Entrectinib

UK SPC (Rozlytrek 100 mg hard capsules, https://www.medicines.org.uk/emc/product/11686/smpc). Treatment should be initiated by a physician experienced in the use of anticancer medicinal products. PATIENT SELECTION: a validated assay is required - NTRK gene fusion-positive status must be established before starting therapy for NTRK fusion-positive solid tumours, and ROS1-positive status must be established before starting therapy in adults with ROS1-positive NSCLC. ADMINISTRATION: capsules must be swallowed whole and must not be opened, crushed, chewed or dissolved (the contents are very bitter); may be taken with or without food, but not with grapefruit, grapefruit juice or Seville oranges. Missed dose: patients can make up a missed dose unless the next dose is due within 12 hours. If vomiting occurs immediately after a dose, the dose may be repeated. ADULT DOSE REDUCTIONS (up to 2 reductions, based on tolerability): 600 mg once daily -> 400 mg once daily -> 200 mg once daily; permanently discontinue if the patient cannot tolerate 200 mg once daily. CYP3A INHIBITORS: avoid concomitant strong or moderate CYP3A inhibitors; if unavoidable in adults, limit co-administration to 14 days and reduce entrectinib to 100 mg once daily with a strong CYP3A inhibitor or 200 mg once daily with a moderate CYP3A inhibitor, resuming the previous dose after the inhibitor is stopped (a wash-out period may be required for inhibitors with a long half-life). TOXICITY MODIFICATIONS (SPC Table 4) cover congestive heart failure, cognitive disorders, hyperuricaemia, QT interval prolongation (withhold for QTc 481-500 ms until baseline then resume at the same dose; withhold for QTc >500 ms and resume at the same or a reduced dose; permanently discontinue for torsade de pointes, polymorphic ventricular tachycardia or serious arrhythmia), transaminase elevations (permanently discontinue for ALT or AST >3x ULN with concurrent total bilirubin >2x ULN in the absence of cholestasis or haemolysis), anaemia/neutropenia and other Grade 3-4 reactions. Elderly: no dose adjustment for patients aged 65 years and over. Hepatic impairment: no dose adjustment recommended for mild (Child-Pugh A), moderate (Child-Pugh B) or severe (Child-Pugh C) impairment, but patients with severe impairment should be carefully monitored for hepatic function and adverse reactions. PAEDIATRIC: the SPC gives a separate body-surface-area-based paediatric posology for patients aged 12 years and older, with its own dose-reduction schedule (including an intermittent 5-days-per-week option at the lowest reduced dose level) - this is BSA-based rather than per-kg so it is not encoded in paedDose here; any under-18 use must be verified against a children's formulary and the SPC / specialist paediatric oncology protocol. Safety and efficacy in children below 12 years of age have not been established and no posology recommendation can be made (UK SPC). US labelling differs, stating that safety and effectiveness have been established in paediatric patients older than 1 month of age (but not in paediatric ROS1-positive NSCLC) - verify before any paediatric use.