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enzalutamide
Enzalutamide is an androgen receptor inhibitor, which has no known agonistic properties. Enzalutamide competitively inhibits the binding of androgen to the receptor, inhibiting nuclear translocation of androgen receptors and their interaction with DNA.
| Bioavailability |
At least 84.2% |
| Effects with food |
Food had no significant effect on enzalutamide exposure, although a Cmax of 30% higher was observed when this drug was given in fasting state. |
| Time to reach steady state | 28 days; accumulates approximately 8.3x relative to a single dose. |
| Peak plasma levels |
~ 1 hr (range: 0.52 h to 3.02 h) |
Extensive extravascular distribution.
| Cross blood brain barrier? | Yes, both enzalutamide and the active metabolite |
| PPB |
Enzalutamide: 97-98%; metabolites: 95% No protein binding displacement between enzalutamide and other highly bound drugs in vitro. |
Extensively metabolized by CYP2C8 and a lesser extent by CYP3A4/5.
| Active metabolites |
Yes |
| Inactive metabolites |
Yes |
Cleared via renal excretion of hepatic metabolites.
| Urine |
71% (primarily as inactive metabolites) |
| Feces | 14% (0.4% unchanged) |
| Half-life |
5.8 days (enzalutamide); 8-9 days (active metabolite) |
- Prostate cancer
Refer to the product monograph for a full list and details of approved indications
Emetogenic Potential:
Extravasation Potential: Not applicable
The following adverse effects were reported in ≥ 2% of patients with non-metastatic castration resistant prostate cancer (nmCRPC) in the phase III trial comparing enzalutamide to placebo, where incidence was at least 2% or more compared to placebo. It also includes severe, life-threatening and post-marketing adverse effects from other sources.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Hypertension (12%) (may be severe) | E | |||
| Other - Ischemic heart disease (3% , may be severe) | E D | ||||
| QT interval prolonged (rare) | E | ||||
| Dermatological | Rash (4%) (including dry skin) | E | |||
| Gastrointestinal | Anorexia, weight loss (10%) | E | |||
| Constipation (9%) | E | ||||
| Diarrhea (22%) | E | ||||
| Nausea (11%) | E | ||||
| Other - Gastrointestinal bleed (<2%) | E | ||||
| General | Edema (15%) | E | |||
| Fatigue (40%) (4% severe) | E | ||||
| Hematological | Myelosuppression ± infection (1%) (severe) | E | |||
| Hypersensitivity | Hypersensitivity (rare) | E | |||
| Musculoskeletal | Musculoskeletal pain (26%) | E | |||
| Other - fall / fracture (11%) | E D | ||||
| Neoplastic | Secondary malignancy (rare) | L | |||
| Nervous System | Anxiety (6%) | E | |||
| Cognitive disturbance (5%) | E | ||||
| Dizziness (12%) | E | ||||
| Hallucinations (<2%) | E | ||||
| Headache (9%) | E | ||||
| Insomnia (9%) | E | ||||
| Other - Hypoesthesia (4%) | E | ||||
| Paresthesia (7%) | E | ||||
| Posterior reversible encephalopathy syndrome (PRES) (rare) | E | ||||
| Seizure (1%) | E | ||||
| Reproductive and breast disorders | Androgen deprivation symptoms (13%) | E | |||
| Urinary | Urinary symptoms (7%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for enzalutamide include fatigue, musculoskeletal pain, diarrhea, edema, androgen deprivation symptoms, dizziness, hypertension, fall, nausea, anorexia and weight loss.
Enzalutamide is associated with an increased risk of seizure, especially at doses above 160mg. The lowering of the seizure threshold may be due to enzalutamide and its active metabolite crossing the blood brain barrier and inhibiting GABA-gated chloride channel activity.
Enzalutamide was associated with increases in systolic and diastolic blood pressure and an increased risk of hypertension or worsening of pre-existing hypertension in studies.
Posterior reversible encephalopathy syndrome (PRES) has been reported rarely, with and without associated hypertension.
Increases in non-pathological fractures and falls were observed as compared to placebo. Fall-related injuries included contusion, excoriation, head injury, joint injury, laceration, periorbital hematoma, and skeletal injury. Concomitant neurological symptoms or pre-syncope were rarely reported with the falls.
Hypersensitivity reactions, including facial, tongue, lip or pharyngeal edema have been observed with enzalutamide.
Refer to protocol by which patient is being treated.
Prior to starting enzalutamide treatment:
- Patients with cardiac history should be assessed for active cardiac disease.
- Management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia should be optimized.
- Patients should be assessed for the risk of fracture and fall and managed according to guidelines with consideration given to the use of bone-targeted agents.
| Dose Level | Enzalutamide Dose (mg/day) |
| 0 | 160 |
| -1 | 120 |
| -2 | 80 |
| -3 | Discontinue |
| Toxicity | Grade | Action |
| Hypersensitivity reactions | Any | Hold and promptly seek medical care. |
| ≥ grade 3 | Discontinue. | |
| PRES | Any | Discontinue. |
| Seizure | ||
| Ischemic heart disease | ≥ grade 3 | Discontinue. |
| Treatment emergent hypertension | Any | Monitor blood pressure and treat appropriately. |
| All other toxicities | Intolerable or ≥ grade 3 |
Hold until ≤ grade 2. Resume at the same dose OR ↓ dose level. Consider discontinuing if grade 4. |
| Hepatic Impairment | Enzalutamide Dose (mg/day) |
| Mild or moderate (Child-Pugh Class A or B) | No adjustment required |
| Severe (Child-Pugh C) | Increased drug half-life was observed; clinical significance unknown. No dosage adjustment required. |
| Creatinine Clearance (mL/min) | Enzalutamide Dose (mg/day) |
| ≥ 30 | No adjustment required |
| < 30 | Has not been studied. Exercise caution. |
No dose adjustment required. No overall differences in safety or efficacy were found in patients ≥ 65 years compared to younger patients; however, an increased frequency of dose interruption/reduction and discontinuation was observed.
Based on a pharmacokinetic study in Japanese patients, no clinically relevant differences in exposure were found between Japanese and Caucasians.
Safety and efficacy have not been established.
- Swallow capsules whole with a glass of water, with or without food.
- Do not chew, dissolve, or open the capsules.
- Take the dose at around the same time each day.
- If a dose is missed for the day, give it as soon as it is remembered on the same day. If it is forgotten for the whole day, skip this dose and give the next usual dose. Do not double the dose to make up for the missed one.
- Store at room temperature (15 to 30°C).
- Patients who have a hypersensitivity to this drug or any of its components
-
Exercise caution in these patient populations:
-
Non-metastatic castration resistant prostate cancer (nmCRPC) at low risk of developing metastatic disease. Enzalutamide has not been studied in this population and the benefit and risk profile in these patients is unknown.
-
Significant cardiovascular disease. Patients with significant cardiovascular disease (i.e. recent MI, unstable angina, LVEF < 45%, bradycardia or uncontrolled hypertension) were excluded from clinical trials.
-
History of QT prolongation, risk factors for Torsades de Pointes, or on medications known for QT prolongation.
-
History of seizures or have risk factors for seizures (i.e. brain injury with loss of consciousness, recent TIA, CVA, brain metastases, or on medications that lower the seizure threshold). These patients were excluded from clinical trials. Avoid dosing above 160mg as this was observed to have a greater risk of seizures.
-
Enzalutamide may cause neuropsychiatric events such as cognitive or memory impairment, seizures, hallucinations, etc. Patients should take caution and avoid tasks in which mental impairment or loss of consciousness may harm themselves or others.
-
Severe hepatic impairment (Child-Pugh C) at baseline. These patients were excluded from clinical trials.
-
-
Patients with hereditary fructose intolerance should not take enzalutamide as it contains sorbitol.
Other Drug Properties:
-
Carcinogenicity:
No
-
Genotoxicity:
Yes
(metabolite, only at cytotoxic concentrations))
-
Embryotoxicity:
Yes
-
Fetotoxicity:
Yes
Enzalutamide is not indicated in women and is contraindicated in pregnancy or in women who may become pregnant. Two effective forms of contraception (one of which must include condoms) should be used during treatment and for 3 months after the last dose.
-
Excretion into breast milk:
Yes
Breastfeeding is contraindicated.
-
Fertility effects:
Yes
Enzalutamide is a substrate of CYP2C8 and to a lesser extent, CYP3A4. It is an inducer and inhibitor of several CYP isoenzymes and susceptible to many drug interactions. Since the half-life of enzalutamide is 5.8 days, the effects on enzymes may persist for ≥1 month after stopping the drug.
CYP3A4 inhibitors may increase enzalutamide exposure, but no dosage adjustment is recommended.
Enzalutamide is an inhibitor of CYP2C8 and an inducer/inhibitor of CYP2B6, but no dosage adjustment is required.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| CYP2C8 inhibitors (i.e. gemfibrozil, montelukast) | ↑ enzalutamide exposure (up to 2.2x) and/or toxicity | ↓ metabolism of enzalutamide | Avoid; if concomitant use with strong CYP2C8 inhibitor cannot be avoided, reduce enzalutamide dose to 80mg daily. |
| CYP3A4 and CYP2C8 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) | ↓ enzalutamide concentration and/or efficacy (rifampin ↓ enzalutamide AUC 37% with no effect on Cmax) | ↑ metabolism of enzalutamide | No dosage adjustment required. Avoid concomitant use with strong CYP3A4 inducers. |
| CYP3A4 substrates (i.e. midazolam, cyclosporine, pimozide, tacrolimus, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors) | ↓ substrate exposure and/or efficacy (up to 86% ↓) | enzalutamide is a strong CYP3A4 inducer | Avoid substrates with narrow therapeutic range; consider dose adjustment of substrate if concomitant use cannot be avoided. |
| CYP 2C9 substrates (i.e. warfarin, meloxicam, fluvastatin) | ↓ substrate exposure and/or efficacy (up to 56% ↓), or ↑ substrate exposure | enzalutamide is a moderate CYP2C9 inducer, also has potential to inhibit CYP2C9 | Avoid substrates with narrow therapeutic range; monitor INR closely (e.g. with warfarin); consider dose adjustment of substrate if concomitant use cannot be avoided. |
| CYP2C19 substrates (i.e. omeprazole) | ↓ substrate exposure and/or efficacy (up to 70% ↓), or ↑ substrate exposure | enzalutamide is a moderate CYP2C19 inducer, also has potential to inhibit CYP2C19 | Avoid substrates with narrow therapeutic range; consider dose adjustment of substrate if concomitant use cannot be avoided. |
| UGT1A1 substrates (i.e. irinotecan), CYP2B6 or UGT1A4 substrates | ↓ substrate exposure and/or efficacy | enzalutamide can induce these enzymes or transporters | Avoid substrates with narrow therapeutic range; consider dose adjustment of substrate if concomitant use cannot be avoided. |
| P-glycoprotein substrates (i.e. verapamil, digoxin, morphine, ondansetron) | ↑ P-gp substrate exposure/toxicity (↑ single dose digoxin exposure by 33%, after at least 55 days of enzalutamide 160 mg); ↓ in substrate concentration at higher enzalutamide concentrations | Inhibition or possible induction of P-gp | Caution with substrates with a narrow therapeutic range; dose adjustment of substrate may be required. |
| MRP2 substrates (i.e. topotecan, cisplatin) | ↑ substrate exposure and/or toxicity | enzalutamide can inhibit MRP2 | Caution with substrates with a narrow therapeutic range; dose adjustment of substrate may be required. |
| Substrates of OATP1B1/3 (i.e. statins), OAT3 (i.e. furosemide, methotrexate), and OCT1 (i.e. metformin) | ↑ substrate exposure and/or toxicity | enzalutamide may inhibit these enzymes | Caution |
| Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc) | ↑ risk of QT prolongation | Additive | Caution |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
Blood pressure |
Baseline and as clinically indicated |
ECG and electrolytes |
Baseline and as clinically indicated, in patients at risk of QT prolongation |
Disease progression radiographically in addition to serum PSA |
As clinically indicated, in patients with nmCRPC |
INR monitoring for patients on warfarin |
Baseline and as clinically indicated |
Clinical toxicity assessment for ischemic heart disease, androgen withdrawal, gastrointestinal effects, hypersensitivity, fatigue, seizures and other neuropsychiatric effects, musculoskeletal effects including falls/fractures and edema |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Exceptional Access Program (EAP Website)
- enzalutamide - For the treatment of metastatic castrate-resistant prostate cancer (mCRPC), with specific clinical criteria
- enzalutamide - For the treatment of high risk non-metastatic castration-resistant prostate cancer (nmCRPC), with specific clinical criteria
- enzalutamide - For the treatment metastatic castration sensitive prostate cancer (mCSPC), with specific clinical criteria
Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol 2019 Nov 10;37(32):2974-2986.
Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014 Jul 31;371(5):424-33.
Hussain M, et al. Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2018 Jun 28;378(26):2465-2474.
Prescribing Information: Xtandi® (enzalutamide). Astellas Pharma US Inc., December 2019.
Product Monograph: Xtandi® (enzalutamide). Astellas Pharma Canada Inc., March 2023.
December 2023 Modified Interactions section
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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