Xtandi Adverse Reactions

Summary of the safety profile: The most common adverse reactions are asthenia/fatigue, hot flush, hypertension, fracture and fall. Other important adverse reactions include ischemic heart disease and seizure.
Seizure occurred in 0.6% 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). (See Table 6.)

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Description of selected adverse reactions: Seizures: In controlled clinical studies, 31 patients (0.6%) experienced a seizure out of 5110 patients treated with a daily dose of 160 mg enzalutamide, whereas four patients (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 9785-CL-0403 (UPWARD) 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 3.5% of patients treated with enzalutamide plus ADT compared to 2% of patients treated with placebo plus ADT. Fourteen (0.4%) patients treated with enzalutamide plus ADT and 3 (0.1%) patients treated with placebo plus ADT had an ischemic heart disease event that led to death.
In the EMBARK study, ischemic heart disease occurred in 5.4% of patients treated with enzalutamide plus leuprolide and 9% of patients treated with enzalutamide as monotherapy. No patients treated with enzalutamide plus leuprolide and one (0.3%) patient treated with enzalutamide as monotherapy had an ischemic heart disease event that led to death.
Gynaecomastia: In patients with high-risk BCR enrolled in the EMBARK study, gynaecomastia (all grades) was observed in 29 of 353 patients (8.2%) who were treated with enzalutamide plus leuprolide, 159 of 354 patients (44.9%) who were treated with enzalutamide as monotherapy, and 32 of 354 patients (9%) who were treated with placebo plus leuprolide. Grade 3 or higher gynaecomastia was not observed in any patients who were treated with enzalutamide plus leuprolide or placebo plus leuprolide, and was observed in 3 patients (0.8%) who were treated with enzalutamide as monotherapy.
Nipple pain: In patients with high-risk BCR enrolled in the EMBARK study, nipple pain (all grades) was observed in 54 of 354 patients (15.3%) who were treated with enzalutamide as monotherapy (very common frequency). It was also observed in 11 of 353 patients (3.1%) who were treated with enzalutamide plus leuprolide and 4 of 354 patients (1.1%) who were treated with placebo plus leuprolide. Grade 3 or higher nipple pain was not observed in any patients who were treated with enzalutamide plus leuprolide, enzalutamide as monotherapy, or placebo plus leuprolide.
Breast tenderness: In patients with high-risk BCR enrolled in the EMBARK study, breast tenderness (all grades) was observed in 51 of 354 patients (14.4%) who were treated with enzalutamide as monotherapy (very common frequency). It was also observed in 5 of 353 patients (1.4%) who were treated with enzalutamide plus leuprolide and 4 of 354 patients (1.1%) who were treated with placebo plus leuprolide. Grade 3 or higher breast tenderness was not observed in any patients who were treated with enzalutamide plus leuprolide, enzalutamide as monotherapy, or placebo plus leuprolide.