Intuniv Drug Information

® is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications. INTUNIV is a central alpha 2A -adrenergic receptor agonist indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications.

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) 1 mg The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. (N=61) 2 mg (N=150) 3 mg (N=151) 4 mg (N=151) All Doses of INTUNIV (N=513) Somnolence The somnolence term includes somnolence, sedation, and hypersomnia. 11% 28% 30% 38% 51% 38% Fatigue 3% 10% 13% 17% 15% 14% Hypotension The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). 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 INTUNIV and >rate than in placebo) in Fixed Dose Studies 1 and 2 INTUNIV (mg) Adverse Reaction Term Placebo (N=149) 1 mg The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. (N=61) 2 mg (N=150) 3 mg (N=151) 4 mg (N=151) All Doses of INTUNIV (N=513) n (%) n (%) n (%) n (%) n (%) n (%) 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. Total patients 4 (3%) 2 (3%) 10 (7%) 15 (10%) 27 (18%) 54 (11%) Somnolence The somnolence term includes somnolence, sedation, and hypersomnia. 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 INTUNIV and >rate than in placebo) in Fixed Dose Studies 1 and 2 INTUNIV (mg) Adverse Reaction Term Placebo (N=149) 1 mg The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. (N=61) 2 mg (N=150) 3 mg (N=151) 4 mg (N=151) All Doses of INTUNIV (N=513) 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.

Headache 19% 26% 25% 16% 28% 23% Abdominal Pain The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. 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 The nightmare term includes abnormal dreams, nightmare, and sleep terror. 0% 0% 0% 3% 4% 2% Enuresis The enuresis term includes enuresis, nocturia, and urinary incontinence. 1% 0% 1% 3% 2% 2% Affect Lability The affect lability term includes affect lability and mood swings. 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 INTUNIV Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of INTUNIV (N=221) Somnolence The somnolence term includes somnolence, sedation, and hypersomnia. 15% 57% 54% 56% Abdominal Pain The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness 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 The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). 0% 6% 4% 5% Decreased Appetite 3% 6% 3% 4% Enuresis The enuresis term includes enuresis, nocturia, and urinary incontinence. 1% 2% 5% 4% 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 (%) Adverse reactions leading to discontinuation in ≥2% in any dose group but did not meet this criteria in all doses combined: fatigue Total patients 0 (0%) 8 (7%) 7 (6%) 15 (7%) Somnolence The somnolence term includes somnolence, sedation, and hypersomnia. 0 (0%) 4 (4%) 3 (3%) 7 (3%) 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) 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). Headache 11% 18% 16% 17% Insomnia The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. 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 Adverse Reaction Term Placebo (N=155) All Doses of INTUNIV (N=157) Somnolence The somnolence term includes somnolence, sedation, and hypersomnia. 23% 54% Insomnia The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. 6% 13% Hypotension The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). 3% 9% Dry Mouth 0% 8% Postural Dizziness 2% 5% Bradycardia The bradycardia term includes bradycardia and sinus bradycardia. 0% 5% There were no specific adverse reactions ≥2% in any treatment group that led to discontinuation in the monotherapy flexible dose study (Study 5). 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) 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). Headache 18% 27% Fatigue 12% 22% Dizziness 10% 16% Decreased Appetite 14% 15% Abdominal Pain The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. 8% 12% Irritability 4% 7% Anxiety The anxiety term includes anxiety and nervousness. 3% 5% Rash The rash term includes rash, rash generalized, and rash papular. 1% 3% Constipation 0% 3% Increased Weight 2% 3% Abdominal/Stomach Discomfort The abdominal/stomach discomfort term includes abdominal discomfort, epigastric discomfort, and stomach discomfort. 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 INTUNIV + stimulant Adverse Reaction Term Placebo+ stimulant (N=153) AM (N=150) PM (N=152) All Doses (N=302) Somnolence The somnolence term includes somnolence, sedation, and hypersomnia. 7% 18% 18% 18% Insomnia The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. 6% 10% 14% 12% Abdominal Pain The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. 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 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) 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). Headache 13% 21% 21% 21% Diarrhea 1% 4% 3% 4% Hypotension The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased. 0% 4% 2% 3% Constipation 0% 2% 3% 2% Affect Lability The affect lability term includes affect lability and mood swings. 1% 3% 2% 2% Dry Mouth 0% 1% 3% 2% Bradycardia The bradycardia term includes bradycardia and sinus bradycardia. 0% 1% 3% 2% Postural Dizziness 0% 1% 3% 2% Rash The rash term includes rash, rash generalized, and rash papular. 1% 1% 2% 2% Nightmare The nightmare term includes abnormal dreams, nightmare, and sleep terror. 1% 2% 1% 2% Tachycardia The tachycardia term includes tachycardia and sinus tachycardia. 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 -4.8 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 , 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 . 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.

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

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 INTUNIV. 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 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 Strong and moderate CYP3A4 inhibitors increase guanfacine exposure. Decrease INTUNIV to 50% of target dosage when coadministered with strong and moderate CYP3A4 inhibitors. 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.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including INTUNIV, 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/m 2 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.

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 to 17 who met DSM-IV ® criteria for ADHD. 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.

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. History of hypersensitivity to INTUNIV, its inactive ingredients, or other products containing guanfacine.

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.