Summary of the safety profile: The most common adverse reactions are asthenia/fatigue, hot flush, fractures, and hypertension. Other important adverse reactions include fall, cognitive disorder, and neutropenia.
Seizure occurred in 0.4% of enzalutamide-treated patients, 0.1% of placebo-treated patients, and 0.3% in bicalutamide-treated patients.
Rare cases of posterior reversible encephalopathy syndrome have been reported in enzalutamide treated patients (see Precautions).
Tabulated summary of adverse reactions: Adverse reactions observed during clinical studies are listed as follows by frequency category. Frequency categories are defined as follows: 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 4).
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Description of selected adverse reactions: Seizure: In controlled clinical studies, 13 patients (0.4%) experienced a seizure out of 3179 patients treated with a daily dose of 160 mg enzalutamide, whereas one patient (0.1%) receiving placebo and one patient (0.3%) receiving bicalutamide, experienced a seizure. Dose appears to be an important predictor of the risk of seizure, as reflected by preclinical data, and data from a dose-escalation study. In the controlled clinical studies, patients with prior seizure or risk factors for seizure were excluded. In the AFFIRM trial, seven patients (0.9%) experienced a seizure out of 800 post-chemotherapy patients treated with a daily dose of 160 mg enzalutamide, whereas no seizures occurred in patients receiving placebo. Potentially contributing factors were present in several of these patients that may have independently increased their risk of seizure. In the PREVAIL trial, one patient (0.1%) out of 871 chemotherapy-naive patients treated with a daily dose of 160 mg enzalutamide, and one patient (0.1%) receiving placebo experienced a seizure. In bicalutamide-controlled trials, 3 patients (0.8%) out of 380 chemotherapy-naïve patients treated with enzalutamide and 1 patient (0.3%) out of 387 receiving bicalutamide experienced a seizure.
In a single-arm trial to assess incidence of seizure in patients with predisposing factors for seizure (whereof 1.6% had a history of seizures), 8 of 366 (2.2%) patients treated with enzalutamide experienced a seizure. The median duration of treatment was 9.3 months.
The mechanism by which enzalutamide may lower the seizure threshold is not known, but could be related to data from in vitro studies showing that enzalutamide and its active metabolite bind to and can inhibit the activity of the GABA-gated chloride channel.
Ischemic Heart Disease: In randomized placebo-controlled clinical studies, ischemic heart disease occurred in 2.7% of patients treated with enzalutamide plus ADT compared to 1.3 % patients treated with placebo plus ADT.