Apalutamide (Monograph)

Brand name: Erleada
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Dec 10, 2024. Written by ASHP.

Introduction

Antineoplastic agent; a nonsteroidal antiandrogen.

Uses for Apalutamide

Prostate Cancer

Treatment of metastatic castration-sensitive prostate cancer in patients who are either receiving concomitant treatment with a gonadotropin-releasing hormone (GnRH) analog or who have had a bilateral orchiectomy. Guidelines recommend androgen deprivation therapy combined with abiraterone, apalutamide, darolutamide, 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 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.
Monitor patients for symptoms indicative of interstitial lung disease (ILD)/pneumonitis (e.g., dyspnea, cough, fever).

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; do not crush or split tablets.

For patients who have difficulty swallowing, disperse apalutamide in non-carbonated water and then administer with either orange juice, applesauce, or additional water. Place the entire prescribed dose of apalutamide tablet(s) in a cup; do not crush or split the tablet(s). For the 240 mg tablet, add approximately 2 teaspoons (10 mL) of non-carbonated water to fully immerse the tablet in water. For the 60 mg tablets (prescribed dose of 240 mg, 180 mg, or 120 mg), add approximately 4 teaspoons (20 mL) of non-carbonated water to fully immerse the tablets in water. Wait 2 minutes until the tablet(s) are broken up, then stir mixture. Add 2 tablespoons (30 mL) of either orange juice, applesauce, or additional water and stir mixture. Swallow mixture immediately. Rinse the cup with enough water to ensure the whole dose is administered and drink immediately. Do not store apalutamide mixed with non-carbonated water, orange juice, or applesauce for later use.

Apalutamide tablets can be administered through a feeding tube (8 French or greater). For the 240 mg tablet, place the tablet in the barrel of at least a 20 mL syringe and draw up 10 mL of non-carbonated water into the syringe. For the 60 mg tablets (prescribed dose of 240 mg, 180 mg, or 120 mg), place the entire prescribed dose of tablets in the barrel of at least a 50 mL syringe and draw up 20 mL of non-carbonated water into the syringe. Wait 10 minutes and then shake the syringe vigorously to disperse contents completely. Administer immediately through the feeding tube. Refill the syringe with non-carbonated water and administer. Repeat this process until no tablet residue is left in the syringe or feeding tube.

Dosage

Adults

Prostate Cancer

Metastatic Castration-Resistant Prostate Cancer

Oral

240 mg once daily (given as four 60 mg tablets or one 240 mg tablet).

Nonmetastatic Castration-Resistant Prostate Cancer

Oral

240 mg once daily (given as four 60 mg tablets or one 240 mg tablet).

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 severe interstitial lung disease (ILD)/pneumonitis or if no other etiologies of ILD/pneumonitis are identified, or 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.

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.

If a severe cutaneous adverse reaction is suspected, interrupt apalutamide therapy until the cause of the reaction is determined. Consult a dermatologist. If a severe cutaneous adverse reaction (or other grade 4 skin reaction) is confirmed, permanently discontinue apalutamide.

Interstitial Lung Disease (ILD)/Pneumonitis

Fatal and life-threatening ILD or pneumonitis can occur with therapy. Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold therapy if ILD/pneumonitis suspected. Permanently discontinue therapy in patients with severe ILD/pneumonitis or if no other potential causes of ILD/pneumonitis are identified.

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

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

Drug	Interaction	Comments
Antacids	Clinically important effect on apalutamide solubility or bioavailability unlikely
Antifungals, azole	Itraconazole: Decreased peak plasma concentrations of apalutamide and N-desmethylapalutamide, but no change in AUCs, after single apalutamide dose Ketoconazole: Increased steady-state AUC and peak plasma concentrations of total active apalutamide forms expected	Initial dosage adjustment of apalutamide not needed; adjust dosage based on tolerability
Fexofenadine	Decreased fexofenadine AUC	Use caution and monitor for decreased therapeutic effect of fexofenadine
Gemfibrozil	Decreased peak plasma concentration and increased AUC of apalutamide after single apalutamide dose; increased AUC and peak plasma concentration of total active apalutamide forms expected at steady state	Initial dosage adjustment of apalutamide not needed; adjust dosage based on tolerability
Histamine H₂-receptor antagonists	Clinically important effect on apalutamide solubility or bioavailability unlikely
Leuprolide	No apparent effect on steady-state exposure to leuprolide
Midazolam	Decreased AUC of oral midazolam	Avoid concomitant use; consider alternative CNS agent that is not metabolized by CYP3A4 If concomitant use cannot be avoided, monitor for decreased therapeutic effect of midazolam
Omeprazole	Decreased omeprazole AUC	Avoid concomitant use; consider alternative acid-suppressive agent that is not metabolized by CYP2C19 If concomitant use cannot be avoided, monitor for decreased therapeutic effect of omeprazole
Penicillin G	Pharmacokinetic interaction unlikely
Pioglitazone	No substantial change in pioglitazone AUC
Proton-pump inhibitors	Clinically important effect on apalutamide solubility or bioavailability unlikely
Rifampin	Decreased steady-state AUC and peak plasma concentration of apalutamide expected
Rosuvastatin	Decreased rosuvastatin AUC; no change in rosuvastatin peak plasma concentration	Use caution and monitor for decreased therapeutic effect of rosuvastatin
Warfarin	Decreased S-warfarin AUC	Monitor INR at initiation of concomitant therapy and upon discontinuance of apalutamide

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

Stress importance of reading the manufacturer's patient information.
For patients concurrently receiving GnRH analog therapy, stress importance of continuing this therapy during apalutamide therapy.
Advise patients to take apalutamide at the same time each day without regard to food and to swallow tablets whole. Instruct patients who cannot swallow tablets whole to follow the instructions for the prescribed strength of apalutamide tablets for alternate methods of administration. If a dose is missed, stress 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. Advise patients to seek immediate medical attention if any symptoms of a cardiovascular or cerebrovascular event develop.
Advise patients regarding the 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. Stress 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 interstitial lung disease (ILD)/pneumonitis. Advise patients to stop apalutamide and contact their clinician or seek immediate medical attention if new or worsening respiratory symptoms develop.
Risk of fetal harm. Advise 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.
Stress 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).
Inform patients of other important precautionary information.

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.