Intuniv Drug Information

INTUNIV ® is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications.

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).

Table 1: Recommended Target Dose Range for Therapy with INTUNIV In the adjunctive trial which evaluated INTUNIV 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.

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 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.

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 to 0.12 mg/kg/day range.

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.

Missed Doses

When reinitiating patients to the previous maintenance dose after two or more missed consecutive doses, consider titration based on patient tolerability.

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). Table 2: INTUNIV Dosage Adjustments for Patients Taking Concomitant CYP3A4 Inhibitors or Inducers

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. 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) and >rate than in placebo in Fixed Dose Studies 1 and 2 and >rate than in placebo in Fixed Dose Studies 1 and 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 and >rate than in placebo in Monotherapy Flexible Dose Study 4 and >rate than in placebo in the Monotherapy Flexible Dose Study 4 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 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 Adjunctive Trial Table 11: Percentage of Patients Experiencing Most Common (≥5% and at least twice the rate for placebo) 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 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).

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. 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.

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 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 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. These findings were not observed with guanfacine alone at 1 mg/kg/day or methylphenidate alone at 50 mg/kg/day.

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.

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.