Cabozantinib

Source: UK SPC (eMC) 4.2 for Cabozantinib Ipsen 20 mg film-coated tablets (https://www.medicines.org.uk/emc/product/15682/smpc). CRITICAL FORMULATION WARNING (verbatim): 'Cabozantinib Ipsen tablets and cabozantinib capsules are not bioequivalent and should not be used interchangeably.' The doses above are the TABLET doses; the capsule product has its own separate posology (the US label in this bundle is for COMETRIQ capsules and has deliberately NOT been used for the dose). PRESCRIBER RESTRICTION: therapy should be initiated by a physician experienced in the administration of anticancer medicinal products. COMBINATION WITH NIVOLUMAB: cabozantinib 40 mg once daily with nivolumab solution for infusion given intravenously at either 240 mg every 2 weeks or 480 mg every 4 weeks, or nivolumab solution for injection given subcutaneously at either 600 mg every 2 weeks or 1200 mg every 4 weeks; treatment should continue until disease progression or unacceptable toxicity, and nivolumab should be continued until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression (refer to the nivolumab SmPC for its posology). DOSE REDUCTIONS: in monotherapy reduce to 40 mg daily and then to 20 mg daily; in combination with nivolumab reduce to 20 mg once daily and then to 20 mg every other day. Dose interruptions are recommended for management of CTCAE grade 3 or greater toxicities or intolerable grade 2 toxicities; dose reductions are recommended for events that, if persistent, could become serious or intolerable. MISSED DOSE: the missed dose should not be taken if it is less than 12 hours before the next dose. TOXICITY MANAGEMENT (Table 1): Grade 1 and Grade 2 reactions that are tolerable and easily managed - dose adjustment usually not required, add supportive care. Grade 2 reactions that are intolerable and cannot be managed with a dose reduction or supportive care - interrupt until the reaction resolves to grade 1 or less, add supportive care, consider re-initiating at a reduced dose. Grade 3 reactions (except clinically non-relevant laboratory abnormalities) - interrupt until resolution to grade 1 or less, add supportive care, re-initiate at a reduced dose. Grade 4 reactions (except clinically non-relevant laboratory abnormalities) - interrupt and institute appropriate medical care; if the reaction resolves to grade 1 or less re-initiate at a reduced dose, and if it does not resolve permanently discontinue. LIVER ENZYME ELEVATIONS in RCC patients on cabozantinib with nivolumab: ALT or AST above 3 x ULN but 10 x ULN or less without concurrent total bilirubin 2 x ULN or greater - interrupt both medicines until the reaction resolves to Grade 1 or less; corticosteroid therapy may be considered if an immune-mediated reaction is suspected, and re-initiation with a single medicine or sequential re-initiation of both may be considered after recovery. ALT or AST above 10 x ULN, or above 3 x ULN with concurrent total bilirubin 2 x ULN or greater - permanently discontinue both medicines. HEPATIC IMPAIRMENT: no dose adjustment required in mild impairment; only limited data in moderate impairment (Child-Pugh B) so no dosing recommendation can be provided and close monitoring of overall safety is recommended; no clinical experience in severe impairment (Child-Pugh C) so it is not recommended for use in these patients. CARDIAC IMPAIRMENT: limited data - no specific dosing recommendations can be made. ELDERLY: no specific dose adjustment for patients aged 65 years or over. RACE: no dose adjustment based on ethnicity. PAEDIATRIC: safety and efficacy in children and adolescents under 18 years have not yet been established and no recommendation on a posology can be made. NOTE: the eMC 4.5 interactions section was not retrieved in this bundle - the CYP3A4 guidance below comes from eMC 4.2 (which cross-refers to 4.4 and 4.5) and from the US COMETRIQ label; source the UK SPC 4.5 separately.