take INTUNIV together with a high-fat meal, since this can raise blood levels of INTUNIV .  Instruct the parent or caregiver to supervise the child or adolescent taking INTUNIV and to keep the bottle of tablets out of reach of children. ®Tablets should not be crushed, chewed or broken prior to administration because this may increase the rate of release of the active drug .®®® Instruct patients on how to properly taper the medication, if the physician decides to discontinue treatment. [ ]. [see Dosage and Administration (2.5)](#LINK_11fbf218-ba09-49be-92eb-33c3efc85082) Adverse Reactions Advise patients that sedation can occur, particularly early in treatment or with dose increases. Caution against operating heavy equipment or driving until they know how they respond to treatment with INTUNIV Headache and abdominal pain can also occur. If any of these symptoms persist, or other symptoms occur, the patient should be advised to discuss the symptoms with the physician. ®[ ]. [see Warnings and Precautions (5.2)](#LINK_e61b0637-c331-4016-a9e6-c2bd9231d51b) Advise patients to avoid becoming dehydrated or overheated, which may potentially increase the risks of hypotension and syncope Advise patients  to avoid use with alcohol. [ ]. [see Warnings and Precautions (5.1)](#LINK_3220e0a6-fdcf-4bf6-aff6-b62016536ef0) # Patient Information   INTUNIV ( ®in-TOO-niv)   (guanfacine)   Extended-Release Tablets   Read the Patient Information that comes with INTUNIV before you start taking it and each time you get a refill. There may be new information. ®This leaflet does not take the place of talking with your doctor about your medical condition or your treatment. What is INTUNIV ? ® INTUNIV is a prescription medicine used to treat the symptoms of attention deficit/hyperactivity disorder (ADHD). ® INTUNIV is not a central nervous system (CNS) stimulant. ® What should I tell my doctor before taking INTUNIV ? ® Before you take INTUNIV , tell your doctor if you:   ® Tell your doctor about all of the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. INTUNIV may affect the way other medicines work, and other medicines may affect how INTUNIV works. ®® Especially tell your doctor if you take: Ask your doctor or pharmacist for a list of these medicines, if you are not sure. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine. How should I take INTUNIV ?   ® What should I avoid while taking INTUNIV ?   ® What are the possible side effects of INTUNIV ? ® INTUNIV may cause serious side effects including: ® Get medical help right away, if you have any of the symptoms listed above. The most common side effects of INTUNIV include: ® Tell the doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of INTUNIV . For more information, ask your doctor or pharmacist. ® Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store INTUNIV ?   ® Keep INTUNIV and all medicines out of the reach of children. ® General Information about INTUNIV ® Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use INTUNIV for a condition for which it was not prescribed. Do not give INTUNIV to other people, even if they have the same symptoms that you have. It may harm them. ®® This leaflet summarizes the most important information about INTUNIV . If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about INTUNIV that is written for health professionals. For more information, go to ®® www.INTUNIV.comor call 1-800-828-2088. What are the ingredients in INTUNIV ? ® guanfacine hydrochloride Active ingredient: hypromellose, methacrylic acid copolymer, lactose, povidone, crospovidone, microcrystalline cellulose, fumaric acid, and glycerol behenate. In addition, the 3mg and 4mg tablets also contain green pigment blend PB-1763. Inactive ingredients: Manufactured for Shire US Inc., Wayne, PA 19087. INTUNIV is a registered trademark of Shire LLC.   ©2013 Shire US Inc. This product is covered by US patents including 6,287,599; 6,811,794. Version: 08 2013 ®  #  | | | --- | | **INTUNIV** guanfacine tablet, extended release | | | | | | | | --- | --- | --- | --- | | Product Information | | | | | Product Type | HUMAN PRESCRIPTION DRUG | Item Code (Source) | NDC:64725-0515(NDC:[54092-515](/dailymed/search.cfm?searchdb=ndc&query=54092-515)) | | Route of Administration | ORAL | | | | | | | | --- | --- | --- | | Active Ingredient/Active Moiety | | | | Ingredient Name | Basis of Strength | Strength | | **GUANFACINE HYDROCHLORIDE** (UNII: PML56A160O) (GUANFACINE - UNII:30OMY4G3MK) | GUANFACINE | 2 mg | | | | | | | --- | --- | | Inactive Ingredients | | | Ingredient Name | Strength | | **HYPROMELLOSE 2208 (15000 MPA.S)** (UNII: Z78RG6M2N2) | | | **LACTOSE MONOHYDRATE** (UNII: EWQ57Q8I5X) | | | **POVIDONES** (UNII: FZ989GH94E) | | | **CROSPOVIDONE** (UNII: 68401960MK) | | | **METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1)** (UNII: 74G4R6TH13) | | | **CELLULOSE, MICROCRYSTALLINE** (UNII: OP1R32D61U) | | | **GLYCERYL DIBEHENATE** (UNII: R8WTH25YS2) | | | **FUMARIC ACID** (UNII: 88XHZ13131) | | | | | | | | | | --- | --- | --- | --- | | Product Characteristics | | | | | Color | WHITE (white) | Score | no score | | Shape | OVAL | Size | 12mm | | Flavor | | Imprint Code | 503;2mg | | Contains | | | | | | | | | | | --- | --- | --- | --- | --- | | Packaging | | | | | | # | Item Code | Package Description | Marketing Start Date | Marketing End Date | | 1 | NDC:64725-0515-1 | 30 in 1 CONTAINER | | | | | | | | | | | | | --- | --- | --- | --- | | Marketing Information | | | | | Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date | | NDA | NDA022037 | 09/02/2009 | | | | | | | | | --- | --- | --- | --- | | Product Information | | | | | Product Type | HUMAN PRESCRIPTION DRUG | Item Code (Source) | NDC:64725-0515(NDC:[54092-515](/dailymed/search.cfm?searchdb=ndc&query=54092-515)) | | Route of Administration | ORAL | | | | | | --- | --- | --- | | Active Ingredient/Active Moiety | | | | Ingredient Name | Basis of Strength | Strength | | **GUANFACINE HYDROCHLORIDE** (UNII: PML56A160O) (GUANFACINE - UNII:30OMY4G3MK) | GUANFACINE | 2 mg | | | | | --- | --- | | Inactive Ingredients | | | Ingredient Name | Strength | | **HYPROMELLOSE 2208 (15000 MPA.S)** (UNII: Z78RG6M2N2) | | | **LACTOSE MONOHYDRATE** (UNII: EWQ57Q8I5X) | | | **POVIDONES** (UNII: FZ989GH94E) | | | **CROSPOVIDONE** (UNII: 68401960MK) | | | **METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1)** (UNII: 74G4R6TH13) | | | **CELLULOSE, MICROCRYSTALLINE** (UNII: OP1R32D61U) | | | **GLYCERYL DIBEHENATE** (UNII: R8WTH25YS2) | | | **FUMARIC ACID** (UNII: 88XHZ13131) | | | | | | | | --- | --- | --- | --- | | Product Characteristics | | | | | Color | WHITE (white) | Score | no score | | Shape | OVAL | Size | 12mm | | Flavor | | Imprint Code | 503;2mg | | Contains | | | | | | | | | --- | --- | --- | --- | --- | | Packaging | | | | | | # | Item Code | Package Description | Marketing Start Date | Marketing End Date | | 1 | NDC:64725-0515-1 | 30 in 1 CONTAINER | | | | | | | | | --- | --- | --- | --- | | Marketing Information | | | | | Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date | | NDA | NDA022037 | 09/02/2009 | | | | | --- | | **INTUNIV** guanfacine tablet, extended release | | | | | | | | --- | --- | --- | --- | | Product Information | | | | | Product Type | HUMAN PRESCRIPTION DRUG | Item Code (Source) | NDC:64725-0513(NDC:[54092-513](/dailymed/search.cfm?searchdb=ndc&query=54092-513)) | | Route of Administration | ORAL | | | | | | | | --- | --- | --- | | Active Ingredient/Active Moiety | | | | Ingredient Name | Basis of Strength | Strength | | **GUANFACINE HYDROCHLORIDE** (UNII: PML56A160O) (GUANFACINE - UNII:30OMY4G3MK) | GUANFACINE | 1 mg | | | | | | | --- | --- | | Inactive Ingredients | | | Ingredient Name | Strength | | **HYPROMELLOSE 2208 (15000 MPA.S)** (UNII: Z78RG6M2N2) | | | **LACTOSE MONOHYDRATE** (UNII: EWQ57Q8I5X) | | | **POVIDONES** (UNII: FZ989GH94E) | | | **CROSPOVIDONE** (UNII: 68401960MK) | | | **METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1)** (UNII: 74G4R6TH13) | | | **CELLULOSE, MICROCRYSTALLINE** (UNII: OP1R32D61U) | | | **GLYCERYL DIBEHENATE** (UNII: R8WTH25YS2) | | | **FUMARIC ACID** (UNII: 88XHZ13131) | | | | | | | | | | --- | --- | --- | --- | | Product Characteristics | | | | | Color | WHITE (white) | Score | no score | | Shape | ROUND | Size | 7mm | | Flavor | | Imprint Code | 503;1mg | | Contains | | | | | | | | | | | --- | --- | --- | --- | --- | | Packaging | | | | | | # | Item Code | Package Description | Marketing Start Date | Marketing End Date | | 1 | NDC:64725-0513-1 | 100 in 1 BOTTLE | | | | | | | | | | | | | --- | --- | --- | --- | | Marketing Information | | | | | Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date | | NDA | NDA022037 | 09/02/2009 | | | | | | | | | --- | --- | --- | --- | | Product Information | | | | | Product Type | HUMAN PRESCRIPTION DRUG | Item Code (Source) | NDC:64725-0513(NDC:[54092-513](/dailymed/search.cfm?searchdb=ndc&query=54092-513)) | | Route of Administration | ORAL | | | | | | --- | --- | --- | | Active Ingredient/Active Moiety | | | | Ingredient Name | Basis of Strength | Strength | | **GUANFACINE HYDROCHLORIDE** (UNII: PML56A160O) (GUANFACINE - UNII:30OMY4G3MK) | GUANFACINE | 1 mg | | | | | --- | --- | | Inactive Ingredients | | | Ingredient Name | Strength | | **HYPROMELLOSE 2208 (15000 MPA.S)** (UNII: Z78RG6M2N2) | | | **LACTOSE MONOHYDRATE** (UNII: EWQ57Q8I5X) | | | **POVIDONES** (UNII: FZ989GH94E) | | | **CROSPOVIDONE** (UNII: 68401960MK) | | | **METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1)** (UNII: 74G4R6TH13) | | | **CELLULOSE, MICROCRYSTALLINE** (UNII: OP1R32D61U) | | | **GLYCERYL DIBEHENATE** (UNII: R8WTH25YS2) | | | **FUMARIC ACID** (UNII: 88XHZ13131) | | | | | | | | --- | --- | --- | --- | | Product Characteristics | | | | | Color | WHITE (white) | Score | no score | | Shape | ROUND | Size | 7mm | | Flavor | | Imprint Code | 503;1mg | | Contains | | | | | | | | | --- | --- | --- | --- | --- | | Packaging | | | | | | # | Item Code | Package Description | Marketing Start Date | Marketing End Date | | 1 | NDC:64725-0513-1 | 100 in 1 BOTTLE | | | | | | | | | --- | --- | --- | --- | | Marketing Information | | | | | Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date | | NDA | NDA022037 | 09/02/2009 | | | | | | | | --- | --- | --- | --- | | Labeler - TYA Pharmaceuticals (938389038) | | | | | | | | | | --- | --- | --- | --- | | Registrant - TYA Pharmaceuticals (938389038) | | | | | | | | | | --- | --- | --- | --- | | Establishment | | | | | Name | Address | ID/FEI | Business Operations | | TYA Pharmaceuticals | | 938389038 | RELABEL(64725-0515, 64725-0513) , REPACK(64725-0515) | ## Find additional resources ### Safety [Report Adverse Events](//www.accessdata.fda.gov/scripts/medwatch/ ), [FDA Safety Recalls](https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts), [Presence in Breast Milk](https://ncbi.nlm.nih.gov/books/n/lactmed/LM631) ### Related Resources [Medline Plus](//vsearch.nlm.nih.gov/vivisimo/cgi-bin/query-meta?v:project=medlineplus&query=GUANFACINE), [Clinical Trials](//www.clinicaltrials.gov/ct/search?submit=Search&term=GUANFACINE), [PubMed](#pubmed-menu), [Biochemical Data Summary](https://www.drugbank.ca/search?utf8=%E2%9C%93&query=APRD00075&search_type=drugs&button=) ### More Info on this Drug [View Labeling Archives](#modal-label-archives), [RxNorm](#modal-rx-norm), [Get Label RSS Feed](#modal-label-rss), [View NDC Code(s)](#modal-codes) ## View Labeling Archives for this drug ### INTUNIV- guanfacine tablet, extended release #### Number of versions: 2 | Published Date [(What is this?)](# "<b>Published Date</b> - The date that a drug label is published on DailyMed for public view. This is distinct from <b>Updated Date</b>*. <br><br> *<b>Updated Date</b> (also known as <b>Effective Time</b>) - The label revision date included in the SPL.") | Version | Files | | --- | --- | --- | | Oct 20, 2014 | 4 (current) | [download](/dailymed/getArchivalFile.cfm?archive_id=154741) | | Sep 29, 2014 | 2 | [download](/dailymed/getArchivalFile.cfm?archive_id=152195) | ## RxNorm ### INTUNIV- guanfacine tablet, extended release | | RxCUI | RxNorm NAME | RxTTY | | --- | --- | --- | --- | | 1 | [862006](/dailymed/search.cfm?searchdb=rxcui&query=862006) | guanFACINE 1 MG 24HR Extended Release Oral Tablet | PSN | | 2 | [862006](/dailymed/search.cfm?searchdb=rxcui&query=862006) | 24 HR guanfacine 1 MG Extended Release Oral Tablet | SCD | | 3 | [862006](/dailymed/search.cfm?searchdb=rxcui&query=862006) | guanfacine 1 MG (as guanfacine hydrochloride 1.14 MG) 24 HR Extended Release Oral Tablet | SY | | 4 | [862006](/dailymed/search.cfm?searchdb=rxcui&query=862006) | guanfacine 1 MG (as guanfacine hydrochloride 1.15 MG) 24 HR Extended Release Oral Tablet | SY | | 5 | [862010](/dailymed/search.cfm?searchdb=rxcui&query=862010) | intuniv 1 MG 24HR Extended Release Oral Tablet | PSN | | 6 | [862010](/dailymed/search.cfm?searchdb=rxcui&query=862010) | 24 HR guanfacine 1 MG Extended Release Oral Tablet [Intuniv] | SBD | | 7 | [862010](/dailymed/search.cfm?searchdb=rxcui&query=862010) | Intuniv 1 MG 24 HR Extended Release Oral Tablet | SY | | 8 | [862010](/dailymed/search.cfm?searchdb=rxcui&query=862010) | Intuniv 1 MG (guanfacine hydrochloride 1.15 MG) 24 HR Extended Release Oral Tablet | SY | | 9 | [862013](/dailymed/search.cfm?searchdb=rxcui&query=862013) | guanFACINE 2 MG 24HR Extended Release Oral Tablet | PSN | | 10 | [862013](/dailymed/search.cfm?searchdb=rxcui&query=862013) | 24 HR guanfacine 2 MG Extended Release Oral Tablet | SCD | | 11 | [862013](/dailymed/search.cfm?searchdb=rxcui&query=862013) | guanfacine 2 MG (as guanfacine hydrochloride 2.28 MG) 24 HR Extended Release Oral Tablet | SY | | 12 | [862013](/dailymed/search.cfm?searchdb=rxcui&query=862013) | guanfacine 2 MG (as guanfacine hydrochloride 2.3 MG) 24 HR Extended Release Oral Tablet | SY | | 13 | [862015](/dailymed/search.cfm?searchdb=rxcui&query=862015) | intuniv 2 MG 24HR Extended Release Oral Tablet | PSN | | 14 | [862015](/dailymed/search.cfm?searchdb=rxcui&query=862015) | 24 HR guanfacine 2 MG Extended Release Oral Tablet [Intuniv] | SBD | | 15 | [862015](/dailymed/search.cfm?searchdb=rxcui&query=862015) | Intuniv 2 MG 24 HR Extended Release Oral Tablet | SY | | 16 | [862015](/dailymed/search.cfm?searchdb=rxcui&query=862015) | Intuniv 2 MG (as guanfacine hydrochloride 2.3 MG) 24 HR Extended Release Oral Tablet | SY | ## Get Label RSS Feed for this Drug ### INTUNIV- guanfacine tablet, extended release #### To receive this label RSS feed Copy the URL below and paste it into your RSS Reader application. 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We anticipate reposting the images once we are able identify and filter out images that do not match the information provided in the drug labels. ## NDC Codes ### INTUNIV- guanfacine tablet, extended release #### If this SPL contains inactivated NDCs listed by the FDA initiated compliance action, they will be specified as such. | | NDC | | --- | --- | | 1 | 64725-0513-1 (inactivated) | | 2 | 64725-0515-1 (inactivated) |   

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use INTUNIV ® safely and effectively. See full prescribing information for INTUNIV ® . INTUNIV ® (guanfacine) extended-release tablets, for oral use Initial U.S. Approval: 1986 ----------------------------RECENT MAJOR CHANGES---------------------- Dosage and Administration, Dose Selection (2.2), 02/2013 -----------------------------INDICATIONS AND USAGE---------------------­ INTUNIV ® is a central alpha2A-adrenergic receptor agonist indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications (1). ------------------------------DOSAGE AND ADMINISTRATION------------ • Recommended dose: 1 to 4 mg once daily in the morning or evening (2.2). • Begin at a dose of 1 mg once daily and adjust in increments of no more than 1 mg/week (2.2). • Do not crush, chew or break tablets before swallowing (2.1). • Do not administer with high-fat meals, because of increased exposure (2.1). • Do not substitute for immediate-release guanfacine tablets on a mg-per-mg basis, because of differing pharmacokinetic profiles (2.3). • If switching from immediate-release guanfacine, discontinue that treatment and titrate with INTUNIV ® as directed (2.3). • Consider dosing on a mg/kg basis. Improvements observed starting at doses of 0.05-0.08 mg/kg once daily. Doses up to 0.12 mg/kg once daily may provide additional benefit (2.2). • When discontinuing, taper the dose in decrements of no more than 1 mg every 3 to 7 days (2.5). -------------------------------DOSAGE FORMS AND STRENGTHS------­ Extended-release tablets: 1 mg, 2 mg, 3 mg and 4 mg (3) -------------------------------CONTRAINDICATIONS-------------------------­ History of hypersensitivity to INTUNIV ®, its inactive ingredients, or other products containing guanfacine (4). --------------------------WARNINGS AND PRECAUTIONS-----------------­ • Hypotension, bradycardia, and syncope: Use INTUNIV® with caution in patients at risk for hypotension, bradycardia, heart block, or syncope (e.g., those taking antihypertensives). Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Advise patients to avoid becoming dehydrated or overheated (5.1). • Sedation and somnolence: Occur commonly with INTUNIV ® . Consider the potential for additive sedative effects with CNS depressant drugs. Caution patients against operating heavy equipment or driving until they know how they respond to INTUNIV ® (5.2). -------------------------------ADVERSE REACTIONS--------------------------- Most common adverse reactions (≥5% and at least twice placebo rate) in the monotherapy trials: somnolence, fatigue, nausea, lethargy, and hypotension (6). Most common adverse reactions (≥5% and at least twice placebo rate) in the adjunctive trial: somnolence, fatigue, insomnia, dizziness, and abdominal pain (6). To report SUSPECTED ADVERSE REACTIONS, contact Shire US Inc. at 1-800-828-2088 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ---------------------------------DRUG INTERACTIONS------------------------­ • Strong CYP3A4 inhibitors (e.g., ketoconazole): Coadministration increases guanfacine exposure. Guanfacine dose should be limited to no more than 2 mg/day. When discontinuing CYP3A4 inhibitors, guanfacine dose should be doubled based on patient tolerability. The maximum dose should not exceed 4 mg/day (2.7 and 7). • Strong CYP3A4 inducers (e.g., rifampin): Coadministration decreases guanfacine exposure. Guanfacine dose may be titrated up to 8 mg/day. When discontinuing CYP3A4 inducers, guanfacine dose should be decreased by half in 1-2 weeks based on patient tolerability. The maximum dose should not exceed 4 mg/day (2.7 and 7). --------------------------USE IN SPECIFIC POPULATIONS--------------­ Hepatic or Renal Impairment: dose reduction may be required in patients with clinically significant impairment of hepatic or renal function (8.6). See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 02/2013 Page 1 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Instructions for Use 2.2 Dose Selection 2.3 Switching from Immediate-Release Guanfacine to INTUNIV 2.4 Maintenance Treatment 2.5 Discontinuation 2.6 Missed Doses 2.7 Dose Adjustment with Concomitant Use of Strong CYP3A4 Inhibitors or Inducers 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypotension, Bradycardia, and Syncope 5.2 Sedation and Somnolence 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Post-marketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Use in Patients with Renal or Hepatic Impairment 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Safety and Efficacy Studies 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Page 2 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE INTUNIV® is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications. The efficacy of INTUNIV® was studied for the treatment of ADHD in three controlled monotherapy clinical trials (up to 8 weeks in duration) and one controlled adjunctive trial with psychostimulants (8 weeks in duration) in children and adolescents ages 6-17 who met DSM-IV® criteria for ADHD [see Clinical Studies (14)]. The effectiveness of INTUNIV® for longer-term use (more than 8 weeks) has not been systematically evaluated in controlled trials. 2 DOSAGE AND ADMINISTRATION 2.1 General Instruction for Use Swallow tablets whole. Do not crush, chew, or break tablets because this will increase the rate of guanfacine release. Do not administer with high fat meals, due to increased exposure. 2.2 Dose Selection INTUNIV should be taken once daily, either in the morning or evening, at approximately same time each day. Begin at a dose of 1 mg/day, and adjust in increments of no more than 1 mg/week. Maintain the dose within the range of 1 mg to 4 mg once daily, depending on clinical response and tolerability, for both monotherapy and adjunctive therapy to a psychostimulant. Doses above 4 mg/day have not been systematically studied in controlled clinical studies [see Clinical Studies (14.1)]. Clinically relevant improvements were observed beginning at doses in the range 0.05­ 0.08 mg/kg once daily in both mono- and adjunctive therapy. Efficacy increased with increasing weight-adjusted dose (mg/kg). If well tolerated, doses up to 0.12 mg/kg once daily may provide additional benefit. In clinical trials, there were dose-related and exposure-related risks for several clinically significant adverse reactions (hypotension, bradycardia, sedative events). Thus, consideration should be given to dosing INTUNIV® on a mg/kg basis, in order to balance the exposure-related potential benefits and risks of treatment. 2.3 Switching from Immediate-Release Guanfacine to INTUNIV If switching from immediate-release guanfacine, discontinue that treatment, and titrate with INTUNIV® following above recommended schedule. Do not substitute for immediate-release guanfacine tablets on a milligram-per-milligram basis, because of differing pharmacokinetic profiles. INTUNIV® has a delayed Tmax, reduced Cmax and lower bioavailability compared to those of the same dose of immediate-release guanfacine [see Clinical Pharmacology (12.3)]. Page 3 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 2.4 Maintenance Treatment It is generally agreed that pharmacological treatment of ADHD may be needed for extended period. The effectiveness of INTUNIV® for longer-term use (more than 9 weeks) has not been systematically evaluated in controlled trials. Therefore the physician electing to use INTUNIV® for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. 2.5 Discontinuation Infrequent, transient elevations in blood pressure above original baseline (i.e., rebound) have been reported to occur upon abrupt discontinuation of guanfacine. To minimize these effects, the dose should generally be tapered in decrements of no more than 1 mg every 3 to 7 days. 2.6 Missed Doses When reinitiating patients to the previous maintenance dose after two or more missed consecutive doses, physicians should consider titration based on patient tolerability. 2.7 Dose Adjustment with Concomitant Use of Strong CYP3A4 Inhibitors or Inducers Dosage adjustments for INTUNIV ® are recommended with concomitant use of strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole), or CYP3A4 inducers (e.g., avasimibe, carbamazepine, phenytoin, rifampin, and St.John’s wort) (Table 1) [see Drug Interactions (7)]. Table 1: Dose Adjustments in Patients Taking Concomitant CYP3A4 Inhibitors or Inducers Comedications Scenarios Initiate INTUNIV ® when taking comedications Continue INTUNIV ® when adding a comedication Stop a comedication when continuing INTUNIV ® Strong CYP3A4 Inhibitors INTUNIV ® dose should be limited to 2 mg/day INTUNIV ® dose should be decreased by half. INTUNIV ® dose should be doubled based on patient tolerability. The maximum dose should not exceed 4 mg/day Strong CYP3A4 Inducers INTUNIV ® dose may be titrated up to 8 mg/day. Consider faster titration (e.g. in increments of 2 mg/week) Consider increase INTUNIV ® dose gradually in 1-2 weeks to 2 fold of the original dose based on patient tolerability. INTUNIV ® dose should be decreased by half in 1-2 weeks based on patient tolerability. The maximum dose should not exceed 4 mg/day Page 4 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 3 DOSAGE FORMS AND STRENGTHS 1 mg, 2 mg, 3 mg and 4 mg extended-release tablets 4 CONTRAINDICATIONS Patients with a history of hypersensitivity to INTUNIV®, its inactive ingredients [see Description (11)] or other products containing guanfacine should not take INTUNIV® . 5 WARNINGS AND PRECAUTIONS 5.1 Hypotension, Bradycardia, and Syncope Treatment with INTUNIV® can cause dose-dependent decreases in blood pressure and heart rate. Decreases were less pronounced over time of treatment. Orthostatic hypotension and syncope have been reported [see Adverse Reactions (6.1)]. Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Use INTUNIV® with caution in patients with a history of hypotension, heart block, bradycardia, cardiovascular disease, or who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Use INTUNIV® with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. Advise patients to avoid becoming dehydrated or overheated. 5.2 Sedation and Somnolence Somnolence and sedation were commonly reported adverse reactions in clinical studies [see Adverse Reactions (6.1)]. Before using INTUNIV® with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with INTUNIV® . Advise patients to avoid use with alcohol. 6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labelling: • Hypotension, bradycardia, and syncope [see Warnings and Precautions (5.1)] • Sedation and somnolence [see Warnings and Precautions (5.2)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Page 5 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda A total of 2,028 subjects have been exposed to INTUNIV® while participating in clinical trials. This includes 1,533 patients from completed studies in children and adolescents, and 495 subjects in completed studies in adult healthy volunteers. The mean duration of exposure of 446 patients that previously participated in two 2-year, open-label long-term studies was approximately 10 months. Monotherapy Trials Most Common Adverse Reactions - The most commonly observed adverse reactions (incidence ≥ 5% and at least twice the rate for placebo) in the monotherapy trials (Studies 1 and 2) with INTUNIV® were: somnolence, fatigue, nausea, lethargy, and hypotension. Adverse Reactions Leading to Discontinuation - Twelve percent (12%) of patients receiving INTUNIV® discontinued from the monotherapy clinical studies (Studies 1 and 2) due to adverse reactions, compared to 4% in the placebo group. The most common adverse reactions leading to discontinuation of INTUNIV®-treated patients from the studies were somnolence/sedation (6%) and fatigue (2%). Less common adverse reactions leading to discontinuation (occurring in approximately 1% of patients) included: hypotension, headache, and dizziness. Adjunctive Trial Most Common Adverse Reactions - The most commonly observed adverse reactions (incidence ≥ 5% and at least twice the rate for placebo) in the adjunctive trial with INTUNIV® were: somnolence, fatigue, insomnia, dizziness, and abdominal pain. Adverse Reactions Leading to Discontinuation – In the adjunctive clinical study, 3% of patients receiving INTUNIV® discontinued due to adverse reactions, compared to 1% in the placebo group. Each adverse reaction leading to discontinuation occurred in less than 1% of INTUNIV®-treated patients. Short Term Monotherapy Clinical Studies Common Adverse Reactions - Two short-term, placebo-controlled, double-blind pivotal studies (Studies 1 and 2) were conducted in children and adolescents with ADHD, using fixed doses of INTUNIV® (1 mg, 2 mg, 3 mg, and 4 mg/day). The most commonly reported adverse reactions (occurring in ≥ 2% of patients) that were considered drug-related and reported in a greater percentage of patients taking INTUNIV® compared to patients taking placebo are shown in Table 1. Adverse reactions that were dose-related include: somnolence/sedation, abdominal pain, dizziness, hypotension, dry mouth and constipation. Page 6 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 1: Percentage of Patients Experiencing Common (≥ 2%) Adverse Reactions in Short-Term Monotherapy Studies 1 and 2 Adverse Reaction Term All Doses of INTUNIV® (N=513) Placebo (N=149) Somnolencea 38% 12% Headache 24% 19% Fatigue 14% 3% Abdominal pain b 11% 9% Hypotensionc 7% 3% Nausea 6% 2% Lethargy 6% 3% Dizziness 6% 4% Irritability 6% 4% Decreased appetite 5% 3% Dry mouth 4% 1% Constipation 3% 1% a: The somnolence term includes somnolence, sedation, and hypersomnia. b: The abdominal pain term includes abdominal pain, abdominal pain upper, and abdominal pain lower c: The hypotension term includes hypotension, orthostatic hypotension, and decreased blood pressure. In an 8-week, placebo-controlled study in children 6-12 years of age with ADHD in which INTUNIV® was dosed once (1-4 mg/day) in the morning or evening (Study 4), the safety profile was consistent with the once daily morning dosing of INTUNIV® . Short Term Adjunctive Clinical Study Common Adverse Reactions - A 8-week, placebo-controlled, double-blind, dose-optimized pivotal study (Study 3) was conducted in children and adolescents aged 6-17 years with a diagnosis of ADHD who were identified as having a sub-optimal response to psychostimulants. Patients received INTUNIV® (1 mg, 2 mg, 3 mg, and 4 mg/day) or placebo, dosed in the morning or in the evening, in combination with their morning dose of psychostimulant. The most commonly reported adverse reactions (occurring in ≥ 2% Page 7 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda of patients in the overall INTUNIV® group) that were reported in a greater percentage of patients taking INTUNIV® compared to patients taking placebo are shown in Table 2. Table 2: Percentage of Patients Experiencing Common (≥ 2%) Adverse Reactions in Short-Term Adjunctive Study 3 Adverse Reaction Term All Doses of INTUNIV® (N=302)a Placebo (N=153) Headache 21% 13% Somnolenceb 18% 7% Insomniac 12% 6% Fatigue 10% 3% Abdominal paind 10% 3% Dizziness 8% 4% Decreased appetite 7% 4% Nausea 5% 3% Diarrhea 4% 1% Hypotensione 3% 0% Affect lability 2% 1% Bradycardia 2% 0% Constipation 2% 0% Dry mouth 2% 0% a: The morning and evening dose groups of INTUNIV® are combined. b: The somnolence term includes somnolence, sedation, and hypersomnia. c: The insomnia term includes insomnia, initial insomnia, and middle insomnia. d: The abdominal pain term includes abdominal pain, abdominal pain upper, and abdominal pain lower e: The hypotension term includes hypotension, orthostatic hypotension, and decreased blood pressure. Effects on Blood Pressure and Heart Rate In the monotherapy pediatric, short-term, controlled trials (Studies 1 and 2), the maximum mean changes from baseline in systolic blood pressure, diastolic blood pressure, and pulse were −5 mmHg, −3 mmHg, and −6 bpm, respectively, for all dose groups combined (generally one week after reaching target doses of 1 mg/day, 2 mg/day, 3 mg/day or 4 mg/day). These changes were dose dependent. Decreases in blood pressure and heart rate were usually modest and asymptomatic; however, hypotension and bradycardia can occur. Hypotension was reported as an adverse reaction for 7% of the INTUNIV® group and 3% of the placebo group. This includes orthostatic hypotension, which was reported for 1% of the INTUNIV® group and none in the placebo group. In the adjunctive trial, hypotension (3%) and bradycardia (2%) were observed in patients treated with INTUNIV® as compared to none in the placebo group. In long-term, open label studies, (mean exposure of approximately 10 months), maximum decreases in systolic and diastolic blood pressure occurred in the first month Reference ID: 3361918 Page 8 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda of therapy. Decreases were less pronounced over time. Syncope occurred in 1% of pediatric subjects in the clinical program. The majority of these cases occurred in the long-term, open-label studies. Other Adverse Reactions Observed in Clinical Studies Table 3 includes additional adverse reactions observed in short-term, placebo-controlled and long-term, open-label clinical studies not included elsewhere in section 6.1, listed by organ system. Table 3: Other adverse reactions observed in clinical studies Body System Adverse Reaction Cardiac Atrioventricular block, sinus arrhythmia Gastrointestinal Dyspepsia, stomach discomfort, vomiting General Asthenia, chest pain Immune System Hypersensitivity Disorders Investigations Increased alanine amino transferase, increased weight Nervous system Convulsion, Psychiatric Agitation, anxiety, depression, nightmare Renal Increased urinary frequency, enuresis Respiratory Asthma Vascular Hypertension, pallor 6.2 Post-marketing Experience The following adverse reactions have been identified during post-approval use of guanfacine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure An open-label post-marketing study involving 21,718 patients was conducted to assess the safety of guanfacine (as the hydrochloride) 1 mg/day given at bedtime for 28 days. Guanfacine was administered with or without other antihypertensive agents. Adverse events reported in the post-marketing study at an incidence greater than 1% included dry mouth, dizziness, somnolence, fatigue, headache and nausea. The most commonly Page 9 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda reported adverse events in this study were the same as those observed in controlled clinical trials. Less frequent, possibly guanfacine-related events observed in the post-marketing study and/or reported spontaneously, not included in section 6.1, include: General: edema, malaise, tremor Cardiovascular: palpitations, tachycardia Central Nervous System: paresthesias, vertigo Eye Disorders: blurred vision Musculo-Skeletal System: arthralgia, leg cramps, leg pain, myalgia Psychiatric: confusion, hallucinations Reproductive System, Male: impotence Respiratory System: dyspnea Skin and Appendages: alopecia, dermatitis, exfoliative dermatitis, pruritus, rash Special Senses: alterations in taste 7 DRUG INTERACTIONS Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be affected significantly by CYP3A4 inhibitors or inducers (Figure 1). Dose adjustments are recommended [see Dosage and Administration (2.7)]. Guanfacine does not significantly affect exposures of methylphenidate and lisdexamfetamine when coadministered (Figure 2). Therefore, no dose adjustments in methylphenidate or lisdexamfetamine are necessary. Figure 1: Impact of Other Drugs on the Pharmacokinetics (PK) of Intuniv Page 10 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Figure 2: Impact of Intuniv on the Pharmacokinetics (PK) of Other Drugs Page 11 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B Risk Summary There are no adequate and well-controlled studies of INTUNIV in pregnant women. No fetal harm was observed in rats and rabbits with administration of guanfacine at 6 and 4 times, respectively, the maximum recommended human dose. Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Animal data Reproduction studies conducted in rats have shown that guanfacine crosses the placenta. However, administration of guanfacine to rats and rabbits at 6 and 4 times, respectively, the maximum recommended human dose of 4 mg/day on a mg/m2 basis resulted in no evidence of harm to the fetus. Higher doses (20 times the maximum recommended human dose in both rabbits and rats) were associated with reduced fetal survival and maternal toxicity. 8.3 Nursing Mothers It is not known whether guanfacine is excreted in human milk; however, guanfacine is excreted in rat milk. Because many drugs are excreted in human milk, caution should be exercised when INTUNIV® is administered to a nursing woman. Observe human milk-fed infants for sedation and somnolence. 8.4 Pediatric Use Safety and efficacy of INTUNIV® in pediatric patients less than 6 years of age have not been established Animal Data In studies in juvenile rats, guanfacine alone produced a slight delay in sexual maturation in males and females at 2-3 times the maximum recommended human dose (MRHD). Guanfacine in combination with methylphenidate produced a slight delay in sexual maturation and decreased growth as measured by a decrease in bone length in males at a dose of guanfacine comparable to the MRHD and a dose of methylphenidate approximately 4 times the MRHD. In a study where juvenile rats were treated with guanfacine alone from 7 to 59 days of age, development was delayed as indicated by a slight delay in sexual maturation and decreased body weight gain in males at 2 mg/kg/day and in females at 3 mg/kg/day. The No Adverse Effect Level (NOAEL) for delayed sexual maturation was 1 mg/kg/day, which is equivalent to the MRHD of 4 mg/day, on a mg/m2 basis. The effects on fertility were not evaluated in this study. Page 12 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda In a study where juvenile rats were treated with guanfacine in combination with methylphenidate from 7 to 59 days of age, a decrease in ulna bone length and a slight delay in sexual maturation were observed in males given 1 mg/kg/day of guanfacine in combination with 50 mg/kg/day of methylphenidate. The NOAELs for these findings were 0.3 mg/kg of guanfacine in combination with 16 mg/kg/day of methylphenidate, which are equivalent to 0.3 and 1.4 times the MRHD of 4 mg/day and 54 mg/day for guanfacine and methylphenidate, respectively, on a mg/m2 basis. These findings were not observed with guanfacine alone at 1 mg/kg/day or methylphenidate alone at 50 mg/kg/day. 8.5 Geriatric Use The safety and efficacy of INTUNIV® in geriatric patients have not been established. 8.6 Use in Patients with Renal or Hepatic Impairment Renal Impairment The impact of renal impairment on the pharmacokinetics of guanfacine in children was not assessed. In adult patients with impaired renal function, the cumulative urinary excretion of guanfacine and the renal clearance diminished as renal function decreased. In patients on hemodialysis, the dialysis clearance was about 15% of the total clearance. The low dialysis clearance suggests that the hepatic elimination (metabolism) increases as renal function decreases. It may be necessary to adjust the dose in patients with significant impairment of renal function. Hepatic Impairment The impact of hepatic impairment on PK of guanfacine in children was not assessed. Guanfacine in adults is cleared both by the liver and the kidney, and approximately 50% of the clearance of guanfacine is hepatic. It may be necessary to adjust the dose in patients with significant impairment of hepatic function. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance INTUNIV® is not a controlled substance and has no known potential for abuse or dependence. 10 OVERDOSAGE Symptoms Post-marketing reports of guanfacine overdosage indicate that hypotension, drowsiness, lethargy, and bradycardia have been observed following overdose. Initial hypertension may develop early and may be followed by hypotension. Similar symptoms have been described in voluntary reports to the American Association of Poison Control Center’s National Poison Data System. Miosis of the pupils may be noted on examination. No fatal overdoses of guanfacine have been reported in published literature. Page 13 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Treatment Consult a Certified Poison Control Center by calling 1-800-222-1222 for up to date guidance and advice. Management of INTUNIV® overdose should include monitoring for and the treatment of initial hypertension, if that occurs, as well as hypotension, bradycardia, lethargy and respiratory depression. Children and adolescents who develop lethargy should be observed for the development of more serious toxicity including coma, bradycardia and hypotension for up to 24 hours, due to the possibility of delayed onset hypotension. 11 DESCRIPTION INTUNIV® is a once-daily, extended-release formulation of guanfacine hydrochloride (HCl) in a matrix tablet formulation for oral administration only. The chemical designation is N-amidino-2-(2,6-dichlorophenyl) acetamide monohydrochloride. The molecular formula is C9H9Cl2 N3O·HCl corresponding to a molecular weight of 282.55. The chemical structure is: Cl Cl O H N NH2 HCl NH Guanfacine HCl is a white to off-white crystalline powder, sparingly soluble in water (approximately 1 mg/mL) and alcohol and slightly soluble in acetone. The only organic solvent in which it has relatively high solubility is methanol (>30 mg/mL). Each tablet contains guanfacine HCl equivalent to 1 mg, 2 mg, 3 mg, or 4 mg of guanfacine base. The tablets also contain hypromellose, methacrylic acid copolymer, lactose, povidone, crospovidone, microcrystalline cellulose, fumaric acid, and glyceryl behenate. In addition, the 3mg and 4mg tablets also contain green pigment blend PB-1763. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Guanfacine is a central alpha2A-adrenergic receptor agonist. Guanfacine is not a central nervous system (CNS) stimulant. The mechanism of action of guanfacine in ADHD is not known. 12.2 Pharmacodynamics Guanfacine is a selective central alpha2A-adrenergic receptor agonist in that it has a 15­ 20 times higher affinity for this receptor subtype than for the alpha2B or alpha2C subtypes. Guanfacine is a known antihypertensive agent. By stimulating central alpha2A-adrenergic receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to Page 14 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate. Effects on Height, Weight, and Body Mass Index (BMI) Patients taking INTUNIV® demonstrated similar growth compared to normative data. Patients taking INTUNIV® had a mean increase in weight of 0.5 kg (1 lb) compared to those receiving placebo over a comparative treatment period. Patients receiving INTUNIV® for at least 12 months in open-label studies gained an average of 8 kg (17 lbs) in weight and 8 cm (3 in) in height. The height, weight, and BMI percentile remained stable in patients at 12 months in the long-term studies compared to when they began receiving INTUNIV® . Effect on ECG The effect of two dose levels of immediate-release guanfacine (4 mg and 8 mg) on the QT interval was evaluated in a double-blind, randomized, placebo- and active-controlled, cross-over study in healthy adults. A dose-dependent decrease in heart rate was observed during the first 12 hours, at time of maximal concentrations. The mean change in heart rate was -13 bpm at 4 mg and -22 bpm at 8 mg. An apparent increase in mean QTc was observed for both doses. However, guanfacine does not appear to interfere with cardiac repolarization of the form associated with pro-arrhythmic drugs. This finding has no known clinical relevance. 12.3 Pharmacokinetics Absorption and Distribution Guanfacine is readily absorbed and approximately 70% bound to plasma proteins independent of drug concentration. After oral administration of INTUNIV® the time to peak plasma concentration is approximately 5 hours in children and adolescents with ADHD. Immediate-release guanfacine and INTUNIV® have different pharmacokinetic characteristics; dose substitution on a milligram for milligram basis will result in differences in exposure. A comparison across studies suggests that the Cmax is 60% lower and AUC0-∞ 43% lower, respectively, for INTUNIV® compared to immediate-release guanfacine. Therefore, the relative bioavailability of INTUNIV® to immediate-release guanfacine is 58%. The mean pharmacokinetic parameters in adults following the administration of INTUNIV® 1 mg once daily and immediate-release guanfacine 1mg once daily are summarized in Table 4. Page 15 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Table 4: Pharmacokinetic Parameters in Adults Parameter INTUNIV® 1 mg once daily (n=52) Immediate-release guanfacine 1 mg once daily (n=12) Cmax (ng/mL) 1.0 ± 0.3 2.5 ± 0.6 AUC0-∞ (ng.h/mL) 32 ± 9 56 ± 15 tmax (h) 6.0 (4.0 – 8.0) 3.0 (1.5-4.0) t½ (h) 18 ± 4 16 ± 3 Note: Values are mean +/- SD, except for tmax which is median (range) Exposure to guanfacine was higher in children (ages 6-12) compared to adolescents (ages 13-17) and adults. After oral administration of multiple doses of INTUNIV® 4 mg, the Cmax was 10 ng/mL compared to 7 ng/mL and the AUC was 162 ng h/mL compared to 116 ng h/mL in children (ages 6-12) and adolescents (ages 13-17), respectively. These differences are probably attributable to the lower body weight of children compared to adolescents and adults. The pharmacokinetics were affected by intake of food when a single dose of INTUNIV® 4 mg was administered with a high-fat breakfast. The mean exposure increased (Cmax ~75% and AUC ~40%) compared to dosing in a fasted state. Dose Proportionality Following administration of INTUNIV® in single doses of 1 mg, 2 mg, 3 mg, and 4 mg to adults, Cmax and AUC0-∞ of guanfacine were proportional to dose. Metabolism and Elimination In vitro studies with human liver microsomes and recombinant CYP’s demonstrated that guanfacine was primarily metabolized by CYP3A4. In pooled human hepatic microsomes, guanfacine did not inhibit the activities of the major cytochrome P450 isoenzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5). Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5 inducers/inhibitors. Renal and Hepatic Impairment The impact of renal impairment on PK of guanfacine in children was not assessed [see Use in Specific Populations (8.6)]. Page 16 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenic effect of guanfacine was observed in studies of 78 weeks in mice or 102 weeks in rats at doses up to 6-7 times the maximum recommended human dose of 4 mg/day on a mg/ m2 basis. Mutagenesis Guanfacine was not genotoxic in a variety of test models, including the Ames test and an in vitro chromosomal aberration test; however, a marginal increase in numerical aberrations (polyploidy) was observed in the latter study. Impairment of Fertility No adverse effects were observed in fertility studies in male and female rats at doses up to 30 times the maximum recommended human dose on a mg/ m2 basis. 14 CLINICAL STUDIES 14.1 Safety and Efficacy Studies The efficacy of INTUNIV® in the treatment of ADHD was established in 3 placebo-controlled monotherapy trials (Studies 1, 2 and 4) and in 1 placebo-controlled adjunctive trial with psychostimulants (Study 3) in pediatric population. Studies 1, 2, and 3 were conducted in children and adolescents ages 6-17 and Study 4 was conducted in children ages 6-12 years. Studies 1 and 2: Fixed-dose INTUNIV® Monotherapy Study 1 was a double-blind, placebo-controlled, parallel-group, fixed dose study, in which efficacy of once daily dosing with INTUNIV® (2 mg, 3 mg and 4 mg) was evaluated for 5 weeks (n=345). Study 2 was a double-blind, placebo-controlled, parallel-group, fixed-dose study, in which efficacy of once daily dosing with INTUNIV® (1 mg, 2 mg, 3 mg and 4 mg) was evaluated for 6 weeks (n=324). In both studies, randomized subjects in 2 mg, 3 mg and 4 mg dose groups were titrated to their target fixed dose, and continued on the same dose until a dose tapering phase started The lowest dose of 1 mg used in Study 2 was assigned only to patients less than 50 kg (110 lbs). Patients who weighed less than 25 kg (55 lbs) were not included in either study. Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week for which a valid score was obtained prior to dose tapering (up to Week 5 in Study 1 and up to Week 6 in Study 2). The mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV® compared to placebo for Studies 1 and 2. Placebo-adjusted changes from baseline were statistically significant for each of the 2 mg, 3 mg, and 4 mg INTUNIV® randomized treatment groups in both studies, as well as the 1 mg Page 17 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda INTUNIV® treatment group (for patients 55-110 lbs) that was included only in Study 2 (see Table 5). Dose-responsive efficacy was evident, particularly when data were examined on a weight-adjusted (mg/kg) basis. When evaluated over the dose range of 0.01-0.17 mg/kg/day, clinically relevant improvements were observed beginning at doses in the range 0.05-0.08 mg/kg/day. Doses up to 0.12 mg/kg/day were shown to provide additional benefit. Controlled, monotherapy long-term efficacy studies (>9 weeks) have not been conducted. In the monotherapy trials (Studies 1 and 2), subgroup analyses were performed to identify any differences in response based on gender or age (6-12 vs. 13-17). Analyses of the primary outcome did not suggest any differential responsiveness on the basis of gender. Analyses by age revealed a statistically significant treatment effect only in the 6-12 age subgroup. Due to the relatively small proportion of adolescent patients (ages 13-17) enrolled into these studies (approximately 25%), these data may not be sufficient to demonstrate efficacy in the adolescent patients. In these studies, patients were randomized to a fixed dose of INTUNIV® rather than optimized by body weight. Therefore, some adolescent patients were randomized to a dose that might have resulted in relatively lower plasma guanfacine concentrations compared to the younger patients. Over half (55%) of the adolescent patients received doses of 0.01-0.04mg/kg. In studies in which systematic pharmacokinetic data were obtained, there was a strong inverse correlation between body weight and plasma guanfacine concentrations. Table 5: Fixed dose Studies Study Primary Treatment Group Efficacy (Age Measure Placebo Intuniv® Intuniv® Intuniv® Intuniv® Range) 1mg 2mg 3mg 4mg 1 (6 – 17 years) Mean Baseline (SD) LS Mean Change from Baseline (SE) LS Mean Difference from Placebo (95% CI) 38.1 (9.34) --36.1 (9.99) 36.8 (8.72) 38.4 (9.21) -8.5 (1.42) ---15.9 (1.37) -16.0 (1.38) -18.5 (1.39) -----7.4a (­ 11.3, -3.5) -7.5a (­ 11.4, -3.6) -10.0a (-13.9, -6.1) Page 18 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Mean Baseline (SD) 39.3 (8.85) 41.7 (7.81) 39.9 (8.74) 39.1 (9.22) 40.6 (8.57) LS Mean 2 (6 – 17 years) Change from Baseline (SE) -12.7 (1.60) -19.4 (1.69) -18.1 (1.60) -20.0 (1.64) -20.6 (1.60) LS Mean Difference from Placebo ---6.8a (­ 11.3, -2.2) -5.4a (­ 9.9, -0.9) -7.3a (­ 11.8, -2.8) -7.9a (­ 12.3, -3.4) (95% CI) LS Mean: least-square mean; SD: standard deviation; SE: standard error; 95% CI (unadjusted) a Doses were shown to be statistically significantly superior to placebo. Study 3: Flexible-dose INTUNIV® as Adjunctive Therapy to Psychostimulants Study 3 was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily optimized dosing (morning or evening) with INTUNIV® (1mg, 2mg, 3mg and 4mg), when co-administered with psychostimulants, was evaluated for 8 weeks, in children and adolescents aged 6-17 years with a diagnosis of ADHD, with a sub-optimal response to stimulants (n=455). Subjects were started at the 1 mg INTUNIV® dose level and were titrated weekly over a 5-week dose-optimization period to an optimal INTUNIV® dose not to exceed 4 mg/day based on tolerability and clinical response. The dose was then maintained for a 3-week dose maintenance period before entry to 1 week of dose tapering. Subjects took INTUNIV® either in the morning or the evening while maintaining their current dose of psychostimulant treatment given each morning. Allowable psychostimulants in the study were ADDERALL XR®, VYVANSE® , CONCERTA®, FOCALIN XR®, RITALIN LA®, METADATE CD® or FDA-approved generic equivalents. Symptoms of ADHD were evaluated on a weekly basis by clinicians using the ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week prior to dose tapering for which a valid score was obtained (up to Week 8). Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV® given in combination with a psychostimulant compared to placebo given with a psychostimulant for Study 3, for both morning and evening INTUNIV® dosing (see Table 6). Nearly two-thirds (64.2%) of subjects reached optimal doses in the 0.05-0.12 mg/kg/day range. Study 4: Flexible-dose INTUNIV® Monotherapy Reference ID: 3361918 Page 19 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda -- Study 4 was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily dosing (morning or evening) with INTUNIV® (1mg, 2mg, 3mg, and 4mg) was evaluated for 8 weeks in children aged 6-12 years (n=340). Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline score at endpoint on the ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week for which a valid score was obtained prior to dose tapering (up to Week 8). Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV® compared to placebo in both AM and PM dosing groups of INTUNIV® (see Table 6). Table 6: Flexible-Dose studies Study Treatment Group (Age Range) Placebo Intuniv® 1mg – 4mg AM PM 3a (6 – 17 years) Mean Baseline (SD) LS Mean Change from Baseline (SE) LS Mean Difference from Placebo (95% CI) 37.7 (7.75) -15.9 (0.96) 37.6 (8.13) -20.3 (0.97) -4.5b (-7.5, -1.4) 37.0 (7.65) -21.2 (0.97) -5.3b (-8.3, -2.3) Mean 42.9 41.7 41.6 Baseline (SD) (6.21) (6.39) (6.66) 4 (6 – 12 years) LS Mean Change from Baseline (SE) -10.6 (1.20) -20.0 (1.23) -20.4 (1.19) LS Mean -9.4b -9.8b --Difference (-12.8, -6.0) (-13.1, -6.4) from Placebo Page 20 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda (95% CI) LS Mean: least-square mean; SD: standard deviation; SE: standard error; 95% CI (unadjusted) a Treatment was given in combination with a psychostimulant. b Doses were shown to be statistically significantly superior to placebo. 16 HOW SUPPLIED/STORAGE AND HANDLING INTUNIV® is supplied in 1 mg, 2 mg, 3 mg, and 4 mg strength extended-release tablets in 100 count bottles. 1 mg 2 mg 3 mg 4 mg Color White/off-white White/off-white Green Green Shape Round Caplet Round Caplet Debossment (top/bottom) 503 / 1mg 503 / 2mg 503 / 3mg 503 / 4mg NDC number 54092-513-02 54092-515-02 54092-517-02 54092-519-02 Storage - Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). See USP Controlled Room Temperature. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) Dosing and Administration Instruct patients to swallow INTUNIV® whole with water, milk or other liquid. Tablets should not be crushed, chewed or broken prior to administration because this may increase the rate of release of the active drug. Patients should not take INTUNIV® together with a high-fat meal, since this can raise blood levels of INTUNIV® . Instruct the parent or caregiver to supervise the child or adolescent taking INTUNIV® and to keep the bottle of tablets out of reach of children. Instruct patients on how to properly taper the medication, if the physician decides to discontinue treatment. [see Dosage and Administration (2.5)]. Adverse Reactions Advise patients that sedation can occur, particularly early in treatment or with dose increases. Caution against operating heavy equipment or driving until they know how they respond to treatment with INTUNIV® [see Warnings and Precautions (5.2)]. Headache and abdominal pain can also occur. If any of these symptoms persist, or other symptoms occur, the patient should be advised to discuss the symptoms with the physician. Page 21 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Advise patients to avoid becoming dehydrated or overheated which may potentially increase the risks of hypotension and syncope.[see Warnings and Precautions (5.1)], Advise patients to avoid use with alcohol. Patient Information INTUNIV® (in-TOO-niv) (guanfacine) Extended-Release Tablets Read the Patient Information that comes with INTUNIV® before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment. What is INTUNIV®? INTUNIV® is a prescription medicine used to treat the symptoms of attention deficit/hyperactivity disorder (ADHD). INTUNIV® is not a central nervous system (CNS) stimulant. What should I tell my doctor before taking INTUNIV®? Before you take INTUNIV®, tell your doctor if you:  have heart problems or a low heart rate  have fainted  have low blood pressure  have liver or kidney problems  have any other medical conditions  are pregnant or plan to become pregnant. It is not known if INTUNIV® will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.  are breast-feeding or plan to breast-feed. It is not known if INTUNIV® passes into your breast milk. Talk to your doctor about the best way to feed your baby while taking INTUNIV® . Tell your doctor about all of the medicines you take, including prescription and non­ prescription medicines, vitamins, and herbal supplements. INTUNIV® may affect the way other medicines work, and other medicines may affect how INTUNIV® works. Reference ID: 3361918 Page 22 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda Especially tell your doctor if you take:  ketoconazole  medicines that can affect enzyme metabolism  high blood pressure medicine  sedatives  benzodiazepines  barbiturates  antipsychotics Ask your doctor or pharmacist for a list of these medicines, if you are not sure. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine. How should I take INTUNIV®?  Take INTUNIV® exactly as your doctor tells you.  Your doctor may change your dose. Do not change your dose of INTUNIV® without talking to your doctor.  Do not stop taking INTUNIV® without talking to your doctor.  INTUNIV® should be taken 1 time a day in the morning or in the evening, either alone or in combination with an ADHD stimulant medication that your doctor may prescribe. Your doctor will tell you when to take INTUNIV® and when to take your ADHD stimulant medication.  INTUNIV® should be swallowed whole with a small amount of water, milk, or other liquid.  Do not crush, chew, or break INTUNIV®. Tell your doctor if you can not swallow INTUNIV® whole.  Do not take INTUNIV® with a high-fat meal.  Your doctor will check your blood pressure and heart rate while you take INTUNIV® .  If you take too much INTUNIV®, call your local Poison Control Center or go to the nearest emergency room right away. What should I avoid while taking INTUNIV®?  Do not drive, operate heavy machinery, or do other dangerous activities until you know how INTUNIV® affects you. INTUNIV® can slow your thinking and motor skills. Page 23 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda  Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking INTUNIV® until you talk with your doctor. INTUNIV® taken with alcohol or medicines that cause sleepiness or dizziness may make your sleepiness or dizziness worse. What are the possible side effects of INTUNIV®? INTUNIV® may cause serious side effects including:  low blood pressure  low heart rate  fainting  sleepiness Get medical help right away, if you have any of the symptoms listed above. The most common side effects of INTUNIV® include:  sleepiness  nausea  tiredness  stomach pain  trouble sleeping  dizziness  low blood pressure Tell the doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of INTUNIV®. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store INTUNIV®?  Store INTUNIV® between 590F to 860F (15oC to 30oC) Keep INTUNIV® and all medicines out of the reach of children. General Information about INTUNIV® Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use INTUNIV® for a condition for which it was not prescribed. Do not give INTUNIV® to other people, even if they have the same symptoms that you have. It may harm them. This leaflet summarizes the most important information about INTUNIV®. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for Page 24 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda information about INTUNIV® that is written for health professionals. For more information, go to www.INTUNIV.com or call 1­ 800-828-2088. What are the ingredients in INTUNIV®? Active ingredient: guanfacine hydrochloride Inactive ingredients: hypromellose, methacrylic acid copolymer, lactose, povidone, crospovidone, microcrystalline cellulose, fumaric acid, and glycerol behenate. In addition, the 3mg and 4mg tablets also contain green pigment blend PB­ 1763. Manufactured for Shire US Inc., Wayne, PA 19087. INTUNIV® is a registered trademark of Shire LLC. © 201X Shire US Inc. This product is covered by US patents including 6,287,599; 6,811,794. Version: 0X XXXX Page 25 Reference ID: 3361918 This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda

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NIH Websites Are Changing    # Label: GUANFACINE EXTENDED-RELEASE- guanfacine tablet, extended release ## View Package Photos   #### VIEW MORE   ## [Drug Label Info](#drug-information) ## [Safety](#) ## [Related Resources](#) ## [More Info For This Drug](#) ## Drug Label Information Updated September 30, 2026 If you are a consumer or patient please visit [this version.](/dailymed/drugInfo.cfm?setid=07a701e2-39b7-4bb1-a7c7-d9baed4ab18a&audience=consumer) # INDICATIONS AND USAGE Guanfacine extended-release tablets are central alpha2A-adrenergic receptor agonist indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapyand as adjunctive therapy to stimulant medications ([1](#A3f33c6e9-1b78-4a48-88b3-4ebf8adc0b50), [14](#A53f28d4d-fd44-49b1-a806-8f23d9ecf03f)). # DOSAGE AND ADMINISTRATION # DOSAGE FORMS AND STRENGTHS Extended-release tablets: 1 mg, 2 mg, 3 mg and 4 mg ([3](#A574f4764-c412-40a1-962f-6b4072b152c7)) # CONTRAINDICATIONS History of hypersensitivity to guanfacine extended-release tablets, its inactive ingredients, or other products containing guanfacine ([4](#A1790dc39-4c99-4dd9-98fa-ffe2f38c5bc2)) . # WARNINGS AND PRECAUTIONS # ADVERSE REACTIONS Most common adverse reactions (≥5% and at least twice placebo rate) in fixed-dose monotherapy ADHD trials in children and adolescents (6 to 17 years): hypotension, somnolence, fatigue, nausea, and lethargy ([6.1](#Aeb11a5f7-481b-4ee4-89c9-f207c47fac3b)). Flexible dose-optimization ADHD trials in children (6 to 12 years) and adolescents (13 to 17 years): somnolence, hypotension, abdominal pain, insomnia, fatigue, dizziness, dry mouth, irritability, nausea, vomiting, and bradycardia ([6.1](#Aeb11a5f7-481b-4ee4-89c9-f207c47fac3b)). Adjunctive treatment to psychostimulant ADHD trial in children and adolescents (6 to 17 years): somnolence, fatigue, insomnia, dizziness, and abdominal pain ([6.1](#Aeb11a5f7-481b-4ee4-89c9-f207c47fac3b)). To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith Laboratories, LLC at 1-855-899-9180 or FDA at 1-800-FDA-1088 or [www.fda.gov/medwatch.](http://www.fda.gov/medwatch) # DRUG INTERACTIONS See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 2/2025 # FULL PRESCRIBING INFORMATION: CONTENTS[\*](#footnote-content) # [1 INDICATIONS AND USAGE](#section-1) # [2 DOSAGE AND ADMINISTRATION](#section-2) ## [2.1 General Instruction for Use](#section-2.1) ## [2.2 Dose Selection](#section-2.2) ## [2.3 Switching from Immediate-Release Guanfacine to Guanfacine Extended-Release Tablets](#section-2.3) ## [2.4 Maintenance Treatment](#section-2.4) ## [2.5 Discontinuation of Treatment](#section-2.5) ## [2.6 Missed Doses](#section-2.6) ## [2.7 Dosage Adjustment with Concomitant Use of Strong and Moderate CYP3A4 Inhibitors or Inducers](#section-2.7) # [3 DOSAGE FORMS AND STRENGTHS](#section-3) # [4 CONTRAINDICATIONS](#section-4) # [5 WARNINGS AND PRECAUTIONS](#section-5) ## [5.1 Hypotension, Bradycardia, and Syncope](#section-5.1) ## [5.2 Sedation and Somnolence](#section-5.2) ## [5.3 Cardiac Conduction Abnormalities](#section-5.3) ## [5.4 Rebound Hypertension](#section-5.4) # [6 ADVERSE REACTIONS](#section-6) ## [6.1 Clinical Trials Experience](#section-6.1) ## [6.2 Postmarketing Experience](#section-6.2) # [7 DRUG INTERACTIONS](#section-7) # [8 USE IN SPECIFIC POPULATIONS](#section-8) ## [8.1 Pregnancy](#section-8.1) ## [8.2 Lactation](#section-8.2) ## [8.4 Pediatric Use](#section-8.3) ## [8.5 Geriatric Use](#section-8.4) ## [8.6 Renal Impairment](#section-8.5) ## [8.7 Hepatic Impairment](#section-8.6) # [9 DRUG ABUSE AND DEPENDENCE](#section-9) ## [9.1 Controlled Substance](#section-9.1) # [10 OVERDOSAGE](#section-10) # [11 DESCRIPTION](#section-11) # [12 CLINICAL PHARMACOLOGY](#section-12) ## [12.1 Mechanism of Action](#section-12.1) ## [12.2 Pharmacodynamics](#section-12.2) ## [12.3 Pharmacokinetics](#section-12.3) # [13 NONCLINICAL TOXICOLOGY](#section-13) ## [13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility](#section-13.1) # [14 CLINICAL STUDIES](#section-14) # [16 HOW SUPPLIED/STORAGE AND HANDLING](#section-15) # [17 PATIENT COUNSELING INFORMATION](#section-16) Guanfacine extended-release tablets are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications [ see Clinical Studies ([14](#A53f28d4d-fd44-49b1-a806-8f23d9ecf03f)) ]. ## 2.1 General Instruction for Use Swallow tablets whole. Do not crush, chew, or break tablets because this will increase the rate of guanfacine release. Do not administer with high fat meals, due to increased exposure. ## 2.2 Dose Selection Take guanfacine extended-release tablets orally once daily, either in the morning or evening, at approximately the same time each day. Begin at a dose of 1 mg/day, and adjust in increments of no more than 1 mg/week. In monotherapy clinical trials, there was dose- and exposure-related clinical improvement as well as risks for several clinically significant adverse reactions (hypotension, bradycardia, sedative events). To balance the exposure-related potential benefits and risks, the recommended target dose range depending on clinical response and tolerability for guanfacine extended-release tablets is 0.05 to 0.12 mg/kg/day (total daily dose between 1 to 7 mg)  (See Table 1 ). Table 1: Recommended Target Dose Range for Therapy with Guanfacine Extended-Release Tablets | | | | --- | --- | | Doses above 4 mg/day have not been evaluated in children (ages 6 to 12 years) and doses above 7 mg/day have not been evaluated in adolescents (ages 13 to 17 years) | | | | | | --- | --- | | Weight | Target dose range (0.05 to 0.12 mg/kg/day) | | 25 to 33.9 kg | 2 to 3 mg/day | | 34 to 41.4 kg | 2 to 4 mg/day | | 41.5 to 49.4 kg | 3 to 5 mg/day | | 49.5 to 58.4 kg | 3 to 6 mg/day | | 58.5 to 91 kg | 4 to 7 mg/day | | >91 kg | 5 to 7 mg/day | In the adjunctive trial which evaluated guanfacine extended-release tablets treatment with psychostimulants, the majority of patients reached optimal doses in the 0.05 to 0.12 mg/kg/day range. Doses above 4 mg/day have not been studied in adjunctive trials. ## 2.3 Switching from Immediate-Release Guanfacine to Guanfacine Extended-Release Tablets If switching from immediate-release guanfacine, discontinue that treatment, and titrate with guanfacine extended-release tablets following above recommended schedule. Do not substitute for immediate-release guanfacine tablets on a milligram-per-milligram basis, because of differing pharmacokinetic profiles. Guanfacine extended-release tablets have significantly reduced C max (60% lower), bioavailability (43% lower), and a delayed T max (3 hours later) compared to those of the same dose of immediate-release guanfacine [see Clinical Pharmacology ([12.3](#A9601d89a-8ee2-4566-9ff4-0b92d03ac275))] . ## 2.4 Maintenance Treatment Pharmacological treatment of ADHD may be needed for extended periods. Healthcare providers should periodically re-evaluate the long-term use of guanfacine extended-release tablets, and adjust weight-based dosage as needed. The majority of children and adolescents reach optimal doses in the 0.05 to 0.12 mg/kg/day range. Doses above 4 mg/day have not been evaluated in children (ages 6 to 12 years) and above 7 mg/day have not been evaluated in adolescents (ages 13 to 17 years) [see Clinical Studies ([14](#A53f28d4d-fd44-49b1-a806-8f23d9ecf03f))] . ## 2.5 Discontinuation of Treatment Following discontinuation of guanfacine extended-release tablets, patients may experience increases in blood pressure and heart rate [see Warnings and Precautions ([5.4](#L69c5a197-23f6-4c9c-97d3-2d40adc6bd22)) and Adverse Reactions ([6](#A78137972-46e1-4a77-962a-814dad873097))]. Patients/caregivers should be instructed not to discontinue guanfacine extended-release tablets without consulting their health care provider. Monitor blood pressure and pulse when reducing the dose or discontinuing the drug. Taper the daily dose in decrements of no more than 1 mg every 3 to 7 days to minimize the risk of rebound hypertension. ## 2.6 Missed Doses When reinitiating patients to the previous maintenance dose after two or more missed consecutive doses, consider titration based on patient tolerability. ## 2.7 Dosage Adjustment with Concomitant Use of Strong and Moderate CYP3A4 Inhibitors or Inducers Dosage adjustments for guanfacine extended-release tablets are recommended with concomitant use of strong and moderate CYP3A4 inhibitors (e.g., ketoconazole), or CYP3A4 inducers (e.g., carbamazepine) ( Table 2 ) [see Drug Interactions ([7](#A4e5ef577-06e1-4530-a03c-dc7cbbfaf4f4))] . Table 2: Guanfacine Extended-Release Tablets Dosage Adjustments for Patients Taking Concomitant CYP3A4 Inhibitors or Inducers | | | | | | --- | --- | --- | --- | | | Clinical Scenarios | | | | | Starting guanfacine extended-release tablets while currently on a CYP3A4 modulator | Continuing guanfacine extended-release tablets while adding a CYP3A4 modulator | Continuing guanfacine extended-release tablets while stopping a CYP3A4 modulator | | CYP3A4 Strong and moderate Inhibitors | Decrease guanfacine extended-release tablets dosage to half the recommended level. (see Table 1 ) | Decrease guanfacine extended-release tablets dosage to half the recommended level. (see Table 1 ) | Increase guanfacine extended-release tablets dosage to recommended level. (see Table 1 ) | | CYP3A4 Strong and moderate Inducers | Consider increasing guanfacine extended-release tablets dosage up to double the recommended level. (see Table 1 ) | Consider increasing guanfacine extended-release tablets dosage up to double the recommended level over 1 to 2 weeks. (see Table 1 ) | Decrease guanfacine extended-release tablets dosage to recommended level over 1 to 2 weeks. (see Table 1 ) | Guanfacine extended-release tablets, USP, 1 mg, 2 mg, 3 mg and 4 mg Guanfacine extended-release tablets are contraindicated in patients with a history of a hypersensitivity reaction to guanfacine extended-release tablets or its inactive ingredients, or other products containing guanfacine. Rash and pruritus have been reported. ## 5.1 Hypotension, Bradycardia, and Syncope Treatment with guanfacine extended-release tablets can cause dose-dependent decreases in blood pressure and heart rate. Decreases were less pronounced over time of treatment. Orthostatic hypotension and syncope have been reported [see Adverse Reactions ([6.1](#Aeb11a5f7-481b-4ee4-89c9-f207c47fac3b))] . Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Titrate guanfacine extended-release tablets slowly in patients with a history of hypotension, and those with underlying conditions that may be worsened by hypotension and bradycardia; e.g., heart block, bradycardia, cardiovascular disease, vascular disease, cerebrovascular disease, or chronic renal failure. In patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration, advise patients to avoid becoming dehydrated or overheated. Monitor blood pressure and heart rate, and adjust dosages accordingly in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. ## 5.2 Sedation and Somnolence Somnolence and sedation were commonly reported adverse reactions in clinical studies [see Adverse Reactions ([6.1](#Aeb11a5f7-481b-4ee4-89c9-f207c47fac3b))]. Before using guanfacine extended-release tablets with other centrally active depressants, consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with guanfacine extended-release tablets . Advise patients to avoid use with alcohol. ## 5.3 Cardiac Conduction Abnormalities The sympatholytic action of guanfacine extended-release tablets may worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. Titrate guanfacine extended-release tablets slowly and monitor vital signs frequently in patients with cardiac conduction abnormalities or patients concomitantly treated with other sympatholytic drugs. ## 5.4 Rebound Hypertension In post marketing experience, abrupt discontinuation of guanfacine extended-release tablets has resulted in clinically significant and persistent rebound hypertension above baseline levels and increases in heart rate. Hypertensive encephalopathy has also been reported in association with rebound hypertension with both guanfacine extended-release tablets and immediate release guanfacine [see Adverse Reactions ([6.2](#A65fb9fcd-fc2c-4b52-9043-0f271df0dab8))]. In these cases, high-dosage guanfacine was discontinued; concomitant stimulant use was also reported, which may potentially increase hypertensive response upon abrupt discontinuation of guanfacine. Children commonly have gastrointestinal illnesses that lead to vomiting, and a resulting inability to take medications, so they may be especially at risk for rebound hypertension. To minimize the risk of rebound hypertension upon discontinuation, the total daily dose of guanfacine extended-release tablets should be tapered in decrements of no more than 1 mg every 3 to 7 days [see Dosage and Administration ([2.5](#Ad2b99e6a-6754-4ad4-b435-434525fd562a))]. Blood pressure and heart rate should be monitored when reducing the dose or discontinuing guanfacine extended-release tablets. If abrupt discontinuation occurs (especially with concomitant stimulant use), patients should be closely followed for rebound hypertension. The following serious adverse reactions are described elsewhere in the labeling: ## 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect clinical trial exposure to guanfacine extended-release tablets in 2,825 patients. This includes 2,330 patients from completed studies in children and adolescents, ages 6 to 17 years and 495 patients in completed studies in adult healthy volunteers. The mean duration of exposure of 446 patients that previously participated in two 2-year, open-label long-term studies was approximately 10 months. Fixed Dose Trials Table 3: Percentage of Patients Experiencing Most Common (≥ 5% and at least twice the rate for placebo) Adverse Reactions in Fixed Dose Studies 1 and 2 | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | | \*The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. a: The somnolence term includes somnolence, sedation, and hypersomnia. b: The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | | | | Guanfacine Extended-Release Tablets (mg) | | | | | | Adverse Reaction Term | Placebo (N=149) | 1mg\* (N=61) | 2mg (N=150) | 3mg (N=151) | 4mg (N=151) | All Doses of guanfacine extended-release tablets (N=513) | | Somnolence a | 11% | 28% | 30% | 38% | 51% | 38% | | Fatigue | 3% | 10% | 13% | 17% | 15% | 14% | | Hypotension b | 3% | 8% | 5% | 7% | 8% | 7% | | Dizziness | 4% | 5% | 3% | 7% | 10% | 6% | | Lethargy | 3% | 2% | 3% | 8% | 7% | 6% | | Nausea | 2% | 7% | 5% | 5% | 6% | 6% | | Dry mouth | 1% | 0% | 1% | 6% | 7% | 4% | Table 4: Adverse Reactions Leading to Discontinuation (≥ 2% for all doses of guanfacine extended-release tablets and > rate than in placebo) in Fixed Dose Studies 1 and 2 | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Adverse reactions leading to discontinuation in ≥ 2% in any dose group but did not meet this criteria in all doses combined: hypotension (hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased), headache, and dizziness. \* The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. a: The somnolence term includes somnolence, sedation, and hypersomnia. | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | | | | Guanfacine Extended-Release Tablets (mg) | | | | | | Adverse Reaction Term | Placebo (N=149) | 1mg\* (N=61) | 2mg (N=150) | 3mg (N=151) | 4mg (N=151) | All Doses of guanfacine extended-release tablets (N=513) | | | n (%) | n (%) | n (%) | n (%) | n (%) | n (%) | | Total patients | 4 (3%) | 2 (3%) | 10 (7%) | 15 (10%) | 27 (18%) | 54 (11%) | | Somnolence a | 1 (1%) | 2 (3%) | 5 (3%) | 6 (4%) | 17 (11%) | 30 (6%) | | Fatigue | 0 (0%) | 0 (0%) | 2 (1%) | 2 (1%) | 4 (3%) | 8 (2%) | Table 5: Other Common Adverse Reactions (≥ 2% for all doses of guanfacine extended-release tablets and > rate than in placebo) in Fixed Dose Studies 1 and 2 | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Adverse reactions ≥ 2% for all doses of guanfacine extended-release tablets and > rate in placebo in any dose group but did not meet this criteria in all doses combined: insomnia (insomnia, initial insomnia, middle insomnia, terminal insomnia, sleep disorder), vomiting, diarrhea, abdominal/stomach discomfort (abdominal discomfort, epigastric discomfort, stomach discomfort), rash (rash, rash generalized, rash papular), dyspepsia, increased weight, bradycardia (bradycardia, sinus bradycardia), asthma (asthma, bronchospasm, wheezing), agitation, anxiety (anxiety, nervousness), sinus arrhythmia, blood pressure increased (blood pressure increased, blood pressure diastolic increased), and first degree atrioventricular block. \* The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. a: The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. b: The nightmare term includes abnormal dreams, nightmare, and sleep terror. c: The enuresis term includes enuresis, nocturia, and urinary incontinence. d: The affect lability term includes affect lability and mood swings. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | | | | Guanfacine Extended-Release Tablets (mg) | | | | | | Adverse Reaction Term | Placebo (N=149) | 1mg\* (N=61) | 2mg (N=150) | 3mg (N=151) | 4mg (N=151) | All Doses of guanfacine extended-release tablets (N=513) | | Headache | 19% | 26% | 25% | 16% | 28% | 23% | | Abdominal Pain a | 9% | 10% | 7% | 11% | 15% | 11% | | Decreased Appetite | 4% | 5% | 4% | 9% | 6% | 6% | | Irritability | 4% | 5% | 8% | 3% | 7% | 6% | | Constipation | 1% | 2% | 2% | 3% | 4% | 3% | | Nightmare b | 0% | 0% | 0% | 3% | 4% | 2% | | Enuresis c | 1% | 0% | 1% | 3% | 2% | 2% | | Affect Lability d | 1% | 2% | 1% | 3% | 1% | 2% | Monotherapy Flexible Dose Trials Table 6: Percentage of Patients Experiencing Most Common (≥ 5% and at least twice the rate for placebo) Adverse Reactions in the Monotherapy Flexible Dose Study 4 | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | a: The somnolence term includes somnolence, sedation, and hypersomnia. b: The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness c: The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). d: The enuresis term includes enuresis, nocturia, and urinary incontinence. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | | | | Guanfacine Extended-Release Tablets | | | | Adverse Reaction Term | Placebo (N=112) | AM (N=107) | PM (N=114) | All Doses of guanfacine extended-release tablets (N=221) | | Somnolence a | 15% | 57% | 54% | 56% | | Abdominal Pain b | 7% | 8% | 19% | 14% | | Fatigue | 3% | 10% | 11% | 11% | | Irritability | 3% | 7% | 7% | 7% | | Nausea | 1% | 6% | 5% | 5% | | Dizziness | 3% | 6% | 4% | 5% | | Vomiting | 2% | 7% | 4% | 5% | | Hypotension c | 0% | 6% | 4% | 5% | | Decreased Appetite | 3% | 6% | 3% | 4% | | Enursis d | 1% | 2% | 5% | 4% | Table 7: Adverse Reactions Leading to Discontinuation (≥ 2% for all doses of guanfacine extended-release tablets and > rate than in placebo) in Monotherapy Flexible Dose Studies 4 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Adverse reactions leading to discontinuation in ≥ 2% in any dose group but did not meet this criteria in all doses combined: fatigue a: The somnolence term includes somnolence, sedation, and hypersomnia. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | | | | Guanfacine Extended-Release Tablets | | | | Adverse Reaction Term | Placebo (N=112) | AM (N=107) | PM (N=114) | All Doses of guanfacine extended-release tablets (N=221) | | | n (%) | n (%) | n (%) | n (%) | | Total patients | 0 (0%) | 8 (7%) | 7 (6%) | 15 (7%) | | Somnolence a | 0 (0%) | 4 (4%) | 3 (3%) | 7 (3%) | Table 8: Other Common Adverse Reactions (≥2% for all doses of guanfacine extended-release tablets and > rate than in placebo) in the Monotherapy Flexible Dose Study 4 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Adverse reactions ≥ 2% for all doses of guanfacine extended-release tablets and > rate in placebo in any dose group but did not meet this criteria inall doses combined: affect lability (affect lability, mood swings), increased weight, syncope/loss of consciousness (loss ofconsciousness, presyncope, syncope), dyspepsia, tachycardia (tachycardia, sinus tachycardia), and bradycardia (bradycardia, sinus bradycardia). a: The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | | | | Guanfacine Extended-Release Tablets | | | | Adverse Reaction Term | Placebo (N=112) | AM (N=107) | PM (N=114) | All Doses of guanfacine extended-release tablets (N=221) | | Headache | 11% | 18% | 16% | 17% | | Insomnia a | 6% | 8% | 6% | 7% | | Diarrhea | 4% | 4% | 6% | 5% | | Lethargy | 0% | 4% | 3% | 3% | | Constipation | 2% | 2% | 4% | 3% | | Dry Mouth | 1% | 3% | 3% | 3% | Table 9: Percentage of Patients Experiencing Most Common (≥ 5% and at least twice the rate for placebo) Adverse Reactions in the Monotherapy Flexible Dose Study 5 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | a: The somnolence term includes somnolence, sedation, and hypersomnia. b: The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. c: The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). d: The bradycardia term includes bradycardia and sinus bradycardia. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | | Adverse Reaction Term | Placebo (N=155) | All Doses of guanfacine extended-release tablets (N=157) | | Somnolence a | 23% | 54% | | Insomnia b | 6% | 13% | | Hypotension c | 3% | 9% | | Dry Mouth | 0% | 8% | | Postural Dizziness | 2% | 5% | | Bradycardia d | 0% | 5% | There were no specific adverse reactions ≥ 2% in any treatment group that led to discontinuation in themonotherapy flexible dose study (Study 5). Table 10: Other Common Adverse Reactions (≥ 2% for all doses of guanfacine extended-release tablets and > rate than in placebo) in the Monotherapy Flexible Dose Study 5 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Adverse reactions ≥ 2% for all doses of guanfacine extended-release tablets and > rate in placebo in any dose group but did not meet this criteria in all doses combined: nausea, diarrhea, vomiting, and depression (depressed mood, depression, depressive symptom). a: The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. b: The anxiety term includes anxiety and nervousness. c: The rash term includes rash, rash generalized, and rash papular. d: The abdominal/stomach discomfort term includes abdominal discomfort, epigastric discomfort, and stomach discomfort. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | | | | Guanfacine Extended-Release Tablets | | Adverse Reaction Term | Placebo (N=155) | All Doses of guanfacine extended-release tablets (N=157) | | Headache | 18% | 27% | | Fatigue | 12% | 22% | | Dizziness | 10% | 16% | | Decreased Appetite | 14% | 15% | | Abdominal Pain a | 8% | 12% | | Irritability | 4% | 7% | | Anxiety b | 3% | 5% | | Rash c | 1% | 3% | | Constipation | 0% | 3% | | Increased Weight | 2% | 3% | | Abdominal/Stomach Discomfort d | 1% | 2% | | Pruritus | 1% | 2% | Adjunctive Trial Table 11: Percentage of Patients Experiencing Most Common (≥ 5% and at least twice the rate for placebo) Adverse Reactions in the Short-Term Adjunctive Study 3 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | a: The somnolence term includes somnolence, sedation, and hypersomnia. b: The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. c: The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | | | | Guanfacine Extended-Release Tablets + stimulant | | | | Adverse Reaction Term | Placebo+stimulant (N=153) | AM (N=150) | PM (N=152) | All Doses (N=302) | | Somnolence a | 7% | 18% | 18% | 18% | | Insomnia b | 6% | 10% | 14% | 12% | | Abdominal Pain c | 3% | 8% | 12% | 10% | | Fatigue | 3% | 12% | 7% | 10% | | Dizziness | 4% | 10% | 5% | 8% | | Decreased Appetite | 4% | 7% | 8% | 7% | | Nausea | 3% | 3% | 7% | 5% | There were no specific adverse reactions ≥ 2% in any treatment group that led to discontinuation in the short-term adjunctive study (Study 3). Table 12: Other Common Adverse Reactions (≥ 2% for all doses of guanfacine extended-release tablets and > rate than in placebo) in the Short-Term Adjunctive Study 3 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Adverse reactions ≥ 2% for all doses of guanfacine extended-release tablets and > rate in placebo in any dose group but did not meet this criteria in all doses combined: irritability, vomiting, asthma (asthma, bronchospasm, wheezing), and enuresis (enuresis, nocturia, urinary incontinence). a: The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased. b: The affect lability term includes affect lability and mood swings. c: The bradycardia term includes bradycardia and sinus bradycardia. d: The rash term includes rash, rash generalized, and rash papular. e: The nightmare term includes abnormal dreams, nightmare, and sleep terror. f: The tachycardia term includes tachycardia and sinus tachycardia. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | | | | Guanfacine Extended-Release Tablets + stimulant | | | | Adverse Reaction Term | Placebo (N=153) | AM (N=150) | PM (N=152) | All Doses of Guanfacine Extended-Release Tablets (N=302) | | Headache | 13% | 21% | 21% | 21% | | Diarrhea | 1% | 4% | 3% | 4% | | Hypotension a | 0% | 4% | 2% | 3% | | Constipation | 0% | 2% | 3% | 2% | | Affect Lability b | 1% | 3% | 2% | 2% | | Dry Mouth | 0% | 1% | 3% | 2% | | Bradycardia c | 0% | 1% | 3% | 2% | | Postural Dizziness | 0% | 1% | 3% | 2% | | Rash d | 1% | 1% | 2% | 2% | | Nightmare e | 1% | 2% | 1% | 2% | | Tachycardia f | 1% | 2% | 1% | 2% | Effects on Blood Pressure and Heart Rate In the monotherapy pediatric, short-term, controlled trials (Studies 1 and 2), the maximum mean changes from baseline in seated systolic blood pressure, diastolic blood pressure, and pulse were -5.4 mmHg, -3.4 mmHg, and -5.5 bpm, respectively, for all doses combined (generally one week after reaching target doses). For the respective fixed doses 1 mg/day, 2 mg/day, 3 mg/day or 4 mg/day the maximum mean changes in seated systolic blood pressure were -4.3 mmHg, -5.5 mmHg, -5.4 mmHg and -8.2 mmHg. For these respective fixed doses the maximum mean changes in seated diastolic blood pressure were -3.4 mmHg, -3.3 mmHg, -4.4 mmHg and -5.4 mmHg. For these respective fixed doses the maximum mean changes in seated pulse were -4.8bpm, -3.1 bpm, -6.5 bpm and -8.6 bpm. Decreases in blood pressure and heart rate were usually modest and asymptomatic; however, hypotension and bradycardia can occur. Hypotension was reported as an adverse reaction for 7% of the guanfacine extended-release tabletsgroup and 3% of the placebo group. This includes orthostatic hypotension, which was reported for 1% of the guanfacine extended-release tablets group and none in the placebo group. These findings were generally similar in the monotherapy flexible dose trials (Studies 4 and 5). In the adjunctive trial, hypotension (3%) and bradycardia (2%) were observed in patients treated with guanfacine extended-release tablets as compared to none in the placebo group. In long-term, open-label studies, (mean exposure of approximately 10 months), maximum decreases in systolic and diastolic blood pressure occurred in the first month of therapy. Decreases were less pronounced over time. Syncope occurred in 1% of pediatric patients in the clinical program. The majority of these cases occurred in the long-term, open-label studies. Discontinuation of Treatment Blood pressure and pulse may increase above baseline values following discontinuation of guanfacine extended-release tablets. In five studies of children and adolescents [see Clinical Studies ([14](#A53f28d4d-fd44-49b1-a806-8f23d9ecf03f))] , increases in mean systolic and diastolic blood pressure averaging approximately 3 mmHg and increases in heart rate averaging 5 beats per minute above original baseline were observed upon discontinuation with tapering of guanfacine extended-release tablets. In a maintenance of efficacy study, increases in blood pressure and heart rate above baseline slowly diminished over the follow up period, which ranged between 3 and 26 weeks post final dose; the estimated average time to return to baseline was between six and twelve months. In this study, the increases in blood pressure and pulse were not considered serious or associated with adverse events. However, individuals may have larger increases than reflected by the mean changes. In postmarketing experience, following abrupt discontinuation of guanfacine extended-release tablets, rebound hypertension and hypertensive encephalopathy have been reported [see Warnings and Precautions ([5.4](#L69c5a197-23f6-4c9c-97d3-2d40adc6bd22)) and Adverse Reactions ([6.2](#A65fb9fcd-fc2c-4b52-9043-0f271df0dab8)] Effects on Height, Weight, and Body Mass Index (BMI) Patients taking guanfacine extended-release tablets demonstrated similar growth compared to normative data. Patients taking guanfacine extended-release tablets had a mean increase in weight of 0.5 kg compared to those receiving placebo over a comparable treatment period. Patients receiving guanfacine extended-release tablets for at least 12 months in open-label studies gained an average of 8 kg inweight and 8 cm (3 in) in height. The height, weight, and BMI percentile remained stable in patients at 12 months in the long-term studies compared to when they began receiving guanfacine extended-release tablets. Other Adverse Reactions Observed in Clinical Studies Table 13 includes additional adverse reactions observed in short-term, placebo-controlled and long-term, open-label clinical studies not included elsewhere in section 6.1, listed by organ system. Table 13: Other Adverse Reactions Observed In Clinical Studies | | | | --- | --- | | Body System | Adverse Reaction | | Cardiac | Atrioventricular block | | General | Asthenia, chest pain | | Immune System Disorders | Hypersensitivity | | Investigations | Increased alanine amino transferase | | Nervous system | Convulsion | | Renal | Increased urinary frequency | | Vascular | Hypertension, pallor | ## 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of guanfacine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Less frequent, possibly guanfacine-related events observed in the post-marketing study and/or reported spontaneously, not included in section 6.1, include: General : edema, malaise, tremor Cardiovascular : palpitations, tachycardia, rebound hypertension, hypertensive encephalopathy Central Nervous System : paresthesias, vertigo Eye Disorders : blurred vision Musculo-Skeletal System : arthralgia, leg cramps, leg pain, myalgia Psychiatric : confusion, hallucinations Reproductive System, Male : erectile dysfunction Respiratory System : dyspnea Skin and Appendages : alopecia, dermatitis, exfoliative dermatitis, pruritus, rash Special Senses : alterations in taste Table 14 contains clinically important drug interactions with guanfacine extended-release tablets [see Clinical Pharmacology ([12.3](#A9601d89a-8ee2-4566-9ff4-0b92d03ac275))] . Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine Extended-Release Tablets | | | | | --- | --- | --- | | Concomitant Drug Name or Drug Class | Clinical Rationale and Magnitude of Drug Interaction | Clinical Recommendation | | Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole | Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure | Consider dose reduction [see Dosage and administration ([2.7](#A2a181186-c7e2-4a4a-aaf2-5bd13010e9ae))] | | Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz | Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure | Consider dose increase[see Dosage and administration ([2.7](#A2a181186-c7e2-4a4a-aaf2-5bd13010e9ae))] | ## 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including guanfacine extended-release tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388. Risk Summary Available data with guanfacine over decades of use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. However, use of guanfacine in pregnant women over this time has been infrequent. In animal reproduction studies, rabbits and rats exposed to 3 and 4 times the maximum recommended human dose (MRHD), respectively, showed no adverse outcomes. However, higher doses were associated with reduced fetal survival and maternal toxicity (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal data Reproduction studies conducted in rats have shown that guanfacine crosses the placenta. However, administration of guanfacine to rabbits and rats during organogenesis at 3 (rabbit) and 4 (rat) times the MRHD of 0.12 mg/kg/day on a mg/m2 basis resulted in no evidence of harm to the fetus. Higher doses (13.5 times the MRHD in both rabbits and rats) were associated with reduced fetal survival and maternal toxicity. ## 8.2 Lactation Risk Summary There are no data on the presence of guanfacine in human milk or the effects on the breastfed infant. The effects on milk production are also unknown. Guanfacine is present in the milk of lactating rats (see Data). If a drug is present in animal milk, it is likely that the drug will be present in human milk. If an infant is exposed to guanfacine through breastmilk, monitor for symptoms of hypotension and bradycardia such as sedation, lethargy and poor feeding (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for guanfacine extended-release tablets and any potential adverse effects on the breastfed child from guanfacine extended-release tablets or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants exposed to guanfacine through breastmilk for sedation, lethargy, and poor feeding. Data Guanfacine was excreted in breast milk of lactating rats at a concentration comparable to that observed in blood, but slightly less than the concentration in plasma when administered following a single oral dose of 5 mg/kg. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk. ## 8.4 Pediatric Use Safety and efficacy of guanfacine extended-release tabletsin pediatric patients less than 6 years of age have not been established. The efficacy of guanfacine extended-release tablets was studied for the treatment of ADHD in five controlled monotherapy clinical trials (up to 15 weeks in duration), one randomized withdrawal study and one controlled adjunctive trial with psychostimulants (8 weeks in duration) in children and adolescents ages 6 to 17 who met DSM-IV ® criteria for ADHD [see Adverse Reactions ([6](#A78137972-46e1-4a77-962a-814dad873097)) and Clinical Studies ([14](#A53f28d4d-fd44-49b1-a806-8f23d9ecf03f))] . Animal Data In studies in juvenile rats, guanfacine alone produced a slight delay in sexual maturation in males and females at 2 to 3 times the maximum recommended human dose (MRHD). Guanfacine in combination with methylphenidate produced a slight delay in sexual maturation and decreased growth as measured by a decrease in bone length in males at a dose of guanfacine comparable to the MRHD and a dose of methylphenidate approximately 4 times the MRHD. In a study where juvenile rats were treated with guanfacine alone from 7 to 59 days of age, development was delayed as indicated by a slight delay in sexual maturation and decreased body weight gain in males at 2 mg/kg/day and in females at 3 mg/kg/day. The No Adverse Effect Level (NOAEL) for delayed sexual maturation was 1 mg/kg/day, which is equivalent to the MRHD of 4 mg/day, on a mg/m 2 basis. The effects on fertility were not evaluated in this study. In a study where juvenile rats were treated with guanfacine in combination with methylphenidate from 7 to 59 days of age, a decrease in ulna bone length and a slight delay in sexual maturation were observed in males given 1 mg/kg/day of guanfacine in combination with 50 mg/kg/day of methylphenidate. The NOAELs for these findings were 0.3 mg/kg of guanfacine in combination with 16 mg/kg/day of methylphenidate, which are equivalent to 0.3 and 1.4 times the MRHD of 4 mg/day and 54 mg/day for guanfacine and methylphenidate, respectively, on a mg/m 2 basis. These findings were not observed with guanfacine alone at 1 mg/kg/day or methylphenidate alone at 50 mg/kg/day. ## 8.5 Geriatric Use The safety and efficacy of guanfacine extended-release tablets in geriatric patients have not been established. ## 8.6 Renal Impairment It may be necessary to reduce the dosage in patients with significant impairment of renal function [see Clinical Pharmacology ([12.3](#A9601d89a-8ee2-4566-9ff4-0b92d03ac275))] . ## 8.7 Hepatic Impairment It may be necessary to reduce the dosage in patients with significant impairment of hepatic function [see Clinical Pharmacology ([12.3](#A9601d89a-8ee2-4566-9ff4-0b92d03ac275))] . ## 9.1 Controlled Substance Guanfacine extended-release tablets are not controlled substance and have no known potential for abuse or dependence. Symptoms Postmarketing reports of guanfacine overdosage indicate that hypotension, drowsiness, lethargy, and bradycardia have been observed following overdose. Initial hypertension may develop early and may be followed by hypotension. Similar symptoms have been described in voluntary reports to the American Association of Poison Control Center's National Poison Data System. Miosis of the pupils may be noted on examination. No fatal overdoses of guanfacine have been reported in published literature. Treatment Consult a Certified Poison Control Center by calling 1-800-222-1222 for up-to-date guidance and advice. Management of guanfacine extended-release tablets overdose should include monitoring for and the treatment of initial hypertension, if that occurs, as well as hypotension, bradycardia, lethargy and respiratory depression. Children and adolescents who develop lethargy should be observed for the development of more serious toxicity including coma, bradycardia and hypotension for up to 24 hours, due to the possibility of delayed onset hypotension. Guanfacine extended-release tablets, USP are once-daily, extended-release formulation of guanfacine hydrochloride (HCl), USP in a matrix tablet formulation for oral administration only. The chemical designation is N-amidino-2-(2,6-dichlorophenyl) acetamide monohydrochloride. The molecular formula is C 9 H 9 Cl 2 N 3 O·HCl corresponding to a molecular weight of 282.55. The chemical structure is:  Guanfacine HCl, USP is a white to off-white crystalline powder, sparingly soluble in water (approximately 1 mg/mL) and alcohol and slightly soluble in acetone. The only organic solvent in which it has relatively high solubility is methanol (>30 mg/mL). Each tablet contains guanfacine HCl, USP equivalent to 1 mg, 2 mg, 3 mg, or 4 mg of guanfacine base. The tablets also contain microcrystalline cellulose, hypromellose, polyvinyl acetate, povidone, lactose monohydrate, magnesium stearate, sodium lauryl sulfate and silica. In addition, the 3-mg and 4-mg tablets also contain FD&C Blue #1. ## 12.1 Mechanism of Action Guanfacine is a central alpha 2A -adrenergic receptor agonist. Guanfacine is not a central nervous system (CNS) stimulant. The mechanism of action of guanfacine in ADHD is not known. ## 12.2 Pharmacodynamics Guanfacine is a selective central alpha 2A -adrenergic receptor agonist in that it has a 15 to 20 times higher affinity for this receptor subtype than for the alpha 2B or alpha 2C subtypes. Guanfacine is a known antihypertensive agent. By stimulating central alpha 2A -adrenergic receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate. In a thorough QT study, the administration of two dose levels of immediate-release guanfacine (4 mg and 8 mg) produced concentrations approximately 2 to 4 times the concentrations observed with the maximum recommended dose of guanfacine extended-release tablets of 0.12 mg/kg. Guanfacine was not shown to prolong the QTc interval to any clinically relevant extent. ## 12.3 Pharmacokinetics Absorption and Distribution Guanfacine is readily absorbed and approximately 70% bound to plasma proteins independent of drug concentration. After oral administration of guanfacine extended-release tablets the time to peak plasma concentration is approximately 5 hours in children and adolescents with ADHD. Immediate-release guanfacine and guanfacine extended-release tablets have different pharmacokinetic characteristics; dose substitution on a milligram per milligram basis will result in differences in exposure. A comparison across studies suggests that the C max is 60% lower and AUC 0-∞43% lower, respectively, for guanfacine extended-release tablets compared to immediate-release guanfacine. Therefore, the relative bioavailability of guanfacine extended-release tablets to immediate-release guanfacine is 58%. The mean pharmacokinetic parameters in adults following the administration of guanfacine extended-release tablets 1 mg once daily and immediate-release guanfacine 1 mg once daily are summarized in Table 15 . Table 15: Comparison of Pharmacokinetics: Guanfacine Extended-Release Tablets vs. Immediate release Guanfacine in Adults | | | | | --- | --- | --- | | Note: Values are mean +/- SD, except for t max which is median (range) | | | | | | | | --- | --- | --- | | Parameter | Guanfacine Extended-Release Tablets 1 mg once daily (n=52) | Immediate-release guanfacine 1 mg once daily (n=12) | | C max (ng/mL) | 1.0 ± 0.3 | 2.5 ± 0.6 | | AUC 0-∞ (ng∙h/mL) | 32 ± 9 | 56 ± 15 | | t max (h) | 6.0 (4.0 - 8.0) | 3.0 (1.5-4.0) | | t ½ (h) | 18 ± 4 | 16 ± 3 | Figure 1: Comparison of Pharmacokinetics: Guanfacine Extended-Release Tablets vs. Immediate-release guanfacine in Adults  Exposure to guanfacine was higher in children (ages 6 to 12) compared to adolescents (ages 13 to 17) and adults. After oral administration of multiple doses of guanfacine extended-release tablets 4 mg, the C max was 10 ng/mL compared to 7 ng/mL and the AUC was 162 ng∙h/mL compared to 116 ng∙h/mL in children (ages 6 to 12) and adolescents (ages 13 to 17), respectively. These differences are probably attributable to the lower body weight of children compared to adolescents and adults. The pharmacokinetics were affected by intake of food when a single dose of guanfacine extended-release tablets 4 mg was administered with a high-fat breakfast. The mean exposure increased (C max ~75% and AUC ~40%) compared to dosing in a fasted state. Dose Proportionality Following administration of guanfacine extended-release tablets in single doses of 1 mg, 2 mg, 3 mg, and 4 mg to adults, C max and AUC 0-∞ of guanfacine were proportional to dose. Metabolism and Elimination In vitro studies with human liver microsomes and recombinant CYP's demonstrated that guanfacine was primarily metabolized by CYP3A4. In pooled human hepatic microsomes, guanfacine did not inhibit the activities of the major cytochrome P450 isoenzymes (CYP1A2,CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5); guanfacine is also not an inducer of CYP3A, CYP1A2 and CYP2B6. Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5 inducers/inhibitors. Guanfacine inhibits MATE1 and OCT1, but does not inhibit BSEP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, or MATE2K. Guanfacine is a substrate of OCT1 and OCT2, but not BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, or MATE2. Concomitant administration of guanfacine with OCT1 substrates might potentially increase the exposure of these OCT1 substrates. Studies in Specific Populations Renal Impairment The impact of renal impairment on the pharmacokinetics of guanfacine in children was not assessed. In adult patients with impaired renal function, the cumulative urinary excretion of guanfacine and the renal clearance diminished as renal function decreased. In patients on hemodialysis, the dialysis clearance was about 15% of the total clearance. The low dialysis clearance suggests that the hepatic elimination (metabolism) increases as renal function decreases. Hepatic Impairment The impact of hepatic impairment on PK of guanfacine in children was not assessed. Guanfacine in adults is cleared both by the liver and the kidney, and approximately 50% of the clearance of guanfacine is hepatic [see Hepatic Impairment ([8.7](#Af27fd82b-db1f-49f1-9a53-61dae9406e64))] . Drug Interaction Studies Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be affected significantly by CYP3A4 inhibitors or inducers ( Figure 2 ). Figure 2: Effect of Other Drugs on the Pharmacokinetics (PK) of Guanfacine Extended-Release Tablets  Guanfacine does not significantly affect exposures of methylphenidate and lisdexamfetamine when coadministered ( Figure 3 ). Figure 3: Effect of Guanfacine Extended-Release Tablets on the Pharmacokinetics (PK) of Other Drugs  ## 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenic effect of guanfacine was observed in studies of 78 weeks in mice or 102 weeks in rats at doses up to 6.8 times the maximum recommended human dose of 0.12 mg/kg/day on a mg/m 2 basis. Mutagenesis Guanfacine was not genotoxic in a variety of test models, including the Ames test and an in vitro chromosomal aberration test; however, a marginal increase in numerical aberrations (polyploidy) was observed in the latter study. Impairment of Fertility No adverse effects were observed in fertility studies in male and female rats at doses up to 22 times the maximum recommended human dose on a mg/m 2 basis. Efficacy of guanfacine extended-release tablets in the treatment of ADHD was established in children and adolescents (6 to 17 years) in: Studies 1 and 2: Fixed-dose Guanfacine Extended-Release Tablets Monotherapy Study 1 (301 study) was a double-blind, placebo-controlled, parallel-group, fixed-dose study, in which efficacy of once daily dosing with guanfacine extended-release tablets (2 mg, 3 mg and 4 mg) was evaluated for 5 weeks (n=345) in children and adolescents aged 6 to 17 years. Study 2 (304 study) was a double-blind, placebo-controlled, parallel-group, fixed-dose study, in which efficacy of once daily dosing with guanfacine extended-release tablets (1 mg, 2 mg, 3 mg and 4 mg) was evaluated for 6 weeks (n=324) in children and adolescents aged 6 to 17 years. In both studies, randomized patients in 2 mg, 3 mg and 4 mg dose groups were titrated to their target fixed dose, and continued on the same dose until a dose tapering phase started. The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. Patients who weighed less than 25 kg were not included in either study. Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week for which a valid score was obtained prior to dose tapering (up to Week 5 in Study 1 and up to Week 6 in Study 2). The mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for guanfacine extended-release tablets compared to placebo for Studies 1 and 2. Placebo-adjusted changes from baseline were statistically significant for each of the 2 mg, 3 mg, and 4 mg guanfacine extended-release tablets randomized treatment groups in both studies, as well as the 1 mg guanfacine extended-release tablets treatment group that was included only in Study 2 (see Table 16 ). Dose-responsive efficacy was evident, particularly when data were examined on a weight-adjusted (mg/kg) basis. When evaluated over the dose range of 0.01 to 0.17 mg/kg/day, clinically relevant improvements were observed beginning at doses in the range 0.05 to 0.08 mg/kg/day. Doses up to 0.12 mg/kg/day were shown to provide additional benefit. In the monotherapy trials (Studies 1 and 2), subgroup analyses were performed to identify any differences in response based on gender or age (6 to 12 vs. 13 to 17). Analyses of the primary outcome did not suggest any differential responsiveness on the basis of gender. Analyses by age revealed a statistically significant treatment effect only in the 6 to 12 age subgroup. Due to the relatively small proportion of adolescent patients (ages 13 to 17) enrolled into these studies (approximately 25%), these data may not have been sufficient to demonstrate efficacy in the adolescent patients. In these studies, patients were randomized to a fixed dose of guanfacine extended-release tablets rather than optimized by body weight. Therefore, some adolescent patients were randomized to a dose that might have resulted in relatively lower plasma guanfacine concentrations compared to the younger patients. Over half (55%) of the adolescent patients received doses of 0.01 to 0.04mg/kg. In studies in which systematic pharmacokinetic data were obtained, there was a strong inverse correlation between body weight and plasma guanfacine concentrations. Table 16: Fixed Dose Studies | | | | | | | --- | --- | --- | --- | --- | | SD:standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. a Difference (drug minus placebo) in least-squares mean change from baseline. \* Doses statistically significantly superior to placebo. ^ The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. | | | | | | | | | | | | --- | --- | --- | --- | --- | | Study Number * (Age Range) | Treatment Group | Primary Efficacy Measure: ADHD-RS-IV Total Score | | | | Mean Baseline Score (SD) | LS Mean Change from Baseline (SE) | Placebo-subtracted Difference a (95% CI) | | Study 1 (6 to 17 years) | Guanfacine Extended-Release Tablets 2 mg\* | 36.1 (9.99) | -15.9 (1.37) | -7.4 (-11.3, -3.5) | | Guanfacine Extended-Release Tablets 3 mg\* | 36.8 (8.72) | -16.0 (1.38) | -7.5 (-11.4, -3.6) | | Guanfacine Extended-Release Tablets 4 mg\* | 38.4 (9.21) | -18.5 (1.39) | -10.0 (-13.9, -6.1) | | Placebo | 38.1 (9.34) | -8.5 (1.42) | -- | | Study 2 (6 to 17 years) | Guanfacine Extended-Release Tablets 1 mg\*^ | 41.7 (7.81) | -19.4 (1.69) | -6.8 (-11.3, -2.2) | | Guanfacine Extended-Release Tablets 2 mg\* | 39.9 (8.74) | -18.1 (1.60) | -5.4 (-9.9, -0.9) | | Guanfacine Extended-Release Tablets 3 mg\* | 39.1 (9.22) | -20.0 (1.64) | -7.3 (-11.8, -2.8) | | Guanfacine Extended-Release Tablets 4 mg\* | 40.6 (8.57) | -20.6 (1.60) | -7.9 (-12.3, -3.4) | | Placebo | 39.3 (8.85) | -12.7 (1.60) | -- | Study 3: Flexible-dose Guanfacine Extended-Release Tablets as Adjunctive Therapy to Psychostimulants Study 3 (313 study) was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily optimized dosing (morning or evening) with guanfacine extended-release tablets (1 mg, 2 mg, 3 mg and 4 mg), when co-administered with psychostimulants, was evaluated for 8 weeks, in children and adolescents aged 6 to 17 years with a diagnosis of ADHD, with a sub-optimal response to stimulants (n=455). Patients were started at the 1 mg guanfacine extended-release tablets dose level and were titrated weekly over a 5-week dose-optimization period to an optimal guanfacine extended-release tablets dose not to exceed 4 mg/day based on tolerability and clinical response. The dose was then maintained for a 3-week dose maintenance period before entry to 1 week of dose tapering. Patients took guanfacine extended-release tablets either in the morning or the evening while maintaining their current dose of psychostimulant treatment given each morning. Allowable psychostimulants in the study were ADDERALL XR ® , VYVANSE ® , CONCERTA ® , FOCALIN XR ® , RITALIN LA ® , METADATE CD ® or FDA-approved generic equivalents. Symptoms of ADHD were evaluated on a weekly basis by clinicians using the ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week prior to dose tapering for which a valid score was obtained (up to Week 8). Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for guanfacine extended-release tablets given in combination with a psychostimulant compared to placebo given with a psychostimulant for Study 3, for both morning and evening guanfacine extended-release tablets dosing (see Table 17 ). Nearly two-thirds (64.2%) of patients reached optimal doses in the 0.05 to 0.12 mg/kg/day range. Studies 4, 5 and 6: Flexible-dose Guanfacine Extended-Release Tablets Monotherapy Study 4 (314 study) was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily dosing (morning or evening) with guanfacine extended-release tablets (1mg, 2mg, 3mg, and 4mg) was evaluated for 8 weeks in children aged 6 to 12 years (n=340). Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline score at endpoint on the ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week for which a valid score was obtained prior to dose tapering (up to Week 8). Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for guanfacine extended-release tablets compared to placebo in both AM and PM dosing groups of guanfacine extended-release tablets (see Table 17 ). Study 5 (312 study) was a 15-week, double-blind, randomized, placebo-controlled, dose-optimization study conducted in adolescents aged 13 to 17 years (n=314) to evaluate the efficacy and safety of guanfacine extended-release tablets (1 to 7 mg/day; optimized dose range of 0.05 to 0.12 mg/kg/day) in the treatment of ADHD as measured by the ADHD Rating Scale-IV (ADHD-RS-IV). Patients receiving guanfacine extended-release tablets showed statistically significantly greater improvement on the ADHD-RS-IV total score compared with patients receiving placebo (see Table 17 ). Study 6 (316 study) was a 12-week (for children aged 6 to 12) or 15-week (for adolescents aged 13 to 17), randomized, double-blind, parallel-group, placebo- and active-reference, dose-optimization study conducted in pediatric patients (children and adolescents aged 6 to 17 years old inclusive) (n=337) to assess the efficacy and safety of once-daily dosing (children: 1 to 4 mg/day, adolescents: 1 to 7 mg/day; optimized dose range of 0.05 to 0.12 mg/kg/day) in the treatment of ADHD. Guanfacine extended-release tablets were statistically superior to placebo on symptoms of ADHD in patients 6 to 17 years as measured by change from baseline in ADHD-RS-IV total scores (see Table 17 ). Table 17: Flexible-Dose Studies | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | SD:standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. a Treatment was given in combination with a psychostimulant. b Difference (drug minus placebo) in least-squares mean change from baseline. \* Doses statistically significantly superior to placebo. | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | | Study Number * (Age Range) | Treatment Group | Primary Efficacy Measure: ADHD-RS-IV Total Score | | | | Mean Baseline Score (SD) | LS Mean Change from Baseline (SE) | Placebo-subtracted Difference b (95% CI) | | * Study 3 a (6 to 17 years) | Guanfacine Extended-Release Tablets 1 to 4 mg AM\* | 37.6 (8.13) | -20.3 (0.97) | -4.5 (-7.5, -1.4) | | Guanfacine Extended-Release Tablets 1 to 4 mg PM\* | 37.0 (7.65) | -21.2 (0.97) | -5.3 (-8.3, -2.3) | | Placebo | 37.7 (7.75) | -15.9 (0.96) | -- | | Study 4 (6 to 12 years) | Guanfacine Extended-Release Tablets 1 to 4 mg AM\* | 41.7 (6.39) | -20.0 (1.23) | -9.4 (-12.8, -6.0) | | Guanfacine Extended-Release Tablets 1 to 4 mg PM\* | 41.6 (6.66) | -20.4 (1.19) | -9.8 (-13.1, -6.4) | | Placebo | 42.9 (6.29) | -10.6 (1.20) | -- | | Study 5 (13 to 17 years) | Guanfacine Extended-Release Tablets 1 to 7 mg\* | 39.9 (5.57) | -24.6 (1.06) | -6.03 (-8.87, -3.19) | | Placebo | 40.0 (6.11) | -18.5 (1.08) | -- | | Study 6 (6 to 17 years) | Guanfacine Extended-Release Tablets 1 to 7 mg\* | 43.1 (5.47) | -23.89 (1.15) | -8.88 (-11.94, -5.81) | | Placebo | 43.2 (5.60) | -15.01 (1.16) | -- | Study 7: Long-Term Maintenance of Guanfacine Extended-Release Tablets Efficacy Study 7 (315 study) was a double-blind, placebo-controlled, randomized withdrawal trial in pediatric patients aged 6 to 17 years with DSM-IV-TR diagnosis of ADHD. The study consisted of an open-label phase, including a 7-week dose optimization period to titrate patients to an optimal dose (maximum 4 mg/day for children and 7 mg/day for adolescents; optimized dose range: 0.05 to 0.12 mg/kg/day) and a 6-week dose maintenance period. There were 526 patients included in the open-label phase. Among those, 315 patients who met response criteria in the open-label phase were then randomized (1:1, guanfacine extended-release tablets:placebo) in a 26-week, double-blind, randomized withdrawal phase. The response criteria were defined by ≥ 30% reduction in ADHD-RS-IV total score and a Clinical Global Impression-Improvement (CGI-I) score of 1 or 2 during the open-label phase. A statistically significantly lower proportion of treatment failures occurred among guanfacine extended-release tablets patients compared to placebo at the end of the randomized withdrawal period (Figure 4). Treatment failure was defined as a ≥ 50% increase (worsening) in ADHD-RS-IV total score and a ≥ 2-point increase in Clinical Global Impression-Severity (CGI-S) score. Patients who met the treatment failure criteria on two consecutive visits or discontinued for any reason were classified as treatment failure. Figure 4. Kaplan-Meier Estimation of Proportion of Patients with Treatment Failure for Children and Adolescents Ages 6 to 17 (Study 7)  Guanfacine extended-release tablets, USP are supplied in 1 mg, 2 mg, 3 mg, and 4 mg strength extended-release tablets in 100 count and 1,000 count bottles. | | | | | | | --- | --- | --- | --- | --- | | | 1 mg | 2 mg | 3 mg | 4 mg | | Color | White | White | Blue | Blue | | Shape | Round | Caplet | Round | Caplet | | Debossment (top/bottom) | A533/ 1 mg | A534/ 2 mg | A536/ 3 mg | A538/ 4 mg | | NDC number | 100 count: 24979-533-01 | 100 count: 24979-534-01 | 100 count: 24979-536-01 | 100 count: 24979-538-01 | | 1,000 count: 24979-533-10 | 1,000 count: 24979-534-10 | 1,000 count: 24979-536-10 | 1,000 count: 24979-538-10 | Storage - Store at 20° to 25°C (68° to 77°F). [see USP Controlled Room Temperature]. Advise the patient to read theFDA-approved patient labeling (Patient Information). Dosing and Administration Instruct patients to swallow guanfacine extended-release tablets whole with water, milk or other liquid. Tablets should not be crushed, chewed or broken prior to administration because this may increase the rate of release of the active drug. Patients should not take guanfacine extended-release tablets together with a high-fat meal, since this can raise blood levels of guanfacine extended-release tablets. Instruct the parent or caregiver to supervise the child or adolescent taking guanfacine extended-release tablets and to keep the bottle of tablets out of reach of children. Advise patients not to abruptly discontinue guanfacine extended-release tablets as abrupt discontinuation can result in clinically significant rebound hypertension. Concomitant stimulant use and abrupt discontinuation of guanfacine extended-release tablets may increase this hypertensive response. Instruct patients on how to properly taper the dose to minimize the risk of rebound hypertension [see Dosage and Administration ([2.5](#Af812b528-c251-402e-b20f-338bd99a6775)) and Warnings and Precautions ([5.4](#L69c5a197-23f6-4c9c-97d3-2d40adc6bd22))] . Adverse Reactions Advise patients that sedation can occur, particularly early in treatment or with dose increases. Caution against operating heavy equipment or driving until they know how they respond to treatment with guanfacine extended-release tablets [see Warnings and Precautions ([5.2](#A08aac979-945c-4163-b87f-a1c00e31914d))] . Headache and abdominal pain can also occur. If any of these symptoms persist, or other symptoms occur, the patient should be advised to discuss the symptoms with the health care provider. Advise patients to avoid becoming dehydrated or overheated, which may potentially increase the risks of hypotension and syncope [see Warnings and Precautions ([5.1](#A41d81d22-f337-4e64-bd65-58318155fd4d))] . Advise patients to avoid use with alcohol. Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to guanfacine extended-release tablets during pregnancy [see Use in Specific Populations (8.1)]. Lactation Advise breastfeeding mothers to monitor infants exposed to guanfacine through breastmilk for sedation, lethargy and poor feeding [see Use in Specific Populations (8.2)]. All trademarks are property of their respective owners. Distributed by UPSHER-SMITH LABORATORIES, LLC Maple Grove, MN 55369 Made in Taiwan LA-3040-04 Guanfacine (gwahn-fa-seen) Extended-Release Tablets, USP Read the Patient Information that comes with guanfacine extended-release tablets before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment. What are guanfacine extended-release tablets? Guanfacine extended-release tablets are prescription medicine used to treat the symptoms of attention deficit hyperactivity disorder (ADHD). Guanfacine extended-release tablets may be used alone or with ADHD stimulant medicines. Guanfacine extended-release tablets are not central nervous system (CNS) stimulant. It is not known if guanfacine extended-release tablets are safe and effective in children younger than 6 years of age. Who should not take guanfacine extended-release tablets? Do not take guanfacine extended-release tablets if you are allergic to guanfacine or any of the ingredients in guanfacine extended-release tablets. See the end of this leaflet for a complete list of ingredients in guanfacine extended-release tablets. What should I tell my doctor before taking guanfacine extended-release tablets? Before you take guanfacine extended-release tablets, tell your doctor if you: Tell your doctor about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Guanfacine extended-release tablets may affect the way other medicines work, and other medicines may affect how guanfacine extended-release tablets work. Especially tell your doctor if you take: Ask your doctor or pharmacist for a list of these medicines, if you are not sure. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine. How should I take guanfacine extended-release tablets? What should I avoid while taking guanfacine extended-release tablets? What are the possible side effects of guanfacine extended-release tablets? Guanfacine extended-release tablets may cause serious side effects including: Get medical help right away, if you have any of the symptoms listed above. The most common side effects of guanfacine extended-release tablets include: Tell the doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of guanfacine extended-release tablets. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to Upsher-Smith Laboratories, LLC at 1-855-899-9180 or FDA at 1-800-FDA-1088 or www. fda.gov/medwatch. How should I store guanfacine extended-release tablets? Keep guanfacine extended-release tablets and all medicines out of the reach of children. General Information about the safe and effective use guanfacine extended-release tablets Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use guanfacine extended-release tablets for a condition for which it was not prescribed. Do not give guanfacine extended-release tablets to other people, even if they have the same symptoms that you have. It may harm them. This leaflet summarizes the most important information about guanfacine extended-release tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about guanfacine extended-release tablets that is written for health professionals. What are the ingredients in guanfacine extended-release tablets? Active ingredient: guanfacine hydrochloride Inactive ingredients: microcrystalline cellulose, hypromellose, polyvinyl acetate, povidone, lactose monohydrate, magnesium stearate, sodium lauryl sulfate and silica. In addition, the 3 mg and 4 mg tablets also contain FD&C Blue #1. This Patient Information has been approved by the U.S. Food and Drug Administration. All other trademarks are the property of their respective owners. Distributed by UPSHER-SMITH LABORATORIES, LLC Maple Grove, MN 55369 Made in Taiwan Revised: 02/2025 LA-3040-04 NDC 24979-533-01 Guanfacine Extended-Release Tablets 1 mg 100-count   NDC 24979-534-01 Guanfacine Extended-Release Tablets 2 mg 100-count  NDC 24979-536-01 Guanfacine Extended-Release Tablets 3 mg 100-count  NDC 24979-538-01 Guanfacine Extended-Release Tablets 4 mg 100-count  | | | --- | | **GUANFACINE   EXTENDED-RELEASE** guanfacine tablet, extended release | | | | | | | | --- | --- | --- | --- | | Product Information | | | | | Product Type | HUMAN PRESCRIPTION DRUG | Item Code (Source) | NDC:24979-533 | | Route of Administration | ORAL | | | | | | | | --- | --- | --- | | Active Ingredient/Active Moiety | | | | Ingredient Name | Basis of Strength | Strength | | **GUANFACINE** (UNII: 30OMY4G3MK) (GUANFACINE - UNII:30OMY4G3MK) | GUANFACINE | 1 mg | | | | | | | --- | --- | | Inactive Ingredients | | | Ingredient Name | Strength | | **HYPROMELLOSES** (UNII: 3NXW29V3WO) | | | **POLYVINYL ACETATE PHTHALATE** (UNII: 58QVG85GW3) | | | **POVIDONE K12** (UNII: 333AG72FWJ) | | | **SODIUM LAURYL SULFATE** (UNII: 368GB5141J) | | | **SILICON DIOXIDE** (UNII: ETJ7Z6XBU4) | | | **LACTOSE MONOHYDRATE** (UNII: EWQ57Q8I5X) | | | **MAGNESIUM STEARATE** (UNII: 70097M6I30) | | | **CELLULOSE, MICROCRYSTALLINE** (UNII: OP1R32D61U) | | | | | | | | | | --- | --- | --- | --- | | Product Characteristics | | | | | Color | WHITE | Score | no score | | Shape | ROUND | Size | 8mm | | Flavor | | Imprint Code | A533;1;mg | | Contains | | | | | | | | | | | --- | --- | --- | --- | --- | | Packaging | | | | | | # | Item Code | Package Description | Marketing Start Date | Marketing End Date | | 1 | NDC:24979-533-01 | 100 in 1 BOTTLE; Type 0: Not a Combination Product | 07/07/2017 | | | 2 | NDC:24979-533-10 | 1000 in 1 BOTTLE; Type 0: Not a Combination Product | 07/07/2017 | | | 3 | NDC:24979-533-00 | 100000 in 1 DRUM; Type 0: Not a Combination Product | 07/01/2024 | | | | | | | | | | | | --- | --- | --- | --- | | Marketing Information | | | | | Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date | | ANDA | ANDA201408 | 07/07/2017 | | | | | | | | | --- | --- | --- | --- | | Product Information | | | | | Product Type | HUMAN PRESCRIPTION DRUG | Item Code (Source) | NDC:24979-533 | | Route of Administration | ORAL | | | | | | --- | --- | --- | | Active Ingredient/Active Moiety | | | | Ingredient Name | Basis of Strength | Strength | | **GUANFACINE** (UNII: 30OMY4G3MK) (GUANFACINE - UNII:30OMY4G3MK) | GUANFACINE | 1 mg | | | | | --- | --- | | Inactive Ingredients | | | Ingredient Name | Strength | | **HYPROMELLOSES** (UNII: 3NXW29V3WO) | | | **POLYVINYL ACETATE PHTHALATE** (UNII: 58QVG85GW3) | | | **POVIDONE K12** (UNII: 333AG72FWJ) | | | **SODIUM LAURYL SULFATE** (UNII: 368GB5141J) | | | **SILICON DIOXIDE** (UNII: ETJ7Z6XBU4) | | | **LACTOSE MONOHYDRATE** (UNII: EWQ57Q8I5X) | | | **MAGNESIUM STEARATE** (UNII: 70097M6I30) | | | **CELLULOSE, MICROCRYSTALLINE** (UNII: OP1R32D61U) | | | | | | | | --- | --- | --- | --- | | Product Characteristics | | | | | Color | WHITE | Score | no score | | Shape | ROUND | Size | 8mm | | Flavor | | Imprint Code | A533;1;mg | | Contains | | | | | | | | | --- | --- | --- | --- | --- | | Packaging | | | | | | # | Item Code | Package Description | Marketing Start Date | Marketing End Date | | 1 | NDC:24979-533-01 | 100 in 1 BOTTLE; Type 0: Not a Combination Product | 07/07/2017 | | | 2 | NDC:24979-533-10 | 1000 in 1 BOTTLE; Type 0: Not a Combination Product | 07/07/2017 | | | 3 | NDC:24979-533-00 | 100000 in 1 DRUM; Type 0: Not a Combination Product | 07/01/2024 | | | | | | | | --- | --- | --- | --- | | Marketing Information | | | | | Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date | | ANDA | ANDA201408 | 07/07/2017 | | | | | --- | | **GUANFACINE   EXTENDED-RELEASE** guanfacine tablet, extended release | | | | | | | | --- | --- | --- | --- | | Product Information | | | | | Product Type | HUMAN PRESCRIPTION DRUG | Item Code (Source) | NDC:24979-534 | | Route of Administration | ORAL | | | | | | | | --- | --- | --- | | Active Ingredient/Active Moiety | | | | Ingredient Name | Basis of Strength | Strength | | **GUANFACINE** (UNII: 30OMY4G3MK) (GUANFACINE - UNII:30OMY4G3MK) | GUANFACINE | 2 mg | | | | | | | --- | --- | | Inactive Ingredients | | | Ingredient Name | Strength | | **HYPROMELLOSES** (UNII: 3NXW29V3WO) | | | **POLYVINYL ACETATE PHTHALATE** (UNII: 58QVG85GW3) | | | **POVIDONE K12** (UNII: 333AG72FWJ) | | | **SODIUM LAURYL SULFATE** (UNII: 368GB5141J) | | | **SILICON DIOXIDE** (UNII: ETJ7Z6XBU4) | | | **LACTOSE MONOHYDRATE** (UNII: EWQ57Q8I5X) | | | **MAGNESIUM STEARATE** (UNII: 70097M6I30) | | | **CELLULOSE, MICROCRYSTALLINE** (UNII: OP1R32D61U) | | | | | | | | | | --- | --- | --- | --- | | Product Characteristics | | | | | Color | WHITE | Score | no score | | Shape | OVAL | Size | 12mm | | Flavor | | Imprint Code | A534;2;mg | | Contains | | | | | | | | | | | --- | --- | --- | --- | --- | | Packaging | | | | | | # | Item Code | Package Description | Marketing Start Date | Marketing End Date | | 1 | NDC:24979-534-01 | 100 in 1 BOTTLE; Type 0: Not a Combination Product | 07/07/2017 | | | 2 | NDC:24979-534-10 | 1000 in 1 BOTTLE; Type 0: Not a Combination Product | 07/07/2017 | | | 3 | NDC:24979-534-00 | 100000 in 1 DRUM; Type 0: Not a Combination Product | 07/01/2024 | | | | | | | | | | | | --- | --- | --- | --- | | Marketing Information | | | | | Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date | | ANDA | ANDA201408 | 07/07/2017 | | | | | | | | | --- | --- | --- | --- | | Product Information | | | | | Product Type | HUMAN PRESCRIPTION DRUG | Item Code (Source) | NDC:24979-534 | | Route of Administration | ORAL | | | | | | --- | --- | --- | | Active Ingredient/Active Moiety | | | | Ingredient Name | Basis of Strength | Strength | | **GUANFACINE** (UNII: 30OMY4G3MK) (GUANFACINE - UNII:30OMY4G3MK) | GUANFACINE | 2 mg | | | | | --- | --- | | Inactive Ingredients | | | Ingredient Name | Strength | | **HYPROMELLOSES** (UNII: 3NXW29V3WO) | | | **POLYVINYL ACETATE PHTHALATE** (UNII: 58QVG85GW3) | | | **POVIDONE K12** (UNII: 333AG72FWJ) | | | **SODIUM LAURYL SULFATE** (UNII: 368GB5141J) | | | **SILICON DIOXIDE** (UNII: ETJ7Z6XBU4) | | | **LACTOSE MONOHYDRATE** (UNII: EWQ57Q8I5X) | | | **MAGNESIUM STEARATE** (UNII: 70097M6I30) | | | **CELLULOSE, MICROCRYSTALLINE** (UNII: OP1R32D61U) | | | | | | | | --- | --- | --- | --- | | Product Characteristics | | | | | Color | WHITE | Score | no score | | Shape | OVAL | Size | 12mm | | Flavor | | Imprint Code | A534;2;mg | | Contains | | | | | | | | | --- | --- | --- | --- | --- | | Packaging | | | | | | # | Item Code | Package Description | Marketing Start Date | Marketing End Date | | 1 | NDC:24979-534-01 | 100 in 1 BOTTLE; Type 0: Not a Combination Product | 07/07/2017 | | | 2 | NDC:24979-534-10 | 1000 in 1 BOTTLE; Type 0: Not a Combination Product | 07/07/2017 | | | 3 | NDC:24979-534-00 | 100000 in 1 DRUM; Type 0: Not a Combination Product | 07/01/2024 | | | | | | | | --- | --- | --- | --- | | Marketing Information | | | | | Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date | | ANDA | ANDA201408 | 07/07/2017 | | | | | --- | | **GUANFACINE   EXTENDED-RELEASE** guanfacine tablet, extended release | | | | | | | | --- | --- | --- | --- | | Product Information | | | | | Product Type | HUMAN PRESCRIPTION DRUG | Item Code (Source) | NDC:24979-536 | | Route of Administration | ORAL | | | | | | | | --- | --- | --- | | Active Ingredient/Active Moiety | | | | Ingredient Name | Basis of Strength | Strength | | **GUANFACINE** (UNII: 30OMY4G3MK) (GUANFACINE - UNII:30OMY4G3MK) | GUANFACINE | 3 mg | | | | | | | --- | --- | | Inactive Ingredients | | | Ingredient Name | Strength | | **FD&C BLUE NO. 1** (UNII: H3R47K3TBD) | | | **HYPROMELLOSES** (UNII: 3NXW29V3WO) | | | **POLYVINYL ACETATE PHTHALATE** (UNII: 58QVG85GW3) | | | **POVIDONE K12** (UNII: 333AG72FWJ) | | | **SODIUM LAURYL SULFATE** (UNII: 368GB5141J) | | | **SILICON DIOXIDE** (UNII: ETJ7Z6XBU4) | | | **LACTOSE MONOHYDRATE** (UNII: EWQ57Q8I5X) | | | **MAGNESIUM STEARATE** (UNII: 70097M6I30) | | | **CELLULOSE, MICROCRYSTALLINE** (UNII: OP1R32D61U) | | | | | | | | | | --- | --- | --- | --- | | Product Characteristics | | | | | Color | BLUE | Score | no score | | Shape | ROUND | Size | 8mm | | Flavor | | Imprint Code | A536;3;mg | | Contains | | | | | | | | | | | --- | --- | --- | --- | --- | | Packaging | | | | | | # | Item Code | Package Description | Marketing Start Date | Marketing End Date | | 1 | NDC:24979-536-01 | 100 in 1 BOTTLE; Type 0: Not a Combination Product | 07/07/2017 | | | 2 | NDC:24979-536-10 | 1000 in 1 BOTTLE; Type 0: Not a Combination Product | 07/07/2017 | | | 3 | NDC:24979-536-00 | 100000 in 1 DRUM; Type 0: Not a Combination Product | 07/01/2024 | | | | | | | | | | | | --- | --- | --- | --- | | Marketing Information | | | | | Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date | | ANDA | ANDA201408 | 07/07/2017 | | | | | | | | | --- | --- | --- | --- | | Product Information | | | | | Product Type | HUMAN PRESCRIPTION DRUG | Item Code (Source) | NDC:24979-536 | | Route of Administration | ORAL | | | | | | --- | --- | --- | | Active Ingredient/Active Moiety | | | | Ingredient Name | Basis of Strength | Strength | | **GUANFACINE** (UNII: 30OMY4G3MK) (GUANFACINE - UNII:30OMY4G3MK) | GUANFACINE | 3 mg | | | | | --- | --- | | Inactive Ingredients | | | Ingredient Name | Strength | | **FD&C BLUE NO. 1** (UNII: H3R47K3TBD) | | | **HYPROMELLOSES** (UNII: 3NXW29V3WO) | | | **POLYVINYL ACETATE PHTHALATE** (UNII: 58QVG85GW3) | | | **POVIDONE K12** (UNII: 333AG72FWJ) | | | **SODIUM LAURYL SULFATE** (UNII: 368GB5141J) | | | **SILICON DIOXIDE** (UNII: ETJ7Z6XBU4) | | | **LACTOSE MONOHYDRATE** (UNII: EWQ57Q8I5X) | | | **MAGNESIUM STEARATE** (UNII: 70097M6I30) | | | **CELLULOSE, MICROCRYSTALLINE** (UNII: OP1R32D61U) | | | | | | | | --- | --- | --- | --- | | Product Characteristics | | | | | Color | BLUE | Score | no score | | Shape | ROUND | Size | 8mm | | Flavor | | Imprint Code | A536;3;mg | | Contains | | | | | | | | | --- | --- | --- | --- | --- | | Packaging | | | | | | # | Item Code | Package Description | Marketing Start Date | Marketing End Date | | 1 | NDC:24979-536-01 | 100 in 1 BOTTLE; Type 0: Not a Combination Product | 07/07/2017 | | | 2 | NDC:24979-536-10 | 1000 in 1 BOTTLE; Type 0: Not a Combination Product | 07/07/2017 | | | 3 | NDC:24979-536-00 | 100000 in 1 DRUM; Type 0: Not a Combination Product | 07/01/2024 | | | | | | | | --- | --- | --- | --- | | Marketing Information | | | | | Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date | | ANDA | ANDA201408 | 07/07/2017 | | | | | --- | | **GUANFACINE   EXTENDED-RELEASE** guanfacine tablet, extended release | | | | | | | | --- | --- | --- | --- | | Product Information | | | | | Product Type | HUMAN PRESCRIPTION DRUG | Item Code (Source) | NDC:24979-538 | | Route of Administration | ORAL | | | | | | | | --- | --- | --- | | Active Ingredient/Active Moiety | | | | Ingredient Name | Basis of Strength | Strength | | **GUANFACINE** (UNII: 30OMY4G3MK) (GUANFACINE - UNII:30OMY4G3MK) | GUANFACINE | 4 mg | | | | | | | --- | --- | | Inactive Ingredients | | | Ingredient Name | Strength | | **FD&C BLUE NO. 1** (UNII: H3R47K3TBD) | | | **HYPROMELLOSES** (UNII: 3NXW29V3WO) | | | **POLYVINYL ACETATE PHTHALATE** (UNII: 58QVG85GW3) | | | **POVIDONE K12** (UNII: 333AG72FWJ) | | | **SODIUM LAURYL SULFATE** (UNII: 368GB5141J) | | | **SILICON DIOXIDE** (UNII: ETJ7Z6XBU4) | | | **LACTOSE MONOHYDRATE** (UNII: EWQ57Q8I5X) | | | **MAGNESIUM STEARATE** (UNII: 70097M6I30) | | | **CELLULOSE, MICROCRYSTALLINE** (UNII: OP1R32D61U) | | | | | | | | | | --- | --- | --- | --- | | Product Characteristics | | | | | Color | BLUE | Score | no score | | Shape | OVAL | Size | 12mm | | Flavor | | Imprint Code | A538;4;mg | | Contains | | | | | | | | | | | --- | --- | --- | --- | --- | | Packaging | | | | | | # | Item Code | Package Description | Marketing Start Date | Marketing End Date | | 1 | NDC:24979-538-01 | 100 in 1 BOTTLE; Type 0: Not a Combination Product | 07/07/2017 | | | 2 | NDC:24979-538-10 | 1000 in 1 BOTTLE; Type 0: Not a Combination Product | 07/07/2017 | | | 3 | NDC:24979-538-00 | 100000 in 1 DRUM; Type 0: Not a Combination Product | 07/01/2024 | | | | | | | | | | | | --- | --- | --- | --- | | Marketing Information | | | | | Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date | | ANDA | ANDA201408 | 07/07/2017 | | | | | | | | | --- | --- | --- | --- | | Product Information | | | | | Product Type | HUMAN PRESCRIPTION DRUG | Item Code (Source) | NDC:24979-538 | | Route of Administration | ORAL | | | | | | --- | --- | --- | | Active Ingredient/Active Moiety | | | | Ingredient Name | Basis of Strength | Strength | | **GUANFACINE** (UNII: 30OMY4G3MK) (GUANFACINE - UNII:30OMY4G3MK) | GUANFACINE | 4 mg | | | | | --- | --- | | Inactive Ingredients | | | Ingredient Name | Strength | | **FD&C BLUE NO. 1** (UNII: H3R47K3TBD) | | | **HYPROMELLOSES** (UNII: 3NXW29V3WO) | | | **POLYVINYL ACETATE PHTHALATE** (UNII: 58QVG85GW3) | | | **POVIDONE K12** (UNII: 333AG72FWJ) | | | **SODIUM LAURYL SULFATE** (UNII: 368GB5141J) | | | **SILICON DIOXIDE** (UNII: ETJ7Z6XBU4) | | | **LACTOSE MONOHYDRATE** (UNII: EWQ57Q8I5X) | | | **MAGNESIUM STEARATE** (UNII: 70097M6I30) | | | **CELLULOSE, MICROCRYSTALLINE** (UNII: OP1R32D61U) | | | | | | | | --- | --- | --- | --- | | Product Characteristics | | | | | Color | BLUE | Score | no score | | Shape | OVAL | Size | 12mm | | Flavor | | Imprint Code | A538;4;mg | | Contains | | | | | | | | | --- | --- | --- | --- | --- | | Packaging | | | | | | # | Item Code | Package Description | Marketing Start Date | Marketing End Date | | 1 | NDC:24979-538-01 | 100 in 1 BOTTLE; Type 0: Not a Combination Product | 07/07/2017 | | | 2 | NDC:24979-538-10 | 1000 in 1 BOTTLE; Type 0: Not a Combination Product | 07/07/2017 | | | 3 | NDC:24979-538-00 | 100000 in 1 DRUM; Type 0: Not a Combination Product | 07/01/2024 | | | | | | | | --- | --- | --- | --- | | Marketing Information | | | | | Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date | | ANDA | ANDA201408 | 07/07/2017 | | | | | | | | --- | --- | --- | --- | | Labeler - Upsher-Smith Laboratories, LLC (047251004) | | | | | | | | | | --- | --- | --- | --- | | Registrant - TWi Pharmaceuticals, Inc. (658402052) | | | | | | | | | | --- | --- | --- | --- | | Establishment | | | | | Name | Address | ID/FEI | Business Operations | | Bora Pharmaceutical Laboratories Inc. Zhongli Plant | | 658863394 | ANALYSIS(24979-533, 24979-534, 24979-536, 24979-538) , MANUFACTURE(24979-533, 24979-534, 24979-536, 24979-538) | | | | | | | --- | --- | --- | --- | | Establishment | | | | | Name | Address | ID/FEI | Business Operations | | Apace KY, LLC. | | 361961142 | PACK(24979-533, 24979-534, 24979-536, 24979-538) | | | | | | | --- | --- | --- | --- | | Establishment | | | | | Name | Address | ID/FEI | Business Operations | | Bora Pharmaceutical Laboratories Inc. | | 656139511 | pack(24979-533, 24979-534, 24979-536, 24979-538) | ## Find additional resources ### Safety [Report Adverse Events](//www.accessdata.fda.gov/scripts/medwatch/ ), [FDA Safety Recalls](https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts), [Presence in Breast Milk](https://ncbi.nlm.nih.gov/books/n/lactmed/LM631) ### Related Resources [Medline Plus](//vsearch.nlm.nih.gov/vivisimo/cgi-bin/query-meta?v:project=medlineplus&query=GUANFACINE), [Clinical Trials](//www.clinicaltrials.gov/ct/search?submit=Search&term=GUANFACINE), [PubMed](#pubmed-menu), [Biochemical Data Summary](https://www.drugbank.ca/search?utf8=%E2%9C%93&query=APRD00075&search_type=drugs&button=) ### More Info on this Drug [View Labeling Archives](#modal-label-archives), [RxNorm](#modal-rx-norm), [Get Label RSS Feed](#modal-label-rss), [View NDC Code(s)](#modal-codes) ## View Labeling Archives for this drug ### GUANFACINE EXTENDED-RELEASE- guanfacine tablet, extended release #### Number of versions: 15 | Published Date [(What is this?)](# "<b>Published Date</b> - The date that a drug label is published on DailyMed for public view. This is distinct from <b>Updated Date</b>*. <br><br> *<b>Updated Date</b> (also known as <b>Effective Time</b>) - The label revision date included in the SPL.") | Version | Files | | --- | --- | --- | | Oct 1, 2026 | 16 (current) | [download](/dailymed/getArchivalFile.cfm?archive_id=985655) | | Apr 30, 2025 | 15 | [download](/dailymed/getArchivalFile.cfm?archive_id=886953) | | Apr 10, 2025 | 14 | [download](/dailymed/getArchivalFile.cfm?archive_id=883549) | | Jan 9, 2025 | 13 | [download](/dailymed/getArchivalFile.cfm?archive_id=864753) | | Oct 7, 2024 | 11 | [download](/dailymed/getArchivalFile.cfm?archive_id=828375) | | Sep 10, 2024 | 10 | [download](/dailymed/getArchivalFile.cfm?archive_id=821658) | | Jul 2, 2024 | 9 | [download](/dailymed/getArchivalFile.cfm?archive_id=807346) | | Apr 11, 2024 | 8 | [download](/dailymed/getArchivalFile.cfm?archive_id=793390) | | Dec 4, 2023 | 7 | [download](/dailymed/getArchivalFile.cfm?archive_id=760447) | | Feb 6, 2023 | 6 | [download](/dailymed/getArchivalFile.cfm?archive_id=703561) | | Apr 7, 2020 | 5 | [download](/dailymed/getArchivalFile.cfm?archive_id=477628) | | Jul 30, 2019 | 4 | [download](/dailymed/getArchivalFile.cfm?archive_id=414072) | | Aug 31, 2018 | 3 | [download](/dailymed/getArchivalFile.cfm?archive_id=339884) | | Dec 20, 2017 | 2 | [download](/dailymed/getArchivalFile.cfm?archive_id=297694) | | Jul 7, 2017 | 1 | [download](/dailymed/getArchivalFile.cfm?archive_id=269274) | ## RxNorm ### GUANFACINE EXTENDED-RELEASE- guanfacine tablet, extended release | | RxCUI | RxNorm NAME | RxTTY | | --- | --- | --- | --- | | 1 | [862006](/dailymed/search.cfm?searchdb=rxcui&query=862006) | guanFACINE 1 MG 24HR Extended Release Oral Tablet | PSN | | 2 | [862006](/dailymed/search.cfm?searchdb=rxcui&query=862006) | 24 HR guanfacine 1 MG Extended Release Oral Tablet | SCD | | 3 | [862006](/dailymed/search.cfm?searchdb=rxcui&query=862006) | guanfacine 1 MG (as guanfacine hydrochloride 1.14 MG) 24 HR Extended Release Oral Tablet | SY | | 4 | [862006](/dailymed/search.cfm?searchdb=rxcui&query=862006) | guanfacine 1 MG (as guanfacine hydrochloride 1.15 MG) 24 HR Extended Release Oral Tablet | SY | | 5 | [862013](/dailymed/search.cfm?searchdb=rxcui&query=862013) | guanFACINE 2 MG 24HR Extended Release Oral Tablet | PSN | | 6 | [862013](/dailymed/search.cfm?searchdb=rxcui&query=862013) | 24 HR guanfacine 2 MG Extended Release Oral Tablet | SCD | | 7 | [862013](/dailymed/search.cfm?searchdb=rxcui&query=862013) | guanfacine 2 MG (as guanfacine hydrochloride 2.28 MG) 24 HR Extended Release Oral Tablet | SY | | 8 | [862013](/dailymed/search.cfm?searchdb=rxcui&query=862013) | guanfacine 2 MG (as guanfacine hydrochloride 2.3 MG) 24 HR Extended Release Oral Tablet | SY | | 9 | [862019](/dailymed/search.cfm?searchdb=rxcui&query=862019) | guanFACINE 3 MG 24HR Extended Release Oral Tablet | PSN | | 10 | [862019](/dailymed/search.cfm?searchdb=rxcui&query=862019) | 24 HR guanfacine 3 MG Extended Release Oral Tablet | SCD | | 11 | [862019](/dailymed/search.cfm?searchdb=rxcui&query=862019) | guanfacine 3 MG (as guanfacine hydrochloride 3.42 MG) 24 HR Extended Release Oral Tablet | SY | | 12 | [862019](/dailymed/search.cfm?searchdb=rxcui&query=862019) | guanfacine 3 MG (as guanfacine hydrochloride 3.45 MG) 24 HR Extended Release Oral Tablet | SY | | 13 | [862025](/dailymed/search.cfm?searchdb=rxcui&query=862025) | guanFACINE 4 MG 24HR Extended Release Oral Tablet | PSN | | 14 | [862025](/dailymed/search.cfm?searchdb=rxcui&query=862025) | 24 HR guanfacine 4 MG Extended Release Oral Tablet | SCD | | 15 | [862025](/dailymed/search.cfm?searchdb=rxcui&query=862025) | guanfacine 4 MG (as guanfacine hydrochloride 4.56 MG) 24 HR Extended Release Oral Tablet | SY | | 16 | [862025](/dailymed/search.cfm?searchdb=rxcui&query=862025) | guanfacine 4 MG (as guanfacine hydrochloride 4.6 MG) 24 HR Extended Release Oral Tablet | SY | ## Get Label RSS Feed for this Drug ### GUANFACINE EXTENDED-RELEASE- guanfacine tablet, extended release #### To receive this label RSS feed Copy the URL below and paste it into your RSS Reader application. [https://dailymed.nlm.nih.gov/dailymed/labelrss.cfm?setid=07a701e2-39b7-4bb1-a7c7-d9baed4ab18a](/dailymed/labelrss.cfm?setid=07a701e2-39b7-4bb1-a7c7-d9baed4ab18a) #### To receive all DailyMed Updates for the last seven days Copy the URL below and paste it into your RSS Reader application. [https://dailymed.nlm.nih.gov/dailymed/rss.cfm](/dailymed/rss.cfm) #### What will I get with the DailyMed RSS feed? DailyMed will deliver notification of updates and additions to Drug Label information currently shown on this site through its RSS feed. DailyMed will deliver this notification to your desktop, Web browser, or e-mail depending on the RSS Reader you select to use. To view updated drug label links, paste the RSS feed address (URL) shown below into a RSS reader, or use a browser which supports RSS feeds, such as Safari for Mac OS X. #### How to discontinue the RSS feed If you no longer wish to have this DailyMed RSS service, simply delete the copied URL from your RSS Reader. [More about getting RSS News & Updates from DailyMed](/dailymed/rss-updates.cfm) [https://dailymed.nlm.nih.gov/dailymed/labelrss.cfm?setid=07a701e2-39b7-4bb1-a7c7-d9baed4ab18a](/dailymed/labelrss.cfm?setid=07a701e2-39b7-4bb1-a7c7-d9baed4ab18a) #### To receive all DailyMed Updates for the last seven days Copy the URL below and paste it into your RSS Reader application. [https://dailymed.nlm.nih.gov/dailymed/rss.cfm](/dailymed/rss.cfm) #### What will I get with the DailyMed RSS feed? DailyMed will deliver notification of updates and additions to Drug Label information currently shown on this site through its RSS feed. DailyMed will deliver this notification to your desktop, Web browser, or e-mail depending on the RSS Reader you select to use. To view updated drug label links, paste the RSS feed address (URL) shown below into a RSS reader, or use a browser which supports RSS feeds, such as Safari for Mac OS X. #### How to discontinue the RSS feed If you no longer wish to have this DailyMed RSS service, simply delete the copied URL from your RSS Reader. #### Why is DailyMed no longer displaying pill images on the Search Results and Drug Info pages? Due to inconsistencies between the drug labels on DailyMed and the pill images provided by [RxImage](https://rximage.nlm.nih.gov/docs/doku.php?id=rximageapi_support), we no longer display the RxImage pill images associated with drug labels. We anticipate reposting the images once we are able identify and filter out images that do not match the information provided in the drug labels. ## NDC Codes ### GUANFACINE EXTENDED-RELEASE- guanfacine tablet, extended release #### If this SPL contains inactivated NDCs listed by the FDA initiated compliance action, they will be specified as such. | | NDC | | --- | --- | | 1 | 24979-533-00 | | 2 | 24979-533-01 | | 3 | 24979-533-10 | | 4 | 24979-534-00 | | 5 | 24979-534-01 | | 6 | 24979-534-10 | | 7 | 24979-536-00 | | 8 | 24979-536-01 | | 9 | 24979-536-10 | | 10 | 24979-538-00 | | 11 | 24979-538-01 | | 12 | 24979-538-10 |   

                 ## Benefits icon Benefits  Review benefits covered under your plan, get cost estimates, and track medical expenses. ### Benefits & coverage ### Cost estimates ### Need help with benefits?    ## Get care icon Appointments & Care  Find the care you need, from 24/7 advice to on-demand or scheduled visits. ### Appointments ### Care options ### Doctors & locations ### Care while traveling ### Need help getting care?    ## Records Icon Records  Track test results and vaccines or review After Visit and health summaries. ### Frequently used records ### Other records ### Managing your records ### Need help with records & forms?    ## Pharmacy Icon Pharmacy  Conveniently order and manage medications for you and your family. ### Refilling medications ### Managing medications ### Need help with medications?    ## Billing icon Billing  Manage medical bills, payment options, cost estimates, and claims. ### Billing & payments ### Claims & costs ### Need help with billing?    ## Health & Wellness Icon Health & Wellness  Explore articles, opportunities, & tips for health conditions and staying fit. ### Ways to stay healthy ### Resource directories ### Topics of special interest ### Prevention       ## Appointments and Care icon Appointments & Care  Find the care you need, from 24/7 advice to on-demand or scheduled visits. ### Care options ### Messaging ### Doctors & locations ### Medical records    ## Pharmacy Icon Pharmacy  Conveniently order and manage medications for you and your family. ### Refilling medications ### Managing medications ### Need help with medications?    ## Health & Wellness Icon Health & Wellness  Explore articles, opportunities, & tips for health conditions and staying fit. ### Ways to stay healthy ### Resource directories ### Topics of special interest ### Prevention    ## Benefits Icon Benefits  Review benefits covered under your plan, get cost estimates, and track medical expenses. ### Benefits & coverage ### Cost estimates ### Need help with benefits?    ## Billing Icon Billing  Manage medical bills, payment options, cost estimates, and claims. ### Billing & payments ### Claims & costs ### Need help with billing? ### Additional resources    There's a chat in progress. # guanfacine ER 1 mg tablet,extended release 24 hr The photos shown are samples only Not all photos of the drug may be displayed. Your medication may look different. If you have questions, ask your pharmacist. close popup Generic name: Guanfacine extended-release - oral Pronunciation (GWAN-fuh-seen) Brand name(s) Intuniv This medication is used to treat attention deficit hyperactivity disorder (ADHD), as part of a total treatment plan including psychological, educational, and social measures. Unlike other drugs used to treat ADHD, guanfacine is not a stimulant. The exact way that guanfacine works to treat ADHD is unknown. Guanfacine is thought to affect receptors in the parts of the brain that lead to strengthening working memory, reducing distraction, and improving attention and impulse control. Guanfacine may help lessen ADHD symptoms such as being disruptive, inattentive, hyperactive, impulsive, and arguing with adults or losing one's temper. Read the Patient Information Leaflet if available from your pharmacist before you start using guanfacine and each time you get a refill. If you have any questions, ask your doctor or pharmacist. Take this medication by mouth as directed by your doctor, usually once daily in the morning or evening. Do not take this medication with a high-fat meal. Doing so may increase the amount of drug you absorb, leading to increased side effects. Swallow this medication whole. Do not crush, chew, or split tablets. Doing so can release all of the drug at once, increasing the risk of side effects. Do not switch between different forms of this medication without talking with your doctor, because different forms of this medication may not provide the same amount of guanfacine. Use this medication exactly as prescribed. The dosage is based on your medical condition, weight, response to treatment, and other medications you may be taking. Be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products). To reduce the risks of side effects (such as low blood pressure, slow heart rate, drowsiness), your doctor may start you at a low dose and gradually increase your dose. Follow your doctor's instructions carefully. Do not take more or less medication or take it more often than prescribed. Your condition will not improve any faster and your risks of side effects will increase. Use this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day. Do not stop taking this medication without consulting your doctor. Some conditions may become worse when this drug is suddenly stopped. Also, you may experience symptoms such as headache, nervousness, agitation, tremor, fast heartbeat, and high blood pressure. To prevent these symptoms while you are stopping treatment with this drug, your doctor may reduce your dose gradually. Ask your doctor or pharmacist for more details. Report any new or worsening symptoms right away. Tell your doctor if your condition lasts or gets worse. Drowsiness, dizziness, dry mouth, constipation, tiredness, nausea, headache, and stomach pain may occur. If any of these effects last or get worse, tell your doctor or pharmacist promptly. To reduce the risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position. To relieve dry mouth, suck on (sugarless) hard candy or ice chips, chew (sugarless) gum, drink water, or use a saliva substitute. Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects. Tell your doctor right away if you have any serious side effects, including: A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist. In the US - Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch. In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345. Before taking guanfacine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details. Before using this medication, tell your doctor or pharmacist your medical history, especially of: This drug may make you dizzy or drowsy. Alcohol or marijuana (cannabis) can make you more dizzy or drowsy. Do not drive, use machinery, or do anything that needs alertness until you can do it safely. Avoid alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis). To reduce the risk of dizziness and fainting, avoid becoming dehydrated or overheated during exercise, especially in hot weather. If dizziness occurs, sit or lie down. Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products). Children may be more sensitive to the side effects of this drug, especially hallucinations and mental/mood changes. Older adults may be more sensitive to the side effects of this drug, especially dizziness (more likely when standing up), drowsiness, slow heartbeat, or depression. Dizziness and drowsiness can increase the risk of falling. During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor. It is unknown if this medication passes into breast milk. Consult your doctor before breastfeeding. Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval. Tell your doctor or pharmacist if you are taking other products that cause drowsiness including alcohol, marijuana (cannabis), antihistamines (such as cetirizine, diphenhydramine), drugs for sleep or anxiety (such as alprazolam, diazepam, zolpidem), muscle relaxants (such as carisoprodol, cyclobenzaprine), and opioid pain relievers (such as codeine, hydrocodone). Check the labels on all your medicines (such as allergy or cough-and-cold products) because they may contain ingredients that cause drowsiness. Ask your pharmacist about using those products safely. If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call 1-800-222-1222. Canada residents can call 1-844-764-7669. Symptoms of overdose may include: severe drowsiness, severe dizziness, severe tiredness, very slow heartbeat, pinpoint pupils. Do not share this medication with others. Lab and/or medical tests (such as blood pressure, heart rate) should be done while you are taking this medication. Keep all medical and lab appointments. Consult your doctor for more details. If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up. If you miss more than 2 doses in a row, call your doctor to get a new dosing schedule. Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets. Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company. HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs. Information last revised May 2024. Copyright(c) 2026 First Databank, Inc. Selected from NATIONAL DRUG DATA FILE (NDDF) data included with permission and copyrighted by First Databank, Inc., 2019. This copyrighted material has been downloaded from a licensed data provider. The above information is intended to supplement, not substitute for, the expertise and judgment of your health care professional. You should consult your health care professional before taking any drug, changing your diet, or commencing or discontinuing any course of treatment. 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INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 1 of 42 Product Monograph Including Patient Medication Information PrINTUNIV XR® guanfacine hydrochloride extended-release tablets For oral use 1 mg, 2 mg, 3 mg, and 4 mg of guanfacine hydrochloride selective alpha2A-adrenergic receptor agonist Takeda Canada Inc. 22 Adelaide Street. West, Suite 3800 Toronto, Ontario, M5H 4E3 Date of Authorization: 2025-10-14 Control No: 298089 INTUNIV XR is a registered trademark of Takeda Pharmaceuticals U.S.A., Inc. Takeda and the Takeda Logo are trademarks of Takeda Pharmaceutical Company Limited, used under license. INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 2 of 42 Recent Major Label Changes Table of Contents Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed. Recent Major Label Changes .................................................................................................. 2 Table of Contents .................................................................................................................. 2 Part 1: Healthcare Professional Information........................................................................... 4 1. Indications ......................................................................................................................... 4 1.1. Pediatrics .......................................................................................................................... 4 1.2. Geriatrics .......................................................................................................................... 4 2. Contraindications ............................................................................................................... 4 4. Dosage and Administration ................................................................................................ 5 4.1 Dosing Considerations ....................................................................................................... 5 4.2. Recommended Dose and Dosage Adjustment ................................................................. 5 4.4. Administration .................................................................................................................. 7 4.5. Missed Dose ..................................................................................................................... 7 5. Overdose ........................................................................................................................... 7 6. Dosage Forms, Strengths, Composition, and Packaging ....................................................... 7 7. Warnings and Precautions .................................................................................................. 8 General .................................................................................................................................... 8 Cardiovascular ......................................................................................................................... 8 Dependence, Tolerance and/or Abuse Liability .................................................................... 10 Driving and Operating Machinery ......................................................................................... 10 Hepatic/Biliary/Pancreatic .................................................................................................... 10 Monitoring and Laboratory Tests .......................................................................................... 10 Psychiatric .............................................................................................................................. 11 Renal ...................................................................................................................................... 11 7.1. Special Populations ........................................................................................................ 12 7.1.1. Pregnancy ................................................................................................................ 12 7.1.2. Breastfeeding .......................................................................................................... 12 INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 3 of 42 7.1.3. Pediatrics ................................................................................................................. 12 7.1.4. Geriatrics ................................................................................................................. 12 8. Adverse Reactions ........................................................................................................... 12 8.1. Adverse Reaction Overview ........................................................................................... 12 8.2. Clinical Trial Adverse Reactions ...................................................................................... 13 8.2.1. Clinical Trial Adverse Reactions – Pediatrics........................................................... 13 8.3. Less Common Clinical Trial Adverse Reactions .............................................................. 19 8.3.1. Less Common Clinical Trial Adverse Reactions – Pediatrics ................................... 19 8.5. Post-Market Adverse Reactions ..................................................................................... 20 9. Drug Interactions ............................................................................................................. 21 9.2. Drug Interactions Overview ........................................................................................... 21 9.3. Drug-Behaviour Interactions .......................................................................................... 22 9.4. Drug-Drug Interactions ................................................................................................... 22 9.5. Drug-Food Interactions .................................................................................................. 25 9.6. Drug-Herb Interactions ................................................................................................... 25 9.7. Drug-Laboratory Test Interactions ................................................................................. 25 10. Clinical Pharmacology .................................................................................................... 25 10.1. Mechanism of Action ................................................................................................... 25 10.2. Pharmacodynamics ...................................................................................................... 25 10.3. Pharmacokinetics ......................................................................................................... 26 11. Storage, Stability, and Disposal ....................................................................................... 27 Part 2: Scientific Information ............................................................................................... 28 13. Pharmaceutical Information ........................................................................................... 28 14. Clinical Trials .................................................................................................................. 29 14.1. Clinical Trials by Indication ........................................................................................... 29 16. Non-Clinical Toxicology .................................................................................................. 34 Patient Medication Information .......................................................................................... 36 INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 4 of 42 Part 1: Healthcare Professional Information 1. Indications Pediatrics (6 to 17 years of age) INTUNIV XR (guanfacine hydrochloride extended-release tablets) is indicated as: • monotherapy for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children and adolescents aged 6 to 17 years. • adjunctive therapy to psychostimulants for the treatment of ADHD in children and adolescents, aged 6 to 17 years, with a sub-optimal response to psychostimulants. Adults (>18 years of age): INTUNIV XR has not been systematically studied in and is therefore not indicated for use in adults (over 18 years of age). Need for Comprehensive Treatment Program INTUNIV XR is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational/vocational, social) for patients with this syndrome. Drug treatment may not be indicated for all patients with this syndrome. Drug treatment is not intended for use in a patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational/vocational placement is essential for patients with this diagnosis and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe drug treatment will depend upon the physician's assessment of the chronicity and severity of the child's symptoms and on the level of functional impairment. Long-term Use The effectiveness of INTUNIV XR for long-term use, i.e., for more than 9 weeks in 6-12 year olds and more than 15 weeks in 13-17 year olds, has not been systematically evaluated in controlled monotherapy trials, nor has it been systematically evaluated in controlled adjunctive trials for longer than 9 weeks in 6-17 year olds. Therefore the physician electing to use INTUNIV XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. 1.1. Pediatrics Pediatrics (<6 years of age): The safety and efficacy of INTUNIV XR in children less than 6 years of age have not been studied. 1.2. Geriatrics INTUNIV XR has not been systematically studied in and is therefore not indicated for use in adults (over 18 years of age), including in geriatrics. 2. Contraindications INTUNIV XR is contraindicated in patients with a history of hypersensitivity to this drug, to any ingredient in the formulation, to any other product containing guanfacine, or component of the container. For a complete listing, see 6. Dosage Forms, Strengths, Composition and Packaging. INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 5 of 42 4. Dosage and Administration 4.1 Dosing Considerations The tablets should not be administered with high-fat meals, due to increased exposure (see 10.3. Pharmacokinetics). Do not substitute for immediate-release guanfacine tablets on a milligram for milligram basis, because of differing pharmacokinetic profiles. INTUNIV XR has a delayed Tmax, reduced Cmax and lower bioavailability compared to those of the same dose of immediate-release guanfacine. The safety and efficacy of INTUNIV XR in pediatric patients less than 25 kg/55 lbs in weight have not been studied. Heart rate and blood pressure should be monitored at baseline, after dose adjustments, periodically during treatment and following drug discontinuation (see 7. Warnings and Precautions, Cardiovascular, and 7. Warnings and Precautions, Monitoring and Laboratory Tests). Advise patients that sedation can occur, particularly early in treatment or with dose increases. If sedation is judged to be clinically concerning or persistent, a dose decrease or discontinuation should be considered (see 7. Warnings and Precautions, Cardiovascular, and 4.2.1 Discontinuing Treatment). 4.2. Recommended Dose and Dosage Adjustment Children (6-17 years old) The recommended starting dose for both INTUNIV XR monotherapy and adjunct therapy to psychostimulants is 1 mg, taken orally once a day (morning or evening). The dose should be adjusted, depending on clinical response and tolerability, in increments of no more than 1 mg per week up to a maximum daily dose of 4 mg (6-12 years) or 7 mg (13-17 years), for monotherapy and up to a maximum daily dose of 4 mg for adjunctive therapy to psychostimulants. In monotherapy clinical trials, there were dose-related and exposure-related risks for several clinically significant adverse reactions (hypotension, bradycardia, sedative events). To balance the exposure-related potential benefits and risks, the recommended dose range, depending on clinical response and tolerability for INTUNIV XR, is 0.05-0.12 mg/kg/day (total daily dose 1-7 mg) (Table 1). Table 1 - Recommended Target Dose Range for INTUNIV XR monotherapy* (depending on clinical response and tolerability) Weight Target dose range (0.05 - 0.12 mg/kg/day) 25.0-33.9 kg 2-3 mg/day 34.0-41.4 kg 2-4 mg/day 41.5-49.4 kg 3-5 mg/day 49.5-58.4 kg 3-6 mg/day ≥58.5 kg 4-7 mg/day *Doses above 4 mg/day have not been evaluated in children (ages 6-12 years) and doses above 7 mg/day have not been evaluated in adolescents (ages 13-17 years) In the adjunctive clinical trial which evaluated INTUNIV XR treatment added to psychostimulants, the INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 6 of 42 majority of subjects reached their optimal doses in the 0.05-0.12 mg/kg/day range. Doses above 4 mg/day have not been studied in adjunctive trials. Renal Impairment The impact of renal impairment on the pharmacokinetics of guanfacine in children and adolescents, 6-17 years old, was not assessed. In adult patients with impaired renal function, the cumulative urinary excretion of guanfacine and the renal clearance diminished as renal function decreased. In patients on hemodialysis, the dialysis clearance was about 15% of the total clearance. The low dialysis clearance suggests that the hepatic elimination (metabolism) increases as renal function decreases. It may be necessary to adjust the dose in patients with significant impairment of renal function (see 7. Warnings and Precautions, Renal). Hepatic Impairment The impact of hepatic impairment on the pharmacokinetics of guanfacine in children and adolescents, 6-17 years old, was not assessed. Guanfacine in adults is cleared both by the liver and the kidney, and approximately 50% of the clearance of guanfacine is hepatic. It may be necessary to adjust the dose in patients with significant impairment of hepatic function (see 7. Warnings and Precautions, Hepatic/Biliary/Pancreatic). Patients treated with CYP3A4/5 inhibitors /inducers CYP3A4/5 inhibitors and inducers have been shown to have a significant effect on the pharmacokinetics of guanfacine when co-administered (see 9.4. Drug-Drug Interactions). Dose adjustment is recommended with concomitant use of moderate/strong CYP3A4/5 inhibitors (e.g. ketoconazole, grapefruit juice), or strong CYP3A4 inducers (e.g. carbamazepine). In the case of concomitant use of strong and moderate CYP3A inhibitors, an initial 50% reduction of the guanfacine dose is recommended. Further individualized dose titration may then be needed. If guanfacine is combined with strong enzyme inducers, a retitration to increase the dose up to a maximum daily dose 7 mg, may be considered if needed. If the inducing treatment is ended, retitration to reduce the guanfacine dose is recommended during the following weeks. 4.2.1. Discontinuing Treatment Patients/caregivers should be instructed not to discontinue INTUNIV XR without consulting their physician. The total daily dose should be tapered in decrements of no more than 1 mg every 3 to 7 days to minimize the risk of an increase in blood pressure upon discontinuation (see 7. Warnings and Precautions, Cardiovascular, Elevated Blood Pressure and Heart Rate Upon Discontinuation and 7. Warnings and Precautions, Monitoring and Laboratory Tests). Elevations in blood pressure and heart rate above original baseline (i.e., rebound) have been reported to occur upon discontinuation of INTUNIV XR monotherapy. Patients should be monitored during dose downward titration and following INTUNIV XR discontinuation until blood pressure and heart rate have returned to baseline (see 7. Warnings and Precautions, Monitoring and Laboratory Tests). Caution is warranted when ending INTUNIV XR treatments in patients on the adjunctive to psychostimulant therapy while maintaining psychostimulant treatments. Use caution when prescribing drugs that can elevate blood pressure and heart rate immediately following INTUNIV XR discontinuation (see 9.4. Drug-Drug Interactions). INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 7 of 42 4.4. Administration INTUNIV XR is an extended-release tablet and should be dosed once daily. Tablets should not be crushed, chewed or broken before swallowing because this will increase the rate of guanfacine release. The initial starting dose for INTUNIV XR as an adjunctive therapy with psychostimulants is 1 mg, taken orally once a day; evening dosing may be considered (see 14. Clinical Trials). See also 4.1. Dosing Considerations and 4.2. Recommended Dose and Dosage Adjustment. 4.5. Missed Dose If two or more consecutive doses are missed, re-titration is recommended based on the patient’s tolerability to INTUNIV XR (see 4.2.1. Discontinuing Treatment). 5. Overdose Signs and symptoms of overdose may include hypotension, bradycardia, lethargy, electrocardiogram QT prolonged and respiratory depression. Initial hypertension may develop early and may be followed by hypotension. Management of INTUNIV XR overdose should include monitoring for and the treatment of these signs and symptoms. ECG monitoring is recommended. Children and adolescents who develop lethargy should be observed for the development of more serious toxicity including coma, bradycardia and hypotension for up to 24 hours, due to the possibility of delayed onset of these symptoms. Treatment of overdose may include gastric lavage if it is performed soon after ingestion. Activated charcoal may be useful in limiting the absorption. Guanfacine is not dialyzable in clinically significant amounts (2.4%). For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669). 6. Dosage Forms, Strengths, Composition, and Packaging Table 2 – Dosage Forms, Strengths, and Composition. Description INTUNIV XR tablets 1 mg: white/off-white, round (debossed on top 503/on bottom 1MG), bottles of 100. Route of Administration Dosage Form / Strength/Composition Non-medicinal Ingredients oral Tablet / 1 mg, 2 mg, 3 mg, 4 mg [milligrams] / guanfacine as guanfacine hydrochloride crospovidone, fumaric acid, glyceryl behenate, hypromellose, lactose monohydrate, methacrylic acid copolymer, microcrystalline cellulose and povidone. In addition, the 3 mg and 4 mg tablets also contain green pigment blend PB-1763. INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 8 of 42 INTUNIV XR tablets 2 mg: white/off-white, oblong (debossed on top 503/on bottom 2MG), bottles of 100. INTUNIV XR tablets 3 mg: green, round (debossed on top 503/on bottom 3MG), bottles of 100. INTUNIV XR tablets 4 mg: green, oblong (debossed on top 503/on bottom 4MG), bottles of 100. 7. Warnings and Precautions General Somnolence and Sedation Sedative events, especially during initial use, were commonly reported adverse reactions in clinical trials. In two 8-and 9-week monotherapy trial (Studies 1 and 2) in 6-17 year olds, sedative events reported as adverse reactions were 38% for INTUNIV XR vs. 12% for placebo and in a separate monotherapy trial in adolescents (Study 3), were 54% for INTUNIV XR vs. 23% for placebo. In an adjunctive trial (Study 4) in 6-17 year olds, sedative events reported as adverse events were 18% for INTUNIV XR vs. 7% for placebo. INTUNIV XR should be dosed based on clinical response and tolerability. Advise patients that sedation can occur, particularly early in treatment or with dose increases. If sedation is judged to be clinically concerning or persistent, a dose decrease or discontinuation should be considered. Before INTUNIV XR is used with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), the potential for additive sedative effects should be considered. Patients should avoid use with alcohol (see 9.4. Drug-Drug Interactions - CNS Depressant Drugs and 4.1. Dosing Considerations). Cardiovascular Hypotension, Bradycardia and Syncope INTUNIV XR can cause syncope and dose-dependent decreases in heart rate and blood pressure (systolic and diastolic) (see 8.2.1. Clinical Trial Adverse Reactions – Pediatrics, Effects on Blood Pressure and Heart Rate and 10.2. Pharmacodynamics, Cardiovascular Safety: Effects on Heart Rate and QT Interval). In pediatric (6-17 year olds), short-term (8-9 weeks), controlled monotherapy trials (Studies 1 and 2), the maximum mean changes from baseline in systolic blood pressure, diastolic blood pressure, and heart rate were decreases of 5 mmHg, 3 mmHg, and 6 bpm, respectively, for all dose groups combined (generally one week after reaching target doses of 1 mg/day, 2 mg/day, 3 mg/day or 4 mg/day). In the adolescent controlled monotherapy trial (Study 3), the maximum mean change from baseline in systolic blood pressure, diastolic blood pressure and heart rate were decreases of 5 mmHg, 4 mmHg, and 6 bpm for all dose groups combined. Decreases in blood pressure and heart rate were usually asymptomatic; however, hypotension and bradycardia can occur. In long-term, open-label studies (mean exposure of approximately 10 months), maximum decreases in systolic and diastolic blood pressure occurred in the first month of therapy. Decreases were less pronounced over time. The majority of syncope cases occurred in the long term, open-label studies. In a 9-week controlled adjunctive trial, the maximum mean changes from baseline in supine systolic blood pressure, diastolic blood pressure, and heart rate were decreases of 4 mmHg, 3 mmHg, and 9 bpm, respectively, between weeks 3 and 5 of the study. Decreases in blood pressure and heart rate were usually asymptomatic; however, hypotension and bradycardia can occur. Measurements of heart rate and blood pressure should be performed prior to initiating therapy, following dose adjustments, periodically during treatment and following drug discontinuation. Observe INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 9 of 42 caution if using INTUNIV XR in patients who have a history of hypotension, heart block, bradycardia, or other cardiovascular disease (e.g., arrhythmia, sick sinus syndrome, ischemic heart disease, congestive heart failure, or congenital long QT syndrome), as INTUNIV XR can decrease blood pressure and heart rate. Caution is advised when treating patients with INTUNIV XR who have a history of syncope or a condition that may predispose them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Given the effect on blood pressure and heart rate, caution is advised when treating patients with INTUNIV XR who are being treated concomitantly with antihypertensives or other drugs that reduce blood pressure or heart rate, QT prolonging drugs, and drugs that increase the risk of syncope (see 9.4. Drug-Drug Interactions - Heart Rate Lowering Drugs, and 9.2. Drug Interactions Overview - QT Prolonging Drugs, and 8.2.1. Clinical Trial Adverse Reactions - Pediatrics, Effects on Heart Rate and QT Interval). Patients/caregivers should be advised that patients should avoid becoming dehydrated or overheated. Elevated Blood Pressure and Heart Rate Upon Discontinuation Patients/caregivers should be instructed not to discontinue INTUNIV XR without consulting their physician since elevations in blood pressure and heart rate above original baseline (i.e., rebound) have been reported. In post-marketing experience, hypertensive encephalopathy has been very rarely reported upon abrupt discontinuation of INTUNIV XR. To minimize the risk of an increase in blood pressure upon discontinuation, the total daily dose of INTUNIV XR should be tapered in decrements of no more than 1 mg every 3 to 7 days. Patients should be monitored during dose downward titration and following INTUNIV XR discontinuation until blood pressure and heart rate have returned to baseline (see 7. Warnings and Precautions, Monitoring and Laboratory Tests and 4.2.1. Discontinuing Treatment). Patients/caregivers should be informed about the risk of persistent hypertension following discontinuation, how to identify signs and symptoms (e.g. headaches, feeling confused, nervousness, agitation, and tremors) and to seek immediate medical care. In randomized controlled monotherapy trials, increases of up to 10 mmHg persisted in a few individuals at approximately 30 days post-dose and were not considered serious. In a 26-week long-term randomized withdrawal study in children and adolescents, increases in mean systolic and diastolic blood pressure, of approximately 3 mmHg and 1mmHg respectively were observed upon discontinuation of INTUNIV XR. Increases up to 36 mmHg above normal baseline persisted in a few individuals, which ranged between 3 and 26 weeks post-dose upon discontinuation of INTUNIV XR. More than 90% of patients’ blood pressure measurements remained within normal limits (i.e. less than the 95th percentile based on age, sex and stature). Mean increases in pulse of approximately 1.5 bpm were observed at approximately 2 weeks after the last dose of INTUNIV XR and then decreased to baseline 4 weeks later. A few cases of hypertension were observed in this study, however, the increases in blood pressure and pulse were generally not considered serious or associated with adverse events. One pediatric case had a serious event of withdrawal hypertension despite downward dose titration associated with the adverse event of vomiting (see 8.2.1. Clinical Trial Adverse Reactions – Pediatrics, Effects on Blood Pressure and Heart Rate and 8.5. Post-Market Adverse Drug Reactions). Because of the psychostimulant potential for increasing blood pressure and heart rate, there is a theoretical increased risk of rebound or a risk of greater rebound when discontinuing INTUNIV XR treatments in patients on adjunctive therapy. Caution is warranted if a patient stops INTUNIV XR while maintaining its psychostimulant therapy. Use caution when prescribing drugs that can elevate blood pressure and heart rate immediately following INTUNIV XR discontinuation (see 9.4. Drug-Drug Interactions). INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 10 of 42 QTc Interval QTc increase (placebo-adjusted mean change from baseline approximately 5 msec) has been observed in patients aged 6-17 years with ADHD receiving therapeutic doses of INTUNIV XR at steady-state. In clinical trials of INTUNIV XR in ADHD patients, there were no reports of torsade de pointes. Given the effect of INTUNIV XR on cardiac electrophysiology, consider this observation in clinical decisions to prescribe INTUNIV XR to patients with a known history of QT prolongation, risk factors for torsades de pointes (e.g. heart block, bradycardia, hypokalemia) or patients who are taking medications known to prolong the QT interval (see 8.2.1. Clinical Trial Adverse Reactions – Pediatrics, Effects on Heart Rate and QT Interval and 9.2. Drug Interactions Overview - QT Prolonging Drugs). Dependence, Tolerance and/or Abuse Liability INTUNIV XR is not a controlled substance or a stimulant drug. INTUNIV XR has not been studied for abuse or dependence potential. Driving and Operating Machinery Patients should avoid performing tasks which may require special attention, such as riding a bike, scooter or electronic transportation device, driving/operating machinery or engaging in activities that require alertness or physical coordination until they are reasonably certain that treatment with INTUNIV XR does not adversely affect them (see 7. Warnings and Precautions, General, Somnolence and Sedation). Hepatic/Biliary/Pancreatic The impact of hepatic impairment on the pharmacokinetics of guanfacine in children and adolescents, 6-17 years old, was not assessed. Because guanfacine is metabolized primarily by cytochrome P450 (CYP)3A4, diminished CYP3A4 activity as a result of hepatic impairment would be expected to increase guanfacine exposure. It may be necessary to adjust the dose in patients with significant impairment of hepatic function (see 4.2. Recommended Dose and Dosage Adjustment, Hepatic Impairment). Monitoring and Laboratory Tests Routine laboratory tests are not required. Heart rate and blood pressure should be monitored at baseline, after dose adjustments, periodically during treatment and following drug discontinuation. Withdrawal hypertension may occur within days after cessation of therapy; however, symptoms can occur up to 1-2 weeks after withdrawal of INTUNIV XR (see 7. Warnings and Precautions, Cardiovascular and 4.2.1. Discontinuing Treatment). Particular caution should be observed in patients with pre-existing hypertension or hypotension, bradycardia, heart block, or other cardiovascular disease (e.g., arrhythmia, sick sinus syndrome, ischemic heart disease, congestive heart failure, or congenital long QT syndrome) or a history of syncope (see 9.4. Drug-Drug Interactions). Patients/caregivers should be advised that patients should avoid dehydration or becoming overheated. Advise patients that sedation can occur, particularly early in treatment or with dose increases. If sedation is judged to be clinically concerning or persistent, a dose decrease or discontinuation should be considered. INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 11 of 42 Psychiatric Pre-existing Psychosis Administration of medications for ADHD may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Screening Patients for Bipolar Disorder Particular care should be taken in treating ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with INTUNIV XR, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Emergence of New Psychotic or Manic Symptoms Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can occur with guanfacine use at usual doses. If such symptoms occur, consideration should be given to a possible causal role of guanfacine, and discontinuation of treatment should be considered. Aggression Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the post-marketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that guanfacine causes aggressive behavior or hostility, patients beginning treatment of ADHD should be monitored for the appearance of, or worsening of, aggressive behavior or hostility. Suicidal Behavior and Ideation There have been post-marketing reports of suicide-related events in patients treated with ADHD drugs, including cases of ideation, attempts, and very rarely, completed suicide. The mechanism of this risk is not known. ADHD and its related co-morbidities may be associated with increased risk of suicidal ideation and/or behavior. Therefore, it is recommended for patients treated with ADHD drugs that caregivers and physicians monitor for signs of suicide-related behavior, including at dose initiation/optimization and drug discontinuation. Patients should be encouraged to report any distressing thoughts or feelings at any time to their healthcare professional. Patients with emergent suicidal ideation and behavior should be evaluated immediately. The physician should initiate appropriate treatment of the underlying psychiatric condition and consider a possible change in the ADHD treatment regimen. Renal The impact of renal impairment on the pharmacokinetics of guanfacine in children and adolescents, 6-17 years old, was not assessed. In adult patients with impaired renal function, the cumulative urinary excretion of immediate-release guanfacine and the renal clearance diminished as renal function decreased. In patients on hemodialysis, the dialysis clearance was about 15% of the total clearance. The low dialysis clearance suggests that the hepatic elimination (metabolism) increases as renal function decreases. Guanfacine in adults is cleared both by the liver and the kidney, and approximately 50% of the clearance of guanfacine is hepatic. It may be necessary to adjust the dose in patients with significant impairment of renal function (see 4.2. Recommended Dose and Dosage Adjustment, Renal Impairment). INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 12 of 42 7.1. Special Populations 7.1.1. Pregnancy There are no adequate and well-controlled studies of INTUNIV XR in pregnant women. Non-clinical studies showed fetal and maternal toxicity (see 16. Non-Clinical Toxicology). INTUNIV XR should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. 7.1.2. Breastfeeding There are no clinical data on the use of INTUNIV XR in women who are breastfeeding. In non-clinical studies, guanfacine was excreted into rat milk. It is not known if guanfacine would also be excreted into human milk. Use caution when INTUNIV XR is administered to a woman who is breastfeeding. 7.1.3. Pediatrics The safety and efficacy of INTUNIV XR in children less than 6 years of age have not been studied. Effects on Growth Pediatric patients aged 6-17 years taking INTUNIV XR demonstrated similar growth compared to normative data. Patients taking INTUNIV XR had a mean increase in weight of 0.5 kg (1 pound) compared to those receiving placebo over a comparative treatment period. Patients receiving INTUNIV XR for at least 12 months in open-label studies gained an average of 8 kg (17 pounds) in weight and 8 cm (3 inches) in height. The height, weight, and BMI percentile remained stable in patients at 12 months in the long-term studies compared to when they began receiving INTUNIV XR. Nevertheless, height, weight and BMI should be routinely monitored. 7.1.4. Geriatrics The safety and efficacy of INTUNIV XR in adults, including geriatrics have not been studied. 8. Adverse Reactions 8.1. Adverse Reaction Overview Short-Term Monotherapy Trials (children/adolescents aged 6-17 years) The two forced-dose clinical trials (Studies 1 and 2) with INTUNIV XR alone, one 8-week and one 9-week, were randomized, multi-center, double-blind, parallel-group, placebo-controlled studies in 664 children/adolescents aged 6-17 years with ADHD. Treatment-emergent adverse events with the highest subject incidence rates in INTUNIV XR treatment group combined were fatigue (14%), headache (23.8%) and somnolence/sedation (38%) (see Table 3). Short-Term Monotherapy Trial (adolescents aged 13-17 years) This clinical trial (Study 3) was a 15-week, double-blind, placebo-controlled study conducted in adolescents aged 13-17 years with ADHD. Treatment-emergent adverse events with the highest subject incidence rates in the INTUNIV XR treatment group were decreased appetite (14.6%), dizziness (15.9%), fatigue (22.3%), headache (26.8%), sedation (11.5%) and somnolence (43.9%) (see Table 4). Short-Term Adjunctive Trial (children/adolescents aged 6-17 years) This clinical trial (Study 4) was a 9-week, placebo controlled, double-blind study conducted in children INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 13 of 42 and adolescents aged 6-17 years treated with psychostimulants who were identified as having a sub optimal response to psychostimulants. INTUNIV XR was evaluated as adjunct therapy to their psychostimulant treatment. Treatment-Emergent Adverse Events with the highest subject incidence rates were headache and somnolence (see Table 5). Adverse Events Leading to Discontinuation of Treatment Twelve percent (12%) of patients (6-17 years) receiving INTUNIV XR discontinued from the two pediatric monotherapy clinical studies (Studies 1 and 2) due to adverse events, compared to 4% in the placebo group. The most common adverse reactions leading to discontinuation of INTUNIV XR-treated patients from the studies were somnolence/sedation (6%) and fatigue (2%). Less common adverse reactions leading to discontinuation (occurring in approximately 1% of patients) included: hypotension/decreased blood pressure, headache, dizziness. Six percent (5.7%) of patients (13-17 years) receiving INTUNIV XR discontinued from the adolescent monotherapy clinical trial (Study 3) due to adverse events, compared to 1.9% in the placebo group. The most common adverse event leading to discontinuation of INTUNIV XR- treated patients was fatigue (1.3%). Three percent (3%) of patients receiving INTUNIV XR discontinued from the adjunctive clinical study (Study 4) due to adverse events, compared to 1% in the placebo group. No adverse event to INTUNIV XR causing discontinuation was reported more than once. 8.2. Clinical Trial Adverse Reactions Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. See 8.2.1 Clinical Trial Adverse Reactions - Pediatrics. 8.2.1. Clinical Trial Adverse Reactions – Pediatrics The developmental program for INTUNIV XR included exposures in a total of 2411 participants in clinical trials (1718 children aged 6-12 years, 693 adolescent patients aged 13-17 years). The information included in this section is based on data from 2 monotherapy forced-dose clinical trials in children and adolescents aged 6-17 years (Studies 1 and 2), 1 dose-optimized monotherapy trial in adolescents aged 13-17 years (Study 3) and 1 dose-optimized adjunctive trial in children and adolescents aged 6-17 years (Study 4). The stated frequencies of the listed treatment-emergent adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the kind listed. INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 14 of 42 Short-Term Monotherapy Trials (children/adolescents aged 6-17 years - Studies 1 and 2) Table 3 - Treatment-Emergent Adverse Events Reported by 1% or More and Greater Than Placebo in Pediatric Patients (aged 6-17 years) Taking INTUNIV XR Alone up to 4 mg in One 8-Week or One 9-Week Controlled Clinical Trial (Studies 1 and 2) System Organ Classes Preferred Term INTUNIV XR n=513 (%) Placebo n=149 (%) Gastrointestinal Disorders Abdominal pain upper Nausea Dry mouth Constipation Dyspepsia 9.9 5.7 4.1 2.7 1.2 7.4 2.0 1.3 0.7 0.7 General Disorders and Administration Site Conditions Fatigue 14.0 3.4 Investigations Blood pressure decreased Weight increased 1.9 1.4 0 0 Metabolism and Nutrition Disorders Decreased appetite 6.0 4.0 Nervous System Disorders Somnolence Headache Sedation Dizziness Lethargy 29.2 23.8 9.9 6.4 5.7 6.7 19.5 4.7 4.0 2.7 Psychiatric Disorders Irritability Nightmare Affect lability 5.8 1.6 1.4 4.0 0 0.7 Renal and Urinary Disorders Enuresis 1.4 0.7 Vascular Disorders Hypotension Orthostatic hypotension 2.5 1.0 0.7 0 Other common treatment-emergent adverse events (1% to 5%) included Diarrhea, Vomiting, and Insomnia. INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 15 of 42 Treatment-Emergent Adverse Events (reported by ≥1% of pediatric patients taking INTUNIV XR) in other Phase 2/3 clinical trials: Cardiac Disorders: Bradycardia Gastrointestinal Disorders: Abdominal pain, stomach discomfort Investigations: Blood pressure increased Nervous System Disorders: Syncope/syncope vasovagal/loss of consciousness Psychiatric Disorders: Anxiety, depression, middle insomnia Respiratory, Thoracic, and Mediastinal Disorders: Asthma Two long-term extension studies of the above-mentioned clinical studies were conducted up to 24 months. INTUNIV XR was generally safe and well tolerated. Short-Term Monotherapy Trial (adolescents aged 13-17 years – Study 3) Table 4 - Treatment-Emergent Adverse Events Reported by 1% or More and Greater Than Placebo in Adolescent Patients (aged 13-17 years) Taking INTUNIV XR Alone up to 7 mg in One 15-Week Controlled Clinical Trial (Study 3) System Organ Classes Preferred Term INTUNIV XR n=157 (%) Placebo n=155 (%) Cardiac Disorders Bradycardia 4.5 0 Gastrointestinal Disorders Dry mouth Abdominal pain upper Abdominal pain Constipation Abdominal discomfort 7.6 6.4 5.7 3.2 1.9 0 4.5 3.9 0 1.3 General Disorders and Administration Site Conditions Fatigue Asthenia 22.3 1.3 12.3 0 Investigations Blood pressure diastolic decreased Weight increased Blood pressure decreased 3.2 2.5 1.9 0 1.9 0 Metabolism and Nutrition Disorders Decreased appetite 14.6 13.5 INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 16 of 42 Table 4 - Treatment-Emergent Adverse Events Reported by 1% or More and Greater Than Placebo in Adolescent Patients (aged 13-17 years) Taking INTUNIV XR Alone up to 7 mg in One 15-Week Controlled Clinical Trial (Study 3) System Organ Classes Preferred Term INTUNIV XR n=157 (%) Placebo n=155 (%) Nervous System Disorders Somnolence Headache Dizziness Sedation Insomnia Dizziness postural Initial insomnia Middle insomnia 43.9 26.8 15.9 11.5 8.9 5.1 2.5 2.5 21.3 18.1 10.3 1.9 3.9 1.9 1.3 0 Psychiatric Disorders Irritability Nervousness Anxiety Depressed mood 7.0 3.2 2.5 1.9 3.9 1.3 1.9 0 Renal and Urinary Disorders Enuresis 1.3 0.6 Skin and Subcutaneous Tissue Disorders Rash Pruritus 3.2 1.9 0.6 1.3 Vascular disorders Orthostatic hypotension 3.8 1.9 Short-Term Adjunctive Trial (children/adolescents aged 6-17 years – Study 4) Table 5 - Treatment-Emergent Adverse Events Reported by 1% or More and Greater Than Placebo in Pediatric Patients (aged 6-17 years) Taking INTUNIV XR up to 4 mg as an Adjunct to a Stable Dose of Psychostimulant in a Controlled Clinical Trial (Study 4) System Organ Classes Preferred Term INTUNIV XR n=302 (%) Placebo n=153 (%) Cardiac Disorders Bradycardia 1.7 0 INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 17 of 42 Table 5 - Treatment-Emergent Adverse Events Reported by 1% or More and Greater Than Placebo in Pediatric Patients (aged 6-17 years) Taking INTUNIV XR up to 4 mg as an Adjunct to a Stable Dose of Psychostimulant in a Controlled Clinical Trial (Study 4) System Organ Classes Preferred Term INTUNIV XR n=302 (%) Placebo n=153 (%) Gastrointestinal Disorders Abdominal pain upper Nausea Diarrhea Constipation Dry mouth Abdominal pain 8.3 5.0 3.6 2.3 2.0 1.7 2.0 3.3 0.7 0 0 0.7 General Disorders and Administration Site Conditions Fatigue 9.6 2.6 Metabolism and Nutrition Disorders Decreased appetite 6.6 3.9 Nervous System Disorders Headache Somnolence Dizziness Sedation Dizziness postural Lethargy 21.2 13.6 7.6 4.3 1.7 1.3 13.1 4.6 3.9 2.0 0 0 Psychiatric Disorders Insomnia Affect lability Middle insomnia Nightmare 8.6 2.3 2.3 1.3 3.9 0.7 0 0.7 Respiratory, Thoracic and Mediastinal Disorders Asthma 1.3 0.7 Vascular Disorders Orthostatic hypotension 2.3 0 INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 18 of 42 Other common treatment-emergent adverse events (1% to 5%) included Vomiting, Stomach discomfort, Irritability, and Enuresis. Open-label safety study (children and adolescents aged 6-17 years) A 9-week, open-label safety study was conducted in children and adolescents aged 6-17 years with ADHD whose symptoms were not adequately controlled with psychostimulants alone. In this study, 75 patients who were receiving a stable dose of amphetamine or methylphenidate (with sub-optimal response) were provided an adjunctive, maximum tolerated INTUNIV XR dose up to 4 mg/day for 9 weeks. There was no evidence of additive or unique adverse effects with the combination of INTUNIV XR and psychostimulants relative to what is observed with either medication alone. There were no serious adverse events in this study. Five of 75 subjects (7%) discontinued due to adverse events. There were no evident patterns of clinical importance with regard to hematology, clinical chemistry, urinalysis or physical examination results. Effects on Heart Rate and QT Interval In five double-blind, randomized, placebo-controlled clinical trials in pediatric patients aged 6 17 years, the following effects on heart rate and QTc interval were observed: Table 6 - Effects on Heart Rate (HR) and QTca Interval Study No.a Assessment day N Placebo-Adjusted Mean Change from Baseline in HR bpm (90% CI) Placebo-Adjusted Mean Change from Baseline in QTc ms (90% CI) 1b Day 21 217 -11.4 (-13.9, -8.9) 4.3 (0.9, 7.7) 2b Day 42 176 -4.2 (-7.3, -1.1) 5.9 (2.0, 9.9) 3b Day 91 109 -6.1 (-8.1, -4.0) 4.0 (1.0, 7.0) 4c Day 28 116 -11.2 (-13.8, -8.6) 5.3 (1.8, 8.7) 5c Day 56 107 -10.4 (-13.6, -7.2) 4.7 (0.4, 9.1) aFridericia heart rate correction QTcF=QT/RR0.33 for studies 1,2, and 4 and study population-based heart rate correction QTcP=QT/RR0.31 for study 5 bpivotal studies cother clinical studies Effects on Blood Pressure and Heart Rate In the monotherapy, short-term (8-9 weeks), pivotal trials (Studies 1 and 2), hypotension including orthostatic hypotension was reported as an adverse drug event for 7% of the INTUNIV XR group and 3% of the placebo group. Orthostatic hypotension was reported for 1% of the INTUNIV XR group and none in the placebo group. In the adolescent monotherapy trial (Study 3), hypotension including orthostatic INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 19 of 42 hypotension was reported as an adverse event for 8.9% of the INTUNIV XR group and 3.2% in the placebo group. Orthostatic hypotension was reported as an adverse event for 3.8% of the INTUNIV XR group and 1.9% of the placebo group. In the adjunctive trial (Study 4), hypotension was reported as an adverse drug event for 0.7% of the INTUNIV XR group and none of the placebo group. Orthostatic hypotension was reported in 2.3% of the INTUNIV XR group and none in the placebo group. Discontinuation of Treatment Elevations in blood pressure (up to 10mmHg) and heart rate above original baseline following withdrawal of INTUNIV XR have been reported to persist in a few individuals at approximately 30 days post-dose (see 7. Warnings and Precautions, Cardiovascular, Elevated Blood Pressure and Heart Rate Upon Discontinuation). In a 26-week long-term randomized withdrawal study in children and adolescents, increases in mean systolic and diastolic blood pressure, of approximately 3 mmHg and 1 mmHg respectively were observed upon discontinuation of INTUNIV XR. Increases up to 36 mmHg above normal baseline persisted in a few individuals, which ranged between 3 and 26 weeks post-dose upon discontinuation of INTUNIV XR. More than 90% of patients’ blood pressure measurements remained within normal limits (i.e. less than the 95th percentile based on age, sex and stature). Mean increases in pulse of approximately 1.5 bpm were observed at approximately 2 weeks after the last dose of INTUNIV XR and then decreased to baseline 4 weeks later. A few cases of hypertension were observed in this study, however, the increases in blood pressure and pulse were not considered serious or associated with adverse events. One pediatric case had a serious event of withdrawal hypertension despite downward dose titration associated with the adverse event of vomiting. 8.3. Less Common Clinical Trial Adverse Reactions 8.3.1. Less Common Clinical Trial Adverse Reactions – Pediatrics The stated frequencies of the listed treatment-emergent adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the kind listed. Short-Term Monotherapy Trials (children/adolescents aged 6-17 years - Studies 1 and 2) Uncommon Treatment-Emergent Adverse Events (reported by ≥0.1% and <1% of pediatric patients taking INTUNIV XR) in controlled clinical trials: Cardiac Disorders: Atrioventricular block first degree, sinus arrhythmia General Disorders and Administration Site Conditions: Asthenia, chest pain Immune System Disorders: Hypersensitivity Investigations: Alanine aminotransferase increased, heart rate decreased Nervous System Disorders: Convulsion, dizziness postural, hypersomnia Psychiatric Disorders: Agitation Renal and Urinary Disorders: Pollakiuria Vascular Disorders: Hypertension, pallor. INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 20 of 42 Short-Term Monotherapy Trial (adolescents aged 13-17 years – Study 3) Uncommon Treatment-Emergent Adverse Events (reported by ≥0.1% and <1% of adolescent patients taking INTUNIV XR) in controlled clinical trials: Cardiac Disorders: Tachycardia Eye Disorders: Vision blurred Gastrointestinal Disorders: Dyspepsia Investigations: Heart rate decreased, heart rate increased Nervous System Disorders: Lethargy, syncope/loss of consciousness, tremor Psychiatric Disorders: Affect lability, dysphoria, nightmare, sleep disorder Renal and Urinary Disorders: Pollakiuria Skin and Subcutaneous Tissue Disorders: Alopecia Vascular Disorders: Hypotension, withdrawal hypertension. Short-Term Adjunctive Trial (children/adolescents aged 6-17 years – Study 4) Uncommon Treatment-Emergent Adverse Events (reported by ≥0.1% and <1% of pediatric/adolescent patients taking INTUNIV XR as an adjunct to psychostimulant) in a controlled clinical trial: General Disorders and Administration Site Conditions: Asthenia Investigations: Heart rate decreased, weight increased Nervous System Disorders: Hypersomnia, syncope/syncope vasovagal/loss of consciousness Psychiatric Disorders: Anxiety, depression Renal and Urinary Disorders: Pollakiuria Vascular Disorders: Hypotension, pallor 8.5. Post-Market Adverse Reactions The following adverse events have been identified during post-marketing experience with guanfacine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. An open-label post-marketing study involving 21,718 patients was conducted to assess the safety of immediate-release guanfacine 1 mg/day given at bedtime for 28 days. Guanfacine was administered with or without other antihypertensive agents. Adverse events reported in the post marketing study at an incidence greater than 1% included dry mouth, dizziness, somnolence, fatigue, headache and nausea. The most commonly reported adverse events in this study were the same as those observed in controlled clinical trials. Less frequent, possibly guanfacine-related events observed in the post-marketing study and/or reported spontaneously, not included in the INTUNIV XR clinical trial adverse reactions (see 8.2. Clinical Trial Adverse Reactions), include: Cardiac Disorders: Palpitations, tachycardia Nervous System Disorders: Paresthesia, vertigo INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 21 of 42 Eye Disorders: Vision blurred General and Administration Site Conditions: Edema, malaise, tremor Musculo-Skeletal System: Arthralgia, leg cramps, leg pain, myalgia Psychiatric Disorders: Confusion, hallucination Reproductive System and Breast Disorders: Erectile dysfunction Respiratory, Thoracic, and Mediastinal Disorders: Dyspnea Skin and Subcutaneous Tissue Disorders: Alopecia, dermatitis, exfoliative dermatitis, pruritus, rash Special Senses: Alterations in taste Vascular Disorders: Hypertensive encephalopathy, Raynaud’s Phenomenon Investigations: Electrocardiogram QT prolonged Suicidal Behavior and Ideation There have been post-marketing reports of suicide-related events, including completed suicide, suicide attempt, and suicidal ideation in patients treated with ADHD drugs. In some of these reports, comorbid conditions may have contributed to the event (see 7. Warnings and Precautions, Psychiatric, Suicidal Behavior and Ideation). 9. Drug Interactions 9.2. Drug Interactions Overview QT Prolonging Drugs QTc interval increase (placebo-adjusted mean change from baseline approximately 5 msec) has been observed in patients aged 6-17 years with ADHD receiving therapeutic doses of INTUNIV XR at steady-state (see 7. Warnings and Precautions, Cardiovascular, QTc Interval and 8.2.1. Clinical Trial Adverse Reactions – Pediatrics, Effects on Heart Rate and QT Interval). INTUNIV XR causes a decrease in heart rate (see 7. Warnings and Precautions, Cardiovascular, and 8.2.1. Clinical Trial Adverse Reactions – Pediatrics, Effects on Heart Rate and QT Interval). Given the effect of INTUNIV XR on heart rate, the concomitant use of INTUNIV XR with QT prolonging drugs is generally not recommended. Drugs that have been associated with QTc interval prolongation and/or torsade de pointes (a polymorphic ventricular tachyarrhythmia) that can be fatal include, but are not limited to, the examples in the following list. Chemical/pharmacological classes are listed if some, although not necessarily all class members have been implicated in QT/QTc prolongation and/or torsade de pointes: Class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide); Class III antiarrhythmics (e.g., amiodarone, sotalol, ibutilide, dronedarone); Class 1C antiarrhythmics (e.g., flecainide, propafenone); antipsychotics (e.g., chlorpromazine, pimozide, haloperidol, droperidol, ziprasidone, olanzapine, risperidone); antidepressants (e.g., fluoxetine, citalopram, venlafaxine, tricyclic/tetracyclic antidepressants e.g., amitriptyline, imipramine, maprotiline); opioids (e.g., methadone); macrolide antibiotics and analogues (e.g., erythromycin, clarithromycin, tacrolimus); quinolone antibiotics (e.g., moxifloxacin, levofloxacin, ciprofloxacin); antimalarials (e.g., quinine, chloroquine); azole antifungals INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 22 of 42 (e.g., ketoconazole, fluconazole, voriconazole); domperidone; 5-HT3 receptor antagonists (e.g., ondansetron); tyrosine kinase inhibitors (e.g., sunitinib, nilotinib, lapatinib, vandetanib); arsenic trioxide; histone deacetylase inhibitors (e.g., vorinostat); beta-2 adrenoceptor agonists (e.g., salmeterol, formoterol). The above list of potentially interacting drugs is not comprehensive. Current information sources should be consulted for newly approved drugs that decrease heart rate, prolong the QTc interval, or inhibit CYP3A4/CYP3A5 as well as for older drugs for which these effects have recently been established. 9.3. Drug-Behaviour Interactions Patients should avoid use with alcohol (see 9.4. Drug-Drug Interactions - CNS Depressant Drugs and 4.1. Dosing Considerations). 9.4. Drug-Drug Interactions The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated). Table 7 - Established or Potential Drug-Drug Interactions Proper /Common name Source of Evidence Effect Clinical comment CYP3A4 and CYP3A5 Inhibitors CT There was a substantial increase in the rate and extent of guanfacine exposure when administered with ketoconazole; the guanfacine exposure (AUC) increased 3-fold. Use caution when INTUNIV XR is administered to patients taking ketoconazole and other moderate and strong CYP3A4/5 inhibitors (see 4.2. Recommended Dose and Dosage Adjustment), since elevation of plasma guanfacine concentration increases the risk of adverse events such as hypotension, bradycardia, and sedation. CYP3A4 Inducers CT There was a significant decrease in the rate and extent of guanfacine exposure when co-administered with rifampin, a CYP3A4 inducer. The exposure (AUC) to guanfacine decreased by 70%. When patients are taking INTUNIV XR concomitantly with a CYP3A4 inducer, an increase in the dose of INTUNIV XR within the recommended dose range may be considered (see 4.2. Recommended Dose and Dosage Adjustment). INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 23 of 42 Table 7 - Established or Potential Drug-Drug Interactions Proper /Common name Source of Evidence Effect Clinical comment Transporters T Concomitant administration of guanfacine with MATE1 substrates may result in increases in the plasma concentrations of these medicinal products. Based on in vitro studies, guanfacine may be an inhibitor of OCT1 at maximal portal vein concentrations. Concomitant administration of guanfacine with OCT1 substrates with a similar Tmax (e.g. metformin) may result in increases in Cmax of these medicinal products. Guanfacine is an in vitro inhibitor of MATE1 and the clinical relevance of MATE1 inhibition cannot be excluded. Valproic Acid CT Co-administration of INTUNIV XR and valproic acid can result in increased concentrations of valproic acid. The mechanism of this interaction is unknown, although both guanfacine and valproic acid are metabolized by glucuronidation, possibly resulting in competitive inhibition. When INTUNIV XR is co-administered with valproic acid, monitor patients for potential additive central nervous system (CNS) effects, and give consideration to the monitoring of serum valproic acid concentrations. Adjustments in the dose of valproic acid and INTUNIV XR may be indicated when co-administered. Heart Rate-Lowering Drugs T INTUNIV XR causes a decrease in heart rate (see 7. Warnings and Precautions, Cardiovascular and; 8.2.1 Clinical Trial Adverse Reactions – Pediatrics, Effects on Heart Rate and QT Interval). The concomitant use of INTUNIV XR with other heart rate lowering drugs, such as antiarrhythmics, beta blockers, non-dihydropyridine calcium channel blockers, cholinesterase inhibitors, and sphingosine-1 phosphate receptor modulators is not recommended. INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 24 of 42 Table 7 - Established or Potential Drug-Drug Interactions Proper /Common name Source of Evidence Effect Clinical comment Antihypertens ive Drugs T Potential for additive pharmacodynamic effects such as hypotension and syncope (see 7. Warnings and Precautions, Cardiovascular, Hypotension, Bradycardia and Syncope). Use caution when INTUNIV XR is administered concomitantly with antihypertensive drugs CNS Depressant Drugs T Potential for additive pharmacodynamic effects such as sedation and somnolence (see 7. Warnings and Precautions, General, Somnolence and Sedation). Use caution when INTUNIV XR is administered concomitantly with CNS depressant drugs (e.g., alcohol, sedatives, hypnotics, benzodiazepines, barbiturates, and antipsychotics) Oral Methyl-phenidate CT In a drug interaction study, neither INTUNIV XR (4 mg) nor methylphenidate HCl extended release (36 mg) were found to affect the pharmacokinetics of the other drug when administered concomitantly in healthy adult volunteers. The effect of methylphenidate HCl at a dose of 54 mg when administered concomitantly with INTUNIV XR was not studied. Please see Effect. Lisdexam-fetamine Dimesylate CT In a drug interaction study, administration of INTUNIV XR (4 mg) to healthy adult volunteers in combination with lisdexamfetamine dimesylate (50 mg) induced a 19% increase in guanfacine maximum plasma concentrations, whereas exposure (AUC) was increased by 7%. These small changes are not expected to be clinically meaningful. In this study, no effect on d-amphetamine exposure was observed following concomitant administration of INTUNIV XR and lisdexamfetamine dimesylate. Drug interaction studies have not been conducted with higher doses of lisdexamfetamine dimesylate. INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 25 of 42 Table 7 - Established or Potential Drug-Drug Interactions Proper /Common name Source of Evidence Effect Clinical comment Drugs That are 5-HT2B Receptor Agonists T Please see clinical comment. Drugs that are potent 5-HT2B receptor agonists should not be used during treatment with INTUNIV XR since the risk of fibrotic complications have not been specifically studied with INTUNIV XR (see 10.2. Pharmacodynamics). Legend: C = Case Study; CT = Clinical Trial; T = Theoretical 9.5. Drug-Food Interactions INTUNIV XR should not be administered with high-fat meals due to increased exposure (see 10.3. Pharmacokinetics). Grapefruit, grapefruit juice, or products containing grapefruit extract should not be used during treatment with INTUNIV XR because of the risk of CYP3A4 inhibition but has not been specifically studied. 9.6. Drug-Herb Interactions Interactions with herbal products have not been established. 9.7. Drug-Laboratory Test Interactions Interactions with laboratory tests have not been established. 10. Clinical Pharmacology 10.1. Mechanism of Action Guanfacine is a selective alpha2A-adrenergic receptor agonist. Guanfacine is not a central nervous system (CNS) psychostimulant. The mechanism of action of guanfacine in ADHD is not known. 10.2. Pharmacodynamics Guanfacine is a selective alpha2A-adrenergic receptor agonist in that it has a 15-20 times higher affinity for this receptor subtype than for the alpha2B or alpha2C subtypes. Guanfacine is a known antihypertensive agent. By stimulating alpha2A-adrenergic receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate. Safety Pharmacology: 5HT2B Receptor Agonists and Fibrotic Complications Guanfacine demonstrates a moderate in vitro affinity for the 5-HT2B receptor, an identified likely molecular target for drug-induced valvular heart disease. Regurgitant cardiac valvular disease, primarily INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 26 of 42 affecting the mitral and/or aortic valves, and other fibrotic complications have been reported in patients who took serotonergic drugs with 5-HT2B receptor agonist activity. The etiology of the regurgitant valvular disease is thought to be activation of 5-HT2B receptors on cardiac interstitial cells. While a very small number of possible fibrotic complications, including pleural or pericardial effusion, and cardiac valvulopathy in adult patients treated with immediate release guanfacine (a compound which has been available in the USA for more than 24 years with an exposure of over 3 million person years) for hypertension have been reported, the evidence is not sufficient to establish a causal relationship between guanfacine and these fibrotic complications but a contribution of guanfacine cannot be completely ruled out in rare cases. Guanfacine has not been studied in combination with drugs that are potent 5-HT2B receptor agonists. Cardiovascular Safety: Effects on Heart Rate and QT Interval The effect of two dose levels of immediate-release guanfacine (4 mg/day and 8 mg/day) on the QT interval was evaluated in a double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg) cross-over thorough QT study in 83 healthy adults. On Days 1 (4 mg/day) and 6 (8 mg/day), 12-lead ECGs were obtained by a continuous digital 12-lead ECG recording starting 30 minutes prior to dose administration. The ECGs were extracted within 30 to 10 minutes of dose administration and within 10 minutes before each of the 1, 2, 3, 4, 5, 6, 8, 12, and 24-hour timepoints after dose administration. A dose-dependent decrease in heart rate was observed. The maximal placebo-adjusted mean change in heart rate was -13bpm at 8h post dosing on day 1 in subjects receiving 4 mg/day and -22 bpm at 8h post-dosing on day 6 at the supratherapeutic dose of 8 mg/day. The maximal placebo-adjusted mean change in the QTcF interval was 5 msec at 12h post-dosing on day 1 in subjects receiving 4mg/day and 8msec at 12h post-dosing on day 6 at the supratherapeutic dose of 8 mg/day. The 12h post-dose time point at which maximal QTcF effects are seen occurs 7 hours or more after peak plasma guanfacine concentrations. Guanfacine has not been demonstrated to inhibit hERG potassium channels (see 7. Warnings and Precautions, Cardiovascular, Hypotension, Bradycardia and Syncope; 7. Warnings and Precautions, Cardiovascular, QTc Interval, and 8.2. Clinical Trial Adverse Reactions). 10.3. Pharmacokinetics Absorption: Guanfacine is readily absorbed after administration with INTUNIV XR, with peak plasma concentrations reached approximately 5 hours after oral administration in pediatric patients (children and adolescents). In adults, the mean exposure of guanfacine increased (Cmax ~75% and AUC ~40%) when INTUNIV XR was taken together with a high-fat meal, compared to intake in the fasted state. Immediate-release guanfacine and INTUNIV XR have different pharmacokinetic characteristics, so dose substitution on a milligram for milligram basis is not appropriate because of differing pharmacokinetic profiles. INTUNIV XR has a delayed Tmax, reduced Cmax and lower bioavailability compared to those of the same dose of immediate-release guanfacine. Distribution: Guanfacine is moderately bound to plasma proteins (approximately 70%), independent of drug concentration. Metabolism: Following absorption, the drug is rapidly and extensively metabolised by epoxidation and hydroxylation INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 27 of 42 of the aromatic moiety, followed by conjugation with glucuronic acid, sulphate and glutathione. Guanfacine is metabolized via oxidation and glucuronidation. Guanfacine is primarily metabolized by the CYP3A4 isoenzyme in human liver microsomes, and has been studied in a clinical study. In human hepatic microsomes, guanfacine did not inhibit the activities of the major cytochrome P450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 or CYP3A5) and is therefore unlikely to affect the clearance of other co-administered drugs metabolised by cytochrome P450s clinically; guanfacine is also not expected to be an inducer of CYP3A, CYP1A2 and CYP2B6. Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5 inducers and inhibitors (see 9.4. Drug-Drug Interactions - CYP3A4 and CYP3A5 Inhibitors and 9.4. Drug-Drug Interactions - CYP3A4 Inducers). Transporters Based on in vitro studies, guanfacine is a substrate of OCT1 and OCT2, but not BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1 OR MATE2. Guanfacine is not an inhibitor of BSEP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT2 or MATE2K, but it is an inhibitor of MATE1 and may be an inhibitor of OCT1 at maximal portal vein concentrations. Elimination: Guanfacine is cleared by the kidney and the liver. The main excretion route for guanfacine is the liver. The elimination half-life of guanfacine is approximately 18 hours. Special Populations and Conditions Pediatrics: Exposure to guanfacine was higher in children (aged 6-12 years) compared to adolescents (aged 13-17 years) and adults. After oral administration of multiple doses of INTUNIV XR 4 mg, the Cmax was 10ng/mL compared to 7ng/mL and the AUC was 162ng·h/mL compared to 116ng·h/mL in children (aged 6-12 years) and adolescents (aged 13-17 years), respectively. These differences are probably attributable to the lower body weight of children compared to adolescents and adults. Hepatic Insufficiency: The impact of hepatic impairment on the pharmacokinetics of guanfacine in children and adolescents, 6-17 years old, was not assessed. Approximately 50% of the clearance of guanfacine in adults is hepatic (see 7. Warnings and Precautions, Hepatic/Biliary/Pancreatic). Renal Insufficiency: The impact of renal impairment on the pharmacokinetics of guanfacine in children and adolescents, 6-17 years old, was not assessed. In patients on hemodialysis, the dialysis clearance was about 15% of the total clearance (see 7. Warnings and Precautions, Renal). 11. Storage, Stability, and Disposal Store at 25°C (77°F); excursions permitted from 15° to 30°C (59° to 86°F). Any unused medicinal product should be disposed of in accordance with local requirements. INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 28 of 42 Part 2: Scientific Information 13. Pharmaceutical Information Drug Substance Proper name: guanfacine hydrochloride Chemical name: N-amidino-2-(2,6-dichlorophenyl) acetamide monohydrochloride Molecular formula and molecular mass: C9H9Cl2N3O·HCl 282.56 Structural formula: Physicochemical properties: Guanfacine hydrochloride is a white to off-white crystalline powder, sparingly soluble in water (approximately 1 mg/mL). The only organic solvent in which it has relatively high solubility is methanol (≥30 mg/mL). Cl Cl O H N NH2 HCl NH INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 29 of 42 14. Clinical Trials 14.1. Clinical Trials by Indication Trial Design and Study Demographics Table 8 - Summary of patient demographics for clinical trials in ADHD Study No. Trial design Dosage, route of administration and duration Study subjects (n=number) Mean age (Range) Sex Study 1 Randomized, double-blind, placebo-controlled, parallel-group, forced-dose titration study conducted in children and adolescents aged 6-17 years with ADHD Oral, 2, 3 and 4 mg, once daily, 8 weeks 345 (6-12 yrs: 265) (13-17 yrs: 80) 10.5 yrs (6-17) 257M: 88F Study 2a Randomized, double-blind, placebo-controlled, forced-dose study conducted in children and adolescents aged 6-17 years with ADHD Oral, 1, 2, 3 and 4 mg, once daily, 9 weeks 322 (6-12 yrs: 241) (13-17 yrs: 81) 10.5 yrs (6-17) 233M: 89F Study 3 Randomized, double-blind, placebo-controlled, dose-optimization study conducted in adolescents aged 13-17 years with ADHD to confirm the efficacy, safety, and tolerability Oral, 1, 2, 3, 4, 5, 6, 7 mg, once daily, 15 weeks 312 14.5 yrs (13-17) 202M: 110F Study 4 Randomized, double-blind, placebo-controlled, dose-optimization adjunctive study with psychostimulants in children and adolescents aged 6-17 years with ADHD Oral, 1, 2, 3 and 4 mg, once daily as an adjunct to a current, stable dose of psychostimulant, 9 weeks 455 (6-12 yrs: 361) (13-17 yrs: 94) 10.8 yrs (6-17) 326M: 129F aOnly patients weighing <110lbs could be randomized to 1 mg. INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 30 of 42 The efficacy of INTUNIV XR in the treatment of ADHD was established in 2 placebo-controlled monotherapy trials (Studies 1 and 2) in pediatric patients (children and adolescents; aged 6-17 years, inclusive) and in 1 placebo-controlled monotherapy trial in adolescents (aged 13-17 years). Signs and symptoms of ADHD were evaluated as the change from baseline to endpoint in ADHD Rating Scale IV (ADHD-RS-IV) scores. Daily doses used in these studies were within the range of 1- 4 mg for children and 1-7 mg in adolescents. In Study 4, the safety and efficacy of INTUNIV XR was evaluated as adjunctive therapy in patients treated with psychostimulants (longer-acting formulations of mixed salts of a single-entity amphetamine product, lisdexamfetamine dimesylate, methylphenidate hydrochloride extended-release, methylphenidate hydrochloride, and dexmethylphenidate hydrochloride). The study was conducted in children and adolescents aged 6-17 years with a diagnosis of ADHD, with a sub-optimal response to psychostimulants. Patients continued to take their psychostimulant in the morning and were dosed either in the morning or the evening with INTUNIV XR or with placebo in addition to their psychostimulant. Symptoms of ADHD were evaluated as the change from baseline to endpoint in ADHD Rating Scale (ADHD-RS-IV) scores. Using the Conners’ Global Index-Parent (CGI-P) scale, parents made separate weekly assessments of their child’s ADHD symptoms exhibited in the morning (before school) and evening (before bedtime). Study Results Short-Term Monotherapy Trials Table 9 - Results of Studies 1, 2 and 3 in ADHD (Children and Adolescents aged 6-17 years) Study No. Primary Endpoints Associated value and statistical significance for Drug at specific dosages Associated value and statistical significance for Placebo Study 1a ADHD Rating Scale (ADHD-RS-IV) total score change from baseline to endpoint for the ITT population Mean (SD) 2 mg: -15.40 (12.82) 3 mg: -15.79 (13.00) 4 mg: -18.96 (13.71) Comparison (placebo-adjusted difference)b LS mean (95% CI) -7.42 (-12.07, -2.77) p=0.0006 -7.52 (-12.19, -2.85) p=0.0005 -9.99 (-14.67, -5.32) p<0.0001 Mean (SD) -8.86 (12.90) INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 31 of 42 Table 9 - Results of Studies 1, 2 and 3 in ADHD (Children and Adolescents aged 6-17 years) Study 2c ADHD Rating Scale (ADHD-RS-IV) total score change from baseline to endpoint for the ITT population Mean (SD) 1 mg: -20.4 (14.00) 2 mg: -18.0 (14.88) 3 mg: -19.4 (14.62) 4 mg: -20.9 (11.89) Comparison (placebo-adjusted difference)b LS mean (95% CI) -6.75 (-11.3, -2.2) p=0.0041 -5.41 (-9.9, -0.9) p=0.0176 -7.31 (-11.8, -2.8) p=0.0016 -7.88 (-12.3, -3.4) p=0.0006 Mean (SD) -12.2 (12.96) Study 3 ADHD Rating Scale (ADHD-RS-IV) total score change from baseline to endpoint for the FAS population Mean (SD) -25.7 (10.09) Comparison (placebo-adjusted difference) LS mean (95% CI) -6.026 (-8.865, -3.187) p<0.001 Mean (SD) -19.5 (12.63) ITT: Intent to Treat FAS: Full analysis set ap-value and 95% CI from Dunnett’s adjustment for multiple means comparisons bAge subgroup analysis revealed statistically significant efficacy for only children aged 6 to 12 years cOnly patients weighing <110lbs could be randomized to 1 mg In Study 1, the improvement in ADHD-RS-IV total scores at endpoint in all randomized INTUNIV XR treatment groups was statistically significantly greater than in placebo treatment groups (p<0.001) for each of the 2 mg, 3 mg, and 4 mg INTUNIV XR randomized treatment groups. Improvements in ADHD-RS-IV scores were observed in patients taking INTUNIV XR beginning 2 to 3 weeks after initiation of dosing. When data were examined by age subgroups, only children aged 6 to 12 years demonstrated clinically relevant improvements. INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 32 of 42 The improvement in the ADHD-RS-IV total score demonstrated in the primary efficacy analysis was supported by the results for the ADHD-RS-IV Hyperactivity/Impulsivity and Inattentiveness subscales, Clinical Global Impression of Improvement (CGI-I), Conners’ Parent Rating Scale Revised Short Form (CPRS-R:S) and Conners’ Teachers Rating Scale results. In Study 2, there were statistically significant improvements in ADHD-RS-IV total scores at endpoint in all randomized INTUNIV XR treatment groups compared to the placebo treatment groups (p<0.02) for each of the 2 mg, 3 mg, and 4 mg INTUNIV XR randomized treatment groups, and for the 1 mg INTUNIV XR treatment group (for patients 55-110lbs [24.95 - 49.89kg]). When data were examined by age subgroups, only children aged 6 to 12 years demonstrated clinically relevant improvements. The improvement in the ADHD-RS-IV total score demonstrated in the primary efficacy analysis was supported by the results for the ADHD-RS-IV Hyperactivity/Impulsivity and Inattentiveness subscales, Clinical Global Impression of Improvement (CGI-I), and Conners’ Parent Rating Scale Revised Short Form (CPRS-R:S) results. In Study 3, subjects receiving INTUNIV XR had a statistically significant greater improvement from baseline in ADHD-RS-IV total score compared with subjects who received placebo (p<0.001). The improvement in the ADHD-RS-IV total score demonstrated in the primary efficacy analysis was supported by the results of the Clinical Global Impression of Severity (CGI-S), ADHD-RS-IV Hyperactivity/Impulsivity and Inattentiveness subscales and Clinical Global Impression of Improvement (CGI-I). Controlled, long-term efficacy studies (>9 weeks) have not been conducted in children aged 6 to 12 years and (>15 weeks) in adolescents aged 13-17 years. INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 33 of 42 Short-Term Adjunctive Trial Table 10 - Results of Study 4 in ADHD (Children and Adolescents aged 6-17 years) Primary Endpoints Mean Associated value and statistical significance for Drug + Psychostimulant at all dosages (SD) Mean Associated value and statistical significance for Placebo (SD) LS meana Comparison - placebo-adjusted difference (95% CI) ADHD Rating Scale (ADHD-RS-IV) total score change from baseline to endpoint for FAS population All doses AM: -20.4 (12.77) All doses PM: -21.0 (12.39) Overall: -20.7 (12.56) -16.0 (11.77) -4.5 (-7.5, -1.4) p=0.002b -5.3 (-8.3, -2.3) p<0.001b -4.9 (-7.2, -2.6) p<0.001c FAS – Full analysis set aLS mean, and p-value were based on type III sum of squares from the ANCOVA model for the change from Baseline, including treatment group and psychostimulant type as fixed effects, and baseline value as a covariate. bp-value of INTUNIV XR AM and PM groups based on Dunnett’s multiple comparison procedure. cp-value for all INTUNIV XR was a t-test. This was a secondary efficacy analysis. Mean reductions in ADHD-RS-IV total scores at endpoint were significantly greater for INTUNIV XR given as an adjunct to a stable dose of psychostimulant compared to placebo given with a psychostimulant for Study 4, for both morning and evening INTUNIV XR dosing (p=0.002 and p<0.001 respectively). Both treatment groups had significantly greater improvement on the Hyperactivity/Impulsivity and Inattentive subscales of the ADHD-RS-IV compared with the placebo group regardless of time of administration. The percentage of responders, (defined as a percentage reduction from baseline in the ADHD-RS-IV Total Score of ≥25%), were 69.7% for placebo, 79.2% for INTUNIV XR taken in the morning (AM), and 83.1% for INTUNIV XR in the evening (PM) group. The results indicated a statistically significant difference from placebo in the evening (PM) INTUNIV XR dosing group but not the morning (AM) INTUNIV XR dosing group. Conners’ Global Index-Parent (CGI-P) total score results were supportive of the primary endpoint. Controlled long-term efficacy studies (>9 weeks) for adjunctive treatment have not been conducted. INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 34 of 42 Other Clinical Trials A 9-week, double-blind, randomized, placebo-controlled, dose-optimization study in children aged 6-12 years with ADHD and oppositional symptoms (n=217) was conducted. Oppositional symptoms were evaluated as the change from baseline to endpoint in the Oppositional Subscale of the Conners’ Parent Rating Scale – revised Long Form (CPRS-R:L) score. The mean reduction in the CPRS-R:L at endpoint was significantly greater for INTUNIV XR compared to placebo. ADHD-RS-IV Hyperactivity/Impulsivity and Inattention subscales results supported the pivotal study primary endpoint results. CGI-I and CGI-S rating scales and the 40-item Conduct Problem Scale of the New York Parent’s Rating Scale (NYPRS-S) results also support the primary efficacy endpoint in treating oppositional symptoms and conduct problems in children with a diagnosis of ADHD. A 9-week, double-blind, randomized, placebo-controlled, dose-optimization study in children aged 6-12 years to assess the efficacy of once daily dosing with optimized INTUNIV XR administered either in the morning or the evening was conducted. Symptoms of ADHD were evaluated as the change from baseline to endpoint in ADHD Rating Scale (ADHD-RS-IV) Total Score. INTUNIV XR showed significantly (p<0.001) greater improvement compared to placebo on the change from baseline to endpoint in the ADHD rating scale (ADHD-RS-IV) score regardless of time of administration (morning or evening) of INTUNIV XR. Conners’ Parent Rating Scale – Revised Short Form (CPRS-R:S) results were supportive of the primary endpoint. CPRS total scores, Weiss Functional Impairment Rating Scale - Parent (WFIRS-P) global score and WFIRS-P domain subscale scores for Family, Learning and School, Academic Performance, Behavior in School, Social Score, and Risk score results were also supportive of the primary endpoint. A 15-week, double-blind, dose-optimization, safety and tolerability study compared the effects of INTUNIV XR to placebo using the Choice Reaction Time Test from the Cambridge Neuropsychological Test Automated Battery (CANTAB) in patients aged 6 17 years (n=182). Patients were titrated to an optimal dose within a 1-3 mg range. There was no evidence of impairment in speed processing compared to placebo. The 5-point Pictorial Sleepiness Scale (PSS), designed to assess sleepiness in school-age children and adolescents, was used to measure sleepiness throughout the course of the day and study. Patient and observer (healthcare professional) reported outcomes on the PSS were similar during the daytime in a classroom setting for the INTUNIV XR and placebo groups. However, patients and observer (parent) scores suggested a greater degree of sleepiness in the evening hours before bedtime in the INTUNIV XR group compared to the placebo group. These trends were consistent throughout the study. The frequency and intensity of sedative adverse events was similar in this study to that observed in the pivotal studies. 16. Non-Clinical Toxicology No carcinogenic effect of guanfacine was observed in studies of 78 weeks in mice or 102 weeks in rats at doses up to 6.8 times the maximum recommended human dose of 0.12 mg/kg/day on a mg/m2 basis. Guanfacine was not genotoxic in a variety of test models, including the Ames test and an in vitro chromosomal aberration test; however, a marginal increase in numerical aberrations (polyploidy) was observed in the latter study. No adverse effects were observed in fertility studies in male and female rats at doses up to 22 times the maximum recommended human dose on a mg/m2 basis. Rat experiments have shown that guanfacine crosses the placenta. However, administration of guanfacine to rats and rabbits at 4 and 2.7 times, respectively, the maximum recommended human dose of 0.12 mg/kg/day on a mg/m2 basis resulted in no evidence of harm to the fetus. Higher doses (13.5 times the maximum recommended human dose in both rabbits and rats) were associated with INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 35 of 42 reduced fetal survival and maternal toxicity. INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 36 of 42 Patient Medication Information READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINE PrINTUNIV XR® guanfacine hydrochloride extended-release tablets This Patient Medication Information is written for the person who will be taking INTUNIV XR. This may be you or a person you are caring for. Read this information carefully. Keep it as you may need to read it again. This Patient Medication Information is a summary. It will not tell you everything about this medication. If you have more questions about this medication or want more information about INTUNIV XR, talk to a healthcare professional. What INTUNIV XR is used for: • INTUNIV XR is used to treat Attention Deficit Hyperactivity Disorder (ADHD) in children and adolescents 6-17 years of age. It can be used alone or with another medicine called a psychostimulant. INTUNIV XR may be a part of your/your child’s overall treatment plan for ADHD. The healthcare professional may also recommend counselling or other therapy. How INTUNIV XR works: INTUNIV XR contains the medicinal ingredient guanfacine. Guanfacine is not a central nervous system (CNS) stimulant. The exact way guanfacine works to treat ADHD in not known. INTUNIV XR is thought to affect receptors (alpha2A-adrenergic receptors) in the brain to reduce nerve impulses. This helps increase attention (including the ability to follow and finish tasks) and decrease impulsiveness and hyperactivity in patients with ADHD. The ingredients in INTUNIV XR are: Medicinal ingredient: guanfacine (as guanfacine hydrochloride) Non-medicinal ingredients: crospovidone, fumaric acid, glyceryl behenate, green pigment blend PB-1763 (3 mg and 4 mg tablets only), hypromellose, lactose monohydrate, methacrylic acid copolymer, microcrystalline cellulose, and povidone. INTUNIV XR comes in the following dosage forms: Tablets; 1 mg, 2 mg, 3 mg, and 4 mg Do not use INTUNIV XR if: • you/your child are/is allergic to guanfacine or any other non-medicinal ingredients in INTUNIV XR (see The ingredients in INTUNIV XR are:) To help avoid side effects and ensure proper use, talk to your healthcare professional before you take INTUNIV XR. Talk about any health conditions or problems you may have, including if you or your child: • has a heart problem such as: - a very slow heart rate (pulse) INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 37 of 42 - a heart rhythm problem (arrhythmia) - heart disease - congestive heart failure - a hereditary disorder of the heart’s electrical system (called congenital long QT syndrome) • has fainted in the past (or has a history of fainting) • has low or high blood pressure • has liver or kidney problems • have mental health problems or a family history of mental health problems including psychosis, mania, bipolar illness, depression, or suicide • has any other medical condition • is pregnant. Your healthcare professional will decide if you can take this medicine if you are pregnant. • is breastfeeding or plans to breastfeed. It is not known if INTUNIV XR passes into breast milk. Other warnings you should know about: The following have been reported with use of medicines used to treat ADHD such as INTUNIV XR: Mental Health problems (psychiatric): Suicidal behaviour and thoughts: New or worsening thoughts or feelings related to: • thoughts about suicide (thinking about or feeling like killing yourself) • suicide actions (a suicide attempt or completed suicide) Suicidal thoughts or behaviours may occur at any time during treatment, particularly: • when you or your child starts treatment • when there is a change to the dose • after you or your child stops taking INTUNIV XR Should this happen to you or your child, talk to your healthcare professional right away. Bipolar Disorder: New or worsening bipolar illness (extreme mood swings with periods of mania (unusually excited, over-active or un-inhibited) alternating with periods of depression (feelings of sadness, worthlessness or hopelessness). Tell your/your child’s healthcare professional about: • any mental health problems you or your child has • family history of suicide, bipolar disorder or depression Psychotic or Manic Symptoms: New or worsening of psychotic or manic symptoms can occur when taking INTUNIV XR at usual doses. Symptoms can include: • hallucinations (hearing voices, believing things that are not true or feeling suspicious) • feeling unusually excited, over-active or un-inhibited Call your healthcare professional right away if you or your child has any new or worsening mental health symptoms while taking INTUNIV XR, especially seeing or hearing things that are not real, INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 38 of 42 believing things that are not real, or you start feeling suspicious. Aggressive behaviour: New or worse aggressive behaviour, hostility can occur. These new or worsening mental health problems may be more likely to occur if your child has mental disorders that you may or may not have known about. Feeling sleepy/drowsy: INTUNIV XR can make you or your child feel sleepy and drowsy. Avoid doing tasks that require special attention such as riding a bike, driving/operating machinery or doing other dangerous activities until you know how INTUNIV XR affects you or your child. If you notice you or your child is feeling sleepy or drowsy often, talk to your healthcare professional. Do NOT take INTUNIV XR with alcohol or other medicines that make you or your child feel sleepy or drowsy. This can make it worse. Dehydration: While on INTUNIV XR, you/your child should avoid becoming dehydrated or overheated. Weight: Talk to your/your child’s healthcare professional about any problem with weight while taking INTUNIV XR. Monitoring: Your/your child’s healthcare professional should monitor your/your child’s heart rate and blood pressure before starting treatment, periodically during treatment, when the dose is changed and after stopping treatment. Tell your healthcare professional about all the medicines you take, including any drugs, vitamins, minerals, natural supplements or alternative medicines. The following may interact with INTUNIV XR: • ketoconazole (used to treat yeast or fungal infections) • rifampin (used to treat tuberculosis (TB)) • valproic acid (used to treat bipolar disorder) • medicines that can lower your heart rate, such as antiarrhythmics and beta blockers • medicines used to treat chest pain (angina) • medicines used to treat high blood pressure • medicines that can cause QT prolongation • medicines that can increase your risk of fainting • medicines that cause sleepiness (sedatives) • medicines inducing sleep in surgical anesthesia or in the treatment of insomnia (hypnotics) • medicines used as tranquilizer (benzodiazepines) • medicines used as central nervous system depressants (barbiturates) • medicines used to treat psychosis (antipsychotics) • other medicines for ADHD (such as methylphenidate, lisdexamfetamine dimesylate) • any medicine that may cause heart valve problems • alcohol INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 39 of 42 • grapefruit, grapefruit juice or products containing grapefruit extract How to take INTUNIV XR: • Take/give INTUNIV XR exactly as your/your child’s healthcare professional has told you. • Take/give INTUNIV XR once a day, either alone or with an ADHD psychostimulant medication prescribed by your/your child’s healthcare professional. Your healthcare professional will tell you when you/your child should take INTUNIV XR and when to take the other ADHD psychostimulant medication. • Swallow the tablet whole with a small amount of liquid. Do NOT crush, chew or break the tablet before swallowing and do NOT take it with a high-fat meal. • Do NOT stop taking INTUNIV XR or giving it to your child without talking to your healthcare professional. Stopping this medication suddenly may lead to a serious increase in blood pressure and heart rate. Your healthcare professional will decrease the dose slowly over time to avoid side effects. This is especially important if you/your child are taking a psychostimulant along with INTUNIV XR. Usual dose: Usual child and adolescent (6-17 years of age) dose: The recommended starting dose is 1 mg tablet once a day. Your healthcare professional may change the dose until it is right for you/your child. Overdose: If you think you, or a person you are caring for, have taken or been given too much INTUNIV XR, contact a healthcare professional, hospital emergency department, regional poison control centre or Health Canada's toll-free number, 1-844 POISON-X (1-844-764-7669) immediately, even if there are no signs or symptoms. Possible symptoms of an overdose include: • low blood pressure • initial high blood pressure • slowing of heart rhythm • trouble breathing • feeling tired/having low energy Missed Dose: • If you miss two or more doses in a row, talk to your healthcare professional or your child’s healthcare professional. Your healthcare professional may need to restart you/your child on a lower dose. Possible side effects from using INTUNIV XR: These are not all the possible side effects you may have when taking INTUNIV XR. If you experience any side effects not listed here, tell your healthcare professional. Side effects may include: • feeling sleepy, trouble sleeping • feeling tired • feeling dizzy INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 40 of 42 • headache • nausea • stomach pain • not feeling hungry (decreased appetite) • feeling drowsy • dry mouth • constipation Serious side effects and what to do about them Frequency/Side Effect/Symptom Talk to your healthcare professional Stop taking this drug and get immediate medical help Only if severe In all cases Common Feeling sleepy x Hypotension (low blood pressure): dizziness, fainting, light-headedness, blurred vision, nausea, vomiting, fatigue (may occur when you go from lying or sitting to standing up) x Uncommon Fainting x Low heart rate (pulse) x Seizures (fits): muscle twitching, changes in emotions, confusion, uncontrollable shaking with or without loss of consciousness x Unknown Aggressive Behavior or Hostility x Allergic Reaction: difficulty swallowing or breathing, wheezing; drop in blood pressure; feeling sick to your stomach and throwing up; hives or rash; swelling of the face, lips, tongue or throat x Hallucinations: seeing, feeling or hearing things that are not there x High Blood Pressure after suddenly stopping INTUNIV XR: headaches, feeling confused, nervousness, x INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 41 of 42 Frequency/Side Effect/Symptom Talk to your healthcare professional Stop taking this drug and get immediate medical help Only if severe In all cases agitation, tremors Mania: feeling unusually excited, over-active, or un-inhibited x New Psychotic or Manic Symptoms: paranoia, delusions x Suicidal Behavior: thoughts or actions about hurting or killing yourself x If you have a troublesome symptom or side effect that is not listed here or becomes bad enough to interfere with your daily activities, tell your healthcare professional. Reporting side effects You can report any suspected side effects associated with the use of health products to Health Canada by: • Visiting the Web page on Adverse Reaction Reporting (canada.ca/drug-device-reporting) for information on how to report online, by mail or by fax; or • Calling toll-free at 1-866-234-2345. NOTE: Contact your healthcare professional if you need information about how to manage your side effects. The Canada Vigilance Program does not provide medical advice. Storage: Store: 15° to 30°C. Keep out of reach and sight of children. If you want more information about INTUNIV XR: • Talk to your healthcare professional • Find the full product monograph that is prepared for healthcare professionals and includes the Patient Medication Information by visiting the Health Canada Drug Product Database website (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html); the manufacturer’s website (https://takeda.info/ca-medicines), or by calling 1-800-268-2772. This leaflet was prepared by Takeda Canada Inc. 22 Adelaide Street West, Suite 3800 Toronto, Ontario M5H 4E3 Date of Authorization: 2025-10-14 INTUNIV XR® (guanfacine hydrochloride extended-release tablets) Page 42 of 42 INTUNIV XR is a registered trademark of Takeda Pharmaceuticals U.S.A., Inc. Takeda and the Takeda Logo are trademarks of Takeda Pharmaceutical Company Limited, used under license.