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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ROZLYTREK (ROZLYTREK).
| Breastfeeding | There are no data on the presence of entrectinib in human milk, its effects on the breastfed infant, or its effects on milk production. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment and for at least 7 days after the last dose. The milk-to-plasma ratio (M/P) is unknown. |
| 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. |
■ FDA Black Box Warning
No FDA boxed warning.
| Serious Effects |
None.
| 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"] |
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| 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. |