Prescribing information

Overview

Enzalutamide is an androgen receptor inhibitor. Androgens are a group of hormones that includes testosterone. Androgen receptor inhibitors interfere with the connection between androgens and their receptors, which can help slow cancer cell growth.

Composition

Mode of action

Enzalutamide acts on several steps in the androgen receptor signalling pathway. It competitively inhibits androgen binding to androgen receptors and, as a result, inhibits nuclear translocation of the receptors and their interaction with DNA.

A major metabolite, N-desmethyl enzalutamide, showed similar in vitro activity. Enzalutamide decreased proliferation and induced death of prostate cancer cells in vitro, and decreased tumour volume in a mouse prostate cancer xenograft model.

Indications

Enzalutamide is indicated for the treatment of patients with:

• nmCRPCNon-metastatic castration-resistant prostate cancer
• mCRPCMetastatic castration-resistant prostate cancer
• mCSPCMetastatic castration-sensitive prostate cancer

Dosage and administration

Dosing. The recommended dose is 160 mg (two 80 mg tablets or four 40 mg tablets) taken orally once daily.

Method of administration

Take with or without food. Swallow tablets whole; do not cut, crush or chew them.

Dose modifications

If a patient has a Grade 3 or higher toxicity or an intolerable side effect, withhold dosing for one week or until symptoms improve to Grade 2 or lower, then resume at the same or a reduced dose (120 mg or 80 mg), if warranted.

Strong CYP2C8 inhibitors

Avoid if possible. If co-administration is necessary, reduce the dose to 80 mg once daily. When the inhibitor is stopped, return to the dose used before it was started.

Strong CYP3A4 inducers

Avoid if possible. If co-administration is necessary, increase the dose from 160 mg to 240 mg once daily. When the inducer is stopped, return to the previous dose.

Important

Patients receiving enzalutamide should also receive a gonadotropin-releasing hormone (GnRH) analogue concurrently, or should have had a bilateral orchiectomy.

Warnings and precautions

Seizure

Seizure occurred in 0.5% of patients receiving enzalutamide, and in 2.2% of patients with predisposing factors. Permanently discontinue in patients who develop a seizure during treatment.

Posterior reversible encephalopathy syndrome (PRES)

Discontinue enzalutamide in patients who develop PRES.

Hypersensitivity

Reactions including oedema of the face (0.5%), tongue (0.1%) or lip (0.1%) were observed across seven randomised clinical trials. Pharyngeal oedema has been reported post-marketing. Patients with symptoms should temporarily stop treatment and seek medical care promptly. Permanently discontinue for serious reactions.

Ischaemic heart disease

In four randomised, placebo-controlled studies, ischaemic heart disease was more common with enzalutamide than placebo. Monitor for signs and symptoms, optimise management of cardiovascular risk factors such as hypertension, diabetes or dyslipidaemia, and discontinue for Grade 3–4 events.

All ischaemic events 2.9% 1.3%

Grade 3–4 events 1.4% 0.7%

Leading to death 0.4% 0.1%

Falls and fractures

Falls and fractures occurred in 11% and 10% of patients, respectively. Evaluate patients for fracture and fall risk, and treat with bone-targeted agents according to established guidelines.

Embryo-fetal toxicity

Enzalutamide can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception.

Side effects

Overdosage

In the event of an overdose, stop treatment and start general supportive measures, taking into account the half-life of 5.8 days. In a dose-escalation study, no seizures were reported below 240 mg daily, while three seizures were reported, one each at 360 mg, 480 mg and 600 mg daily. Patients may be at increased risk of seizure after an overdose.