VITRAKVI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for VITRAKVI (VITRAKVI).
Larotrectinib is a selective inhibitor of the tropomyosin receptor kinases (TRK) A, B, and C. It binds to the ATP-binding site of TRK kinases, preventing their activation and downstream signaling pathways, thereby inhibiting proliferation and inducing apoptosis in tumors with NTRK gene fusions.
| Metabolism | Primarily metabolized by CYP3A4 and CYP2C8; minor contribution from other CYP enzymes. The major active metabolite (M5) is formed via CYP3A4. |
| Excretion | Primarily hepatic metabolism, with 39% recovered in feces (36% as unchanged drug) and 18% in urine (0.5% unchanged). |
| Half-life | Terminal elimination half-life is approximately 16.2 hours (range 12-20 h) in patients; supports twice-daily dosing. |
| Protein binding | >99% bound to human plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Volume of distribution is approximately 4.6 L (range 2.6-8.2 L), corresponding to ~0.07 L/kg (based on 70 kg). Indicates extensive tissue distribution, exceeding total body water. |
| Bioavailability | Oral bioavailability is approximately 95% under fasting conditions; absorption is unaffected by food. |
| Onset of Action | Oral: Clinical response (tumor shrinkage) typically observed within 2-4 weeks of starting therapy; for tropomyosin receptor kinase (TRK) fusion-positive tumors. |
| Duration of Action | Duration of action is continuous with twice-daily dosing; sustained inhibition of TRK fusion proteins over the dosing interval. Duration of response varies; median duration of response not yet reached in some trials. |
100 mg orally twice daily
| Dosage form | SOLUTION |
| Renal impairment | No dose adjustment recommended for mild to moderate renal impairment (CrCl ≥30 mL/min). Insufficient data for severe renal impairment (CrCl <30 mL/min) or end-stage renal disease. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B: reduce to 50 mg twice daily. Child-Pugh Class C: reduce to 50 mg twice daily. |
| Pediatric use | Body surface area (BSA) ≥1.0 m²: 100 mg twice daily; BSA 0.6 to <1.0 m²: 75 mg twice daily; BSA <0.6 m²: 50 mg twice daily. Administer orally. |
| Geriatric use | No specific dose adjustment recommended. Use with caution due to age-related renal and hepatic decline; monitor for adverse effects. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for VITRAKVI (VITRAKVI).
| Breastfeeding | There are no data on the presence of larotrectinib 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 with VITRAKVI and for 1 week after the final dose. The M/P ratio is unknown. |
| Teratogenic Risk | Based on its mechanism of action (TRK inhibition) and animal studies, VITRAKVI (larotrectinib) is expected to cause fetal harm when administered to pregnant women. Animal reproduction studies have not been conducted, but in rats, embryo-fetal developmental toxicity was observed at maternal exposures below the clinical exposure at the recommended dose. There are no adequate and well-controlled studies in pregnant women. The risk is present throughout all trimesters due to potential effects on fetal neurodevelopment and growth. Discuss with the patient the potential risks to the fetus. |
■ FDA Black Box Warning
None.
| Serious Effects |
None.
| Precautions | ["Neurologic adverse reactions including dizziness, gait disturbance, and paresthesia; monitor for symptoms and manage with dose adjustment or discontinuation.","Hepatotoxicity: Monitor liver function tests before and during treatment; dose adjustment recommended for Grade 3 or higher elevations.","Embryo-fetal toxicity: Can cause fetal harm; advise females of reproductive potential of the risk and to use effective contraception during treatment and for at least 1 week after the last dose."] |
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| Fetal Monitoring | Monitor pregnant women for fetal growth and development with serial ultrasound examinations. Assess for potential adverse effects on the fetus, including neurodevelopmental outcomes. Monitor liver function tests, neurological status, and growth parameters in the infant after birth. For the mother, monitor for adverse events such as hepatotoxicity, neurotoxicity, and QT prolongation as per standard prescribing information. |
| Fertility Effects | Based on animal studies, VITRAKVI may impair fertility in females. In rats, ovarian follicular degeneration was observed at exposures similar to the clinical exposure. The effect on human fertility is unknown, but may be reversible. Advise patients of the potential risk to reproductive capacity. |