Erleada (Tablets) Instructions for Use

Marketing Authorization Holder

Johnson & Johnson, LLC (Russia)

Manufactured By

Janssen Ortho, LLC (Puerto Rico)

Labeled By

JANSSEN ORTHO, LLC (Puerto Rico)

Packaging and Quality Control Release

JANSSEN-CILAG S.p.A. (Italy)

Contact Information

JANSSEN, a pharmaceutical division of Johnson & Johnson LLC

ATC Code

L02BB05 (Apalutamide)

Active Substance

Apalutamide (Rec.INN registered by WHO)

Dosage Form

Erleada

Film-coated tablets, 60 mg: 120 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from slightly yellowish-green to greenish-gray in color, oblong, slightly biconvex, with the engraving “AR 60” on one side.

Excipients: hypromellose acetate succinate, colloidal silicon dioxide, croscarmellose sodium, microcrystalline cellulose type 101, silicified microcrystalline cellulose, magnesium stearate.

Film coating composition Opadry^® II 85F210036 green (partially hydrolyzed polyvinyl alcohol, titanium dioxide, macrogol, talc, yellow iron oxide, black iron oxide).

120 pcs. – high-density polyethylene bottles (1) – cardboard packs.
24 pcs. – blisters (1) – cardboard cases (5) – cardboard packs^×.

^× a first-opening control may be present on the cardboard pack.

Clinical-Pharmacological Group

Antiandrogenic drug with antitumor activity

Pharmacotherapeutic Group

Antineoplastic hormonal preparations and hormone antagonists; hormone antagonists and related compounds; antiandrogens

Pharmacological Action

Mechanism of action

Apalutamide is an oral selective androgen receptor inhibitor that directly binds to the ligand-binding domain of the androgen receptor. Apalutamide inhibits nuclear translocation of the androgen receptor, inhibits DNA binding, and impairs androgen receptor-mediated transcription and has no agonist activity at the androgen receptor (based on preclinical data). In mouse models of prostate cancer, administration of apalutamide led to decreased proliferation of tumor cells and increased apoptosis, which was accompanied by significant antitumor activity. The activity of the main metabolite, N-desmethylapalutamide, was one-third of the in vitro activity of apalutamide.

Pharmacodynamics

Cardiac electrophysiology

The effect of apalutamide 240 mg once daily on the QT_c interval was studied in an open-label, uncontrolled, multicenter QT study in a single group of 45 participants with castration-resistant prostate cancer. The maximum mean change in QTcF interval from baseline was 12.4 ms (upper bound of the two-sided 90% CI: 16.0 ms). An analysis of the relationship between systemic exposure and QT interval suggested a concentration-dependent prolongation of the QTcF interval by apalutamide and its active metabolite.

Pharmacokinetics

With multiple once-daily administration, a dose-proportional increase in apalutamide exposure (C_max and AUC) was observed in the dose range from 30 to 480 mg. After administration of the drug at a dose of 240 mg once daily, steady-state concentrations of apalutamide were reached after 4 weeks, and the mean accumulation ratio compared to a single dose was 5. At steady state, the mean values (CV%) for C_max and AUC for apalutamide were 6 µg/ml (28%) and 100 µg×h/ml (32%), respectively. Daily fluctuations in apalutamide plasma concentrations were small, with a mean ratio between C_max and minimum concentrations of 1.63. Upon repeated administration, an increase in apparent clearance (CL/F) was observed, which is likely associated with apalutamide inducing its own metabolism.

At steady state, the mean values (CV%) for C_max and AUC for the main active metabolite, N-desmethylapalutamide, were 5.9 µg/ml (18%) and 124 µg×h/ml (19%), respectively. N-desmethylapalutamide is characterized by a flat concentration-time profile at steady state with a mean peak-to-trough ratio of 1.27. The mean (CV%) metabolite/parent drug AUC ratio for N-desmethylapalutamide after multiple administration was approximately 1.3 (21%). Based on systemic exposure, relative activity, and pharmacokinetic properties, it is likely that N-desmethylapalutamide contributes to the clinical activity of apalutamide.

Absorption

After oral administration of the drug, the median time to reach peak plasma concentration (T_max) was 2 hours (range: from 1 to 5 hours). The mean absolute bioavailability after oral administration was approximately 100%, which corresponds to complete absorption of apalutamide after oral administration of the drug.

Administration of apalutamide to healthy volunteers on an empty stomach and after a high-fat meal was not accompanied by clinically significant changes in C_max and AUC. When the drug was taken with food, an increase in the median time to T_max by approximately 2 hours was noted.

After oral administration of 4 tablets of apalutamide 60 mg, dispersed in applesauce, C_max and AUC were 28% and 5% higher, respectively, compared to taking 4 tablets of 60 mg whole on an empty stomach (see section “Dosage Regimen”).

Distribution

The mean apparent V_d of apalutamide at steady state is approximately 276 L. The V_d of apalutamide exceeds the total body water, indicating significant extravascular distribution.

Apalutamide and N-desmethylapalutamide are 96% and 95% bound to plasma proteins, respectively, binding occurs predominantly with plasma albumin and is concentration-independent.

Metabolism

After a single oral dose of radiolabeled ¹⁴C-apalutamide at a dose of 240 mg, the majority of ¹⁴C-radioactivity in plasma was represented by Apalutamide, its active metabolite N-desmethylapalutamide, and an inactive carboxylic acid derivative (45%, 44%, and 3% of the total ¹⁴C-AUC, respectively).

Metabolism is the main route of elimination of apalutamide. Metabolism is primarily carried out by the CYP2C8 and CYP3A4 isoenzymes to form N-desmethylapalutamide. Further, Apalutamide and N-desmethylapalutamide are metabolized by carboxylesterase to an inactive carboxylic acid derivative. The contribution of the CYP2C8 and CYP3A4 isoenzymes to the metabolism of apalutamide is 58% and 13% after a single dose, and with multiple doses at steady state, it is 40% and 37%, respectively.

Excretion

Apalutamide is excreted, mainly in the form of metabolites, primarily in the urine. After a single oral dose of radiolabeled apalutamide, excretion of 89% of the dose occurred for up to 70 days after drug administration; 65% of the dose was excreted in the urine (1.2% as the parent compound, 2.7% as N-desmethylapalutamide), and 24% in the feces (1.5% as the parent compound, 2% as N-desmethylapalutamide).

After a single dose, the CL/F value of apalutamide was 1.3 L/h, increasing to 2 L/h at steady state after once-daily administration. The mean effective T_1/2 of apalutamide at steady state is about 3 days.

Special patient populations

Patients with renal or hepatic impairment. No significant differences in the pharmacokinetics of apalutamide and N-desmethylapalutamide were observed in patients with mild renal impairment (estimated glomerular filtration rate (eGFR) 60-89 ml/min/1.73 m²) or moderate renal impairment (eGFR 30-59 ml/min/1.73 m²), mild hepatic impairment (Child-Pugh class A) or moderate hepatic impairment (Child-Pugh class B), for age ranging from 18 to 94 years, and for different races.

The potential impact of severe renal impairment or end-stage renal disease (eGFR ≤ 29 ml/min/1.73 m²) has not been established due to insufficient data. For patients with severe hepatic impairment (Child-Pugh class C), clinical and pharmacokinetic data are not available.

Indications

For the treatment of adult men with

• Non-metastatic castration-resistant prostate cancer (PC) at high risk of metastasis;
• Metastatic hormone-sensitive PC in combination with androgen deprivation therapy (ADT).

ICD codes

Dosage Regimen

The drug should be prescribed and used under the regular supervision of a physician experienced in the treatment of oncological diseases and in specialized departments.

The recommended dose of Erleada is 240 mg (4 tablets of 60 mg), taken orally once daily. The tablets should be swallowed whole. Erleada can be taken with or without food. During treatment, patients who have not undergone surgical castration must undergo medical castration with a gonadotropin-releasing hormone (GnRH) analogue.

Alternative method of administration

For patients who have difficulty swallowing tablets whole, the recommended dose of Erleada tablets can be mixed with 120 ml of applesauce. Do not crush the tablets. Stir the applesauce after adding the tablets, and again after 15 minutes and 30 minutes, to ensure the tablets are completely dispersed (well mixed with the sauce and no tablet residue remains). Use a spoon to swallow the mixture immediately. Rinse the mixing container with 60 ml of water and immediately drink the contents. Repeat rinsing with 60 ml of water once more to ensure the entire dose is taken. The mixture should be consumed within 1 hour of preparation (see section “Pharmacokinetics”).

Dose adjustment

If a patient experiences toxicity of ≥ grade 3 or intolerance, administration should be suspended until symptoms improve to ≤ grade 1 or baseline, then administration should be resumed at the same dose or, if necessary, at a reduced dose (180 mg or 120 mg).

Missed dose

If a patient misses a dose, it should be taken as soon as possible on the same day; the usual dosing schedule should be followed the next day. The patient should not take an additional number of tablets to make up for the missed dose.

Special patient groups

Children under 18 years of age. The safety and efficacy of Erleada in children have not been established. There are no relevant data on the use of Erleada in patients under 18 years of age.

Elderly patients (65 years and older). Of the 1327 patients who received Erleada in clinical studies, 19% were under 65 years of age, 41% were between 65 and 74 years of age, and 40% were 75 years of age and older. No significant differences in safety or efficacy were found between these patients and younger patients.

Renal impairment. No specific study of Erleada has been conducted in patients with renal impairment. Based on pharmacokinetic analysis data from clinical studies in subjects with castration-resistant PC and healthy subjects, it can be stated that no significant differences were observed in systemic levels in subjects with pre-existing mild or moderate renal impairment (GFR from 30 to 89 ml/min/1.73 m²) compared to subjects with normal renal function (GFR≥90 ml/min/1.73 m²). For patients with mild and moderate renal impairment, dose adjustment is not required. There are no data for patients with severe renal impairment or end-stage renal disease (GFR≤29 ml/min/1.73 m²).

Hepatic impairment. In a specific study investigating hepatic impairment, systemic levels of apalutamide and N-desmethylapalutamide in subjects with pre-existing mild or moderate hepatic impairment (Child-Pugh class A or B, respectively) were compared with those in healthy participants with normal liver function. Systemic concentrations of apalutamide and N-desmethylapalutamide were similar in patients with mild or moderate hepatic impairment compared to patients with normal liver function. Dose adjustment in patients with mild or moderate hepatic impairment is not required. There are no data for patients with severe hepatic impairment (Child-Pugh class C).

Adverse Reactions

The most common adverse reactions (ARs) are: fatigue (26%), skin rash (26% any grade and 6% grade 3 or 4), hypertension (22%), hot flush (18%), arthralgia (17%), diarrhea (16%), falls (13%) and weight decreased (13%). Other important ARs are fractures (11%) and hypothyroidism (8%).

ARs observed during clinical studies are presented in the table below and grouped by frequency. Reactions are classified by frequency as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10,000), frequency not known (frequency cannot be estimated from the available data).

Within each frequency group, ARs are presented in order of decreasing severity.

Table 1. Adverse reactions identified in clinical studies

^a The frequency of adverse reactions presented is based on data from the placebo-controlled period of clinical studies

^b Includes hypothyroidism, increased blood thyroid-stimulating hormone, decreased thyroxine, autoimmune thyroiditis, decreased free thyroxine, decreased triiodothyronine

^c Includes transient ischemic attack, acute cerebrovascular accident, cerebrovascular disorder, ischemic stroke, carotid artery arteriosclerosis, carotid artery stenosis, hemiparesis, lacunar infarction, lacunar stroke, thrombotic brain infarction, vascular encephalopathy, cerebellar infarction, cerebral infarction and cerebral ischemia

^d Including tongue biting

^e Includes angina pectoris, unstable angina, myocardial infarction, acute myocardial infarction, coronary artery occlusion, coronary artery stenosis, acute coronary syndrome, coronary artery arteriosclerosis, abnormal cardiac stress test, increased troponin, myocardial ischemia

^f See “Skin rash” in the “Description of Selected Adverse Reactions” section

^g Adverse reactions identified during the post-marketing period

^hIncludes rib fracture, lumbar vertebral fracture, spinal compression fracture, spinal fracture, foot fracture, hip fracture, humerus fracture, thoracic vertebral fracture, upper limb fracture, sacral fracture, arm fracture, pubic ramus fracture, acetabulum fracture, ankle fracture, compression fracture, costal cartilage fracture, facial bone fracture, lower limb fracture, osteoporotic fracture, carpal bone fracture, avulsion fracture, fibula fracture, coccygeal fracture, pelvic fracture, radius fracture, sternal fracture, stress fracture, traumatic fracture, cervical vertebral fracture, femoral neck fracture, tibia fracture (see below “Falls and fractures”).

Description of selected adverse reactions

Skin rash

Skin rash associated with the use of apalutamide was most often described as macular or maculopapular rash. The following variants of skin rash were recorded in patients: rash, maculopapular rash, generalized rash, urticaria, pruritic rash, macular rash, conjunctivitis, erythema multiforme, papular rash, skin exfoliation, genital rash, erythematous rash, stomatitis, drug eruption, ulcerative stomatitis, pustular rash, blisters, papules, pemphigoid, skin erosion, dermatitis and vesicular rash. ARs in the form of skin rash were noted in 26% of patients receiving Apalutamide. Grade 3 rash (defined as covering >30% of the total body surface area) was observed in 6% of patients receiving Apalutamide.

The median number of days to the onset of skin rash was 83 days. In 78% of patients, the rash resolved in an average of 78 days. Medications for rash management included topical corticosteroids, oral antihistamines; 19% of patients received systemic corticosteroids. Among patients with skin rash, the drug was temporarily discontinued in 28% and the dose was reduced in 14% (see section “Dosage and Administration” – Dose Adjustment). Skin rash recurred in 59% of patients in whom the drug was re-administered after temporary therapy interruption. Treatment with apalutamide was discontinued due to skin rash in 7% of patients.

Falls and Fractures

In clinical study ARN-509-003, fractures were reported in 11.7% of patients receiving Apalutamide and in 6.5% of patients receiving placebo. In both treatment groups, half of the patients had a fall recorded within 7 days prior to the fracture. Falls were observed in 15.6% of patients receiving Apalutamide and in 9.0% of patients receiving placebo (see section “Special Precautions”).

Ischemic Heart Disease and Ischemic Cerebrovascular Events

In a randomized clinical study in patients with non-metastatic castration-resistant prostate cancer (SPARTAN), ischemic heart disease was observed in 4% of patients receiving Apalutamide and in 3% of patients receiving placebo. In a randomized clinical study in patients with metastatic hormone-sensitive prostate cancer (TITAN), ischemic heart disease was observed in 4% of patients receiving Apalutamide and in 2% of patients receiving placebo. In the SPARTAN and TITAN studies, 6 patients (0.5%) receiving Apalutamide and 2 patients (0.2%) receiving placebo died from ischemic heart disease (see section “Special Precautions”).

In the SPARTAN study, with median durations of therapy with apalutamide and placebo of 32.9 and 11.5 months, respectively, ischemic cerebrovascular events were observed in 4% of patients receiving Apalutamide and in 1% of patients receiving placebo (see above). In the TITAN study, ischemic cerebrovascular events occurred in a similar proportion of patients in the apalutamide (1.5%) and placebo (1.5%) groups. Across the SPARTAN and TITAN studies, 2 patients (0.2%) receiving Apalutamide died from an ischemic cerebrovascular event, and no patients receiving placebo died from an ischemic cerebrovascular event (see section “Special Precautions”).

Hypothyroidism

Hypothyroidism, based on thyroid-stimulating hormone (TSH) testing every 4 months, was reported in 8% of patients receiving Apalutamide and in 2% of patients receiving placebo. There were no Grade 3 or 4 adverse events. Development of hypothyroidism was observed in 30% of patients already receiving thyroid hormone replacement therapy in the apalutamide group and in 3% of patients in the placebo group. In patients without hormone replacement therapy, hypothyroidism developed in 7% of patients receiving Apalutamide and in 2% of patients receiving placebo. If clinically indicated, thyroid hormone replacement therapy should be initiated or its dose adjusted (see section “Drug Interactions”).

Contraindications

• Hypersensitivity to the active substance or any excipient of the drug;
• Severe renal impairment;
• Severe hepatic impairment;
• Women of childbearing potential, pregnant women;
• Children under 18 years of age.

Use with Caution

In patients at risk of seizures or with a history of seizures, at risk of falls and fractures; concomitant use with drugs that are substrates of CYP3A4 isoenzymes (e.g., darunavir, felodipine, midazolam, simvastatin), CYP2C19 (e.g., diazepam, omeprazole), CYP2C9 (e.g., warfarin, phenytoin), UDP-glucuronosyltransferase (UGT) (e.g., levothyroxine, valproic acid), with drugs that are substrates of P-glycoprotein (Pgp) transporters (e.g., colchicine, dabigatran etexilate, digoxin), Breast Cancer Resistance Protein (BCRP) or Organic Anion Transporting Polypeptide 1B1 (OATP1B1) (e.g., lapatinib, methotrexate, rosuvastatin, repaglinide), with an anticoagulant metabolized by CYP2C9 (such as warfarin or acenocoumarol); in patients with clinically significant cardiovascular diseases that occurred within the last 6 months; in patients with a history of prolonged QT interval or relevant risk factors, and in patients receiving concomitant medications that may prolong the QT interval (see section “Special Precautions”).

Use in Pregnancy and Lactation

Pregnancy

Erleada should not be used during pregnancy or in women who may become pregnant. Information on the mechanism of action suggests that taking Erleada during pregnancy may adversely affect the fetus. There are insufficient data on the use of Erleada during pregnancy.

Contraception

Erleada may cause harm to the developing fetus. Patients having sexual intercourse with partners who are able to bear children should use condoms in combination with another highly effective method of contraception throughout treatment and for 3 months after taking the last dose of the drug.

Breast-feeding

It is unknown whether Apalutamide or its metabolites are excreted in human milk, whether it affects the health of breast-fed children, or maternal milk production.

Fertility

Based on animal studies, Erleada may reduce fertility in men with active reproductive function.

Use in Hepatic Impairment

Contraindicated in patients with severe hepatic impairment. Dose adjustment is not required in patients with mild or moderate hepatic impairment.

Use in Renal Impairment

Contraindicated in patients with severe renal impairment. For patients with mild and moderate renal impairment, dose adjustment is not required.

Pediatric Use

Contraindicated in patients under 18 years of age.

Geriatric Use

No significant differences in safety or efficacy of Erleada were found between patients over 65 years of age and younger patients.

Special Precautions

Seizures

Erleada is not recommended for patients with a history of seizures or other predisposing factors, particularly traumatic brain injury, recent stroke (within 1 year), primary brain tumors, or brain metastases. If seizures develop during treatment with Erleada, the drug should be permanently discontinued. The risk of seizures is higher in patients receiving additional medications that lower the seizure threshold.

In two randomized studies (SPARTAN and TITAN), seizures were reported in 0.6% of patients receiving Apalutamide and in 0.2% of patients receiving placebo. These studies excluded patients with a history of seizures or predisposing factors.

There is no clinical experience with re-administration of Erleada in patients who experienced seizures.

Falls and Fractures

Cases of falls and fractures have been observed in patients receiving Apalutamide (see section “Adverse Reactions”). The risk of falls and fractures should be assessed before starting Erleada, patients should be monitored during treatment, and the possibility of using specialized bone-strengthening agents should be considered.

Ischemic Heart Disease and Ischemic Cerebrovascular Events

Cases of ischemic heart disease and ischemic cerebrovascular events, including fatal ones, have been reported in patients receiving Apalutamide (see section “Adverse Reactions”). Most patients had risk factors for coronary/cerebral ischemia. Patients should be monitored for signs and symptoms of ischemic heart disease and ischemic cerebrovascular events. Management of risk factors such as hypertension, diabetes, or dyslipidemia should be optimized according to current standards of care.

Concomitant Use with Other Medicinal Products

Apalutamide is a potent enzyme inducer and may reduce the efficacy of many commonly used drugs (see section “Drug Interactions”). Therefore, the use of concomitant medications should be reviewed before starting treatment with apalutamide. Concomitant use of apalutamide with drugs that are sensitive substrates of many metabolizing enzymes or transporters should be avoided if their therapeutic effect is critical for the patient and if dose adjustment cannot be easily performed based on monitoring of efficacy or plasma concentration.

Concomitant use of apalutamide with warfarin and coumarin-like anticoagulants should be avoided. If Erleada is co-administered with an anticoagulant metabolized by CYP2C9 (such as warfarin or acenocoumarol), additional INR monitoring should be performed (see section “Drug Interactions”).

Recent Cardiovascular Diseases

Patients with clinically significant cardiovascular diseases that occurred within the last 6 months, including severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident, including transient ischemic attacks), or clinically significant ventricular arrhythmias, were excluded from clinical studies. Therefore, the safety of apalutamide in these patients has not been established. In patients with clinically significant cardiovascular diseases, risk factors, including hypercholesterolemia, hypertriglyceridemia, and other cardiometabolic disorders, should be monitored when prescribing Erleada (see section “Adverse Reactions”). These conditions should be treated as necessary after starting Erleada, according to established treatment protocols.

Antiandrogen Therapy May Prolong the QT Interval

In patients with a history of prolonged QT interval or relevant risk factors, and in patients receiving concomitant medications that may prolong the QT interval (see section “Drug Interactions”), the benefit-risk ratio, including the potential for Torsade de Pointes, should be assessed before starting therapy with Erleada.

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

Post-marketing reports of Stevens-Johnson syndrome/toxic epidermal necrolysis, which can be life-threatening or fatal, have been observed in association with Erleada treatment with an unknown frequency (see section “Adverse Reactions”).

Patients should be advised of the signs and symptoms suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis. If these symptoms are observed, Erleada should be discontinued immediately and a doctor should be consulted promptly.

Re-administration of Erleada is not permitted in patients who developed Stevens-Johnson syndrome/toxic epidermal necrolysis at any time during Erleada treatment; alternative treatment should be considered.

Effects on Ability to Drive and Use Machines

Studies on the effect of Erleada on the ability to drive or operate machinery have not been conducted. There is no information that Erleada affects the ability to drive and use machines. Given the side effect profile, including the occurrence of seizures, caution should be exercised when driving or engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms at a dose of 480 mg once daily (twice the recommended daily dose) did not reveal dose-limiting toxicity.

Treatment there is no specific antidote for apalutamide. In case of overdose, administration of Erleada should be discontinued and general supportive care should be initiated until clinical toxicity decreases or resolves.

Drug Interactions

The metabolism of apalutamide and the formation of its active metabolite, N-desmethylapalutamide, are mediated at steady state equally by both the CYP2C8 and CYP3A4 isoenzymes. Clinically significant changes in their overall exposure due to drug interactions with inhibitors or inducers of the CYP2C8 or CYP3A4 isoenzymes are not expected. Apalutamide is an inducer of enzymes and transporters and may increase the clearance of many commonly used medicinal products.

Effect of Other Medicinal Products on Apalutamide Exposure

CYP2C8 Inhibitors

The CYP2C8 isoenzyme plays a role in the clearance of apalutamide and the formation of its active metabolite. In a drug interaction study, a 21% decrease in apalutamide C_max and a 68% increase in AUC were observed when a single 240 mg dose of Erleada was co-administered with gemfibrozil (a potent CYP2C8 inhibitor). For the active moiety (the combined measure for apalutamide and the potency-adjusted active metabolite) C_max decreased by 21%, while AUC increased by 45%. No initial dose adjustment is necessary when Erleada is co-administered with a potent CYP2C8 inhibitor (e.g., gemfibrozil, clopidogrel); however, a dose reduction of Erleada should be considered based on tolerability (see section “Dosage and Administration” – Dose Adjustment). Weak or moderate CYP2C8 inhibitors are not expected to affect the pharmacokinetics of apalutamide.

CYP3A4 Inhibitors

The CYP3A4 isoenzyme is involved in the clearance of apalutamide and the formation of its active metabolite. In a drug interaction study, a 22% decrease in apalutamide C_max with no change in AUC was observed when a single 240 mg dose of Erleada was co-administered with itraconazole (a potent CYP3A4 inhibitor). For the active moiety (the combined measure for apalutamide and the potency-adjusted active metabolite) C_max decreased by 22% with no change in AUC. No initial dose adjustment is necessary when Erleada is co-administered with a potent CYP3A4 inhibitor (e.g., ketoconazole, ritonavir, clarithromycin); however, a dose reduction of Erleada should be considered based on tolerability (see section “Dosage and Administration” – Dose Adjustment). Weak or moderate CYP3A4 inhibitors are not expected to affect the pharmacokinetics of apalutamide.

CYP3A4 or CYP2C8 Inducers

The effects of CYP3A4 or CYP2C8 inducers on the pharmacokinetics of apalutamide have not been evaluated in vivo. Based on the results of the interaction study with potent CYP3A4 and CYP2C8 inhibitors, CYP3A4 or CYP2C8 inducers are not expected to clinically significantly affect the pharmacokinetics of apalutamide and the active moiety; therefore, no dose adjustment is required when Erleada is co-administered with CYP3A4 or CYP2C8 inducers.

Effect of Apalutamide on the Exposure of Other Medicinal Products

Apalutamide is a potent enzyme inducer and increases the synthesis of many enzymes and transporters; therefore, interaction of apalutamide with many common drugs that are substrates of enzymes or transporters is expected. The decrease in their plasma concentration may be substantial and lead to loss or reduction of clinical effect. There is also a risk of increased formation of active metabolites.

Effect of Apalutamide on Drug-Metabolizing Enzymes

In vitro studies have shown that Apalutamide and N-desmethylapalutamide are moderate or potent inducers of CYP3A4 and CYP2B6 isoenzymes, moderate inhibitors of CYP2B6 and CYP2C8 isoenzymes, and weak inhibitors of CYP2C9, CYP2C19, and CYP3A4 isoenzymes. Apalutamide and N-desmethylapalutamide do not affect CYP1A2 and CYP2D6 isoenzymes at therapeutically relevant concentrations. The effect of apalutamide on CYP2B6 substrates has not been evaluated in vivo, and the net effect is currently unknown. When CYP2B6 substrates (e.g., efavirenz) are used concomitantly with Erleada, monitoring for adverse reactions and loss of substrate efficacy should be performed, and dose adjustment of the substrate may be necessary to maintain optimal plasma concentrations.

In humans, Apalutamide is a potent inducer of CYP3A4 and CYP2C19 isoenzymes and a weak inducer of the CYP2C9 isoenzyme. In a drug interaction study using a “cocktail” approach, co-administration of Erleada with a single oral dose of sensitive CYP substrates resulted in a 92% decrease in the AUC of midazolam (a CYP3A4 substrate), an 85% decrease in the AUC of omeprazole (a CYP2C19 substrate), and a 46% decrease in the AUC of S-warfarin (a CYP2C9 substrate).

Erleada did not have a clinically significant effect on a CYP2C8 substrate. Co-administration of Erleada with drugs that are primarily metabolized by CYP3A4 (e.g., darunavir, felodipine, midazolam, simvastatin), CYP2C19 (e.g., diazepam, omeprazole), or CYP2C9 (e.g., warfarin, phenytoin) may lead to reduced efficacy of these drugs. Substitution of these drugs is recommended if possible, or monitoring for reduced efficacy should be performed if therapy is continued. When Erleada is co-administered with warfarin, INR levels should be monitored.

Induction of the CYP3A4 isoenzyme by apalutamide suggests that UDP-glucuronosyltransferase (UGT) may also be induced via activation of the nuclear pregnane X receptor (PXR). Co-administration of Erleada with drugs that are substrates of UGT (e.g., levothyroxine, valproic acid) may lead to reduced exposure of these drugs. When Erleada is co-administered with UGT substrates, loss of substrate efficacy should be assessed, and dose adjustment of the substrate may be necessary to maintain optimal plasma concentrations.

Effect of Apalutamide on Drug Transporters

Apalutamide has been shown to be a weak inducer of P-glycoprotein (Pgp), Breast Cancer Resistance Protein (BCRP), and Organic Anion Transporting Polypeptide 1B1 (OATP1B1). A drug interaction study using a “cocktail” approach showed that co-administration of Erleada with single oral doses of sensitive transporter substrates led to a 30% decrease in the AUC of fexofenadine (a Pgp substrate) and a 41% decrease in the AUC of rosuvastatin (a BCRP/OATP1B1 substrate), but did not affect C_max. Co-administration of Erleada with drugs that are substrates of Pgp, BCRP, or OATP1B1 may lead to reduced efficacy of these drugs. When Erleada is co-administered with substrates of Pgp, BCRP, or OATP1B1, loss of substrate efficacy should be assessed, and dose adjustment of the substrate may be necessary to maintain optimal plasma concentrations.

Based on in vitro data, inhibition of the organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3), and multidrug and toxin extrusion (MATE) proteins by apalutamide and its N-desmethyl metabolite cannot be excluded. No in vitro inhibition of the organic anion transporter 1 (OAT1) was observed.

Gonadotropin-releasing hormone (GnRH) analogue

In patients with metastatic hormone-sensitive prostate cancer receiving leuprorelin acetate (a GnRH analogue), concomitant use with Erleada had no apparent effect on the steady-state exposure of leuprorelin.

Drugs that prolong the QT interval

Since antiandrogen therapy may contribute to QT interval prolongation, the potential for concomitant use of Erleada with other medicinal products known to prolong the QT interval or able to induce Torsade de Pointes, such as class IA (e.g., quinidine, disopyramide) or class III (e.g., amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic drugs, methadone, moxifloxacin, antipsychotics (e.g., haloperidol), etc., should be carefully evaluated (see section “Special Precautions”).

Children

Drug interaction studies have been conducted only in adults.

Storage Conditions

The medicinal product should be stored in the original packaging (bottle or blister) out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The medicinal product is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.