Enzalutamide

Chemical formula: C₂₁H₁₆F₄N₄O₂S  Molecular mass: 464.436 g/mol  PubChem compound: 15951529

Interactions

Enzalutamide interacts in the following cases:

Medicinal products which prolong the QT interval, risk factors for QT prolongation

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of enzalutamide with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated.

In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Xtandi.

Strong CYP2C8 inhibitors

The concomitant use of strong CYP2C8 inhibitors should be avoided if possible. If patients must be co-administered a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced to 80 mg once daily. If co-administration of the strong CYP2C8 inhibitor is discontinued, the enzalutamide dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor.

CYP2C8 plays an important role in the elimination of enzalutamide and in the formation of its active metabolite. Following oral administration of the strong CYP2C8 inhibitor gemfibrozil (600 mg twice daily) to healthy male subjects, the AUC of enzalutamide increased by 326% while Cmax of enzalutamide decreased by 18%. For the sum of unbound enzalutamide plus the unbound active metabolite, the AUC increased by 77% while Cmax decreased by 19%.

CYP2C8 inducers, CYP3A4 inducers

Following oral administration of the moderate CYP2C8 and strong CYP3A4 inducer rifampin (600 mg once daily) to healthy male subjects, the AUC of enzalutamide plus the active metabolite decreased by 37% while Cmax remained unchanged. No dose adjustment is necessary when enzalutamide is coadministered with inducers of CYP2C8 or CYP3A4.

MRP2, OAT3 and OCT1 substrates

Based on in vitro data, inhibition of MRP2 (in the intestine), as well as organic anion transporter 3 (OAT3) and organic cation transporter 1 (OCT1) (systemically) cannot be excluded. Theoretically, induction of these transporters is also possible, and the net effect is presently unknown.

BCRP substrates

At steady-state, enzalutamide did not cause a clinically meaningful change in exposure to the probe breast cancer resistance protein (BCRP) substrate rosuvastatin in patients with prostate cancer that received a single oral dose of rosuvastatin before and concomitantly with enzalutamide (concomitant administration followed at least 55 days of once daily dosing of 160 mg enzalutamide). The AUC of rosuvastatin decreased by 14% while Cmax increased by 6%. No dose adjustment is necessary when a BCRP substrate is co-administered with Xtandi.

CYP1A2 substrates, CYP2C8 substrates

Enzalutamide (160 mg once daily) did not cause a clinically relevant change in the AUC or Cmax of caffeine (CYP1A2 substrate) or pioglitazone (CYP2C8 substrate). The AUC of pioglitazone increased by 20% while Cmax decreased by 18%. The AUC and Cmax of caffeine decreased by 11% and 4% respectively. No dose adjustment is indicated when a CYP1A2 or CYP2C8 substrate is co-administered with enzalutamide.

CYP3A4 inhibitors

CYP3A4 plays a minor role in the metabolism of enzalutamide. Following oral administration of the strong CYP3A4 inhibitor itraconazole (200 mg once daily) to healthy male subjects, the AUC of enzalutamide increased by 41% while Cmax was unchanged. For the sum of unbound enzalutamide plus the unbound active metabolite, the AUC increased by 27% while Cmax was again unchanged. No dose adjustment is necessary when enzalutamide is co-administered with inhibitors of CYP3A4.

CYP3A, CYP2B6, CYP2C9, CYP2C19, UGTs, OATP1B1 substrates

Enzalutamide is a potent enzyme inducer and increases the synthesis of many enzymes and transporters; therefore, interaction with many common medicinal products that are substrates of enzymes or transporters is expected. The reduction in plasma concentrations can be substantial, and lead to lost or reduced clinical effect. There is also a risk of increased formation of active metabolites. Enzymes that may be induced include CYP3A in the liver and gut, CYP2B6, CYP2C9, CYP2C19, and uridine 5'-diphospho-glucuronosyltransferase (UGTs – glucuronide conjugating enzymes). Some transporters may also be induced, e.g. multidrug resistance-associated protein 2 (MRP2) and the organic anion transporting polypeptide 1B1 (OATP1B1).

In vivo studies have shown that enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Co-administration of enzalutamide (160 mg once daily) with single oral doses of sensitive CYP substrates in prostate cancer patients resulted in an 86% decrease in the AUC of midazolam (CYP3A4 substrate), a 56% decrease in the AUC of S-warfarin (CYP2C9 substrate), and a 70% decrease in the AUC of omeprazole (CYP2C19 substrate). UGT1A1 may have been induced as well. In a clinical study in patients with metastatic CRPC, enzalutamide (160 mg once daily) had no clinically relevant effect on the pharmacokinetics of intravenously administered docetaxel (75 mg/m² by infusion every 3 weeks). The AUC of docetaxel decreased by 12% [geometric mean ratio (GMR) = 0.882 (90% CI: 0.767, 1.02)] while Cmax decreased by 4% [GMR = 0.963 (90% CI: 0.834, 1.11)].

Interactions with certain medicinal products that are eliminated through metabolism or active transport are expected. If their therapeutic effect is of large importance to the patient, and dose adjustments are not easily performed based on monitoring of efficacy or plasma concentrations, these medicinal products are to be avoided or used with caution. The risk for liver injury after paracetamol administration is suspected to be higher in patients concomitantly treated with enzyme inducers.

Groups of medicinal products that can be affected include, but are not limited to:

  • Analgesics (e.g. fentanyl, tramadol)
  • Antibiotics (e.g. clarithromycin, doxycycline)
  • Anticancer agents (e.g. cabazitaxel)
  • Antiepileptics (e.g. carbamazepine, clonazepam, phenytoin, primidone, valproic acid)
  • Antipsychotics (e.g. haloperidol)
  • Antithrombotics (e.g. acenocoumarol, warfarin, clopidogrel)
  • Betablockers (e.g. bisoprolol, propranolol)
  • Calcium channel blockers (e.g. diltiazem, felodipine, nicardipine, nifedipine, verapamil)
  • Cardiac glycosides (e.g. digoxin)
  • Corticosteroids (e.g. dexamethasone, prednisolone)
  • HIV antivirals (e.g. indinavir, ritonavir)
  • Hypnotics (e.g. diazepam, midazolam, zolpidem)
  • Immunosuppressant (e.g. tacrolimus)
  • Proton pump inhibitor (e.g. omeprazole)
  • Statins metabolised by CYP3A4 (e.g. atorvastatin, simvastatin)
  • Thyroid agents (e.g. levothyroxine)

The full induction potential of enzalutamide may not occur until approximately 1 month after the start of treatment, when steady-state plasma concentrations of enzalutamide are reached, although some induction effects may be apparent earlier. Patients taking medicinal products that are substrates of CYP2B6, CYP3A4, CYP2C9, CYP2C19 or UGT1A1 should be evaluated for possible loss of pharmacological effects (or increase in effects in cases where active metabolites are formed) during the first month of enzalutamide treatment and dose adjustment should be considered as appropriate. In consideration of the long half-life of enzalutamide (5.8 days), effects on enzymes may persist for one month or longer after stopping enzalutamide. A gradual dose reduction of the concomitant medicinal product may be necessary when stopping enzalutamide treatment.

P-gp substrates

In vitro data indicate that enzalutamide may be an inhibitor of the efflux transporter P-gp. A mild inhibitory effect of enzalutamide, at steady-state, on P-gp was observed in a study in patients with prostate cancer that received a single oral dose of the probe P-gp substrate digoxin before and concomitantly with enzalutamide (concomitant administration followed at least 55 days of once daily dosing of 160 mg enzalutamide). The AUC and Cmax of digoxin increased by 33% and 17%, respectively. Medicinal products with a narrow therapeutic range that are substrates for P-gp (e.g. colchicine, dabigatran etexilate, digoxin) should be used with caution when administered concomitantly with enzalutamide and may require dose adjustment to maintain optimal plasma concentrations.

Severe renal impairment

No dose adjustment is necessary for patients with mild or moderate renal impairment. Caution is advised in patients with severe renal impairment or end-stage renal disease.

Severe hepatic impairment

An increased half-life of enzalutamide has been observed in patients with severe hepatic impairment, possibly related to increased tissue distribution. The clinical relevance of this observation remains unknown. A prolonged time to reach steady state concentrations is however anticipated, and the time to maximum pharmacological effect as well as time for onset and decline of enzyme induction may be increased.

Coumarin-like anticoagulants

Co-administration with warfarin and coumarin-like anticoagulants should be avoided. If enzalutamide is co-administered with an anticoagulant metabolised by CYP2C9 (such as warfarin or acenocoumarol), additional International Normalised Ratio (INR) monitoring should be conducted.

Fertility

Animal studies showed that enzalutamide affected the reproductive system in male rats and dogs.

Recent cardiovascular disease

The phase 3 studies excluded patients with recent myocardial infarction (in the past 6 months) or unstable angina (in the past 3 months), New York Heart Association Class (NYHA) III or IV heart failure except if Left Ventricular Ejection Fraction (LVEF) ≥45%, bradycardia or uncontrolled hypertension. This should be taken into account if enzalutamide is prescribed in these patients.

Pregnancy

Enzalutamide is not for use in women. Enzalutamide is contraindicated in women who are or may become pregnant.

Nursing mothers

Enzalutamide is not for use in women. It is not known if enzalutamide is present in human milk. Enzalutamide and/or its metabolites are secreted in rat milk.

Carcinogenesis, mutagenesis and fertility

Women of childbearing potential

There are no human data on the use of enzalutamide in pregnancy and this medicinal product is not for use in women of childbearing potential. This medicine may cause harm to the unborn child or potential loss of pregnancy if taken by women who are pregnant.

Contraception in males and females

It is not known whether enzalutamide or its metabolites are present in semen. A condom is required during and for 3 months after treatment with enzalutamide if the patient is engaged in sexual activity with a pregnant woman. If the patient engages in sexual intercourse with a woman of childbearing potential, a condom and another form of birth control must be used during and for 3 months after treatment. Studies in animals have shown reproductive toxicity.

Fertility

Animal studies showed that enzalutamide affected the reproductive system in male rats and dogs.

Effects on ability to drive and use machines

Enzalutamide may have moderate influence on the ability to drive and use machines as psychiatric and neurologic events including seizure have been reported. Patients should be advised of the potential risk of experiencing a psychiatric or neurological event while driving or operating machines. No studies to evaluate the effects of enzalutamide on the ability to drive and use machines have been conducted.

Adverse reactions


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 0.6% 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.

Stevens-Johnson syndrome has been reported with enzalutamide treatment.

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.

Adverse reactions identified in controlled clinical trials and post-marketing:

MedDRA System organ class Adverse reaction and frequency
Blood and lymphatic system
disorders
Uncommon: leucopenia, neutropenia
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,
cognitive disorder
Uncommon: seizure¥
Not known*: posterior reversible encephalopathy syndrome
Cardiac disorders Common: ischemic heart disease
Not known* : QT-prolongation
Vascular disorders Very common: hot flush, hypertension
Gastrointestinal disorders Not known*: nausea, vomiting, diarrhoea
Hepatobiliary disorders Uncommon: hepatic enzymes increased
Skin and subcutaneous tissue
disorders
Common: dry skin, pruritus
Not known*: erythema multiforme, Stevens-Johnson syndrome,
rash
Musculoskeletal and connective
tissue disorders
Very common: fractures
Not known*: myalgia, muscle spasms, muscular weakness, back
pain
Reproductive system and breast
disorder
Common: gynaecomastia, nipple pain#, breast tenderness#
General disorders and
administration site conditions
Very common: asthenia, fatigue
Injury, poisoning and
procedural complications
Very common: fall

* 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.
# Adverse reactions for enzalutamide as monotherapy.

Description of selected adverse reactions

Seizure

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 10 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 3.5% 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 the EMBARK study, gynaecomastia (all grades) was observed in 29 of 353 patients (8.2%) who were treated with enzalutamide plus leuprolide and 159 of 354 patients (44.9%) who were treated with enzalutamide as monotherapy. Grade 3 or higher gynaecomastia was not observed in any patients who were treated with enzalutamide plus leuprolide, and was observed in 3 patients (0.8%) who were treated with enzalutamide as monotherapy.

Nipple pain

In the EMBARK study, nipple pain (all grades) was observed in 11 of 353 patients (3.1%) who were treated with enzalutamide plus leuprolide and 54 of 354 patients (15.3%) who were treated with enzalutamide as monotherapy. Grade 3 or higher nipple pain was not observed in any patients who were treated with enzalutamide plus leuprolide or with enzalutamide as monotherapy.

Breast tenderness

In the EMBARK study, breast tenderness (all grades) was observed in 5 of 353 patients (1.4%) who were treated with enzalutamide plus leuprolide and 51 of 354 patients (14.4%) who were treated with enzalutamide as monotherapy. Grade 3 or higher breast tenderness was not observed in any patients who were treated with enzalutamide plus leuprolide or with enzalutamide as monotherapy.

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