AFINITOR is a kinase inhibitor indicated for the treatment of:

• Postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole. (1.1)
• 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. AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors. (1.2)
• Adults with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. (1.3)
• Adults with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. (1.4)

AFINITOR and AFINITOR DISPERZ are kinase inhibitors indicated for the treatment of:

• Pediatric and adult patients with tuberous sclerosis complex (TSC) who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected. (1.5)

• Advanced HR+ BC, advanced NET, advanced RCC, or renal angiomyolipoma with TSC:
  • 10 mg once daily with or without food. (2.1)
  • For patients with hepatic impairment, reduce the AFINITOR dose. (2.2)
  • If moderate inhibitors of CYP3A4/P-glycoprotein (PgP) are required, reduce the AFINITOR dose to 2.5 mg once daily; if tolerated, consider increasing to 5 mg once daily. (2.2)
  • If strong inducers of CYP3A4 are required, consider doubling the daily dose of AFINITOR using increments of 5 mg or less. (2.2)
• SEGA with TSC:
  • 4.5 mg/m2 once daily; adjust dose to attain trough concentrations of 5-15 ng/mL. (2.3)
  • Assess trough concentrations approximately 2 weeks after initiation of treatment, a change in dose, a change in co-administration of CYP3A4/PgP inducers or inhibitors, a change in hepatic function, or a change in dosage form between AFINITOR Tablets and AFINITOR DISPERZ. (2.3, 2.4)
  • For patients with severe hepatic impairment reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ. (2.3, 2.5)
  • If concomitant use of moderate inhibitors of CYP3A4/PgP is required, reduce the dose of AFINITOR Tablets or AFINITOR DISPERZ by 50%. (2.3, 2.5)
  • If concomitant use of strong inducers of CYP3A4/PgP is required, double the dose of AFINITOR Tablets or AFINITOR DISPERZ. (2.3, 2.5)

AFINITOR Tablets: 2.5 mg, 5 mg, 7.5 mg, and 10 mg tablets (3.1)

AFINITOR DISPERZ Tablets, for oral suspension: 2 mg, 3 mg, and 5 mg tablets (3.2)

Hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients (4)
WARNINGS AND PRECAUTIONS

• Non-infectious pneumonitis: Monitor for clinical symptoms or radiological changes; fatal cases have occurred. Manage by dose reduction or discontinuation until symptoms resolve, and consider use of corticosteroids. (5.1)
• Infections: Increased risk of infections, some fatal. Monitor for signs and symptoms, and treat promptly. (5.2)
• Angioedema: Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema. (5.3)
• Oral ulceration: Mouth ulcers, stomatitis, and oral mucositis are common. Management includes mouthwashes and topical treatments. (5.4)
• Renal failure: Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed. (5.5)
• Impaired wound healing: Increased risk of wound-related complications. Monitor signs and symptoms. Exercise caution in the peri-surgical period. (5.6)
• Laboratory test alterations: Elevations of serum creatinine, urinary protein, blood glucose, and lipids may occur. Decreases in hemoglobin, neutrophils, and platelets may also occur. Monitor renal function, blood glucose, lipids, and hematologic parameters prior to treatment and periodically thereafter. (5.8)
• Vaccinations: Avoid live vaccines and close contact with those who have received live vaccines. (5.11)
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with AFINITOR and for 8 weeks after final dose. (5.12, 8.1, 8.3)

Advanced HR+ BC, advanced NET, advanced RCC: Most common adverse reactions (incidence ≥30%) include stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache and decreased appetite. (6.1, 6.2, 6.3)

Renal angiomyolipoma with TSC: Most common adverse reaction (incidence ≥ 30%) is stomatitis. (6.4)

SEGA with TSC: Most common adverse reactions (incidence ≥ 30%) are stomatitis and respiratory tract infection. (6.5)
To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

• Strong CYP3A4/PgP inhibitors: Avoid concomitant use. (2.2, 2.5, 5.9, 7.1)
• Moderate CYP3A4/PgP inhibitors: If combination is required, use caution and reduce dose of AFINITOR. (2.2, 2.3, 2.5, 5.9, 7.1)
• Strong CYP3A4/PgP inducers: Avoid concomitant use. If combination cannot be avoided, increase dose of AFINITOR. (2.2, 2.3, 2.5, 5.9, 7.2)