Everolimus

AFINITOR is a kinase inhibitor indicated for the treatment of: Postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole. Adults with progressive neuroendocrine tumors of pancreatic origin (PNET) and adults with progressive, well-differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic. Limitations of Use: AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors. Adults with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. Adults with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers and in tuberous sclerosis complex (TSC). Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) and thus inhibition of mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic initiation factor 4E-binding protein (4E-BP1), downstream effectors of mTOR, involved in protein synthesis. S6K1 is a substrate of mTORC1 and phosphorylates the activation domain 1 of the estrogen receptor which results in ligand-independent activation of the receptor.

Do not combine AFINITOR and AFINITOR DISPERZ to achieve the total daily dose. Breast Cancer: 10 mg orally once daily. NET: 10 mg orally once daily. RCC: 10 mg orally once daily. TSC-Associated Renal Angiomyolipoma: 10 mg orally once daily. TSC-Associated SEGA: 4.5 mg/m 2 orally once daily, adjust dose to attain trough concentrations of 5-15 ng/mL. TSC-Associated Partial-Onset Seizures: 5 mg/m 2 orally once daily, adjust dose to attain trough concentrations of 5-15 ng/mL.

AFINITOR/AFINITOR DISPERZ is contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives. Clinically significant hypersensitivity to everolimus or to other rapamycin derivatives.

Non-Infectious Pneumonitis: Monitor for clinical symptoms or radiological changes. Withhold or permanently discontinue based on severity. Infections: Monitor for signs and symptoms of infection. Severe Hypersensitivity Reactions: Permanently discontinue for clinically significant hypersensitivity. Angioedema: Patients taking concomitant angiotensin-converting-enzyme (ACE) inhibitors may be at increased risk for angioedema. Permanently discontinue for angioedema. Stomatitis: Initiate dexamethasone alcohol-free mouthwash when starting treatment. Renal Failure: Monitor renal function prior to treatment and periodically thereafter. Risk of Impaired Wound Healing: Withhold for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing.

The following serious adverse reactions are described elsewhere in the labeling: Non-Infectious Pneumonitis Infections Severe Hypersensitivity Reactions Angioedema with Concomitant Use of ACE inhibitors Stomatitis Renal Failure Impaired Wound Healing Metabolic Disorders Myelosuppression Radiation Sensitization and Radiation Recall Breast cancer, NET, RCC: Most common adverse reactions (incidence ≥ 30%) include stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache, and decreased appetite. TSC-Associated Renal Angiomyolipoma: Most common adverse reaction (incidence ≥ 30%) is stomatitis. TSC-Associated SEGA: Most common adverse reactions (incidence ≥ 30%) are stomatitis and respiratory tract infection. TSC-Associated Partial-Onset Seizures: Most common adverse reaction (incidence ≥ 30%) is stomatitis.

Strong CYP3A inhibitor and P-gp inhibitor: Avoid coadministration. Moderate CYP3A inhibitor and P-gp inhibitor: Reduce the dosage as recommended. Cannabidiol oral solution: Reduce the dosage as recommended. Strong CYP3A inducer and P-gp inducer: Increase the dosage as recommended.

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F). See USP Controlled Room Temperature. Store in the original container, protect from light and moisture.