XTANDI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for XTANDI (XTANDI).
Androgen receptor inhibitor; binds to the androgen receptor, inhibits nuclear translocation, DNA binding, and transcription of androgen-responsive genes.
| Metabolism | Hepatic via CYP2C8 and CYP3A4; active metabolite (M2) formed by CYP2C8; co-administration with strong CYP2C8 inhibitors increases exposure. |
| Excretion | Primarily hepatic metabolism; 77% of dose recovered in feces (as metabolites), 15% in urine (as metabolites); less than 1% excreted unchanged. |
| Half-life | Enzalutamide: 5.8 days; active metabolite N-desmethyl enzalutamide: 7.8-8.6 days. Steady state achieved after ~28 days. |
| Protein binding | Enzalutamide: 97-98% bound to plasma proteins (primarily albumin); N-desmethyl enzalutamide: 95% bound. |
| Volume of Distribution | Enzalutamide: ~110 L (approximately 1.4 L/kg for a 70 kg adult); extensive tissue distribution. |
| Bioavailability | Oral bioavailability not directly reported; absorption is rapid with Tmax 1-2 hours post-dose; no significant food effect. |
| Onset of Action | Clinical effects (e.g., PSA decline) observed within 4-12 weeks of continuous oral dosing. |
| Duration of Action | Duration of effect persistent throughout continuous therapy; maximal PSA response by 12-24 weeks; duration dependent on disease progression. |
| Molecular Weight | 464.44 |
160 mg orally once daily.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl 30-89 mL/min). Not studied in severe renal impairment (CrCl <30 mL/min) or end-stage renal disease. |
| Liver impairment | Mild hepatic impairment (Child-Pugh A): no dose adjustment. Moderate hepatic impairment (Child-Pugh B): reduce dose to 80 mg once daily. Severe hepatic impairment (Child-Pugh C): not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients; no dosing guidelines available. |
| Geriatric use | No specific dose adjustment required; clinical studies included patients ≥65 years with no overall differences in safety or efficacy observed. |
| 1st trimester | Contraindicated. XTANDI (enzalutamide) is an androgen receptor inhibitor. Based on its mechanism of action and animal studies, it can cause fetal harm if administered to a pregnant woman. Animal studies showed embryo-fetal toxicity and developmental anomalies. There is no indication for use in women, and pregnancy should be excluded before initiation. |
| 2nd trimester | Contraindicated. Same risks as in first trimester. Potential for fetal harm due to anti-androgenic effects. |
| 3rd trimester | Contraindicated. Risk of fetal harm persists throughout pregnancy. Not indicated for use in women. |
Clinical note
Comprehensive clinical and safety monograph for XTANDI (XTANDI).
| Placental transfer | Based on animal studies, enzalutamide crosses the placenta and can cause fetal harm. Plasma levels in animal fetuses were similar to maternal levels. No human data available, but placental transfer is expected due to molecular weight and lipophilicity. |
| Breastfeeding |
■ FDA Black Box Warning
None
| Serious Effects |
Pregnancy
| Precautions | Seizure risk (higher incidence with dose >160 mg/day), Posterior reversible encephalopathy syndrome (PRES), Hypertension, Falls and fractures, Cardiovascular events, Hyperglycemia in diabetic patients, Fetal harm if used during pregnancy (for patients with partners of childbearing potential) |
| Food/Dietary | Take with food, preferably a meal. Avoid grapefruit juice as it may increase drug levels. |
| Clinical Pearls | Administer with food to reduce seizure risk; avoid coadministration with strong CYP2C8 inhibitors; monitor for hypertension, hypokalemia, and edema due to mineralocorticoid excess; use with caution in patients with history of seizure; QT prolongation possible. |
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| It is not known whether enzalutamide or its metabolites are excreted in human milk. Due to the potential for serious adverse reactions in nursing infants from enzalutamide, breastfeeding is not recommended during treatment and for at least 1 month after the last dose. |
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | Risk category D (positive evidence of human fetal risk). Based on mechanism (androgen receptor inhibitor), can cause fetal harm. First trimester: high risk of external genitalia abnormalities in male fetuses (hypospadias, genital ambiguity). Second and third trimesters: potential for antiandrogenic effects leading to feminization of male fetuses. Avoid in pregnancy. |
| Fetal Monitoring | Pregnancy test before initiation. Monitor for fetal development via ultrasound if exposure occurs. Assess for signs of androgen deprivation in male infants postnatally (e.g., hypospadias, cryptorchidism). |
| Fertility Effects | Reversible impairment of spermatogenesis in males (oligospermia or azoospermia) due to androgen receptor blockade. Effects on female fertility unknown, but ovarian suppression possible. May impair fertility in both sexes; counsel on fertility preservation. |
| Patient Advice | Take with food to reduce risk of seizure. · Do not crush or chew capsules; swallow whole. · Report any symptoms of high blood pressure, low potassium (muscle cramps, weakness), or fluid retention (swelling in legs). · Seek immediate medical attention for seizure or allergic reaction. · Avoid grapefruit juice during treatment. · Use effective contraception during and for 3 months after treatment if partner is of childbearing potential. |