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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 [ ]. The effectiveness of INTUNIV for longer-term use (more than 8 weeks) has not been systematically evaluated in controlled trials. ® ® ® see Clinical Studies (14) ® 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

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Dosage And Administration

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 ®

Dosage Forms And Strengths

1 mg, 2 mg, 3 mg and 4 mg extended-release tablets Extended-release tablets: 1 mg, 2 mg, 3 mg and 4 mg ( ) 3

Contraindications

Patients with a history of hypersensitivity to INTUNIV , its inactive ingredients or other products containing guanfacine should not take INTUNIV . ® [ ] see Description (11) ® History of hypersensitivity to INTUNIV , its inactive ingredients, or other products containing guanfacine ( ). ® 4

Warning and Cautions

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 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 [ . 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) ® ® .

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) 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 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 . 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. 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 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:

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 . 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) Figure 1: Impact of Other Drugs on the Pharmacokinetics (PK) of Intuniv Figure 2: Impact of Intuniv on the Pharmacokinetics (PK) of Other Drugs 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 ( and ). 2.7 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 ( and ). 2.7 7 Figure 1 Figure 2

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 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.