Summary of the safety profile: The most frequently observed adverse drug reactions (ADRs) reported in ≥ 5 % of patients in two double-blind controlled clinical trials of Abilify Maintena were weight increased (9.0 %), akathisia (7.9 %), insomnia (5.8 %), and injection site pain (5.1 %).
Tabulated list of adverse reactions: The incidences of the Adverse Drug Reactions (ADRs) associated with aripiprazole therapy are tabulated as follows. The table is based on adverse events reported during clinical trials and/or post-marketing use.
All ADRs are listed by system organ class and frequency; very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse events is qualified as "not known". (See Table 5A and Table 5B.)
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Description of selected adverse reactions: Injection site reactions: During the double-blind, controlled phases of the two trials, injection site reactions were observed; those seen were generally mild to moderate in severity, and resolved over time. Injection site pain (incidence 5.1 %), has a median onset on day 2 after the injection and a median duration of 4 days.
In an open label study comparing bioavailability of Abilify Maintena administered in the deltoid or gluteal muscle, injection site related reactions were slightly more frequent in the deltoid muscle. The majority were mild and improved on subsequent injections When compared to studies where Abilify Maintena was injected in the gluteal muscle, repeated occurrence of injection site pain is more frequent in the deltoid muscle.
Leukopenia: Neutropenia has been reported in the clinical program with Abilify Maintena and typically starts around day 16 after first injection, and lasts a median of 18 days.
Extrapyramidal Symptoms (EPS): In trials in stable patients with schizophrenia, Abilify Maintena was associated with a higher frequency of EPS symptoms (18.4 %) than oral aripiprazole treatment (11.7 %). Akathisia was the most frequently observed symptom (8.2 %) and typically starts around day 10 after first injection, and lasts a median of 56 days.
Subjects with akathisia typically received anti-cholinergic medicines as treatment, primarily benzatropine mesilate and trihexyphenidyl. Less often substances such as propranolol and benzodiazepines (clonazepam and diazepam) were administered to control akathisia.
Parkinsonism events followed in frequency (6.9 % Abilify Maintena, 4.15 % oral aripiprazole 10-30 mg tablets group and 3.0 % placebo, respectively).
Dystonia: Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic medicinal products. An elevated risk of acute dystonia is observed in males and younger age groups.
Weight: During the double-blind, active-controlled phase of the 38-week trial, the incidence of weight gain of ≥7 % from baseline to last visit was 9.5 % for Abilify Maintena group and 11.7 % for the oral aripiprazole tablets 10-30 mg group. The incidence of weight loss of ≥ 7 % from baseline to last visit was 10.2 % for Abilify Maintena and 4.5 % for oral aripiprazole tablets 10-30 mg.
During the double-blind, placebo-controlled phase of the 52-week trial, the incidence of weight gain of ≥ 7 % from baseline to last visit was 6.4 % for the Abilify Maintena group and 5.2 % for the placebo group.
The incidence of weight loss of ≥ 7 % from baseline to last visit was 6.4 % for the Abilify Maintena group and 6.7 % for the placebo group. During double-blind treatment, mean change in body weight from baseline to last visit was -0.2 kg for Abilify Maintena and -0.4 kg for placebo (p = 0.812).
Prolactin: In the double-blind active-controlled phase of the 38-week, trial, from baseline to last visit there was a mean decrease in prolactin levels in the Abilify Maintena group (-0.33 ng/ml) compared with a mean increase in the oral aripiprazole tablets 10-30 mg group (0.79 ng/ml; p < 0.01). The incidence of Abilify Maintena patients with prolactin levels > 1 time the upper limit of normal range (ULN) at any assessment was 5.4 % compared with 3.5 % of the patients on oral aripiprazole tablets 10-30 mg. Male patients generally had a higher incidence than female patients in each treatment group.
In the double-blind placebo-controlled phase of the 52-week trial, from baseline to last visit there was a mean decrease in prolactin levels in the Abilify Maintena group (-0.38 ng/ml) compared with a mean increase in the placebo group (1.67 ng/ml).
The incidences of Abilify Maintena patients with prolactin levels > 1 time the upper limit of normal range (ULN) was 1.9 % compared to 7.1 % for placebo patients.
Psychiatric disorders: Pathological gambling, hypersexuality, impulse-control problems (see Precautions).
Sleep Apnea: Atypical antipsychotic drugs, including aripiprazole, have been associated with cases of sleep apnea, with or without concomitant weight gain. In patients who have a history of or are at risk for sleep apnea, aripiprazole should be prescribed with caution.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Clinical trial adverse drug reactions: Adverse Drug Reaction Overview: Abilify Maintena has been evaluated for safety in 804 adult patients in clinical trials in bipolar I disorder, with approximately 530 patient-years of exposure to Abilify Maintena. A total of 419 patients were treated with Abilify Maintena for at least 7 consecutive injections (i.e., have been treated for at least 6 months) and 287 patients treated with Abilify Maintena had at least 13 consecutive injections (i.e., have been treated for at least 12 months).
Clinical trial adverse drug reactions: Adverse Events Associated with Discontinuation of Treatment: During the double-blind, placebo-controlled phase of the bipolar I disorder trial, fewer subjects experienced a TEAE resulting in discontinuation in the Abilify Maintena group (23/132; 17.4%) compared to the placebo group (34/133; 25.6%). The following TEAEs led to discontinuation of IMP in more than 1 subject in either treatment group (Abilify Maintena vs placebo): mania (2.3% vs 8.3%), bipolar I disorder (1.5% vs 6.0%), bipolar disorder (3.8% vs 3.0%), depression (3.0% vs 2.3%), akathisia (1.5% vs 0.0%), affective disorder (0.0% vs 1.5%), and major depression (0.0% vs 1.5%).
Commonly Reported Adverse Events: The adverse event profile was similar across placebo-controlled trials of Abilify Maintena.
In the bipolar I disorder trial of Abilify Maintena, none of the adverse events in the double-blind, placebo-controlled phase were reported at an incidence ≥ 5 % of patients AND at least twice the incidence of placebo. Based on the placebo-controlled trial of Abilify Maintena in patients with bipolar I disorder, the most frequently observed adverse events reported in ≥ 5 % of Abilify Maintena patients and greater than placebo were weight increased, akathisia, anxiety, restlessness, and somnolence. Table 6 presents the Adverse Events that occurred in the bipolar I disorder trials at a rate of 2% or greater. (See Table 6.)
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