rsi ad
 
drx ad
 
ad space

Apalutamide Tablets

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. DRUG INTERACTIONS

 

1. DESCRIPTION

Apalutamide is an androgen receptor inhibitor. The chemical name is (4-[7-(6-Cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide). Apalutamide is a white to slightly yellow powder. Apalutamide is practically insoluble in aqueous media over a wide range of pH values. The structural formula is:

Empirical formula: C21H15F4N5O2S - Molecular weight: 477.44 g/mol

Apalutamide is supplied as film-coated tablets for oral administration containing 60 mg of apalutamide. Inactive ingredients of the core tablet are: colloidal anhydrous silica, croscarmellose sodium, hydroxypropyl methylcellulose-acetate succinate, magnesium stearate, microcrystalline cellulose, and silicified microcrystalline cellulose.

The tablets are finished with a commercially available film-coating comprising the following excipients: iron oxide black, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

2. INDICATIONS AND USAGE

Apalutamide is indicated for the treatment of patients with non-metastatic, castration-resistant prostate cancer (NM-CRPC).

3. DOSAGE AND ADMINISTRATION

3.1 Recommended Dosage

The recommended dose of apalutamide is 240 mg (four 60 mg tablets) administered orally once daily. Swallow the tablets whole. Apalutamide 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.

3.2 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.

4. CONTRAINDICATIONS

Pregnancy

Apalutamide can cause fetal harm and potential loss of pregnancy [see Use in Specific Populations (8.1)].

5. WARNINGS AND PRECAUTIONS

5.1 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.

5.2 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.

6. ADVERSE REACTIONS

The following are discussed in more detail in other sections of the labeling:

• Falls and Fractures [see Warnings and Precautions (5.1)].

• Seizure [see Warnings and Precautions (5.2)].

6.1 Clinical Trial 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.

Table 1: Adverse Reactions in SPARTAN

1 Includes fatigue and asthenia

2 Includes rash, rash maculo-papular, rash generalized, urticaria, rash pruritic, rash macular, conjunctivitis, erythema multiforme, rash papular, skin exfoliation, genital rash, rash erythematous, stomatitis, drug eruption, mouth ulceration, rash pustular, blister, papule, pemphigoid, skin erosion, and rash vesicular

3 Includes rib fracture, lumbar vertebral fracture, spinal compression fracture, spinal fracture, foot fracture, hip fracture, humerus fracture, thoracic vertebral fracture, upper limb fracture, fractured sacrum, hand fracture, pubis fracture, acetabulum fracture, ankle fracture, compression fracture, costal cartilage fracture, facial bones fracture, lower limb fracture, osteoporotic fracture, wrist fracture, avulsion fracture, fibula fracture, fractured coccyx, pelvic fracture, radius fracture, sternal fracture, stress fracture, traumatic fracture, cervical vertebral fracture, femoral neck fracture, and tibia fracture

4 Grade 4 definitions do not exist for these reactions

5 Includes appetite disorder, decreased appetite, early satiety, and hypophagia

6 Includes peripheral edema, generalized edema, edema, edema genital, penile edema, peripheral swelling, scrotal edema, lymphedema, swelling, and localized edema

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).

Table 2: Laboratory Abnormalities Occurring in ≥ 15% of Apalutamide-Treated Patients and at a Higher Incidence than Placebo (Between Arm Difference > 5% All Grades) in SPARTAN

1 Does not reflect fasting values

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 [see Drug Interactions (7.2)].

7. DRUG INTERACTIONS

7.1 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 [see Dosage and Administration (2.2)]. Mild or moderate inhibitors of CYP2C8 or CYP3A4 are not expected to affect the exposure of apalutamide.

7.2 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 [see Clinical Pharmacology].

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 [see Clinical Pharmacology].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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.

8.2 Lactation

Risk Summary

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.

8.3 Females and Males of Reproductive Potential

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. [see Use in Specific Populations (8.1)].

Infertility

Males

Based on animal studies, apalutamide may impair fertility in males of reproductive potential [see Nonclinical Toxicology].

8.4 Pediatric Use

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

8.5 Geriatric 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.

9. 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.

10. 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.

11. 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.

12. 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.

UGT 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.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

ERLEADA (apalutamide) 60 mg film-coated tablets are slightly yellowish to greyish green, oblong-shaped tablets debossed with “AR 60” on one side. ERLEADA 60 mg tablets are available in bottles of 120 tablets. Each bottle contains silica gel desiccant.

NDC Number 59676‐600‐12

Storage and Handling:

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Store in the original package. Do not discard desiccant. Protect from light and moisture.

Rx only

Rev 02/18