Generic
Larotrectinib
2 brands available in the market
At a glance
Larotrectinib is indicated for the treatment of patients with solid tumors that have an NTRK gene fusion, are metastatic or where surgical resection is likely to result in severe morbidity, and have no alternative treatments or have progressed following treatment.
Description
Larotrectinib is a highly selective inhibitor of tropomyosin receptor kinases (TRK) TRKA, TRKB, and TRKC. NTRK1, NTRK2, and NTRK3 genes encode TRK proteins; fusions of these genes result in constitutively activated chimeric TRK fusion proteins that act as oncogenic drivers, promoting tumor cell proliferation and survival. Larotrectinib inhibits these fusion proteins, demonstrating antitumor activity. The drug is primarily metabolized by CYP3A4 and excreted in feces (58%) and urine (39%).
Indications
- Solid tumors with NTRK gene fusion (metastatic or where surgical resection would cause severe morbidity, no alternative treatments or progressed following treatment)
Therapeutic class
Cytotoxic Chemotherapy
Pharmacological class
TRK Inhibitor
Pharmacology
Larotrectinib is a highly selective inhibitor of TRKA, TRKB, and TRKC (IC50 5-11 nM). It inhibits chimeric TRK fusion proteins resulting from NTRK gene fusions, which act as oncogenic drivers promoting tumor cell proliferation and survival.
Mechanism of action
Inhibits TRK fusion proteins, blocking tumor cell proliferation and survival.
Dosage
Adult and Pediatric (BSA ≥1 m²):
- 100 mg PO twice daily
- With or without food
- Continue until disease progression or unacceptable toxicity
Pediatric (BSA <1 m²):
- 100 mg/m² PO twice daily
Hepatic Impairment: Moderate to severe (Child-Pugh B/C): Reduce starting dose by 50%
Administration
- Swallow capsules whole with water; do not chew or crush
- Do not take a missed dose within 6 hours of the next scheduled dose
- If vomiting occurs after a dose, take the next dose at the scheduled time
Missed dose
Do not take a missed dose within 6 hours of the next scheduled dose; take the next dose at the scheduled time.
Side effects
Common Side Effects (>10%):
- Increased AST/ALT (45%)
- Anemia (42%)
- Fatigue (37%)
- Hypoalbuminemia (35%)
- Increased alkaline phosphatase (30%)
- Nausea (29%), Dizziness (28%), Vomiting (26%)
- Cough (26%), Constipation (23%), Neutropenia (23%)
- Diarrhea (22%), Pyrexia (18%), Dyspnea (18%)
- Peripheral edema (15%), Increased weight (15%), Headache (14%)
- Arthralgia (14%), Myalgia (14%), Muscular weakness (13%)
- Decreased appetite (13%), Abdominal pain (13%), Back pain (12%)
- Pain in extremity (12%), Hypertension (11%)
Precautions & warnings
- Monitor for neurologic adverse reactions (occur in 53% of patients; most within first 3 months)
- Do not drive or operate hazardous machinery if experiencing neurologic reactions
- Monitor liver tests for hepatotoxicity (every 2 weeks during first month, then monthly)
- Can cause fetal harm in pregnant women
Contraindications
- Hypersensitivity to Larotrectinib or any components of this product
Drug interactions
- Strong CYP3A4 inhibitors: Increase plasma concentrations; avoid use (including grapefruit juice)
- Strong CYP3A4 inducers: Decrease plasma concentrations (reduce efficacy); avoid use
- Sensitive CYP3A4 substrates: Increase plasma concentrations; avoid use
Food interactions
No food interactions known.
Use in pregnancy
Use in Pregnancy: Can cause embryo-fetal harm when administered to pregnant women. Verify pregnancy status and use effective contraception (for 1 week after the last dose).
Use in lactation
Use in Lactation: No data on presence in human milk. Due to potential for serious adverse reactions in breastfed children, do not breastfeed during treatment and for 1 week after the final dose.
Pediatric use
Safety and effectiveness established in pediatric patients 28 days and older.
Geriatric use
Insufficient data in patients 65 years and older.
Renal / hepatic impairment
Renal Impairment: Mild to severe: No dosage adjustment necessary.
Hepatic Impairment: Moderate to severe (Child-Pugh B/C): Reduce starting dose by 50%.
Overdose effects
No specific overdose information available; symptomatic and supportive measures should be employed.
Storage conditions
Store below 30°C in a cool and dry place, away from sunlight; keep out of reach of children.
Chemical structure
Larotrectinib