Apalutamide (Monograph)

Brand name: Erleada
Drug class: Antineoplastic Agents
- Antiandrogens
Chemical name: 4-[7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide
Molecular formula: C₂₁H₁₅F₄N₅O₂S
CAS number: 956104-40-8

Medically reviewed by Drugs.com on Feb 25, 2023. Written by ASHP.

Introduction

Antineoplastic agent; a nonsteroidal antiandrogen.

Uses for Apalutamide

Prostate Cancer

Treatment of metastatic castration-sensitive prostate cancer. Guidelines recommend androgen deprivation therapy combined with abiraterone, apalutamide, enzalutamide, or docetaxel for the treatment of metastatic castration-sensitive prostate cancer.

Treatment of nonmetastatic castration-resistant prostate cancer in patients who are either receiving concomitant treatment with a gonadotropin-releasing hormone (GnRH) analog or who have had a bilateral orchiectomy. The use of an androgen receptor antagonist (i.e., darolutamide, apalutamide, enzalutamide) is recommended for patients with nonmetastatic castration-resistant prostate cancer who are at high risk of metastases.

Apalutamide Dosage and Administration

General

Pretreatment Screening

• Evaluate patients for fracture and fall risk.

Patient Monitoring

• Monitor for signs and symptoms of ischemic heart disease and cerebrovascular disorders. Optimize management of cardiovascular risk factors (e.g., hypertension, diabetes, dyslipidemia).

• In patients at risk for fracture, monitor and manage fracture risk.

• Monitor patients for the development of severe cutaneous adverse reactions.

Other General Considerations

• Patients receiving apalutamide should receive concurrent therapy with a gonadotropin-releasing hormone (GnRH) analog unless they have undergone bilateral orchiectomy.

Administration

Oral Administration

Administer orally once daily without regard to food. Swallow tablets whole.

For patients who have difficulty swallowing, apalutamide tablets may be dispersed into applesauce. Mix whole apalutamide tablets in 4 ounces of applesauce by stirring; do not crush the tablets. After stirring, wait 15 minutes, then stir the mixture again. Wait another 15 minutes and stir the mixture until the tablets are dispersed with no chunks remaining. Use a spoon to administer the mixture, and swallow it right away. After administration of the mixture, rinse the container with 2 ounces of water and immediately drink the contents. Repeat this rinse with 2 ounces of water a second time to ensure that the entire dose is administered. Administer the entire mixture within 1 hour of preparation. Do not store apalutamide that is mixed with applesauce.

Dosage

Adults

Prostate Cancer

Metastatic Castration-Resistant Prostate Cancer

Oral

240 mg once daily.

Nonmetastatic Castration-Resistant Prostate Cancer

Oral

240 mg once daily.

Dosage Modification for Toxicity

Oral

If an intolerable adverse effect or grade 3 or greater toxicity occurs, interrupt therapy until symptoms improve to grade 1 or less or return to baseline; then may resume therapy with or without dosage reduction. If dosage reduction is necessary, reduce dosage to 180 or 120 mg once daily.

Consider permanent discontinuation of apalutamide for Grade 3 or 4 cerebrovascular and ischemic cardiovascular events. Permanently discontinue apalutamide for confirmed severe cutaneous adverse reactions or for other Grade 4 skin reactions.

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): No initial dosage adjustment required.

Severe hepatic impairment (Child-Pugh class C): Not studied.

Renal Impairment

Mild to moderate renal impairment (eGFR 30–89 mL/minute per 1.73 m²): No initial dosage adjustment required.

Severe renal impairment (eGFR ≤29 mL/minute per 1.73 m²): Not studied.

Geriatric Patients

No special dosage recommendations; most patients in the principal efficacy studies were geriatric.

Related/similar drugs

estradiol, Premarin, Xtandi, Zytiga, Casodex, Lynparza

Cautions for Apalutamide

Contraindications

• None.

Warnings/Precautions

Cerebrovascular and Ischemic Cardiovascular Events

Cerebrovascular and ischemic cardiovascular events, including events leading to death, reported. Patients with a history of unstable angina, myocardial infarction, congestive heart failure, stroke, or transient ischemic attack within 6 months of randomization were excluded from clinical studies.

Monitor for signs and symptoms of ischemic heart disease and cerebrovascular disorders during apalutamide therapy. Optimize management of cardiovascular risk factors (e.g., hypertension, diabetes, dyslipidemia), and consider discontinuation of apalutamide for grade 3 and 4 events.

Fractures

Fractures reported. In the principal efficacy studies, median time to onset of fracture was 314 days (range: 20–953 days) in patients with nonmetastatic castration-resistant prostate cancer and 56 days (range: 2–111 days) in patients with metastatic castration-sensitive prostate cancer. Routine bone density assessment and treatment of osteoporosis with bone-targeted agents were not performed in these clinical studies.

Evaluate patients for fracture risk. Monitor and manage patients at risk for fractures according to established treatment guidelines; consider therapy with bone-targeted agents.

Falls

Falls reported, with increased frequency observed in geriatric patients. Falls not associated with loss of consciousness or seizure.

Evaluate patients for fall risk.

Seizures

Seizures reported. Onset occurred 159–650 days following initiation of the drug. Principal efficacy studies excluded patients with a history of seizures, predisposing factors for seizures, or concomitant use of drugs that can lower seizure threshold or induce seizures.

Not known whether anticonvulsants will prevent seizures in apalutamide-treated patients.

Safety of resuming therapy after resolution of a seizure not established; permanently discontinue therapy if seizure occurs.

Severe Cutaneous Adverse Reactions

Fatal and life-threatening severe cutaneous adverse reactions (e.g., Stevens-Johnson syndrome/toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms [DRESS]) reported. Inform patients of the signs and symptoms of these reactions (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy) and monitor for development.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm and loss of pregnancy. Safety and efficacy in females not established. Fetal abnormalities and embryofetal lethality reported in pregnant rats when oral apalutamide was administered during and after organogenesis.

Males with female partners of reproductive potential should use effective methods of contraception during therapy and for 3 months after the last dose of the drug. In addition, males should not donate sperm during therapy and for 3 months after the last dose. Male patients receiving the drug should use a condom during sexual encounters with pregnant females.

Specific Populations

Pregnancy

May cause fetal harm and potential loss of pregnancy. Safety and efficacy in females not established. Fetal abnormalities and embryofetal lethality reported in pregnant rats when oral apalutamide was administered during and after organogenesis.

Lactation

Safety and efficacy in females not established. Not known whether apalutamide or its metabolites are distributed into human milk, affect milk production, or affect nursing infants.

Females and Males of Reproductive Potential

Males with female partners of reproductive potential should use effective methods of contraception during therapy and for 3 months after the last dose of the drug. In addition, males should not donate sperm during therapy and for 3 months after the last dose. Male patients receiving the drug should use a condom during sexual encounters with pregnant females.

Based on animal studies, apalutamide may impair male fertility.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

No overall differences in efficacy relative to younger adults. Grade 3 or 4 adverse reactions reported in 39% of apalutamide-treated patients <65 years of age, 41% of patients 65–74 years of age, and 49% of patients ≥75 years of age. Falls reported in 8% of patients <65 years of age, 10% of patients 65–74 years of age, and 19% of patients ≥75 years of age.

Hepatic Impairment

Exposure and protein binding of apalutamide or N-desmethylapalutamide not substantially altered by mild or moderate hepatic impairment. Pharmacokinetics not established in patients with severe hepatic impairment.

Renal Impairment

Exposure of apalutamide or N-desmethylapalutamide not substantially altered by mild or moderate renal impairment. Pharmacokinetics not established in patients with severe renal impairment.

Common Adverse Effects

Adverse effects reported in ≥10% of patients receiving apalutamide include fatigue, arthralgia, rash, decreased appetite, falls, decreased weight, hypertension, hot flush, diarrhea, and fracture.

Drug Interactions

Metabolized principally by CYP2C8 and 3A4 to form N-desmethylapalutamide (major active metabolite).

Apalutamide and N-desmethylapalutamide are substrates of P-glycoprotein (P-gp) in vitro, but are not substrates of breast cancer resistance protein (BCRP), organic anion transport protein (OATP) 1B1, or OATP1B3.

Apalutamide is a potent inducer of CYP3A4 and 2C19 and weak inducer of CYP2C9, P-gp, BCRP, and OATP1B1 in humans.

In vitro, apalutamide and N-desmethylapalutamide are moderate to potent inducers of CYP3A4 and 2B6, moderate inhibitors of CYP2B6 and 2C8, and weak inhibitors of CYP2C9, 2C19, and 3A4, but do not induce or inhibit CYP1A2 or 2D6 at clinically relevant concentrations.

In vitro, apalutamide and N-desmethylapalutamide inhibit organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3), and multidrug and toxin extrusion (MATE) transporters, but do not inhibit OAT1.

Apalutamide may induce uridine diphosphate-glucuronosyltransferase (UGT).

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP2C8 or 3A4 inhibitors: Possible increased steady-state exposure of total active forms of apalutamide (unbound apalutamide plus potency-adjusted unbound N-desmethylapalutamide). Initial dosage adjustment not necessary; adjust apalutamide dosage based on tolerability.

Mild or moderate CYP2C8 or 3A4 inhibitors: Clinically important pharmacokinetic interactions unlikely.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A4, 2C9, or 2C19 substrates: Possible decreased exposure of the CYP3A4, 2C9, or 2C19 substrate. Avoid concomitant use; consider alternative agent that is not metabolized by these isoenzymes. If concomitant use cannot be avoided, monitor for decreased therapeutic effect of the CYP3A4, 2C9, or 2C19 substrate.

CYP2C8 substrates: Clinically important pharmacokinetic interactions unlikely.

Drugs Affecting or Affected by P-glycoprotein Transport

P-gp inhibitors or inducers: Pharmacokinetic interactions unlikely. P-gp does not limit apalutamide absorption.

P-gp substrates: Possible decreased exposure of the P-gp substrate. If concomitant use is necessary, exercise caution and monitor for decreased therapeutic effect of the P-gp substrate.

Drugs Affected by Breast Cancer Resistance Protein and/or Organic Anion Transport Polypeptide 1B1

BCRP or OATP1B1 substrates: Possible decreased exposure of BCRP or OATP1B1 substrates. If concomitant use is necessary, exercise caution and monitor for decreased therapeutic effect of the BCRP or OATP1B1 substrate.

Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase

UGT substrates: Possible decreased exposure of the UGT substrate. If concomitant use is necessary, exercise caution and monitor for decreased therapeutic effect of the UGT substrate.

Drugs Affected by Other Transporters

OAT3 substrates: Pharmacokinetic interaction unlikely.

Drugs Affecting Gastric Acidity

Drugs that increase gastric pH: Clinically important effect on apalutamide solubility or bioavailability unlikely.

Specific Drugs

Apalutamide Pharmacokinetics

Absorption

Bioavailability

Mean absolute bioavailability is approximately 100%.

Following oral administration, peak plasma concentrations are attained at a median of 2 hours.

Steady-state concentrations are achieved after 4 weeks of once-daily dosing with approximately fivefold accumulation.

Pharmacokinetics are dose proportional over a dosage range of 30–480 mg once daily.

Food

High-fat meal delays time to peak plasma concentration by approximately 2 hours but does not substantially affect peak plasma concentration or AUC.

No clinically relevant changes in peak plasma concentration or AUC were observed when tablets were dispersed in applesauce.

Plasma Concentrations

Apalutamide and N-desmethylapalutamide account for 45 and 44%, respectively, of the total drug exposure following a single 240-mg dose of apalutamide.

Special Populations

Mild or moderate hepatic impairment (Child-Pugh class A or B): No clinically important effect on AUC of apalutamide or N-desmethylapalutamide.

Severe hepatic impairment (Child-Pugh class C): Effect on pharmacokinetics not established.

Mild or moderate renal impairment (eGFR of 30–89 mL/minute per 1.73 m²): No clinically important effect on AUC of apalutamide or N-desmethylapalutamide.

Severe renal impairment (eGFR ≤29 mL/minute per 1.73 m²): Effect on pharmacokinetics not established.

Age (range: 18–94 years): No clinically important effect on pharmacokinetics of apalutamide or N-desmethylapalutamide.

Distribution

Extent

Not known whether apalutamide or N-desmethylapalutamide is distributed into milk.

Plasma Protein Binding

Apalutamide: 96%, independent of plasma concentration.

N-Desmethylapalutamide: 95%, independent of plasma concentration.

Special Populations

Hepatic impairment does not alter unbound fraction of apalutamide or N-desmethylapalutamide.

Elimination

Metabolism

Metabolized principally by CYP2C8 and 3A4 to form major active metabolite, N-desmethylapalutamide. Contributions of CYP2C8 and 3A4 to metabolism of apalutamide are approximately 58 and 13%, respectively, following a single dose and 40 and 37%, respectively, at steady state.

Clearance of apalutamide increases with repeated dosing, suggesting induction of own metabolism by CYP3A4.

Elimination Route

Excreted in urine (65%; 1.2% as unchanged drug and 2.7% as N-desmethylapalutamide) and feces (24%; 1.5% as unchanged drug and 2% as N-desmethylapalutamide).

Half-life

Approximately 3 days.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C). Protect from light and moisture; store in original package and do not remove desiccant.

Actions

• Competitively inhibits androgen binding to androgen receptors; mechanisms of action are similar to those of enzalutamide.

• Binds directly to the ligand-binding domain of the androgen receptor and inhibits nuclear translocation of the activated androgen receptor, androgen-dependent binding of the androgen receptor complex to DNA, and androgen receptor-mediated gene transcription in cells that overexpress the androgen receptor.

• Binding affinity at the androgen receptor is 7–10 times greater than that of bicalutamide.

• Major metabolite, N-desmethylapalutamide, has one-third the antiandrogenic activity of apalutamide in vitro.

• Reduces tumor growth and induces apoptosis of tumor cells, leading to decreased tumor volume, in xenograft models of castration-resistant prostate cancer in mice.

• Exhibits similar antiandrogenic activity to enzalutamide in vitro, but demonstrates greater activity in xenograft models of castration-resistant prostate cancer.

• At equivalent dosages in mice, steady-state concentrations of apalutamide and enzalutamide in xenograft tumors were similar, but steady-state plasma and CNS concentrations of apalutamide were twofold to fourfold and fourfold lower, respectively, compared with enzalutamide. Whether higher murine tumor-to-plasma and tumor-to-CNS ratios for apalutamide translate into lower risk of adverse effects, including seizures and other CNS toxicity, remains to be established.

• Unlike conventional antiandrogens (e.g., bicalutamide, flutamide, nilutamide) but similar to enzalutamide, apalutamide does not exhibit agonistic activity in cells that overexpress the androgen receptor.

Advice to Patients

• Importance of reading the manufacturer's patient information.

• For patients concurrently receiving GnRH analog therapy, importance of continuing this therapy during apalutamide therapy.

• Importance of taking apalutamide at the same time each day without regard to food and of swallowing tablets whole. Patients who have difficulty swallowing whole tablets should be advised to mix the tablets in applesauce without crushing the tablets. If a dose is missed, importance of taking the missed dose as soon as possible on the same day and taking the next dose at the regularly scheduled time on the following day. Advise patients that they should not take extra tablets to make up for a missed dose.

• Risk of cerebrovascular and ischemic cardiovascular events. Importance of advising patients to seek immediate medical attention if any symptoms of a cardiovascular or cerebrovascular event develop.

• Risk of falls and fractures.

• Risk of seizures; discuss conditions that may predispose to seizures and drugs that may lower the seizure threshold. Advise patients of the risk of engaging in activities where sudden loss of consciousness could cause serious harm to self or others. Importance of immediately informing clinician if a seizure occurs.

• Risk of severe cutaneous adverse reactions. Inform patients of the signs and symptoms of severe cutaneous adverse reactions (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy.

• Risk of fetal harm. Necessity of advising male patients with female partners of reproductive potential to use effective methods of contraception during apalutamide therapy and for 3 months after the last dose of the drug; also advise male patients receiving the drug to use a condom during sexual encounters with pregnant females.

• Potential for apalutamide to impair male fertility. Advise patients that they should not donate sperm during apalutamide therapy and for 3 months after the last dose of the drug.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., seizures).

• Importance of informing patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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Frequently asked questions

• How long do you have to take Erleada (apalutamide) for?
• How effective is Erleada (apalutamide)?
• What type of prostate cancer is Erleada used to treat?

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