Intuniv, Page 1

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 two controlled…

INTUNIV- guanfacine hydrochloride tablet, extended release
INTUNIV- guanfacine
Shire US Manufacturing Inc.

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 two controlled monotherapy clinical trials (8 and 9 weeks in duration) and one controlled adjunctive trial with psychostimulants (9 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 9 weeks) has not been systematically evaluated in controlled trials.

A diagnosis of ADHD implies the presence of hyperactive-impulsive and/or inattentive symptoms that cause impairment and were present before the age of 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; “on the go”; excessive talking; blurting answers; can’t wait turn; intrusive. The Combined Type requires both inattentive and hyperactive-impulsive criteria to be met.

Special Diagnostic Considerations

Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but also of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presence of the required number of DSM-IV® characteristics.

Need for Comprehensive Treatment Program

INTUNIV® is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, and social) for patients with this syndrome. Drug treatment may not be indicated for all patients with this syndrome. INTUNIV® is not intended for use in patients who exhibit symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational/vocational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe INTUNIV® will depend upon the physician’s assessment of the chronicity and severity of the patient’s symptoms and on the level of functional impairment.

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

INTUNIV® 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. Do not administer with high fat meals, due to increased exposure.

Do not substitute for immediate-release guanfacine tablets on a mg-per-mg 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)].

2.2 Dose Selection

If switching from immediate-release guanfacine, discontinue that treatment, and titrate with INTUNIV® according to the following recommended schedule.

Begin at a dose of 1 mg/day, and adjust in increments of no more than 1 mg/week, for both monotherapy and adjunctive therapy to a psychostimulant.

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. In clinical trials, patients were randomized or dose optomized to doses of 1 mg, 2 mg, 3 mg or 4 mg and received INTUNIV® once daily in the morning in monotherapy trials and once daily in the morning or the evening in the adjunctive therapy trial [see Clinical Studies (14.1)].

In monotherapy trials, clinically relevant improvements were observed beginning at doses in the range 0.05-0.08 mg/kg once daily. 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. Doses above 4 mg/day have not been systematically studied in controlled clinical trials.

In the adjunctive trial, the majority of subjects reached optimal doses in the 0.05-0.12 mg/kg/day range.

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 Maintenance Treatment

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.

2.4 Discontinuation

In a pharmacodynamic study in healthy young adult volunteers receiving INTUNIV® (4 mg once daily) or placebo, the effects of abrupt discontinuation were compared to tapering. There were greater mean increases in systolic and diastolic blood pressure and heart rate after abrupt discontinuation of INTUNIV®, but these changes generally reflected a return to original baseline and were not meaningfully different for the two discontinuation strategies. However, 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.

2.5 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.

3 DOSAGE FORMS AND STRENGTHS

1 mg, 2 mg, 3 mg and 4 mg extended-release tablets

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

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 Hypotension, Bradycardia, and Syncope

Treatment with INTUNIV® can cause decreases in blood pressure and heart rate. In the monotherapy, pediatric, short-term (8-9 weeks), controlled trials, the maximum mean changes from baseline in systolic blood pressure, diastolic blood pressure, and pulse were -5 mm Hg, -3 mm Hg, 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 event 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.

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, or cardiovascular disease, because it can decrease blood pressure and heart rate. Use caution in treating 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. 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 (38% for INTUNIV® vs. 12% for placebo in monotherapy studies and 18% for INTUNIV® vs. 7% for placebo in the adjunctive study) in children and adolescents with ADHD, especially during initial use [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.

5.3 Other Guanfacine-Containing Products

Guanfacine, the active ingredient in INTUNIV®, is also approved as an antihypertensive. Do not use INTUNIV® in patients concomitantly taking other guanfacine-containing products (e.g., Tenex).

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labelling:

Monotherapy Trials

The most commonly observed adverse reactions (incidence ≥ 5% and at least twice the rate for placebo) in the monotherapy trials with INTUNIV® were: somnolence, fatigue, nausea, lethargy, and hypotension.

Twelve percent (12%) of patients receiving INTUNIV® discontinued from the monotherapy clinical studies due to adverse events, 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

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.

Three percent of patients receiving INTUNIV® discontinued from the adjunctive clinical study due to adverse events, compared to 1% in the placebo group.

6.1 Clinical Trial Experience

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.

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 painb 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.

Short Term Adjunctive Clinical Study

A 9-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 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 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®.

Laboratory Tests

In short and long-term studies, no clinically important effects were identified on any laboratory parameters.

Effects on Heart Rate and QT Interval

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.

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.

The mean duration of exposure of the 446 patients in two 2-year, open-label long-term studies was approximately 10 months. The percentage of patients at each dose upon completion or early withdrawal from the studies was 37% (n=164) for 4 mg, 33% (n=149) for 3 mg, 27% (n=119) for 2 mg, and 3% (n=14) for 1 mg, respectively. The number of patients at each dose (prior to tapering) that completed the 2-year studies was n=27 for 4 mg, n=24 for 3 mg, n=14 for 2 mg, and n=2 for 1 mg, respectively.

Table 3: Other adverse reactions observed in clinical studies
Body System Adverse Reactions
Cardiac Atrioventricular block, sinus arrhythmia
Gastrointestinal Dyspepsia, stomach discomfort, vomiting
General Asthenia, chest pain
Immune System Disorders Hypersensitivity
Investigations Increased alanine amino transferase, increased blood pressure, increased weight
Nervous system Convulsion, postural dizziness, syncope
Psychiatric Agitation, anxiety, depression, nightmare
Renal Increased urinary frequency, enuresis
Respiratory Asthma
Vascular Hypertension, pallor

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