Intuniv (Guanfacine Hydrochloride) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

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

• Hypotension, bradycardia, and syncope [see Warnings and Precautions ]
• Sedation and somnolence [see Warnings and Precautions ]

The most common adverse reactions with INTUNIV™ are: somnolence/sedation, abdominal pain, dizziness, hypotension/decreased blood pressure, dry mouth, and constipation.

Twelve percent (12%) of patients receiving INTUNIV™ discontinued from the 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/decreased blood pressure, headache, and dizziness.

Clinical Trial Experience

Short Term 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, 2, 3, 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/decreased blood pressure, dry mouth and constipation.

Table 1: Percentage of Patients Experiencing Common (≥2%) Adverse Reactions in Short-Term Studies 1 and 2
Adverse Reaction Term	Placebo (N=149)	All Doses of INTUNIV™ (N=513)
Somnolencea	12%	38%
Headache	19%	24%
Fatigue	3%	14%
Abdominal pain (upper)	7%	10%
Nausea	2%	6%
Lethargy	3%	6%
Dizziness	4%	6%
Irritability	4%	6%
Hypotension/Decreased blood pressure	4%	6%
Decreased appetite	3%	5%
Dry mouth	1%	4%
Constipation	1%	3%
a: The somnolence term includes somnolence, sedation, and hypersomnia.

Less Common Adverse Reactions - Less common adverse reactions (< 2%) reported in pivotal Studies 1 and 2 that occurred in more than one patient taking INTUNIV^™ and were more common than in the placebo group are listed below.

Table 2: Less Common Adverse Reactions (< 2%) in Short-Term Studies 1 and 2
Body System	Adverse Reaction
Cardiac	Atrioventricular block, bradycardia, sinus arrhythmia
Gastrointestinal	Dyspepsia
General	Asthenia, chest pain
Investigations	Increased alanine aminotransferase, increased blood pressure, increased weight
Nervous system	Postural dizziness
Renal	Increased urinary frequency, enuresis
Respiratory	Asthma
Vascular	Orthostatic hypotension, pallor

In addition, the following less common (< 2%) psychiatric disorders occurred in more than one patient receiving INTUNIV^™ and were more common than in the placebo group. The relationship to INTUNIV^™ could not be determined because these events may also occur as symptoms in pediatric patients with ADHD: agitation, anxiety, depression, emotional lability, nightmares or interrupted sleep.

Long Term Clinical Studies

Common Adverse Reactions

Patients from the two short-term, placebo-controlled studies 1 and 2 were eligible to participate in one of two long-term, flexible-dose, open-label studies. The mean duration of exposure of the 446 patients who received open-label treatment was approximately 10 months. The distribution of patients among the doses prior to tapering off upon completion of the study was 37%, 33%, 27% and 3% on 4 mg, 3 mg, 2 mg and 1 mg, respectively.

The most common adverse reactions (≥5%) reported during open label treatment are shown in Table 3.

Table 3: Percentage of Patients Experiencing Common (≥5%) Adverse Reactions during Long-Term (Up to 10 months), Flexible-dose, Open-Label Follow-up from Studies 1 and 2
Adverse Reaction Term	All Doses of INTUNIV™ (N=446)
Somnolencea	45%
Headache	26%
Fatigue	15%
Abdominal pain (upper)	11%
Hypotension / Decreased Blood Pressure	10%
Vomiting	9%
Dizziness	7%
Nausea	7%
Weight increased	7%
Irritability	6%
a: The somnolence term includes somnolence, sedation, and hypersomnia.

Adverse Reactions Leading to Discontinuation - Eighteen percent (18%) of patients receiving INTUNIV^™ discontinued from long-term studies due to adverse events. The most frequent adverse reactions leading to discontinuation (≥2%) were somnolence (3%), syncopal events (2%), increased weight (2%), depression (2%), and fatigue (2%). Other adverse reactions leading to discontinuation in the long-term studies (occurring in approximately 1% of patients) included: hypotension/decreased blood pressure, sedation, headache, and lethargy.

Serious Adverse Reactions - In long-term open label studies, serious adverse reactions occurring in more than one patient were syncope (2%) and convulsion (0.4%).

Less Common, Adverse Reactions - Adverse reactions that occurred in < 5% of patients but ≥ 2% in open-label, long-term studies that are considered possibly related to INTUNIV^™ include: syncopal events, constipation, stomach discomfort, hypertension/increased blood pressure, decreased appetite, diarrhea, dry mouth, lethargy, and insomnia.

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 1 kg (2 lbs) 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.

REPORTS OF SUSPECTED INTUNIV SIDE EFFECTS / ADVERSE REACTIONS

Possible Intuniv side effects / adverse reactions in 8 year old male

Reported by a consumer/non-health professional from United States on 2011-10-17

Patient: 8 year old male

Reactions: Hallucination

Suspect drug(s):
Intuniv

Possible Intuniv side effects / adverse reactions in 13 year old male

Reported by a consumer/non-health professional from United States on 2011-10-18

Patient: 13 year old male

Reactions: Syncope, Bradycardia

Suspect drug(s):
Intuniv
    Dosage: 3 mg, unknown
    Administration route: Oral
    Indication: Product Used FOR Unknown Indication

Intuniv
    Dosage: unk, unknown
    Administration route: Oral

Possible Intuniv side effects / adverse reactions in 6 year old female

Reported by a physician from United States on 2011-10-21

Patient: 6 year old female weighing 16.5 kg (36.3 pounds)

Reactions: Grand MAL Convulsion, Drug Effect Decreased, Dyskinesia, Fear, Screaming, Mood Swings, Somnolence, Tremor

Suspect drug(s):
MAS (Mixed Amphetamine Salts)(amphetamine Aspartate, Amphetamine Sulfa
    Dosage: 10 mg(in the afternoon), 1x/day:gd, oral
    Administration route: Oral
    Indication: Product Used FOR Unknown Indication
    Start date: 2011-01-01

Vyvanse
    Dosage: 50 mg, oral
    Administration route: Oral
    Indication: Attention Deficit/hyperactivity Disorder
    Start date: 2010-01-01

Intuniv
    Dosage: 1 mg, oral, 2 mg, oral
    Administration route: Oral
    Indication: Attention Deficit/hyperactivity Disorder
    Start date: 2011-01-01
    End date: 2011-01-01

Intuniv
    Dosage: 1 mg, oral, 2 mg, oral
    Administration route: Oral
    Indication: Attention Deficit/hyperactivity Disorder
    Start date: 2011-04-28
    End date: 2011-01-01

Other drugs received by patient: Corticosteroid NOS (Corticosteroid Nos); Guanfacine (Guanfacine) Tablet