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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]

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 som nolence/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.

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, 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, dry mouth and constipation.

Table 1: Percentage of Patients Experiencing Common ( ≥ 2%) Adverse Reactions in Short-Term Monotherapy Studies 1 and 2

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, 2, 3, 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

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 proarrhythmic 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

CYP3A4/5 Inhibitors

Use caution when INTUNIV® is administered to patients taking ketoconazole and other strong CYP3A4/5 inhibitors, since elevation of plasma guanfacine concentration increases the risk of adverse events such as hypotension, bradycardia, and sedation. There was a substantial increase in the rate and extent of guanfacine exposure when administered with ketoconazole; the guanfacine exposure increased 3-fold (AUC).

CYP3A4 Inducers

When patients are taking INTUNIV® concomitantly with a CYP3A4 inducer, an increase in the dose of INTUNIV® within the recommended dose range may be considered. There was a significant decrease in the rate and extent of guanfacine exposure when coadministered with rifampin, a CYP3A4 inducer. The exposure to guanfacine decreased by 70% (AUC).

Valproic Acid

Co-administration of guanfacine and valproic acid can result in increased concentrations of valproic acid. The mechanism of this interaction is unknown, although both guanfacine (via a Phase I metabolite, 3-hydroxy guanfacine) and valproic acid are metabolized by glucuronidation, possibly resulting in competitive inhibition. When INTUNIV® is co-administered with valproic acid, monitor patients for potential additive CNS effects, and consider monitoring serum valproic acid concentrations. Adjustments in the dose of valproic acid may be indicated when co-administered with INTUNIV®.

Antihypertensive Drugs

Use caution when INTUNIV® is administered concomitantly with antihypertensive drugs, due to the potential for additive pharmacodynamic effects (e.g., hypotension, syncope) [see WARNINGS AND PRECAUTIONS].

CNS Depressant Drugs

Caution should be exercised when INTUNIV® is administered concomitantly with CNS depressant drugs (e.g. alcohol, sedative/hypnotics, benzodiazepines, barbiturates, and antipsychotics) due to the potential for additive pharmacodynamic effects (e.g., sedation, somnolence) [see WARNINGS AND PRECAUTIONS].

Oral Methylphenidate

In a drug interaction study (N=35), neither INTUNIV® (4mg) nor CONCERTAR (methylphenidate HCl) (36mg) were found to affect the pharmacokinetics of the other drug when co-administered.

Lisdexamfetamine Dimesylate

In a drug interaction study (N=40), administration of INTUNIV® in combination with VYVANSE® (lisdexamfetamine dimesylate) (50 mg) increased guanfacine maximum plasma concentration by 19%, whereas exposure (area under the curve; AUC) was increased by 7%. These small changes are not expected to be clinically meaningful. In this study, no effect on d-amphetamine exposure was observed following coadministration of INTUNIV® and VYVANSE®.

Drug Abuse And Dependence

Controlled Substance

INTUNIV® is not a controlled substance and has no known potential for abuse or dependence.

Last reviewed on RxList: 6/17/2011
This monograph has been modified to include the generic and brand name in many instances.