AFINITOR (Everolimus) 5mg, 10mg tablets by Novartis
PHARMACOLOGIC CLASS: Antineoplastic agent (mTOR kinase inhibitor)
ACTIVE INGREDIENT: Everolimus 5mg, 10mg; tabs.
INDICATION: Advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.
PHARMACOLOGY: The mammalian target of rapamycin, mTOR, is a serinethreonine kinase involved in a cellular process that has been shown to be deregulated in several human cancers. Everolimus is a rapamycin derivative that binds to an intracellular protein, forming a complex that inhibits mTOR kinase activity. It also reduces the activity of S6 ribosomal protein kinase and eukaryotic elongation factor 4E-binding protein, which are two other factors involved in protein synthesis in the mTOR pathway. In addition, it reduces the expression of both vascular endothelial growth factor and hypoxia-inducible factor. The inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake.
CLINICAL TRIALS: A study that compared everolimus to placebo, in conjunction with best supportive care, was undertaken in patients with metastatic renal cell carcinoma whose disease had progressed despite prior treatment with sunitinib, sorafenib, or both sequentially. The use of everolimus was shown to be superior to placebo for progression-free survival, which was assessed via a blinded, independent, central radiologic review. The median duration of progression-free survival for 277 patients taking everolimus was 4.9 months, versus 1.9 months for 139 patients given placebo. The treatment effect was similar across prognostic scores and prior treatment with sunitinib and/or sorafenib.
ADULTS: Swallow whole with water. 10mg once daily. Moderate hepatic dysfunction (Child-Pugh class B), or adverse reactions: reduce to 5mg once daily. Concomitant strong CYP3A4 inducers: may increase to 15–20mg once daily. Continue as long as benefit observed or until unacceptable toxicity occurs.
CHILDREN: Not recommended.
CONTRAINDICATIONS: Sirolimus, temsirolimus, rapamycin allergy.
PRECAUTIONS: Severe hepatic impairment (Child-Pugh class C): not recommended. Moderate hepatic impairment: reduce dose. Pre-existing invasive fungal infections: treat before starting. Monitor CBCs, renal function, lipids, blood glucose, and for pneumonitis and infections. Pregnancy (Cat.D), nursing mothers: not recommended.
INTERACTIONS: Avoid live vaccines. Potentiated by moderate to strong CYP3A4 inhibitors, P-glycoprotein inhibitors; avoid (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, fosamprenavir, voriconazole, aprepitant, erythromycin, fluconazole, grapefruit juice, verapamil, diltiazem). Antagonized by strong CYP3A4 inducers; avoid (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital); increase everolimus dose if used.
ADVERSE REACTIONS: Pneumonitis (reduce dose and/or manage with corticosteroids), infections (discontinue if invasive systemic fungal infection develops), stomatitis (treat with non-alcoholic, non-peroxide mouthwash), asthenia, fatigue, cough; increased serum creatinine, blood glucose, lipids; decreased hemoglobin, platelets, neutrophils, serum phosphate; others (see literature).
HOW SUPPLIED: Tabs—28
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