Larotrectinib (Specialist drug)

Source: UK SPC (eMC) 4.2 for VITRAKVI 100 mg hard capsules (https://www.medicines.org.uk/emc/product/12101/smpc). VERBATIM: 'The recommended dose in adults is 100 mg larotrectinib twice daily, until disease progression or until unacceptable toxicity occurs.' Treatment should be initiated by physicians experienced in the administration of anticancer therapies, and the presence of an NTRK gene fusion in a tumour specimen must be confirmed by a validated test before starting. MISSED/VOMITED DOSE: do not take two doses at once to make up for a missed dose - take the next dose at the next scheduled time; do not take an extra dose if the patient vomits after a dose. DOSE MODIFICATION: for grade 2 adverse reactions, continued dosing may be appropriate with close monitoring. For grade 3 or 4 reactions not involving liver function abnormalities, withhold until the reaction resolves or improves to baseline or grade 1, resume at the next dose modification if resolution occurs within 4 weeks, and discontinue permanently if it does not resolve within 4 weeks. Dose modifications for adults (and paediatric patients with body surface area of at least 1.0 m2): first 75 mg twice daily, second 50 mg twice daily, third 100 mg once daily; discontinue permanently in patients unable to tolerate treatment after three dose modifications. LIVER FUNCTION TESTS: grade 2 ALT/AST (>3 to <=5 x ULN) - repeat laboratory evaluations frequently until resolved to decide whether interruption or reduction is needed; grade 3 (>5 to <=20 x ULN) or grade 4 (>20 x ULN) with bilirubin <2 x ULN - withhold until resolution or return to baseline, monitor frequently, resume at the next dose modification if it resolves (only where benefit outweighs risk), discontinue permanently if it does not resolve or if grade 4 recurs after resuming; ALT/AST >=3 x ULN with bilirubin >=2 x ULN - withhold, monitor frequently, consider permanent discontinuation, and if resumed start at the next lower dose. Monitor ALT, AST, ALP and bilirubin before the first dose, every 2 weeks during the first month, then monthly for the next 6 months, then periodically. HEPATIC IMPAIRMENT: reduce the starting dose by 50% in moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment; no adjustment in mild (Child-Pugh A). STRONG CYP3A4 INHIBITORS: if coadministration is necessary, reduce the dose by 50%, and resume the previous dose once the inhibitor has been stopped for 3 to 5 elimination half-lives. ELDERLY: no dose adjustment. PAEDIATRIC (SPC 4.2, dosing is by body surface area, NOT per kg, so paedDose is null): the recommended dose in paediatric patients is 100 mg/m2 larotrectinib twice daily with a maximum of 100 mg per dose, until disease progression or unacceptable toxicity; for paediatric patients from birth to less than 3 months the recommended starting dose is 50 mg/m2 twice daily. Paediatric dose modifications - for patients aged 3 months or older with BSA less than 1.0 m2: first 75 mg/m2 twice daily, second 50 mg/m2 twice daily, third 25 mg/m2 twice daily (patients on the third modification remain at 25 mg/m2 twice daily even if BSA increases); for patients aged less than 3 months the only listed modification is 25 mg/m2 twice daily. Verify all paediatric dosing against a children's formulary and local protocol. NOTE: source SPC sections 4.4/4.5/4.8 were truncated at the fetch limit.