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Apalutamide

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
Brands: Erleada

Medically reviewed by Drugs.com on Sep 28, 2020. Written by ASHP.

Introduction

Antineoplastic agent; a nonsteroidal antiandrogen.

Uses for Apalutamide

Prostate Cancer

Treatment of nonmetastatic castration-resistant prostate cancer.

Apalutamide Dosage and Administration

General

  • Use concurrently with a gonadotropin-releasing hormone (GnRH) analog unless patient has undergone bilateral orchiectomy.

Restricted Distribution

  • Obtain apalutamide through specialty pharmacies. Consult Janssen CarePath at 877-227-3728 or at [Web] for specific availability information.

Administration

Oral Administration

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

Dosage

Adults

Prostate Cancer
Oral

240 mg once daily. In principal efficacy study, therapy was continued until disease progression or unacceptable toxicity occurred.

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 daily.

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 principal efficacy study were geriatric.

Cautions for Apalutamide

Contraindications

  • Pregnant women. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Warnings/Precautions

Falls and Fractures

Falls and fractures reported. Median time to onset of fracture was 314 days (range: 20–953 days). Principal efficacy study excluded patients receiving bone resorption inhibitors (e.g., denosumab, zoledronic acid) at dosages recommended for prevention of tumor-related skeletal events; relatively few patients received these agents at dosages recommended for bone loss prevention in the setting of osteoporosis.

Evaluate patients for fracture and fall risk. Monitor patients at risk for fractures and manage according to established treatment guidelines; consider therapy with bone resorption inhibitors.

Seizures

Seizures reported. Onset occurred 354–475 days following initiation of the drug. Principal efficacy study excluded patients with predisposing factors for seizures (e.g., history of seizure, concomitant use of drugs that lower seizure threshold or can 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.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Contraindicated in pregnant women.

Men with female partners of childbearing potential should use effective methods of contraception during therapy and for 3 months after the last dose of the drug. In addition, men should not donate sperm during therapy and for 3 months after the last dose. Patients receiving the drug should use a condom during sexual encounters with pregnant women.

Effects on Male Fertility

Based on animal studies, apalutamide may impair male fertility.

Specific Populations

Pregnancy

May cause fetal harm and potential loss of pregnancy. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether apalutamide or its metabolites are distributed into milk, affect milk production, or affect nursing infants; drug not indicated for use in women.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

No overall differences in efficacy relative to younger adults. In patients ≥65 years of age, grade 3 or 4 adverse reactions reported in 46% of apalutamide-treated patients and 35% of placebo recipients; in patients ≥75 years of age, respective frequencies were 51 and 37%.

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. (See Pharmacokinetics.)

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. (See Absorption: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Fatigue/asthenia, hypertension, rash, diarrhea, nausea, weight loss, arthralgia, falls, hot flush, decreased appetite, fracture, peripheral edema, hypercholesterolemia, hyperglycemia, anemia, hypertriglyceridemia, leukopenia, lymphopenia, hyperkalemia.

Interactions for Apalutamide

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 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. (See Dosage Modification for Toxicity under Dosage and Administration.)

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

CYP2C8 and/or 3A4 inducers: Possible decreased steady-state plasma concentrations of apalutamide. However, no interactions with CYP3A4 inducers observed in a population pharmacokinetic analysis based on limited data.

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

Abiraterone

No change in pharmacokinetics of apalutamide or abiraterone observed in phase 1 trial of concomitant apalutamide, abiraterone, and prednisone therapy

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 apalutamide 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

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

Prednisone

No change in pharmacokinetics of apalutamide or abiraterone observed in phase 1 trial of concomitant apalutamide, abiraterone, and prednisone therapy

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.

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 or crosses the blood-brain barrier in humans (see Actions).

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-desmethyl apalutamide) and feces (24%; 1.5% as unchanged drug and 2% as N-desmethyl apalutamide).

Half-life

Approximately 3 days.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 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 currently 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. 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 falls and fractures.

  • Risk of seizures; 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.

  • Importance of notifying clinician if a rash develops.

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

  • 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.)

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.

Distribution of apalutamide is restricted. (See Restricted Distribution under Dosage and Administration.)

Apalutamide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

60 mg

Erleada

Janssen

AHFS DI Essentials™. © Copyright 2021, Selected Revisions October 8, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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