Apalutamide

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Apalutamide
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[2], Anmol Pitliya, M.B.B.S. M.D.[3]

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Overview

Apalutamide is an androgen receptor inhibitor that is FDA approved for the treatment of non-metastatic castration-resistant prostate cancer. Common adverse reactions include fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, fall, hot flush, decreased appetite, fracture, and peripheral edema.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Apalutamide is indicated:
  • For the treatment of patients with non-metastatic, castration-resistant prostate cancer (NM-CRPC).
Recommended Dosage
  • The recommended dose of ERLEADA is 240 mg (four 60 mg tablets) administered orally once daily. Swallow the tablets whole. ERLEADA can be taken with or without food.
  • Patients should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had a bilateral orchiectomy.

Dose Modification

  • If a patient experiences a greater than or equal to Grade 3 toxicity or an intolerable side effect, hold dosing until symptoms improve to less than or equal to Grade 1 or original grade, then resume at the same dose or a reduced dose (180 mg or 120 mg), if warranted.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding apalutamide Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

Non–Guideline-Supported Use

There is limited information regarding apalutamide Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Apalutamide FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding apalutamide Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

Non–Guideline-Supported Use

There is limited information regarding apalutamide Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

Contraindications

Pregnancy

  • Apalutamide can cause fetal harm and potential loss of pregnancy.

Warnings

Falls and Fractures
  • Falls and fractures occurred in patients receiving apalutamide. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone targeted agents.
  • In a randomized study (SPARTAN), falls occurred in 16% of patients treated with apalutamide compared to 9% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fractures occurred in 12% of patients treated with apalutamide and in 7% of patients treated with placebo. Grade 3–4 fractures occurred in 3% of patients treated with apalutamide and in 1% of patients treated with placebo. The median time to onset of fracture was 314 days (range: 20 to 953 days) for patients treated with apalutamide. Routine bone density assessment and treatment of osteoporosis with bone targeted agents were not performed in the SPARTAN study.
Seizure
  • Seizure occurred in patients receiving apalutamide. Permanently discontinue apalutamide in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with apalutamide. Advise patients of the risk of developing a seizure while receiving apalutamide and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.
  • In a randomized study (SPARTAN), two patients (0.2%) treated with apalutamide experienced a seizure. Seizure occurred from 354 to 475 days after initiation of apalutamide. No seizures occurred in patients treated with placebo. Patients with a history of seizure, predisposing factors for seizure, or receiving drugs known to decrease the seizure threshold or to induce seizure were excluded. There is no clinical experience in re-administering apalutamide to patients who experienced a seizure.

Adverse Reactions

Clinical Trials Experience

  • Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
  • SPARTAN, a randomized (2:1), double-blind, placebo-controlled, multi-center clinical study, enrolled patients who had non-metastatic, castration-resistant prostate cancer (NM-CRPC). In this study, patients received either apalutamide at a dose of 240 mg daily or a placebo. All patients in the SPARTAN study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. The median duration of exposure was 16.9 months (range: 0.1 to 42 months) in patients who received apalutamide and 11.2 months (range: 0.1 to 37 months) in patients who received placebo.
  • Overall, 8 patients (1%) who were treated with apalutamide died from adverse reactions. The reasons for death were infection (n=4), myocardial infarction (n=3), and cerebral hemorrhage (n=1). One patient (0.3%) treated with placebo died from an adverse reaction of cardiopulmonary arrest (n=1). Apalutamide was discontinued due to adverse reactions in 11% of patients, most commonly from rash (3%). Adverse reactions leading to dose interruption or reduction of apalutamide occurred in 33% of patients; the most common (>1%) were rash, diarrhea, fatigue, nausea, vomiting, hypertension, and hematuria. Serious adverse reactions occurred in 25% of apalutamide-treated patients and 23% in patients receiving placebo. The most common serious adverse reactions (>2%) were fracture (3%) in the apalutamide arm and urinary retention (4%) in the placebo arm.
  • Table 1 shows adverse reactions occurring in ≥10% on the apalutamide arm in SPARTAN that occurred with a 2% absolute increase in frequency compared to placebo. Table 2 shows laboratory abnormalities that occurred in ≥15% of patients, and more frequently (>5%) in the apalutamide arm compared to placebo.
This image is provided by the National Library of Medicine.
  • Additional clinically significant adverse reactions occurring in 2% or more of patients treated with apalutamide included hypothyroidism (8.1% versus 2% on placebo), pruritus (6.2% versus 2% on placebo), ischemic heart disease (3.7% versus 2% on placebo), and heart failure (2.2% versus 1% on placebo).
This image is provided by the National Library of Medicine.

Rash

  • In SPARTAN, rash associated with apalutamide was most commonly described as macular or maculo-papular. Adverse reactions of rash were reported for 24% of patients treated with apalutamide versus 6% of patients treated with placebo. Grade 3 rashes (defined as covering > 30% body surface area [BSA]) were reported with apalutamide treatment (5%) versus placebo (0.3%).
  • The onset of rash occurred at a median of 82 days of apalutamide treatment. Rash resolved in 81% of patients within a median of 60 days (range: 2 to 709 days) from onset of rash. Four (4%) of patients treated with apalutamide received systemic corticosteroids for treatment of rash. Rash recurred in approximately half of patients who were re-challenged with apalutamide.

Hypothyroidism

  • Hypothyroidism was reported for 8% of patients treated with apalutamide and 2% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with apalutamide and 7% of patients treated with placebo. The median onset was Day 113. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy was initiated in 7% of patients treated with apalutamide. Thyroid replacement therapy, when clinically indicated, should be initiated or dose-adjusted.

Postmarketing Experience

There is limited information regarding Apalutamide Postmarketing Experience in the drug label.

Drug Interactions

  • Strong CYP2C8 or CYP3A4 Inhibitors
  • CYP3A4, CYP2C9, CYP2C19 and UGT Substrates
  • P-gp, BCRP or OATP1B1 Substrates

Effect of Other Drugs on apalutamide

Strong CYP2C8 or CYP3A4 Inhibitors

  • Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl-apalutamide). No initial dose adjustment is necessary however, reduce the apalutamide dose based on tolerability. Mild or moderate inhibitors of CYP2C8 or CYP3A4 are not expected to affect the exposure of apalutamide.

Effect of apalutamide on Other Drugs

CYP3A4, CYP2C9, CYP2C19 and UGT Substrates

  • Apalutamide is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of apalutamide with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medication is continued. Concomitant administration of apalutamide with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with apalutamide and evaluate for loss of activity.

P-gp, BCRP or OATP1B1 Substrates

  • Apalutamide was shown to be a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. At steady-state, apalutamide reduced the plasma exposure to fexofenadine (a P-gp substrate) and rosuvastatin (a BCRP/OATP1B1 substrate). Concomitant use of apalutamide with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co-administered with apalutamide and evaluate for loss of activity if medication is continued.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • Apalutamide is contraindicated for use in pregnant women because the drug can cause fetal harm and potential loss of pregnancy. Apalutamide is not indicated for use in females, so animal embryo-fetal developmental toxicology studies were not conducted with apalutamide. There are no human data on the use of apalutamide in pregnant women. Based on its mechanism of action, apalutamide may cause fetal harm when administered during pregnancy.


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Apalutamide in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Apalutamide during labor and delivery.

Nursing Mothers

  • Apalutamide is not indicated for use in females. There are no data on the presence of apalutamide or its metabolites in human milk, the effect on the breastfed child, or the effect on milk production.

Pediatric Use

  • Safety and effectiveness of apalutamide in pediatric patients have not been established.

Geriatic Use

  • Of the 803 patients who received apalutamide in SPARTAN, 87% of patients were 65 years and over and 49% were 75 years and over. Grade 3–4 adverse reactions occurred in 46% (323/697) of patients 65 years or older and in 51% (197/391) of patients 75 years or older treated with apalutamide compared to 35% (124/355) of patients 65 years or older and 37% (70/187) of patients 75 years or older treated with placebo. No overall differences in effectiveness were observed between these patients and younger patients.

Gender

There is no FDA guidance on the use of Apalutamide with respect to specific gender populations.

Race

There is no FDA guidance on the use of Apalutamide with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Apalutamide in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Apalutamide in patients with hepatic impairment.

Females of Reproductive Potential and Males

Contraception (Males)

  • Based on the mechanism of action and findings in an animal reproduction study, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of apalutamide.

Infertility (Males)

  • Based on animal studies, apalutamide may impair fertility in males of reproductive potential.

Immunocompromised Patients

There is no FDA guidance one the use of Apalutamide in patients who are immunocompromised.

Administration and Monitoring

Administration

  • May be given with or without food.

Monitoring

  • Prolongation in the time to PSA progression and the time to symptomatic disease progression may indicate efficacy.
  • Fracture and fall risk: Evaluate for risk and monitor during therapy.

IV Compatibility

There is limited information regarding the compatibility of Apalutamide and IV administrations.

Overdosage

  • There is no known specific antidote for apalutamide overdose. In the event of an overdose, stop apalutamide, undertake general supportive measures until clinical toxicity has been diminished or resolved.

Pharmacology

Apalutamide Pharmocology Box Image.png
Apalutamide
Systematic (IUPAC) 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
Identifiers
CAS number 956104-40-8

1361232-32-7
ATC code L02BB05
PubChem 24872560
DrugBank DB11901
Chemical data
Formula C21H15F4N5O2S 
Mol. mass 477.435 g/mol
Synonyms ARN-509; JNJ-56021927; JNJ-927; A52
Pharmacokinetic data
Bioavailability 100%
Protein binding Apalutamide: 96%
NDMA: 95%
Metabolism Liver (CYP2C8, CYP3A4)
Half life Apalutamide: 3–4 days (at steady-state)
Excretion Urine: 65%
Feces: 24%
Therapeutic considerations
Pregnancy cat.

X (Contraindicated)

Legal status

Prescription only

Routes By mouth

Mechanism of Action

  • Apalutamide is an Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription. A major metabolite, N-desmethyl apalutamide, is a less potent inhibitor of AR, and exhibited one-third the activity of apalutamide in an in vitro transcriptional reporter assay. Apalutamide administration caused decreased tumor cell proliferation and increased apoptosis leading to decreased tumor volume in mouse xenograft models of prostate cancer.

Structure

This image is provided by the National Library of Medicine.

Pharmacodynamics

Cardiac Electrophysiology

  • The effect of apalutamide 240 mg once daily on the QTc interval was assessed in an open-label, uncontrolled, multi-center, single-arm dedicated QT study in 45 patients with CRPC. The maximum mean QTcF change from baseline was 12.4 ms (2-sided 90% upper CI: 16.0 ms). An exposure-QT analysis suggested a concentration-dependent increase in QTcF for apalutamide and its active metabolite.

Pharmacokinetics

  • Apalutamide pharmacokinetic parameters are presented as the mean [standard deviation (SD)] unless otherwise specified. Apalutamide Cmax and area under the concentration curve (AUC) increased proportionally following repeated once-daily dosing of 30 to 480 mg (0.125 to 2 times the recommended dosage). Following administration of the recommended dosage, apalutamide steady-state was achieved after 4 weeks and the mean accumulation ratio was approximately 5-fold. Apalutamide Cmax was 6.0 mcg/mL (1.7) and AUC was 100 mcg∙h/mL (32) at steady-state. Daily fluctuations in apalutamide plasma concentrations were low, with mean peak-to-trough ratio of 1.63. An increase in apparent clearance (CL/F) was observed with repeat dosing, likely due to induction of apalutamide's own metabolism. The auto-induction effect likely reached its maximum at the recommended dosage because exposure of apalutamide across the dose range of 30 to 480 mg is dose-proportional.
  • The major active metabolite N-desmethyl apalutamide Cmax was 5.9 mcg/mL (1.0) and AUC was 124 mcg∙h/mL (23) at steady-state after the recommended dosage. N-desmethyl apalutamide was characterized by a flat concentration-time profile at steady-state with a mean peak-to-trough ratio of 1.27. Mean AUC metabolite/parent drug ratio for N-desmethyl apalutamide following repeat-dose administration was 1.3. Based on systemic exposure, relative potency, and pharmacokinetic properties, N-desmethyl apalutamide likely contributed to the clinical activity of apalutamide.

Absorption

  • Mean absolute oral bioavailability was approximately 100%. Median time to achieve peak plasma concentration (tmax) was 2 hours (range: 1 to 5 hours).

Effect of Food

  • Administration of apalutamide to healthy subjects under fasting conditions and with a high-fat meal (approximately 500 to 600 fat calories, 250 carbohydrate calories, and 150 protein calories) resulted in no clinically relevant changes in Cmax and AUC. Median time to reach tmax was delayed approximately 2 hours with food.

Distribution

  • The mean apparent volume of distribution at steady-state of apalutamide was approximately 276 L.
  • Apalutamide was 96% and N-desmethyl apalutamide was 95% bound to plasma proteins with no concentration dependency.

Elimination

  • The CL/F of apalutamide was 1.3 L/h after single dosing and increased to 2.0 L/h at steady-state after once-daily dosing likely due to CYP3A4 auto-induction. The mean effective half-life for apalutamide in patients was approximately 3 days at steady-state.

Metabolism

  • Metabolism is the main route of elimination of apalutamide. Apalutamide is primarily metabolized by CYP2C8 and CYP3A4 to form active metabolite, N-desmethyl apalutamide. The contribution of CYP2C8 and CYP3A4 in the metabolism of apalutamide is estimated to be 58% and 13% following single dose but changes to 40% and 37%, respectively at steady-state.
  • Apalutamide represented 45% and N-desmethyl apalutamide represented 44% of the total AUC following a single oral administration of radiolabeled apalutamide 240 mg.

Excretion

  • Up to 70 days following a single oral administration of radiolabeled apalutamide, 65% of the dose was recovered in urine (1.2% of dose as unchanged apalutamide and 2.7% as N-desmethyl apalutamide) and 24% was recovered in feces (1.5% of dose as unchanged apalutamide and 2% as N-desmethyl apalutamide).

Specific Populations

  • No clinically significant differences in the pharmacokinetics of apalutamide or N-desmethyl apalutamide were observed based on age (18–94 years), race (Black, non-Japanese Asian, Japanese), mild to moderate (eGFR 30–89 mL/min/1.73m2, estimated by the modification of diet in renal disease [MDRD] equation) renal impairment, or mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment.
  • The effect of severe renal impairment or end stage renal disease (eGFR ≤29 mL/min/1.73m2, MDRD) or severe hepatic impairment (Child-Pugh C) on apalutamide pharmacokinetics is unknown.

Drug Interactions

Effect of Other Drugs on apalutamide

Strong CYP2C8 inhibitors

  • Apalutamide Cmax decreased by 21% while AUC increased by 68% following co-administration of apalutamide as a 240 mg single dose with gemfibrozil (a strong CYP2C8 inhibitor). Gemfibrozil is predicted to increase the steady-state apalutamide Cmax by 32% and AUC by 44%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state Cmax increased by 19% and AUC by 23%.

Strong CYP3A4 inhibitors

  • Apalutamide Cmax decreased by 22% while AUC was similar following co-administration of apalutamide as a 240 mg single dose with itraconazole (a strong CYP3A4 inhibitor). Ketoconazole (a strong CYP3A4 inhibitor) is predicted to increase the single-dose apalutamide AUC by 24% but have no impact on Cmax. Ketoconazole is predicted to increase the steady-state apalutamide Cmax by 38% and AUC by 51%. For the active moieties, the predicted steady-state Cmax increased by 23% and AUC by 28%.

CYP3A4/CYP2C8 inducers

  • Rifampin (a strong CYP3A4 and moderate CYP2C8 inducer) is predicted to decrease the steady-state apalutamide Cmax by 25% and AUC by 34%. For the active moieties, the predicted steady-state Cmax decreased by 15% and AUC by 19%.

Acid lowering agents

  • Apalutamide is not ionizable under relevant physiological pH condition, therefore acid lowering agents (e.g. proton pump inhibitor, H2-receptor antagonist, antacid) are not expected to affect the solubility and bioavailability of apalutamide.

Drugs affecting transporters

  • In vitro, apalutamide and N-desmethyl apalutamide are substrates for P-gp but not BCRP, OATP1B1, and OATP1B3. Because apalutamide is completely absorbed after oral administration, P-gp does not limit the absorption of apalutamide and therefore, inhibition or induction of P-gp is not expected to affect the bioavailability of apalutamide.
Effect of apalutamide on Other Drugs

CYP substrates

  • In vitro studies showed that apalutamide and N-desmethyl apalutamide are moderate to strong CYP3A4 and CYP2B6 inducers, are moderate inhibitors of CYP2B6 and CYP2C8, and weak inhibitors of CYP2C9, CYP2C19, and CYP3A4. Apalutamide and N-desmethyl apalutamide do not affect CYP1A2 and CYP2D6 at therapeutically relevant concentrations.
  • Co-administration of apalutamide with single oral doses of sensitive CYP substrates resulted in a 92% decrease in the AUC of midazolam (a CYP3A4 substrate), 85% decrease in the AUC of omeprazole (a CYP2C19 substrate), and 46% decrease in the AUC of S-warfarin (a CYP2C9 substrate). Apalutamide did not cause clinically significant changes in exposure to a CYP2C8 substrate.

P-gp, BCRP and OATP1B1 substrates

  • Co-administration of apalutamide with single oral doses of transporter substrates resulted in a 30% decrease in the AUC of fexofenadine (a P-gp substrate) and 41% decrease in the AUC of rosuvastatin (a BCRP/OATP1B1 substrate) but had no impact on Cmax.

GT substrates

  • Apalutamide may induce UGT. Concomitant administration of apalutamide with medications that are substrates of UGT may result in lower exposure to these medications.

OCT2, OAT1, OAT3 and MATEs substrates

  • In vitro, apalutamide and N-desmethyl apalutamide inhibit organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3) and multidrug and toxin extrusions (MATEs), and do not inhibit organic anion transporter 1. Apalutamide is not predicted to cause clinically significant changes in exposure to an OAT3 substrate.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

  • Long-term animal studies have not been conducted to evaluate the carcinogenic potential of apalutamide. Apalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either in vitro chromosome aberration assay or the in vivo rat bone marrow micronucleus assay or the in vivo rat Comet assay.
  • In repeat-dose toxicity studies in male rats (up to 26 weeks) and dogs (up to 39 weeks), atrophy of the prostate gland and seminal vesicles, aspermia/hypospermia, tubular degeneration and/or hyperplasia or hypertrophy of the interstitial cells in the reproductive system were observed at ≥ 25 mg/kg/day in rats (1.4 times the human exposure based on AUC) and ≥ 2.5 mg/kg/day in dogs (0.9 times the human exposure based on AUC).
  • In a fertility study in male rats, a decrease in sperm concentration and motility, increased abnormal sperm morphology, lower copulation and fertility rates (upon pairing with untreated females) along with reduced weights of the secondary sex glands and epididymis were observed following 4 weeks of dosing at ≥ 25 mg/kg/day (0.8 times the human exposure based on AUC). A reduced number of live fetuses due to increased pre- and/or post-implantation loss was observed following 4 weeks of 150 mg/kg/day administration (5.7 times the human exposure based on AUC). Effects on male rats were reversible after 8 weeks from the last apalutamide administration.

Clinical Studies

  • SPARTAN (NCT01946204) was a multicenter, double-blind, randomized (2:1), placebo-controlled clinical trial in which 1207 patients with NM-CRPC were randomized (2:1) to receive either apalutamide orally at a dose of 240 mg once daily (N = 806) or placebo once daily (N = 401). All patients in the SPARTAN trial received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. Patients were stratified by Prostate Specific Antigen (PSA) Doubling Time (PSADT), the use of bone-sparing agents, and locoregional disease. Patients were required to have a PSADT ≤ 10 months and confirmation of non-metastatic disease by blinded independent central review (BICR). PSA results were blinded and were not used for treatment discontinuation. Patients randomized to either arm discontinued treatment for radiographic disease progression confirmed by BICR, locoregional-only progression, initiation of new treatment, unacceptable toxicity, or withdrawal.
  • The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 74 years (range 48–97) and 26% of patients were 80 years of age or older. The racial distribution was 66% Caucasian, 12% Asian, and 6% Black. Seventy-seven percent (77%) of patients in both treatment arms had prior surgery or radiotherapy of the prostate. A majority of patients had a Gleason score of 7 or higher (78%). Fifteen percent (15%) of patients had <2 cm pelvic lymph nodes at study entry. Seventy-three percent (73%) of patients received prior treatment with an anti-androgen; 69% of patients received bicalutamide and 10% of patients received flutamide. All patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 at study entry. Among the patients who discontinued study treatment (N = 279 for placebo and N = 314 for apalutamide), a greater proportion (80%) of patients treated with placebo received subsequent therapy compared to patients treated with apalutamide (56%). Locoregional-only progression occurred in 2% of patients overall.
  • The major efficacy outcome measure of the study was metastasis-free survival (MFS), defined as the time from randomization to the time of first evidence of BICR-confirmed distant metastasis, defined as new bone or soft tissue lesions or enlarged lymph nodes above the iliac bifurcation, or death due to any cause, whichever occurred first. Additional efficacy endpoints were time to metastasis (TTM), progression-free survival (PFS) which also includes locoregional progression, time to symptomatic progression, and overall survival (OS).
  • A statistically significant improvement in MFS was demonstrated in patients randomized to receive apalutamide compared with patients randomized to receive placebo. Consistent results were observed across patient subgroups including PSADT (≤ 6 months or > 6 months), use of a prior bone-sparing agent (yes or no), and locoregional disease (N0 or N1). The major efficacy outcome was supported by statistically significant improvements in TTM, PFS, and time to symptomatic progression. Overall survival (OS) data were not mature at the time of final MFS analysis (24% of the required number of events). The efficacy results of MFS, TTM, and PFS from SPARTAN are summarized in Figure 1 and Table 3.
This image is provided by the National Library of Medicine.

How Supplied

  • Apalutamide (apalutamide) 60 mg film-coated tablets are slightly yellowish to greyish green, oblong-shaped tablets debossed with "AR 60" on one side. Apalutamide 60 mg tablets are available in bottles of 120 tablets. Each bottle contains silica gel desiccant.
  • NDC Number is 59676-600-12

Storage

  • Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
  • Store in the original package. Do not discard desiccant. Protect from light and moisture.

Images

Drug Images

Package and Label Display Panel

This image is provided by the National Library of Medicine.

Patient Counseling Information

Falls and Fractures

  • Inform patients that apalutamide is associated with an increased incidence of falls and fractures.

Seizures

  • Inform patients that apalutamide has been associated with an increased risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Inform patients to contact their healthcare provider right away if they experience a seizure.

Rash

  • Inform patients that apalutamide is associated with rashes and to inform their healthcare provider if they develop a rash.

Dosage and Administration

  • Inform patients receiving concomitant gonadotropin-releasing hormone (GnRH) analog therapy that they need to maintain this treatment during the course of treatment with apalutamide.
  • Instruct patients to take their dose at the same time each day (once daily). Apalutamide can be taken with or without food. Each tablet should be swallowed whole.
  • Inform patients that in the event of a missed daily dose of apalutamide, they should take their normal dose as soon as possible on the same day with a return to the normal schedule on the following day. The patient should not take extra tablets to make up the missed dose.

Embryo-Fetal Toxicity

  • Inform patients that apalutamide can be harmful to a developing fetus. Advise patients having sex with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of apalutamide. Advise male patients to use a condom if having sex with a pregnant woman.

Infertility

  • Advise male patients that apalutamide may impair fertility and not to donate sperm during therapy and for 3 months following the last dose of apalutamide.
This image is provided by the National Library of Medicine.

Precautions with Alcohol

Alcohol-Apalutamide interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

  • Erleada

Look-Alike Drug Names

There is limited information regarding Apalutamide Look-Alike Drug Names in the drug label.

Drug Shortage Status

Drug Shortage

Price

References

The contents of this FDA label are provided by the National Library of Medicine.


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