dose. If toxicity recurs at Grade 3, consider discontinuation.
Grade 4 Discontinue AFINITOR and treat with appropriate medical therapy.
Metabolic events
(e.g. hyperglycemia, dyslipidemia) Grade 1 No dose adjustment required.
Initiate appropriate medical therapy and monitor.
Grade 2 No dose adjustment required.
Manage with appropriate medical therapy and monitor.
Grade 3 Temporary dose interruption.
Reinitiate AFINITOR at a lower dose.
Manage with appropriate medical therapy and monitor.
Grade 4 Discontinue AFINITOR and treat with appropriate medical therapy.
Hepatic Impairment
Hepatic impairment will increase the exposure to everolimus [see Warnings and Precautions (5.10) and Use in Specific Populations (8.8)]. Dose adjustments are recommended:
•Mild hepatic impairment (Child-Pugh class A) – The recommended dose is 7.5 mg daily; the dose may be decreased to 5 mg if not well tolerated.
•Moderate hepatic impairment (Child-Pugh class B) – The recommended dose is 5 mg daily; the dose may be decreased to 2.5 mg if not well tolerated.
•Severe hepatic impairment (Child-Pugh class C) – If the desired benefit outweighs the risk, a dose of 2.5 mg daily may be used but must not be exceeded.
Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes during treatment.
CYP3A4/P-glycoprotein (PgP) Inhibitors
Avoid the use of strong CYP3A4/PgP inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) [see Warnings and Precautions (5.9) and Drug Interactions (7.1)].
Use caution when co-administered with moderate CYP3A4/PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). If patients require co-administration of a moderate CYP3A4/PgP inhibitor, reduce the AFINITOR dose to 2.5 mg daily. The reduced dose of AFINITOR is predicted to adjust the area under the curve (AUC) to the range observed without inhibitors. An AFINITOR dose increase from 2.5 mg to 5 mg may be considered based on patient tolerance. If the moderate inhibitor is discontinued, a washout period of approximately 2 to 3 days should be allowed before the AFINITOR dose is increased. If the moderate inhibitor is discontinued, the AFINITOR dose should be returned to the dose used prior to initiation of the moderate CYP3A4/PgP inhibitor.
Grapefruit, grapefruit juice, and other foods that are known to inhibit cytochrome P450 and PgP activity may increase everolimus exposures and should be avoided during treatment.
Strong CYP3A4/PgP Inducers
Avoid the use of concomitant strong CYP3A4/PgP inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). If patients require co-administration of a strong CYP3A4/PgP inducer, consider doubling the daily dose of AFINITOR using increments of 5 mg or less. This dose of AFINITOR is predicted, based on pharmacokinetic data, to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4/PgP inducers. If the strong inducer is discontinued, consider a washout period of 3 to 5 days, before the AFINITOR dose is returned to the dose used prior to initiation of the strong CYP3A4/PgP inducer [see Warnings and Precaut |
