Torisel

1 INDICATIONS AND USAGE TORISEL is indicated for the treatment of advanced renal cell carcinoma. TORISEL ® is a kinase inhibitor indicated for the treatment of advanced renal cell carcinoma. ( 1 )

2 DOSAGE AND ADMINISTRATION • The recommended dose of TORISEL is 25 mg administered as an intravenous infusion over a 30–60 minute period once a week. Treat until disease progression or unacceptable toxicity. ( 2.1 ) • Antihistamine pre-treatment is recommended. ( 2.2 ) • Dose reduction is required in patients with mild hepatic impairment. ( 2.4 ) • TORISEL (temsirolimus) injection vial contents must first be diluted with the enclosed diluent before diluting the resultant solution with 250 mL of 0.9% Sodium Chloride Injection. ( 2.5 ) 2.1 Advanced Renal Cell Carcinoma The recommended dose of TORISEL for advanced renal cell carcinoma is 25 mg administered as an intravenous infusion over a 30 – 60 minute period once a week. Treatment should continue until disease progression or unacceptable toxicity occurs. 2.2 Premedication Patients should receive prophylactic intravenous diphenhydramine 25 to 50 mg (or similar antihistamine) approximately 30 minutes before the start of each dose of TORISEL [see Warnings and Precautions (5.1) ] . 2.3 Dosage Interruption/Adjustment TORISEL should be held for absolute neutrophil count (ANC) <1,000/mm 3 , platelet count <75,000/mm 3 , or NCI CTCAE grade 3 or greater adverse reactions. Once toxicities have resolved to grade 2 or less, TORISEL may be restarted with the dose reduced by 5 mg/week to a dose no lower than 15 mg/week. 2.4 Dose Modification Guidelines Hepatic Impairment : Use caution when treating patients with hepatic impairment. If TORISEL must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5×ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of TORISEL to 15 mg/week. TORISEL is contraindicated in patients with bilirubin >1.5×ULN [see Contraindications (4) , Warnings and Precautions (5.2) and Use in Specific Populations (8.7) ] . Concomitant Strong CYP3A4 Inhibitors : The concomitant use of strong CYP3A4 inhibitors should be avoided (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of sirolimus (a major metabolite of temsirolimus) and should be avoided. If patients must be co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, a TORISEL dose reduction to 12.5 mg/week should be considered. This dose of TORISEL is predicted to adjust the AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the TORISEL dose is adjusted back to the dose used prior to initiation of the strong CYP3A4 inhibitor [see Warnings and Precautions (5.12) and Drug Interactions (7.2) ] . Concomitant Strong CYP3A4 Inducers : The use of concomitant strong CYP3A4 inducers should be avoided (e.g. dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital). If patients must be co-administered a strong CYP3A4 inducer, based on pharmacokinetic studies, a TORISEL dose increase from 25 mg/week up to 50 mg/week should be considered. This dose of TORISEL is predicted 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 inducers. If the strong inducer is discontinued the temsirolimus dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer [see Warnings and Precautions (5.12) and Drug Interactions (7.1) ] . 2.5 Instructions for Preparation TORISEL is a cytotoxic drug. Follow applicable special handling and disposal procedures 1 . TORISEL must be stored under refrigeration at 2°–8°C (36°–46°F) and protected from light. During handling and preparation of admixtures, TORISEL should be protected from excessive room light and sunlight. Parenteral drug products shoul…

5 WARNINGS AND PRECAUTIONS • Hypersensitivity/Infusion Reactions (including some life-threatening and rare fatal reactions) can occur early in the first infusion of TORISEL. Patients should be monitored throughout the infusion. ( 5.1 ) • To treat hypersensitivity reactions, stop TORISEL and treat with an antihistamine. TORISEL may be restarted at physician discretion at a slower rate. ( 5.1 ) • Hepatic Impairment: Use caution when treating patients with mild hepatic impairment and reduce dose. ( 2.4 , 5.2 ) • Hyperglycemia and hyperlipidemia are likely and may require treatment. Monitor glucose and lipid profiles. ( 5.3 , 5.6 ) • Infections may result from immunosuppression. ( 5.4 ) • Monitor for symptoms or radiographic changes of interstitial lung disease (ILD). If ILD is suspected, discontinue TORISEL, and consider use of corticosteroids and/or antibiotics. ( 5.5 ) • Bowel perforation may occur. Evaluate fever, abdominal pain, bloody stools, and/or acute abdomen promptly. ( 5.7 ) • Renal failure, sometimes fatal, has occurred. Monitor renal function at baseline and while on TORISEL. ( 5.8 ) • Due to abnormal wound healing, use TORISEL with caution in the perioperative period. ( 5.9 ) • Proteinuria and nephrotic syndrome may occur. Monitor urine protein prior to the start of TORISEL therapy and periodically thereafter. Discontinue TORISEL in patients with who develop nephrotic syndrome. ( 5.11 ) • Live vaccinations and close contact with those who received live vaccines should be avoided. ( 5.14 ) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential hazard to the fetus and to use effective contraception. ( 5.15 , 8.1 , 8.3 ) • Elderly patients may be more likely to experience certain adverse reactions, including diarrhea, edema and pneumonia. ( 5.16 ) 5.1 Hypersensitivity/Infusion Reactions Hypersensitivity/infusion reactions, including but not limited to flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, hypersensitivity and anaphylaxis, have been associated with the administration of temsirolimus. These reactions can occur very early in the first infusion, but may also occur with subsequent infusions. Patients should be monitored throughout the infusion and appropriate supportive care should be available. Temsirolimus infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered. TORISEL should be used with caution in persons with known hypersensitivity to temsirolimus or its metabolites (including sirolimus), polysorbate 80, or to any other component (including the excipients) of TORISEL. An H 1 antihistamine should be administered to patients before the start of the intravenous temsirolimus infusion. TORISEL should be used with caution in patients with known hypersensitivity to an antihistamine, or patients who cannot receive an antihistamine for other medical reasons. If a patient develops a hypersensitivity reaction during the TORISEL infusion, the infusion should be stopped and the patient should be observed for at least 30 to 60 minutes (depending on the severity of the reaction). At the discretion of the physician, treatment may be resumed with the administration of an H 1 -receptor antagonist (such as diphenhydramine), if not previously administered [see Dosage and Administration (2.2) ] , and/or an H 2 -receptor antagonist (such as intravenous famotidine 20 mg or intravenous ranitidine 50 mg) approximately 30 minutes before restarting the TORISEL infusion. The infusion may then be resumed at a slower rate (up to 60 minutes). A benefit-risk assessment should be done prior to the continuation of temsirolimus therapy in patients with severe or life-threatening reactions. 5.2 Hepatic Impairment The safety and pharmacokinetics of TORISEL were evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment. Patients with baseline bilirubin >1.5×ULN experienced g…

4 CONTRAINDICATIONS TORISEL is contraindicated in patients with bilirubin >1.5×ULN [see Warnings and Precautions (5.2) ] . TORISEL is contraindicated in patients with bilirubin > 1.5×ULN. ( 4 )

7 DRUG INTERACTIONS Strong inducers of CYP3A4/5 and inhibitors of CYP3A4 may affect concentrations of the primary metabolite of TORISEL. If alternatives cannot be used, dose modifications of TORISEL are recommended. ( 7.1 , 7.2 , 7.3 ) 7.1 Agents Inducing CYP3A Metabolism Co-administration of TORISEL with rifampin, a potent CYP3A4/5 inducer, had no significant effect on temsirolimus C max (maximum concentration) and AUC (area under the concentration versus the time curve) after intravenous administration, but decreased sirolimus C max by 65% and AUC by 56% compared to TORISEL treatment alone. If alternative treatment cannot be administered, a dose adjustment should be considered [see Dosage and Administration (2.4) ] . 7.2 Agents Inhibiting CYP3A Metabolism Co-administration of TORISEL with ketoconazole, a potent CYP3A4 inhibitor, had no significant effect on temsirolimus C max or AUC; however, sirolimus AUC increased 3.1-fold, and C max increased 2.2-fold compared to TORISEL alone. If alternative treatment cannot be administered, a dose adjustment should be considered [see Dosage and Administration (2.4) ] . 7.3 Angioedema with ACE inhibitors and Calcium Channel Blockers Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with ramipril and/or amlodipine. Monitor patients for signs and symptoms of angioedema when temsirolimus is given concomitantly with angiotensin converting enzyme (ACE) inhibitors (e.g., ramipril) or calcium channel blockers (CCB) (e.g., amlodipine). Drug Interactions Effect of Temsirolimus on CYP2D6 or CYP3A The concentration of desipramine, a CYP2D6 substrate, was unaffected when 25 mg of temsirolimus was co-administered. No clinically significant effect is anticipated when 25 mg of temsirolimus is co-administered with agents that are metabolized by CYP2D6 or CYP3A.

8.1 Pregnancy Risk Summary Based on findings in animal studies and its mechanism of action, temsirolimus can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . Although there are no data on the use of TORISEL in pregnant women, there are limited data on the use of sirolimus, the active metabolite of temsirolimus, during pregnancy; however, these data are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal reproductive studies, oral daily administration of temsirolimus to pregnant rats and rabbits during organogenesis caused adverse embryo-fetal effects at approximately 0.04 and 0.12 times the AUC in patients at the recommended dose, respectively (see Data ) . Advise pregnant women of the potential hazard to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data Temsirolimus administered daily as an oral formulation throughout organogenesis caused adverse embryo-fetal effects in rats and rabbits at human sub-therapeutic exposures. Embryo-fetal adverse effects in rats consisted of reduced fetal weight and reduced ossifications, and in rabbits included reduced fetal weight, omphalocele, bifurcated sternabrae, notched ribs, and incomplete ossifications. In rats, the adverse embryo-fetal effects were observed at the oral dose of 2.7 mg/m 2 /day (approximately 0.04-fold the AUC in patients with cancer at the human recommended dose). In rabbits, the adverse embryo-fetal effects were observed at the oral dose of ≥7.2 mg/m 2 /day (approximately 0.12-fold the AUC in patients with cancer at the recommended human dose).

6 ADVERSE REACTIONS The following serious adverse reactions have been associated with TORISEL in clinical trials and are discussed in greater detail in other sections of the label [see Warnings and Precautions (5) ] . • Hypersensitivity/Infusion Reactions [see Warnings and Precautions (5.1) ] • Hepatic Impairment [see Warnings and Precautions (5.2) ] • Hyperglycemia/Glucose Intolerance [see Warnings and Precautions (5.3) ] • Infections [see Warnings and Precautions (5.4) ] • Interstitial Lung Disease [see Warnings and Precautions (5.5) ] • Hyperlipidemia [see Warnings and Precautions (5.6) ] • Bowel Perforation [see Warnings and Precautions (5.7) ] • Renal Failure [see Warnings and Precautions (5.8) ] • Wound Healing Complications [see Warnings and Precautions (5.9) ] • Intracerebral Hemorrhage [see Warnings and Precautions (5.10) ] The most common (≥30%) adverse reactions observed with TORISEL are rash, asthenia, mucositis, nausea, edema, and anorexia. The most common (≥30%) laboratory abnormalities observed with TORISEL are anemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, lymphopenia, elevated alkaline phosphatase, elevated serum creatinine, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia. The most common adverse reactions (incidence ≥30%) are rash, asthenia, mucositis, nausea, edema, and anorexia. The most common laboratory abnormalities (incidence ≥30%) are anemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, elevated alkaline phosphatase, elevated serum creatinine, lymphopenia, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia. ( 6 )To report SUSPECTED ADVERSE REACTIONS, contact Wyeth Pharmaceuticals Inc. at 1-800-934-5556 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. In the phase 3 randomized, open-label study of interferon alfa (IFN-α) alone, TORISEL alone, and TORISEL and IFN-α, a total of 616 patients were treated. Two hundred patients received IFN-α weekly, 208 received TORISEL 25 mg weekly, and 208 patients received a combination of TORISEL and IFN-α weekly [see Clinical Studies (14) ] . Treatment with the combination of TORISEL 15 mg and IFN-α was associated with an increased incidence of multiple adverse reactions and did not result in a significant increase in overall survival when compared with IFN-α alone. Table 1 shows the percentage of patients experiencing treatment emergent adverse reactions. Reactions reported in at least 10% of patients who received TORISEL 25 mg alone or IFN-α alone are listed. Table 2 shows the percentage of patients experiencing selected laboratory abnormalities. Data for the same adverse reactions and laboratory abnormalities in the IFN-α alone arm are shown for comparison : Table 1 – Adverse Reactions Reported in at Least 10% of Patients Who Received 25 mg IV TORISEL or IFN-α in the Randomized Trial Adverse Reaction TORISEL 25 mg n = 208 IFN-α n = 200 All Grades Common Toxicity Criteria for Adverse Events (CTCAE), Version 3.0. n (%) Grades 3&4 n (%) All Grades n (%) Grades 3&4 n (%) General disorders Asthenia 106 (51) 23 (11) 127 (64) 52 (26) Edema Includes edema, facial edema, and peripheral edema 73 (35) 7 (3) 21 (11) 1 (1) Pain 59 (28) 10 (5) 31 (16) 4 (2) Pyrexia 50 (24) 1 (1) 99 (50) 7 (4) Weight Loss 39 (19) 3 (1) 50 (25) 4 (2) Headache 31 (15) 1 (1) 30 (15) 0 (0) Chest Pain 34 (16) 2 (1) 18 (9) 2 (1) Chills 17 (8) 1 (1) 59 (30) 3 (2) Gastrointestinal disorders Mucositis Includes aphthous stomatitis, glossitis, mouth ulceration, mucositis, and stomatitis 86 (41) 6 (3) 19 (10) 0 (0) Anorexia 66 (32) 6 (3) 87 (44) 8 (4) Nausea 77 (37) 5 (2) 82 (41) 9 (5) Diarrhea 56 (27) 3 (1) 40 (20) 4 (2) Abdominal Pain 44 (21) 9 (4) 34 (17) 3 (2) Constipation 42 (20) 0 (0) 36 (18) 1 (1) Vomit…