INTUNIV adverse reactions
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
Adverse Reactions
The following serious adverse reactions are described elsewhere in the labelling:
- Hypotension, bradycardia, and syncope [see Warnings and Precautions (5.1)]
- Sedation and somnolence [see Warnings and Precautions (5.2)]
6.1 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 clinical practice.
A total of 2,028 subjects have been exposed to INTUNIV® while participating in clinical trials. This includes 1,533 patients from completed studies in children and adolescents, and 495 subjects 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.
Monotherapy Trials
Most Common Adverse Reactions - The most commonly observed adverse reactions (incidence ≥ 5% and at least twice the rate for placebo) in the monotherapy trials (Studies 1 and 2) with INTUNIV® were: somnolence, fatigue, nausea, lethargy, and hypotension.
Adverse Reactions Leading to Discontinuation - Twelve percent (12%) of patients receiving INTUNIV® discontinued from the monotherapy clinical studies (Studies 1 and 2) due to adverse reactions, 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
Most Common Adverse Reactions - 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.
Adverse Reactions Leading to Discontinuation – In the adjunctive clinical study, 3% of patients receiving INTUNIV® discontinued due to adverse reactions, compared to 1% in the placebo group. Each adverse reaction leading to discontinuation occurred in less than 1% of INTUNIV®-treated patients.
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 2. Adverse reactions that were dose-related include: somnolence/sedation, abdominal pain, dizziness, hypotension, dry mouth and constipation.
 |
In an 8-week, placebo-controlled study in children 6-12 years of age with ADHD in which INTUNIV® was dosed once (1-4 mg/day) in the morning or evening (Study 4), the safety profile was consistent with the once daily morning dosing of INTUNIV®.
Short Term Adjunctive Clinical Study
Common Adverse Reactions - A 8-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 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 systolic blood pressure, diastolic blood pressure, and pulse were −5 mmHg, −3 mmHg, 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 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. 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.
Other Adverse Reactions Observed in Clinical Studies
Table 4 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.
 |
6.2 Post-marketing 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.
An open-label post-marketing study involving 21,718 patients was conducted to assess the safety of guanfacine (as the hydrochloride) 1 mg/day given at bedtime for 28 days. Guanfacine was administered with or without other antihypertensive agents. Adverse events reported in the post-marketing study at an incidence greater than 1% included dry mouth, dizziness, somnolence, fatigue, headache and nausea. The most commonly reported adverse events in this study were the same as those observed in controlled clinical trials.
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
Central Nervous System: paresthesias, vertigo
Eye Disorders: blurred vision
Musculo-Skeletal System: arthralgia, leg cramps, leg pain, myalgia
Psychiatric: confusion, hallucinations
Reproductive System, Male: impotence
Respiratory System: dyspnea
Skin and Appendages: alopecia, dermatitis, exfoliative dermatitis, pruritus, rash
Special Senses: alterations in taste[1]
References
- ↑ "INTUNIV (GUANFACINE) TABLET, EXTENDED RELEASE INTUNIV (GUANFACINE) KIT [SHIRE US MANUFACTURING INC.]". Retrieved 25 February 2014.