Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The most common adverse reactions are asthenia/fatigue, hot flush, hypertension, fractures, and fall. Other important adverse reactions include ischemic heart disease and seizure.

Seizure occurred in 0.5% of enzalutamide-treated patients, 0.2% 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 section 4.4).

Stevens Johnson syndrome has been reported with enzalutamide treatment (see section 4.4).

Tabulated list of adverse reactions
Adverse reactions observed during clinical studies are listed below 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.

Table 1: Adverse reactions identified in controlled clinical trials and post-marketing 
MedDRA System organ                     Adverse reaction and frequency class
Blood and lymphatic system              Uncommon: leucopenia, neutropenia disorders                               Not known*: thrombocytopenia
Immune system disorders                 Not known*: face oedema, tongue oedema, lip oedema, pharyngeal oedema
Psychiatric disorders                   Common: anxiety
Uncommon: visual hallucination
Nervous system disorders                Common: headache, memory impairment, amnesia, disturbance in attention, dysgeusia, restless legs syndrome
Uncommon: cognitive disorder, seizure¥
Not known*: posterior reversible encephalopathy syndrome
Cardiac disorders                       Common: ischemic heart disease† Not known*: QT-prolongation (see sections 4.4 and 4.5)
Vascular disorders                      Very common: hot flush, hypertension Gastrointestinal disorders              Not known*: nausea, vomiting, diarrhoea Hepatobiliary disorders                 Uncommon: hepatic enzymes increased Skin and subcutaneous                   Common: dry skin, pruritus tissue disorders                        Not known*: erythema multiforme, Stevens-Johnson syndrome, rash
Musculoskeletal and                     Very common: fractures‡ connective tissue disorders             Not known*: myalgia, muscle spasms, muscular weakness, back pain
Reproductive system and                 Common: gynaecomastia breast disorder
General disorders and                   Very common: asthenia, fatigue administration site conditions
Injury, poisoning and                   Very common: fall procedural complications
* Spontaneous reports from post-marketing experience.
¥ As evaluated by narrow SMQs of ‘Convulsions’ including convulsion, grand mal convulsion, complex partial seizures, partial seizures, and status epilepticus. This includes rare cases of seizure with complications leading to death.
† As evaluated by narrow SMQs of ‘Myocardial Infarction’ and ‘Other Ischemic Heart Disease’ including the following preferred terms observed in at least two patients in randomized placebo-controlled phase 3 studies: angina pectoris, coronary artery disease, myocardial infarctions, acute myocardial infarction, acute coronary syndrome, angina unstable, myocardial ischaemia, and arteriosclerosis coronary artery.
‡ Includes all preferred terms with the word ‘fracture’ in bones.

Description of selected adverse reactions

Seizure
In controlled clinical studies, 24 patients (0.5%) experienced a seizure out of 4403 patients treated with a daily dose of 160 mg enzalutamide, whereas four patients (0.2%) 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 randomised placebo-controlled clinical studies, ischemic heart disease occurred in 3.9% of patients treated with enzalutamide plus ADT compared to 1.5% patients treated with placebo plus ADT. Fifteen (0.4%) patients treated with enzalutamide and 2 (0.1%) patients treated with placebo had an ischemic heart disease event that led to death.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il.