Product Information
Registration Status: ActiveSIN15698P
ERLEADA FILM-COATED TABLET 60MG is approved to be sold in Singapore with effective from 2019-05-27. It is marketed by JOHNSON & JOHNSON PTE LTD, with the registration number of SIN15698P.
This product contains Apalutamide 60mg in the form of TABLET, FILM COATED. It is approved for ORAL use.
This product is manufactured by Janssen Pharmaceutica NV (intermediate) in UNITED STATES, andJanssen Ortho LLC in BELGIUM.
It is a Prescription Only Medicine that can only be obtained from a doctor or a dentist, or a pharmacist with a prescription from a Singapore-registered doctor or dentist.
Product Reference
Important Note: For generic product, the SPC/PIL provided may not be brand specific.
{{/items}} {{^items}}Description
Apalutamide is a potent androgen receptor (AR) antagonist that selectively binds to the ligand-binding domain of AR and blocks AR nuclear translocation or binding to androgen response elements [A31846]. It has been used in trials studying the treatment of Prostate Cancer, Hepatic Impairment, Prostatic Neoplasms, Castration-Resistant Prostate Cancer, and Prostatic Neoplasms, Castration-Resistant, among others. Exerting an antitumor action, apalutamide blocking the effect of androgens that promote tumor growth. It targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets in prostate tumors [A31846]. In mice bearing human CRPC xenograft models, apalutamide treatment produced tumor regressions in a dose-dependent manner that was more effective than that of [DB01128] or [DB08899]. Unlike bicalutamide, apalutamide antagonized AR-mediated signaling in AR overexpressing human CRPC cell lines [A31846]. Androgen-deprivation therapy, or hormone therapy, can be used as part of maintenance therapy for patients with non-metastatic prostate cancer. Although most patients achieve therapeutic responses at the initial hormone therapy, many patients progress to non-metastatic castration-resistant (resistance to hormone therapy) prostate cancer which is the second-most common cause of cancer-related deaths in American males [A31852]. Castration-resistant prostate cancer is often incurable, which poses significant clinical challenges for patients. Approximately 10 to 20 % of prostate cancer cases are castration-resistant, and up to 16% of these patients show no evidence of cancer metastasis at the time of castration-resistant diagnosis [L1295]. Higher prostate-specific antigen (PSA) and shorter PSA doubling time (PSA DT) are associated with a higher risk for metastases and death [A31846]. In a phase-2 multicenter open-label study, 89% of patients with non-metastatic, castration-resistant prostate cancer had ≥50% PSA decline at week 12 of apalutamide treatment [A31846]. In a randomized trial, the median metastasis-free survival for patients taking apalutamide was 40.5 months compared to 16.2 months for patients taking a placebo [L1295]. Apalutamide displayed good tolerability and safety profile in clinical studies. Apalutamide was approved in February 2018 by the FDA as Erleada for the treatment of patients with non-metastatic prostate cancer that is resistant to treatment with hormone therapy (castration-resistant). It is available as oral tablets. Apalutamide is the first FDA-approved treatment for non-metastatic, castration-resistant prostate cancer [L1295].
Indication
Indicated for the treatment of patients with non-metastatic, castration-resistant prostate cancer (NM-CRPC) [FDA Label].
Mechanism of Action
Persistent androgen receptor (AR) signaling is a common feature of castration-resistant prostate cancer (CRPC), attributed to AR gene-amplification, AR gene mutation, increased AR expression or increased androgen biosynthesis in prostate tumors [A31852]. Apalutamide is an antagonist of AR that to the binding-site in the ligand-binding domain of the receptor with the IC50 of 16 nM. Upon binding, apalutamide disrupts AR signalling, inhibits DNA binding, and impedes AR-mediated gene transcription [FDA Label]. Apalutamide impairs the translocation of AR from the cytoplasm to the nucleus thus reduces the concentrations of AR available to interact with the androgen response-elements (AREs) [A31852]. Upon treatment with apalutamide, AR was not recruited to the DNA promoter-regions [A31852]. Its main 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 [FDA Label].
Pharmacokinetics
- Absorption
- Mean absolute oral bioavailability was approximately 100%. Median time to achieve peak plasma concentration (tmax) was 2 hours (range: 1 to 5 hours). Median tmax may be increased with a high-fat meal. Administration of oral apalutamide at recommended dosages resulted in a steady state within 4 weeks with a maximum peak concentration (Cmax) and AUC of 6.0 mcg/mL and 100 mcg·h/mL, respectively [FDA Label]. Cmax and AUC of apalutamide is expected to increase in a dose-proportional manner. The mean mean peak-to-trough ratio was 1.63 indicating low daily fluctuations in the plasma concentrations of the drug. 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.
- Distribution
- The mean apparent volume of distribution at steady-state of apalutamide was approximately 276 L [FDA Label].
- Metabolism
- Apalutamide primarily undergoes CYP2C8 and CYP3A4-mediated metabolism to its pharmacologically active metabolite, N-desmethyl apalutamide. The contribution of CYP2C8 and CYP3A4 in the total metabolism of apalutamide is approximately 58% and and 13% following single dose but changes to 40% and 37%, respectively at steady-state [FDA Label]. The auto-induction of CYP3A4-mediated metabolism by apalutamide may explain the increase in CYP3A4 enzymatic activity at steady-state. Based on systemic exposure, relative potency, and pharmacokinetic properties, N-desmethyl apalutamide likely contributed to the clinical activity of apalutamide [FDA Label].
- Elimination
Clearance
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. 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 [FDA Label].
Toxicity
There is no known specific antidote for apalutamide overdose. In the event of an overdose, discontinue apalutamide and undertake general supportive measures until clinical toxicity has been diminished or resolved [FDA Label]. Apalutamide was not shown to be mutagenic 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. The carcinogenic potential of the drug has not been evaluated. In repeat-dose toxicity studies in male rats and dogs, 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 doses 0.9-1.4 times the human exposure based on AUC [FDA Label]. In a fertility study of male rats, a decrease in sperm concentration and motility, increased abnormal sperm morphology, lower copulation and fertility rates in addition to reduced weights of the secondary sex glands and epididymis were observed following 4 weeks of dosing at ≥ 25 mg/kg/day [FDA Label].
Active Ingredient/Synonyms
Apalutamide | Apalutamide |
Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.