ROZLYTREK
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ROZLYTREK (ROZLYTREK).
Entrectinib is a potent inhibitor of tropomyosin receptor tyrosine kinases (TRK) A, B, and C, and also inhibits ROS1 and ALK. It blocks downstream signaling pathways including MAPK, PI3K/AKT, and PLCγ, leading to apoptosis and reduced tumor growth in cancers with NTRK or ROS1 fusions.
| Metabolism | Primarily metabolized by CYP3A4 (major) and CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A5 (minor). It is also a substrate of P-glycoprotein (P-gp). |
| Excretion | Primarily hepatic metabolism via CYP3A4; 63% of dose recovered in feces (mostly as metabolites), 18% in urine (9% unchanged). |
| Half-life | Terminal half-life approximately 24 hours; supports once-daily dosing, steady-state reached in ~5 days. |
| Protein binding | 99.8% bound, primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Apparent Vd/F ~ 471 L (approximately 6.7 L/kg for a 70 kg individual); indicates extensive tissue distribution. |
| Bioavailability | Oral bioavailability approximately 30-50% (absolute bioavailability not determined; estimate based on AUC data). |
| Onset of Action | Oral: Onset of clinical effect occurs within 2-4 hours; maximum plasma concentration achieved at 2-4 hours (Tmax). |
| Duration of Action | Duration of action approximately 24 hours with once-daily dosing; sustained receptor occupancy supports continuous inhibition. |
| Molecular Weight | 560.57 |
200 mg orally once daily with or without food.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (eGFR ≥30 mL/min). Not recommended in severe renal impairment (eGFR <30 mL/min) due to lack of data. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Reduce dose to 100 mg once daily. Child-Pugh C: Not recommended. |
| Pediatric use | For patients ≥12 years and ≥40 kg: 200 mg orally once daily. For patients <40 kg or <12 years: Not approved. |
| Geriatric use | No specific dose adjustment; use with caution due to potential for increased adverse effects and age-related renal/hepatic function decline. |
| 1st trimester | There are no adequate and well-controlled studies in pregnant women. Based on animal studies, Rozlytrek may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. |
| 2nd trimester | Same as T1. Potential risk to fetus based on animal studies. Avoid use unless benefit outweighs risk. |
| 3rd trimester | Same as T1. Potential risk to fetus. Consider alternative therapies if possible. |
Clinical note
Comprehensive clinical and safety monograph for ROZLYTREK (ROZLYTREK).
| Placental transfer | Entrectinib (active moiety) is likely to cross the placenta based on its molecular weight and animal studies showing transfer. Specific human placental transfer data are not available. |
| Breastfeeding | No data on presence in human milk, effects on the breastfed infant, or effects on milk production. Because of the potential for serious adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment and for at least 2 weeks after the last dose. |
■ FDA Black Box Warning
No FDA boxed warning.
| Serious Effects |
None known based on FDA labeling. Hypersensitivity to entrectinib or any excipients is a contraindication (anaphylaxis reported).
| Precautions | Congestive heart failure (CHF), Central nervous system (CNS) effects including cognitive impairment, mood disorders, dizziness, and sleep disturbances, Skeletal fractures, Hepatotoxicity, Hyperuricemia, QT interval prolongation, Vision disorders, Embryo-fetal toxicity |
| Food/Dietary | Avoid grapefruit and grapefruit juice. No other food restrictions. Take with or without food. |
| Clinical Pearls |
Loading safety data…
| Lactation Rating | L5 (Contraindicated) per LactMed classification due to potential serious adverse reactions, though not formally assigned; clinical recommendation is to avoid breastfeeding. |
| Teratogenic Risk | Based on animal data and mechanism of action (ROS1/TRK inhibitor), ROZLYTREK (entrectinib) may cause fetal harm when administered to a pregnant woman. In animal reproduction studies, entrectinib was teratogenic in rats and rabbits at maternal exposures below the human exposure at the recommended dose. There are no adequate and well-controlled studies in pregnant women. The drug should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Effective contraception should be used during treatment and for at least 7 weeks after the last dose. |
| Fetal Monitoring | Monitor pregnant women for potential fetal effects via ultrasound and fetal growth assessment. Monitor for maternal adverse reactions including hepatotoxicity, QT prolongation, and neurologic effects. Perform liver function tests (ALT, AST, bilirubin) at baseline and monthly. Obtain ECG at baseline and as clinically indicated. Monitor for symptoms of cognitive impairment, mood disorders, and dizziness. Assess for fractures and monitor bone density if needed. |
| Fertility Effects | Based on animal studies, entrectinib may impair fertility in females. In male rats, adverse effects on testicular function were observed. The effects on human fertility are unknown. Women of reproductive potential should use effective contraception during treatment and for at least 7 weeks after the last dose. |
| Monitor for hepatotoxicity, including ALT and AST elevations, which may require dose modification or discontinuation. Obtain baseline LVEF and monitor for signs of heart failure, as reduced ejection fraction has been reported. Avoid strong and moderate CYP3A inducers and inhibitors; adjust dose with strong CYP3A inhibitors. May cause QTc interval prolongation; monitor electrolytes and ECG in at-risk patients. |
| Patient Advice | Take ROZLYTREK exactly as prescribed, with or without food. · Swallow capsules whole; do not crush or chew. · If a dose is missed by more than 6 hours, skip the missed dose and take the next dose at the regular time. · Avoid grapefruit or grapefruit juice while taking this medication. · Report symptoms of liver problems (yellowing skin/eyes, dark urine, abdominal pain) or heart failure (shortness of breath, swelling of legs/ankles) immediately. · Do not take St. John's wort or other CYP3A inducers. · Use effective contraception during treatment and for at least 5 weeks after the last dose. · Avoid breastfeeding during treatment and for 1 week after the last dose. |