RECENT MAJOR CHANGES

Indications and Usage,Advanced Pancreatic Neuroendocrine

Tumors (1.1), Warnings and Precautions: Non-infectious

Pneumonitis (5.1), Infections (5.2), Oral Ulceration (5.3), Renal Failure Events (5.4),

Laboratory Tests and Monitoring (5.5)05/2011

Indications and Usage, Subependymal Giant Cell Astrocytoma(1.3) 10/2010

Dosage and Administration (2)10/2010

Warnings and Precautions: Non-infectious Pneumonitis (5.1),

Infections (5.2), Oral Ulceration (5.3), Drug-drug Interactions (5.6),

Hepatic Impairment (5.7), Vaccinations (5.8), Use in Pregnancy (5.9)10/2010

INDICATIONS AND USAGE

AFINITOR is a kinase inhibitor indicated for the treatment of patients with:

• progressiveneuroendocrinetumors of pancreatic origin (PNET)that is unresectable, locally advanced or metastatic.The safety and effectiveness of AFINITORin the treatment of patients with carcinoidtumors have not been established. (1.1)
• advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. (1.2)
• subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) who require therapeutic intervention but are not candidates for curative surgical resection. The effectiveness of AFINITOR is based on an analysis of change in SEGA volume. Clinical benefit such as improvement in disease-related symptoms or increase in overall survival has not been demonstrated. (1.3)

DOSAGE AND ADMINISTRATION

Advanced PNET oradvanced RCC:

• 10 mg once daily with or without food. (2.1)
• For patients with Child-Pugh class B hepatic impairment, reduce the AFINITOR dose to 5 mg once daily. (2.2)
• If moderate inhibitors of CYP3A4 and/or 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, increase AFINITOR dose in 5 mg increments to a maximum of 20 mg once daily. (2.2)

SEGA:

• Initial dose based on body surface area with subsequent titration to attain trough concentrations of 5-10ng/mL. (2.3)
• If moderate inhibitors of CYP3A4 and/or PgP are required, reduce the AFINITOR dose by approximately 50%. Subsequent dosing should be based on therapeutic drug monitoring (TDM). (2.4)
• If strong inducers of CYP3A4 are required, double the AFINITOR dose. Subsequent dosing should be based on TDM. (2.4)

Dose reduction and/or treatment interruption may be needed to manage adverse drug reactions. (2.2, 2.4)

DOSAGE FORMS AND STRENGTHS

2.5 mg, 5 mg, 7.5 mg and 10 mg tablets with no score (3)

CONTRAINDICATIONS

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)
• Oral ulceration: Mouth ulcers, stomatitis, and oral mucositis are common. Management includes mouthwashes (without alcohol or peroxide) and topical treatments. (5.3)
• Renal failure events:Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR (5.4)
• Laboratory test alterations: Elevations of serum creatinine, 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. (5.5)
• Vaccinations: Avoid live vaccines and close contact with those who have received live vaccines. (5.8)
• Use in pregnancy: Fetal harm can occur when administered to a pregnant woman. Apprise women of potential harm to the fetus. (5.9, 8.1)

ADVERSE REACTIONS

AdvancedPNET: Most common adverse reactions (incidence ≥30%) are stomatitis, rash, diarrhea, fatigue, edema,abdominal pain, nausea, fever, and headache.(6.1)

Advanced RCC: Most common adverse reactions (incidence ≥30%) are stomatitis, infections, asthenia, fatigue, cough, and diarrhea.(6.2)

SEGA: Most common adverse reactions (incidence ≥30%) arestomatitis, upper respiratory tract infection, sinusitis, otitis media, and pyrexia. (6.3)

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.

DRUG INTERACTIONS

• Strong CYP3A4 inhibitors: Avoid concomitant use. (2.2, 2.4, 5.6, 7.1)
• Moderate CYP3A4 and/or PgP inhibitors: If combination is required, use caution and reduce dose of AFINITOR. (2.2, 2.4, 5.6, 7.1)
• Strong CYP3A4 inducers: Avoid concomitant use. If combination cannot be avoided, increase dose of AFINITOR. (2.2, 2.4,5.6, 7.2)

USE IN SPECIFIC POPULATIONS

• Nursing mothers: Discontinue drug or nursing, taking into consideration the importance of drug to the mother. (8.3)
• Hepatic impairment: AFINITORshould not be used in patients with Child-Pugh class C hepatic impairment. ForadvancedPNET andadvanced RCCpatients with Child-Pugh class B hepatic impairment, reduce AFINITOR dose.For SEGA patients with Child-Pugh class B hepatic impairment, adjustment to the starting dose may not be needed; however, subsequent dosing should be based on TDM.(2.2, 2.5, 5.7, 8.7)