APALUTAMIDE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for APALUTAMIDE (APALUTAMIDE).
Apalutamide is a nonsteroidal antiandrogen that inhibits androgen receptor (AR) nuclear translocation, DNA binding, and transcription of AR target genes. It also decreases AR-mediated tumor cell proliferation and increases apoptosis.
| Metabolism | Primarily metabolized by CYP2C8 and CYP3A4 to active metabolite N-desmethylapalutamide. Also involves glucuronidation by UGTs. |
| Excretion | Apalutamide and its active metabolite N-desmethyl-apalutamide are eliminated primarily via hepatic metabolism and subsequent fecal excretion. Approximately 65% of the dose is recovered in feces (as unchanged drug and metabolites) and 24% in urine (primarily as metabolites). Renal excretion of unchanged drug is negligible. |
| Half-life | Terminal elimination half-life is approximately 3 days (72 hours) for apalutamide and 3–5 days for the active metabolite N-desmethyl-apalutamide. The long half-life supports once-daily dosing and requires approximately 2–3 weeks to reach steady state. |
| Protein binding | Apalutamide is highly protein bound (>96%), primarily to albumin and alpha-1-acid glycoprotein. No significant displacement interactions are expected with other highly bound drugs. |
| Volume of Distribution | Apparent volume of distribution (Vd/F) is approximately 200 L (2.7 L/kg for a 70 kg adult), indicating extensive distribution into tissues including the prostate and other androgen-responsive organs. |
| Bioavailability | Oral bioavailability is not precisely determined due to lack of an intravenous formulation, but absorption is at least 90% based on mass balance studies. Food does not significantly affect absorption, so it can be taken with or without food. |
| Onset of Action | Oral administration: Clinical effects (e.g., suppression of androgen receptor signaling) begin within 1–2 weeks, but maximal prostate-specific antigen (PSA) decline and therapeutic response are typically observed after 4–12 weeks of continuous dosing. |
| Duration of Action | The pharmacodynamic effect persists beyond dosing intervals due to the long half-life. Once-daily dosing maintains therapeutic concentrations; following discontinuation, androgen receptor inhibition wanes over several weeks as the drug and metabolite are cleared. |
240 mg orally once daily with or without food.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (eGFR 30-89 mL/min). For severe renal impairment (eGFR 15-29 mL/min), use with caution; no specific dose recommendation. Not studied in end-stage renal disease (eGFR <15 mL/min) or on hemodialysis. |
| Liver impairment | Mild hepatic impairment (Child-Pugh A): No dose adjustment. Moderate hepatic impairment (Child-Pugh B): Reduce dose to 120 mg once daily. Severe hepatic impairment (Child-Pugh C): Not recommended due to lack of data. |
| Pediatric use | Safety and efficacy not established; no approved pediatric dosing. |
| Geriatric use | No specific dose adjustment required; consider comorbidities and potential for increased adverse effects based on renal and hepatic function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for APALUTAMIDE (APALUTAMIDE).
| Breastfeeding | It is unknown whether apalutamide or its metabolites are excreted in human milk. Due to potential for serious adverse reactions in breastfed infants, breastfeeding is not recommended during treatment and for at least 3 months after the last dose. M/P ratio is not available. |
| Teratogenic Risk | Apalutamide is contraindicated in pregnancy. Based on its mechanism of androgen receptor inhibition, it may cause fetal harm, including feminization of male fetuses and developmental abnormalities. Adequate animal reproduction studies have not been conducted; however, in rats, fetal malformations were observed at exposures below human clinical exposures. Effective contraception is required for females of reproductive potential during treatment and for 3 months after the last dose. |
■ FDA Black Box Warning
None.
| Serious Effects |
["Pregnancy (can cause fetal harm)","Women of reproductive potential (unless using effective contraception)"]
| Precautions | ["Seizures: Discontinue permanently if seizure occurs during treatment.","Fractures and Falls: Increased risk of bone fractures and falls; assess bone density and manage accordingly.","Cardiovascular Events: Increased risk of hypertension, cardiac ischemia, and heart failure; monitor cardiovascular status.","Hypothyroidism: Monitor thyroid function before and during treatment; replacement therapy may be needed.","Embryo-Fetal Toxicity: Can cause fetal harm; advise males with female partners of reproductive potential to use effective contraception."] |
| Food/Dietary | Avoid grapefruit and grapefruit juice due to potential CYP3A4 interaction. No other specific dietary restrictions; can be taken with or without food. |
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| Fetal Monitoring | Perform pregnancy testing prior to initiating therapy in females of reproductive potential. If patient becomes pregnant during therapy, apprise of potential hazard to fetus and consider prenatal monitoring for fetal development. No specific maternal fetal monitoring beyond standard prenatal care is established. |
| Fertility Effects | Based on animal studies, apalutamide may impair fertility in males of reproductive potential. In rats, reversible effects on male fertility (decreased sperm count and motility) were observed at exposures similar to clinical doses. Reversibility in humans is unknown. Effects on female fertility have not been studied. |
| Clinical Pearls | Apalutamide is an androgen receptor inhibitor used for non-metastatic castration-resistant prostate cancer (nmCRPC). It is a strong CYP3A4 inducer and moderate CYP2C8 inhibitor, requiring careful management of drug interactions. Monitor thyroid function and blood pressure. Concomitant use with warfarin or other anticoagulants may necessitate increased monitoring due to reduced efficacy. Apalutamide can cause seizures; avoid in patients with history of seizure disorders. Baseline and periodic serum lipid profiles and glucose levels are recommended. Dose reduction in severe hepatic impairment (Child-Pugh C) is suggested. |
| Patient Advice | Take apalutamide with or without food, at the same time each day. · Do not crush, chew, or split tablets; swallow whole. · Avoid grapefruit and grapefruit juice during treatment. · Report signs of seizure, high blood pressure, or thyroid abnormalities to healthcare provider immediately. · Use effective contraception during treatment and for 3 months after last dose; apalutamide may reduce hormonal contraceptive effectiveness. · Inform all healthcare providers of apalutamide use due to potential drug interactions. · May cause fatigue, dizziness, or hot flashes; avoid driving if affected. · Store at room temperature away from moisture and heat. |