What you should know about your treatment with TORISEL - PfizerPro


What you should know about your treatment with TORISEL - PfizerPro

Wyeth SupportIf you do not have prescription drug insuranceor need help paying for TORISEL, Wyeth may beable to help. Please contact the TORISELReimbursement Support Program:TORISEL Reimbursement Support ProgramPhone: 1-866-WYETH-ONC (1-866-993-8466)Fax: 1-866-993-8411Monday through Friday9:00 a.m. to 6:00 p.m., Eastern TimeAdditional SupportThe organizations listed here can helpyou learn more about kidney cancer:American Cancer Society1-800-ACS-2345 (1-800-227-2345)www.cancer.orgKidney Cancer Association1-800-850-9132 • www.kidneycancer.orgCancer.Net1-888-651-3038 • www.cancer.netPlease see Important Safety Information starting on page 2.For additional information about TORISEL, please see the Prescribing Information in the pocket.You are encouraged to report negative side effects ofprescription drugs to the FDA. Visit www.fda.gov/medwatch,or call 1-800-FDA-1088.© 2008, Wyeth Pharmaceuticals Inc., Philadelphia, PA 19101 November 2008 240126-01What you should know about your treatmentwith TORISEL ® (temsirolimus) injectionPlease review this information before you begin your treatment.Your doctor or nurse can answer any questions you may have.Please see Important Safety Information starting on page 2.Please see accompanying Prescribing Information.

What is TORISEL?• TORISEL is a type of treatment for advanced renalcell carcinoma (RCC)– TORISEL blocks a specific part of cells, including normalcells and cancerous kidney cells, and helps stop them fromgrowing and dividing– TORISEL may help stop the creation of new blood vesselsthat feed the advanced RCC cells• TORISEL has been proven to extend survival longer thanIFN- (another therapy) in patients with advanced RCCRenal cell carcinoma, also calledRCC, is a type of kidney cancer.In advanced RCC, the cancercells have spread to other partsof the kidney or body.Will I receive any medicine before I receiveTORISEL?• Before you begin treatment with TORISEL, your doctormay give you an antihistamine– It is possible to have a serious allergic reaction evenafter you receive an antihistamine– Tell your doctor or nurse if you are allergicto antihistamines– Tell your doctor or nurse if you have any swelling aroundyour face or difficulty breathing during or after treatmentAn antihistamine is a medicinethat can help lower the chancesof an allergic reaction.Benadryl® is an example ofa common antihistamine.An allergic reaction occurswhen the body has a reactionto an allergen, such as food ormedicine. Some signs of anallergic reaction include a rash,trouble breathing, feeling flushed,and chest pain.Benadryl is a registered trademark of Pfizer, its affiliates, related companies or its licensorsor joint venture partners.Please see additional Important Safety Information on pages 7-9.Please see accompanying Prescribing Information.1 2

How will TORISEL be given?• TORISEL is given as an intravenous (IV) infusion• You will receive TORISEL– Once a week as an IV infusion lasting 30 to 60 minutes– In a hospital, clinic, or doctor’s office• Your doctor may decide to stop treatment if– Your disease gets worse– You have side effects that are too seriousAn intravenous (IV) infusionis a common way of givingcertain medicines. The medicineis contained in a bag or bottlehanging upside down. A thintube connects the bag orbottle to a needle, whichgoes into a vein so that themedicine can enter thebloodstream directly.What precautions should I take during treatment with TORISEL?• Before you begin treatment with TORISEL, tell your doctor or nurse aboutALL MEDICINES you are taking, including– Prescription medications, including but not limited to° Antibiotics ° Anticonvulsants ° Antidepressants° Antifungals ° Antivirals ° Blood pressure medications° Blood thinners ° Dexamethasone ° Vaccines– Nonprescription (over the counter) medications– Vitamins– Herbal supplements, including but not limited to St. John’s Wort• Avoid eating grapefruit or drinking grapefruit juice during the course of your treatmentwith TORISEL, including the time between treatments3Please see additional Important Safety Information on pages 7-9.Please see accompanying Prescribing Information.4

What side effects can I expect from treatment?• TORISEL can cause serious side effects• The most common side effects are– Rash– Weakness/fatigue– Mouth sores– Nausea– Swelling/fluid retention– Loss of appetite• TORISEL has caused hair loss in 2% of patients• Patients are likely to experience increased blood sugar levels– This may require treatment with or an increase in thedose of a medicine that lowers blood sugar levels– Tell your doctor or nurse if you are thirstier thanusual or urinate more often than usualTriglycerides are a type of fatfound in the bloodstream.• Patients are likely to experience an increase in cholesterol and/or triglycerides– This may require treatment with or an increase in the dose of a medicine thatlowers cholesterol and/or triglycerides• Your blood may be tested before you begin treatment and at other times overthe course of therapy– Your doctor or nurse may have you fast (not eator drink) before blood testsExamples of rashCourtesy of the Cleveland Clinic Taussig Cancer Center.Please see additional Important Safety Information on pages 7-9.Please see accompanying Prescribing Information.5 6

7What other Important Safety Information should I know about?• Treatment with TORISEL may affect your immune system– You may be at greater risk of getting an infection whilereceiving TORISEL• Patients may get chronic inflammation of the lungsduring treatment with TORISEL– Rare fatal cases have been reported– Tell your doctor or nurse right away if you have anytrouble breathing, get a cough, or develop a fever• TORISEL may cause bowel perforation– Rare fatal cases have been reported– Tell your doctor or nurse right away if you have any newor worsening stomach pain or blood in your stoolThe immune system is the partof the body that fights infections.When the immune system isweak, the body is more likelyto be infected by bacteria andviruses that can cause infections.Chronic inflammation of thelungs is a condition in whichthe lungs become inflamedand swollen.Bowel perforation is a tearin the wall of the intestines.• Treatment with TORISEL may be associated with a risk of kidney failure, sometimes fatal• During treatment with TORISEL, wounds may notheal properly– Tell your doctor or nurse if you are recovering or stillhave an unhealed wound from surgery– Tell your doctor or nurse if you plan to have surgeryduring treatment with TORISELTORISEL may increase the risk of bleeding in the brain, whichhas, in rare cases, been fatal. You are at increased risk if– You have a central nervous system tumor, such asa brain tumor– You are taking medicine to keep your blood from clottingThe central nervous systemincludes the brain and spinal cord.Clotting is the ability of theblood to thicken to help stopbleeding. However, if a bloodclot inside the body is too big,it could stop blood flow. Somepeople with blood clots or a highpotential to develop bloodclots must take medicine tostop their blood from clotting.Please see accompanying Prescribing Information.8

What other Important Safety Information should I know about? (cont.)Helpful Tips• Some vaccines may be less effective when given duringthe course of treatment with TORISEL– You should avoid the use of live vaccines and close contactwith people who have recently received live vaccines° Ask your doctor or nurse if you are eligible to receivea flu shot• Both men and women should use a reliable form of birthcontrol during treatment and for 3 months after the lastdose of TORISELTORISEL can harm an unborn baby• Tell your doctor or nurse before beginning treatmentif you are pregnant or thinking of becoming pregnantExamples of live vaccines are• Intranasal influenza• Measles• Mumps• Rubella• Oral polio• BCG• Yellow fever• Varicella• TY21a typhoid vaccines• Tell all your doctors you are taking TORISEL• Arrange for a friend or family member to drive you to and from your weekly appointments– Treatment with TORISEL may make you feel weak or sick• Maintain good oral hygiene– Basic oral care may help reduce the severity of potential mouth sores• Talk to your doctor or nurse about diet and exercise– An exercise program and balanced diet may help manage potential fatigue• Tell your doctor or nurse about any changes in the way you look or feel during treatment9Please see accompanying Prescribing Information.10

NotesNotes11Please see Important Safety Information starting on page 2.Please see accompanying Prescribing Information.12

NotesTalk to your doctor or nurse if you have any questions about treatment with TORISEL.To learn more about TORISEL, please visit www.TORISEL.com.Doctor’s Name: __________________________________________________________Nurse’s Name: ___________________________________________________________Phone Number: _____________________ Fax Number: _________________________Emergency Phone Number: ________________________________________________Other Information: _______________________________________________________For additional information about TORISEL, please see the Prescribing Informationin the pocket.Please see Important Safety Information starting on page 2.1314

injectionKitHIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the informationneeded to use TORISEL ® safely and effectively. See fullprescribing information for TORISEL.TORISEL Kit (temsirolimus) injection, for intravenousinfusion onlyInitial U.S. approval: 2007INDICATIONS AND USAGETORISEL ® is a kinase inhibitor indicated for the treatment ofadvanced renal cell carcinoma. (1)DOSAGE AND ADMINISTRATION• The recommended dose of TORISEL is 25 mg infused overa 30-60 minute period once a week. Treat until diseaseprogression or unacceptable toxicity. (2.1)• Antihistamine pre-treatment is recommended. (2.2)• TORISEL (temsirolimus) injection vial contents must first bediluted with the enclosed diluent before diluting the resultantsolution with 250 mL of 0.9% sodium chloride injection. (2.5)DOSAGE FORMS AND STRENGTHSTORISEL injection, 25 mg/mL supplied with DILUENT forTORISEL ® . (3)CONTRAINDICATIONS• None. (4)WARNINGS AND PRECAUTIONS• To treat hypersensitivity reactions stop TORISEL and treatwith an antihistamine. TORISEL may be restarted atphysician discretion at a slower rate. (5.1)• Hyperglycemia and hyperlipemia are likely and may requiretreatment. Monitor glucose and lipid profiles. (5.2, 5.5)• Infections may result from immunosuppression. (5.3)• Monitor for symptoms or radiographic changes of interstitiallung disease (ILD). If ILD is suspected, discontinueFULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION2.1 Advanced Renal Cell Carcinoma2.2 Premedication2.3 Dosage Interruption/Adjustment2.4 Dose Modification Guidelines2.5 Instructions for Preparation and Administration3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 Hypersensitivity Reactions5.2 Hyperglycemia/Glucose Intolerance5.3 Infections5.4 Interstitial Lung Disease5.5 Hyperlipemia5.6 Bowel Perforation5.7 Renal Failure5.8 Wound Healing Complications5.9 Intracerebral Hemorrhage5.10 Co-administration with Inducers or Inhibitors ofCYP3A Metabolism5.11 Concomitant use of TORISEL with sunitinib5.12 Vaccinations5.13 Pregnancy5.14 Monitoring Laboratory TestsTORISEL, and consider use of corticosteroids and/orantibiotics. (5.4)• Bowel perforation may occur. Evaluate fever, abdominal pain,bloody stools, and/or acute abdomen promptly. (5.6)• Renal failure, sometimes fatal, has occurred. Monitor renalfunction at baseline and while on TORISEL. (5.7)• Due to abnormal wound healing, use TORISEL with cautionin the perioperative period. (5.8)• Live vaccinations and close contact with those who receivedlive vaccines should be avoided. (5.12)• Women of childbearing potential should be advised of thepotential hazard to the fetus and to avoid becomingpregnant. (5.13)ADVERSE REACTIONSThe most common adverse reactions (incidence ≥30%) arerash, asthenia, mucositis, nausea, edema, and anorexia. Themost common laboratory abnormalities (incidence ≥30%) areanemia, hyperglycemia, hyperlipemia, hypertriglyceridemia,elevated alkaline phosphatase, elevated serum creatinine,lymphopenia, hypophosphatemia, thrombocytopenia, elevatedAST, and leukopenia. (6)To report SUSPECTED ADVERSE REACTIONS, contactWyeth Pharmaceuticals Inc. at 1-800-934-5556 or FDA at1-800-FDA-1088 or www.fda.gov/medwatchDRUG INTERACTIONSStrong inducers of CYP3A4/5 and inhibitors of CYP3A4 mayaffect concentrations of the primary metabolite of TORISEL. Ifalternatives cannot be used, dose modifications of TORISELare recommended. (7.1, 7.2)See 17 for PATIENT COUNSELING INFORMATION.Revised: 09/20086 ADVERSE REACTIONS6.1 Clinical Trials Experience7 DRUG INTERACTIONS7.1 Agents Inducing CYP3A Metabolism7.2 Agents Inhibiting CYP3A Metabolism7.3 Interactions with Drugs Metabolized by CYP2D68 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Renal Impairment8.7 Hepatic Impairment10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility14 CLINICAL STUDIES15 REFERENCES16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION*Sections or subsections omitted from the full prescribinginformation are not listed.1

TORISEL ® Kit(temsirolimus)injectionFULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGETORISEL is indicated for the treatment of advanced renal cellcarcinoma.2 DOSAGE AND ADMINISTRATION2.1 Advanced Renal Cell CarcinomaThe recommended dose of TORISEL for advanced renal cellcarcinoma is 25 mg infused over a 30-60 minute period oncea week.Treatment should continue until disease progression orunacceptable toxicity occurs.2.2 PremedicationPatients should receive prophylactic intravenousdiphenhydramine 25 to 50 mg (or similar antihistamine)approximately 30 minutes before the start of each dose ofTORISEL [see Hypersensitivity Reactions (5.1)].2.3 Dosage Interruption/AdjustmentTORISEL should be held for absolute neutrophil count (ANC)< 1,000/mm 3 , platelet count < 75,000/mm 3 , or NCI CTCAEgrade 3 or greater adverse reactions. Once toxicities haveresolved to grade 2 or less, TORISEL may be restarted withthe dose reduced by 5 mg/week to a dose no lower than15 mg/week.2.4 Dose Modification GuidelinesConcomitant Strong CYP3A4 Inhibitors: The concomitant useof strong CYP3A4 inhibitors should be avoided (e.g.ketoconazole, itraconazole, clarithromycin, atazanavir,indinavir, nefazodone, nelfinavir, ritonavir, saquinavir,telithromycin, and voriconazole). Grapefruit juice may alsoincrease plasma concentrations of sirolimus (a majormetabolite of temsirolimus) and should be avoided. If patientsmust be co-administered a strong CYP3A4 inhibitor, basedon pharmacokinetic studies, a TORISEL dose reduction to12.5 mg/week should be considered. This dose of TORISEL ispredicted to adjust the AUC to the range observed withoutinhibitors. However, there are no clinical data with this doseadjustment in patients receiving strong CYP3A4 inhibitors. Ifthe strong inhibitor is discontinued, a washout period ofapproximately 1 week should be allowed before the TORISELdose is adjusted back to the dose used prior to initiation ofthe strong CYP3A4 inhibitor. [see Drug Interactions (7.2)]Concomitant Strong CYP3A4 Inducers: The use ofconcomitant strong CYP3A4 inducers should be avoided(e.g. dexamethasone, phenytoin, carbamazepine, rifampin,rifabutin, rifampacin, phenobarbital). If patients must beco-administered a strong CYP3A4 inducer, based onpharmacokinetic studies, a TORISEL dose increase from25 mg/week up to 50 mg/week should be considered. Thisdose of TORISEL is predicted to adjust the AUC to the rangeobserved without inducers. However, there are no clinical datawith this dose adjustment in patients receiving strongCYP3A4 inducers. If the strong inducer is discontinued thetemsirolimus dose should be returned to the dose used priorto initiation of the strong CYP3A4 inducer. [see DrugInteractions (7.1)]2.5 Instructions for Preparation and AdministrationTORISEL must be stored under refrigeration at 2º-8ºC(36º-46ºF) and protected from light. During handling andpreparation of admixtures, TORISEL should be protected fromexcessive room light and sunlight. Parenteral drug productsshould be inspected visually for particulate matter anddiscoloration prior to administration, whenever solution andcontainer permit.In order to minimize the patient exposure to the plasticizerDEHP (di-2-ethylhexyl phthalate), which may be leached fromPVC infusion bags or sets, the final TORISEL dilution forinfusion should be stored in bottles (glass, polypropylene) orplastic bags (polypropylene, polyolefin) and administeredthrough polyethylene-lined administration sets.Dilution:In preparing the TORISEL administration solution, follow thistwo-step dilution process in an aseptic manner.Step 1:Inject 1.8 mL of DILUENT for TORISEL ® into the vial ofTORISEL (temsirolimus) injection (25 mg/ml). The TORISEL(temsirolimus) vial contains an overfill of 0.2 mL (30 mg/1.2 mL). Due to the intentional overfill in the TORISELinjection vial, the drug concentration of the resulting solutionwill be 10 mg/mL. A total volume of 3 mL will be obtainedincluding the overfill. Mix well by inversion of the vial. Allowsufficient time for air bubbles to subside. This 10 mg/mL drugsolution/diluent mixture must be further diluted as describedin Step 2 below.The solution is clear to slightly turbid, colorless to yellow, andfree from visual particulates. The 10 mg/mL drugsolution/diluent mixture is stable for up to 24 hours atcontrolled room temperature.Step 2:Withdraw the required amount of temsirolimus from the10 mg/mL drug solution/diluent mixture prepared in Step 1.Inject rapidly into a 250 mL container (glass, polyolefin, orpolyethylene) of 0.9% sodium chloride injection. Mix theadmixture by inversion of the bag or bottle. Avoid excessiveshaking as this may cause foaming.Administration:• The sodium chloride injection container should becomposed of non-DEHP containing materials, such asglass, polyolefin or polyethylene, and the administrationset should consist of non-DEHP tubing to avoidextraction of di-(2-ethylhexyl) phthalate (DEHP).TORISEL contains polysorbate 80, which is known toincrease the rate of di-(2-ethylhexyl) phthalate (DEHP)extraction from PVC.• An inline polyethersulfone filter with a pore size of notgreater than 5 microns is recommended foradministration.• The final diluted solution of TORISEL is intravenouslyinfused over a 30-60 minute period once a week. Theuse of an infusion pump is the preferred method ofadministration to ensure accurate delivery of the drug.• Administration of the final diluted infusion solution shouldbe completed within six hours from the time that thedrug solution/diluent mixture is added to the sodiumchloride injection.Compatibilities and IncompatibilitiesUndiluted TORISEL injection should not be added directly toaqueous infusion solutions. Direct addition of TORISELinjection to aqueous solutions will result in precipitation ofdrug. Always combine TORISEL injection with DILUENT forTORISEL ® before adding to infusion solutions. It isrecommended that TORISEL be administered in 0.9% sodiumchloride injection after combining with diluent. The stability ofTORISEL in other infusion solutions has not been evaluated.Addition of other drugs or nutritional agents to admixtures ofTORISEL in sodium chloride injection has not been evaluatedand should be avoided. Temsirolimus is degraded by both2

TORISEL ® Kit(temsirolimus)injectionacids and bases, and thus combinations of temsirolimus withagents capable of modifying solution pH should be avoided.3 DOSAGE FORMS AND STRENGTHSTORISEL (temsirolimus) is supplied as a kit consisting of thefollowing:TORISEL (temsirolimus) injection (25 mg/ml). TheTORISEL vial includes an overfill of 0.2 mL.DILUENT for TORISEL ® . The DILUENT vial includes adeliverable volume of 1.8 mL.4 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS5.1 Hypersensitivity ReactionsHypersensitivity reactions manifested by symptoms including,but not limited to, anaphylaxis, dyspnea, flushing, and chestpain have been observed with TORISEL.TORISEL should be used with caution in persons with knownhypersensitivity to temsirolimus or its metabolites (includingsirolimus), polysorbate 80, or to any other component(including the excipients) of TORISEL.An H1 antihistamine should be administered to patients beforethe start of the intravenous temsirolimus infusion. TORISELshould be used with caution in patients with knownhypersensitivity to an antihistamine, or patients who cannotreceive an antihistamine for other medical reasons.If a patient develops a hypersensitivity reaction during theTORISEL infusion, the infusion should be stopped and thepatient should be observed for at least 30 to 60 minutes(depending on the severity of the reaction). At the discretionof the physician, treatment may be resumed with theadministration of an H1-receptor antagonist (such asdiphenhydramine), if not previously administered [see Dosageand Administration (2.2)], and/or an H2-receptor antagonist(such as intravenous famotidine 20 mg or intravenousranitidine 50 mg) approximately 30 minutes before restartingthe TORISEL infusion. The infusion may then be resumed ata slower rate (up to 60 minutes).5.2 Hyperglycemia/Glucose IntoleranceThe use of TORISEL is likely to result in increases in serumglucose. In the phase 3 trial, 89% of patients receivingTORISEL had at least one elevated serum glucose while ontreatment, and 26% of patients reported hyperglycemia as anadverse event. This may result in the need for an increase inthe dose of, or initiation of, insulin and/or oral hypoglycemicagent therapy. Serum glucose should be tested before andduring treatment with TORISEL. Patients should be advised toreport excessive thirst or any increase in the volume orfrequency of urination.5.3 InfectionsThe use of TORISEL may result in immunosuppression.Patients should be carefully observed for the occurrence ofinfections, including opportunistic infections [see AdverseReactions (6.1)].5.4 Interstitial Lung DiseaseCases of interstitial lung disease, some resulting in death,occurred in patients who received TORISEL. Some patientswere asymptomatic with infiltrates detected on computedtomography scan or chest radiograph. Others presented withsymptoms such as dyspnea, cough, hypoxia, and fever. Somepatients required discontinuation of TORISEL and/ortreatment with corticosteroids and/or antibiotics, while somepatients continued treatment without additional intervention.Patients should be advised to report promptly any new orworsening respiratory symptoms.5.5 HyperlipemiaThe use of TORISEL is likely to result in increases in serumtriglycerides and cholesterol. In the phase 3 trial, 87% ofpatients receiving TORISEL had at least one elevated serumcholesterol value and 83% had at least one elevated serumtriglyceride value. This may require initiation, or increase inthe dose, of lipid-lowering agents. Serum cholesterol andtriglycerides should be tested before and during treatmentwith TORISEL.5.6 Bowel PerforationCases of fatal bowel perforation occurred in patients whoreceived TORISEL. These patients presented with fever,abdominal pain, metabolic acidosis, bloody stools, diarrhea,and/or acute abdomen. Patients should be advised to reportpromptly any new or worsening abdominal pain or blood intheir stools.5.7 Renal FailureCases of rapidly progressive and sometimes fatal acute renalfailure not clearly related to disease progression occurred inpatients who received TORISEL. Some of these cases werenot responsive to dialysis.5.8 Wound Healing ComplicationsUse of TORISEL has been associated with abnormal woundhealing. Therefore, caution should be exercised with the useof TORISEL in the perioperative period.5.9 Intracerebral HemorrhagePatients with central nervous system tumors (primary CNStumor or metastases) and/or receiving anticoagulation therapymay be at an increased risk of developing intracerebralbleeding (including fatal outcomes) while receiving TORISEL.5.10 Co-administration with Inducers or Inhibitors ofCYP3A MetabolismAgents Inducing CYP3A Metabolism:Strong inducers of CYP3A4/5 such as dexamethasone,carbamazepine, phenytoin, phenobarbital, rifampin, rifabutin,and rifampacin may decrease exposure of the activemetabolite, sirolimus. If alternative treatment cannot beadministered, a dose adjustment should be considered. St.John’s Wort may decrease TORISEL plasma concentrationsunpredictably. Patients receiving TORISEL should not take St.John’s Wort concomitantly. [see Dosage and Administration(2.4) and Drug Interactions (7.1)].Agents Inhibiting CYP3A Metabolism:Strong CYP3A4 inhibitors such as atazanavir, clarithromycin,indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir,ritonavir, saquinavir, and telithromycin may increase bloodconcentrations of the active metabolite sirolimus. If alternativetreatments cannot be administered, a dose adjustment shouldbe considered. [see Dosage and Administration (2.4) andDrug Interactions (7.2)].5.11 Concomitant use of TORISEL with sunitinibThe combination of TORISEL and sunitinib resulted in doselimitingtoxicity. Dose-limiting toxicities (Grade 3/4erythematous maculopapular rash, and gout/cellulitis requiringhospitalization) were observed in two out of three patientstreated in the first cohort of a phase 1 study at doses ofTORISEL 15 mg IV per week and sunitinib 25 mg oral perday (Days 1-28 followed by a 2-week rest).3

TORISEL ® Kit(temsirolimus)injection5.12 VaccinationsThe use of live vaccines and close contact with those whohave received live vaccines should be avoided duringtreatment with TORISEL. Examples of live vaccines are:intranasal influenza, measles, mumps, rubella, oral polio,BCG, yellow fever, varicella, and TY21a typhoid vaccines.5.13 PregnancyPregnancy Category DTemsirolimus administered daily as an oral formulationcaused embryo-fetal and intrauterine toxicities in rats andrabbits at human sub-therapeutic exposures. Embryo-fetaladverse effects in rats consisted of reduced fetal weight andreduced ossifications, and in rabbits included reduced fetalweight, omphalocele, bifurcated sternabrae, notched ribs, andincomplete ossifications.In rats, the intrauterine and embryo-fetal adverse effects wereobserved at the oral dose of 2.7 mg/m 2 /day (approximately0.04-fold the AUC in cancer patients at the humanrecommended dose). In rabbits, the intrauterine and embryofetaladverse effects were observed at the oral dose of≥7.2 mg/m 2 /day (approximately 0.12-fold the AUC in cancerpatients at the recommended human dose).Women of childbearing potential should be advised to avoidbecoming pregnant throughout treatment and for 3 monthsafter TORISEL therapy has stopped. Temsirolimus can causefetal harm when administered to a pregnant woman. If thisdrug is used during pregnancy, or if the patient becomespregnant while taking this drug, the patient should beapprised of the potential hazard to the fetus.Men should be counseled regarding the effects of TORISELon the fetus and sperm prior to starting treatment [seeNonclinical Toxicology (13.1)]. Men with partners ofchildbearing potential should use reliable contraceptionthroughout treatment and are recommended to continue thisfor 3 months after the last dose of TORISEL.5.14 Monitoring Laboratory TestsIn the randomized, phase 3 trial, complete blood counts(CBCs) were checked weekly, and chemistry panels werechecked every two weeks. Laboratory monitoring for patientsreceiving TORISEL may need to be performed more or lessfrequently at the physician’s discretion.6 ADVERSE REACTIONSThe following serious adverse reactions have been associatedwith TORISEL in clinical trials and are discussed in greaterdetail in other sections of the label [see Warnings andPrecautions (5 )].Hypersensitivity Reactions [see Warnings and Precautions (5.1)]Hyperglycemia/Glucose Intolerance [see Warnings andPrecautions (5.2)]Interstitial Lung Disease [see Warnings and Precautions (5.4)]Hyperlipemia [see Warnings and Precautions (5.5)]Bowel Perforation [see Warnings and Precautions (5.6)]Renal Failure [see Warnings and Precautions (5.7)]The most common (≥ 30%) adverse reactions observed withTORISEL are rash, asthenia, mucositis, nausea, edema, andanorexia. The most common (≥ 30%) laboratory abnormalitiesobserved with TORISEL are anemia, hyperglycemia,hyperlipemia, hypertriglyceridemia, lymphopenia, elevatedalkaline phosphatase, elevated serum creatinine,hypophosphatemia, thrombocytopenia, elevated AST, andleukopenia.6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varyingconditions, the adverse reaction rates observed cannot bedirectly compared to rates in other trials and may not reflectthe 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, atotal of 616 patients were treated. Two hundred patientsreceived IFN-α weekly, 208 received TORISEL 25 mg weekly,and 208 patients received a combination of TORISEL andIFN-α weekly [see Clinical Studies (14)].Treatment with the combination of TORISEL 15 mg and IFN-αwas associated with an increased incidence of multipleadverse reactions and did not result in a significant increasein overall survival when compared with IFN-α alone.Table 1 shows the percentage of patients experiencingtreatment emergent adverse reactions. Reactions reported inat least 10% of patients who received TORISEL 25 mg aloneor IFN-α alone are listed. Table 2 shows the percentage ofpatients experiencing selected laboratory abnormalities. Datafor the same adverse reactions and laboratory abnormalitiesin the IFN-α alone arm are shown for comparison.Table 1 – Adverse Reactions Reported in at Least 10% of PatientsWho Received 25 mg IV TORISEL or IFN-α in the Randomized TrialTORISELIFN-α25 mgAdverse Reaction n=208 n=200All Grades All GradesGrades* 3&4* Grades* 3&4*n (%) n (%) n (%) n (%)Any 208 (100) 139 (67) 199 (100) 155 (78)General disordersAsthenia 106 (51) 23 (11) 127 (64) 52 (26)Edema a 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)GastrointestinaldisordersMucositis b 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)Vomiting 40 (19) 4 (2) 57 (29) 5 (3)InfectionsInfections c 42 (20) 6 (3) 19 (10) 4 (2)Urinary tractinfection d 31 (15) 3 (1) 24 (12) 3 (2)Pharyngitis 25 (12) 0 (0) 3 (2) 0 (0)Rhinitis 20 (10) 0 (0) 4 (2) 0 (0)Musculoskeletal andconnective tissuedisordersBack Pain 41 (20) 6 (3) 28 (14) 7 (4)Arthralgia 37 (18) 2 (1) 29 (15) 2 (1)Myalgia 16 (8) 1 (1) 29 (15) 2 (1)4

TORISEL ® Kit(temsirolimus)injectionTable 1 – Adverse Reactions Reported in at Least 10% of PatientsWho Received 25 mg IV TORISEL or IFN-α in the Randomized TrialTORISELIFN-α25 mgAdverse Reaction n=208 n=200All Grades All GradesGrades* 3&4* Grades* 3&4*n (%) n (%) n (%) n (%)Any 208 (100) 139 (67) 199 (100) 155 (78)Respiratory, thoracicand mediastinaldisordersDyspnea 58 (28) 18 (9) 48 (24) 11 (6)Cough 53 (26) 2 (1) 29 (15) 0 (0)Epistaxis 25 (12) 0 (0) 7 (4) 0 (0)Skin andsubcutaneous tissuedisordersRash e 97 (47) 10 (5) 14 (7) 0 (0)Pruritus 40 (19) 1 (1) 16 (8) 0 (0)Nail Disorder 28 (14) 0 (0) 1 (1) 0 (0)Dry Skin 22 (11) 1 (1) 14 (7) 0 (0)Acne 21 (10) 0 (0) 2 (1) 0 (0)Nervous systemdisordersDysgeusia f 41 (20) 0 (0) 17 (9) 0 (0)Insomnia 24 (12) 1 (1) 30 (15) 0 (0)Depression 9 (4) 0 (0) 27 (14) 4 (2)*Common Toxicity Criteria for Adverse Events (CTCAE),Version 3.0.aIncludes edema, facial edema, and peripheral edemabIncludes aphthous stomatitis, glossitis, mouth ulceration,mucositis, and stomatitiscIncludes infections not otherwise specified (NOS) and thefollowing infections that occurred infrequently as distinctentities: abscess, bronchitis, cellulitis, herpes simplex, andherpes zosterdIncludes cystitis, dysuria, hematuria, urinary frequency, andurinary tract infectioneIncludes eczema, exfoliative dermatitis, maculopapularrash, pruritic rash, pustular rash, rash (NOS), andvesiculobullous rashfIncludes taste loss and taste perversionThe following selected adverse reactions were reported lessfrequently (

TORISEL ® Kit(temsirolimus)injectionIt is not known whether TORISEL is excreted into human milk, anddue to the potential for tumorigenicity shown for sirolimus (activemetabolite of TORISEL) in animal studies, a decision should bemade whether to discontinue nursing or discontinue TORISEL,taking into account the importance of the drug to the mother.8.4 Pediatric UseThe safety and effectiveness of TORISEL in pediatric patientshave not been established.8.5 Geriatric UseClinical studies of TORISEL did not include sufficient numbersof subjects aged 65 and older to determine whether theyrespond differently from younger subjects.8.6 Renal ImpairmentNo clinical studies were conducted with TORISEL in patientswith decreased renal function. Less than 5% of totalradioactivity was excreted in the urine following a 25 mgintravenous dose of [ 14 C]-labeled temsirolimus in healthysubjects. Renal impairment is not expected to markedlyinfluence drug exposure, and no dosage adjustment ofTORISEL is recommended in patients with renal impairment.TORISEL has not been studied in patients undergoinghemodialysis.8.7 Hepatic ImpairmentTemsirolimus is cleared predominantly by the liver. No dataare currently available regarding the influence of hepaticdysfunction on temsirolimus disposition.10 OVERDOSAGEThere is no specific treatment for TORISEL intravenousoverdose. TORISEL has been administered to patients withcancer in phase 1 and 2 trials with repeated intravenousdoses as high as 220 mg/m 2 . The risk of several seriousadverse events, including thrombosis, bowel perforation,interstitial lung disease (ILD), seizure, and psychosis, isincreased with doses of TORISEL greater than 25 mg.11 DESCRIPTIONTemsirolimus, an inhibitor of mTOR, is an antineoplastic agent.Temsirolimus is a white to off-white powder with a molecularformula of C56H87NO16 and a molecular weight of 1030.30. It isnon-hygroscopic. Temsirolimus is practically insoluble in waterand soluble in alcohol. It has no ionizable functional groups,and its solubility is independent of pH.The chemical name of temsirolimus is(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy- 3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone 4´-[2,2-bis(hydroxymethyl)propionate]; or Rapamycin, 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate].H3COCH3OOHOOCH3ONOH3CCH3H3COCH3OOHOCH3OOOCH3H3COHOHTORISEL (temsirolimus) injection, 25 mg/mL, is a clear,colorless to light yellow, non-aqueous, ethanolic, sterilesolution. TORISEL (temsirolimus) injection requires twodilutions prior to intravenous infusion. TORISEL (temsirolimus)injection should be diluted only with the supplied DILUENT forTORISEL ® .DILUENT for TORISEL ® is a sterile, non-aqueous solutionthat is supplied with TORISEL injection, as a kit.TORISEL (temsirolimus) injection, 25 mg/mL:Active ingredient: temsirolimus (25 mg/mL)Inactive ingredients: dehydrated alcohol (39.5% w/v), dl-alphatocopherol(0.075% w/v), propylene glycol (50.3% w/v), andanhydrous citric acid (0.0025% w/v).DILUENT for TORISEL ®Inactive ingredients: polysorbate 80 (40.0% w/v), polyethyleneglycol 400 (42.8% w/v) and dehydrated alcohol (19.9% w/v).After the TORISEL (temsirolimus) injection vial has beendiluted with DILUENT for TORISEL ® , in accordance with theinstructions in section 2.5, the solution contains 35.2%alcohol.TORISEL (temsirolimus) injection and DILUENT forTORISEL ® are filled in clear glass vials with butyl rubberstoppers.12 CLINICAL PHARMACOLOGY12.1 Mechanism of ActionTemsirolimus is an inhibitor of mTOR (mammalian target ofrapamycin). Temsirolimus binds to an intracellular protein(FKBP-12), and the protein-drug complex inhibits the activityof mTOR that controls cell division. Inhibition of mTOR activityresulted in a G1 growth arrest in treated tumor cells. WhenmTOR was inhibited, its ability to phosphorylate p70S6k andS6 ribosomal protein, which are downstream of mTOR in thePI3 kinase/AKT pathway was blocked. In in vitro studies usingrenal cell carcinoma cell lines, temsirolimus inhibited theactivity of mTOR and resulted in reduced levels of thehypoxia-inducible factors HIF-1 and HIF-2 alpha, and thevascular endothelial growth factor.12.3 PharmacokineticsAbsorptionFollowing administration of a single 25 mg dose of TORISELin patients with cancer, mean temsirolimus Cmax in wholeblood was 585 ng/mL (coefficient of variation, CV =14%), andmean AUC in blood was 1627 ng·h/mL (CV=26%). TypicallyCmax occurred at the end of infusion. Over the dose range of1 mg to 25 mg, temsirolimus exposure increased in a lessthan dose proportional manner while sirolimus exposureincreased proportionally with dose. Following a single 25 mgintravenous dose in patients with cancer, sirolimus AUC was2.7-fold that of temsirolimus AUC, due principally to the longerhalf-life of sirolimus.DistributionFollowing a single 25 mg intravenous dose, mean steadystatevolume of distribution of temsirolimus in whole blood ofpatients with cancer was 172 liters. Both temsirolimus andsirolimus are extensively partitioned into formed bloodelements.MetabolismCytochrome P450 3A4 is the major isozyme responsible forthe formation of five temsirolimus metabolites. Sirolimus, anactive metabolite of temsirolimus, is the principal metabolite inhumans following intravenous treatment. The remainder of theCH3

TORISEL ® Kit(temsirolimus)injectionmetabolites account for less than 10% of radioactivity in theplasma. In human liver microsomes temsirolimus was aninhibitor of CYP2D6 and 3A4. However, there was no effectobserved in vivo when temsirolimus was administered withdesipramine (a CYP2D6 substrate), and no effect isanticipated with substrates of CYP3A4 metabolism.EliminationElimination is primarily via the feces. After a single IV dose of[ 14 C]-temsirolimus approximately 82% of total radioactivity waseliminated within 14 days, with 4.6% and 78% of theadministered radioactivity recovered in the urine and feces,respectively. Following a single 25 mg dose of TORISEL inpatients with cancer, temsirolimus mean (CV) systemicclearance was 16.2 (22%) L/h. Temsirolimus exhibits a biexponentialdecline in whole blood concentrations and themean half-lives of temsirolimus and sirolimus were 17.3 hrand 54.6 hr, respectively.Effects of Age and GenderIn population pharmacokinetic-based data analyses, norelationship was apparent between drug exposure and patientage or gender.13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenicity studies have not been conducted withtemsirolimus. However, sirolimus, the major metabolite oftemsirolimus in humans, was carcinogenic in mice and rats.The following effects were reported in mice and/or rats in thecarcinogenicity studies conducted with sirolimus: lymphoma,hepatocellular adenoma and carcinoma, and testicularadenoma.Temsirolimus was not genotoxic in a battery of in vitro(bacterial reverse mutation in Salmonella typhimurium andEscherichia coli, forward mutation in mouse lymphoma cells,and chromosome aberrations in Chinese hamster ovary cells)and in vivo (mouse micronucleus) assays.In male rats, the following fertility effects were observed:decreased number of pregnancies, decreased spermconcentration and motility, decreased reproductive organweights, and testicular tubular degeneration. These effectswere observed at oral temsirolimus doses ≥ 3 mg/m 2 /day(approximately 0.2-fold the human recommended intravenousdose). Fertility was absent at 30 mg/m 2 /day.In female rats, an increased incidence of pre- and postimplantationlosses occurred at oral doses ≥ 4.2 mg/m 2 /day(approximately 0.3-fold the human recommended intravenousdose), resulting in decreased numbers of live fetuses.14 CLINICAL STUDIESA phase 3, multi-center, three-arm, randomized, open-labelstudy was conducted in previously untreated patients withadvanced renal cell carcinoma (clear cell and non-clear cellhistologies). The objectives were to compare Overall Survival(OS), Progression-Free Survival (PFS), Objective ResponseRate (ORR), and safety in patients receiving IFN-α to thosereceiving TORISEL or TORISEL plus IFN-α. Patients in thisstudy had 3 or more of 6 pre-selected prognostic risk factors(less than one year from time of initial RCC diagnosis torandomization, Karnofsky performance status of 60 or 70,hemoglobin less than the lower limit of normal, correctedcalcium of greater than 10 mg/dL, lactate dehydrogenase > 1.5times the upper limit of normal, more than one metastaticorgan site). Patients were stratified for prior nephrectomystatus within three geographic regions and were randomlyassigned (1:1:1) to receive IFN-α alone (n=207), TORISELalone (25 mg weekly; n=209), or the combination arm(n=210).The ITT population for this interim analysis included 626patients. Demographics were comparable between the threetreatment arms with regard to age, gender, and race. Themean age of all groups was 59 years (range 23-86). Sixtyninepercent were male and 31% were female. The racialdistribution for all groups was 91% White, 4% Black, 2%Asian, and 3% other. Sixty-seven percent of patients had ahistory of prior nephrectomy.The median duration of treatment in the TORISEL arm was17 weeks (range 1-126 weeks). The median duration oftreatment on the IFN arm was 8 weeks (range 1-124 weeks).There was a statistically significant improvement in OS (timefrom randomization to death) in the TORISEL 25 mg armcompared to IFN-α. The combination of TORISEL 15 mg andIFN-α did not result in a significant increase in overall survivalwhen compared with IFN-α alone. Figure 1 is a Kaplan-Meierplot of OS in this study. The evaluations of PFS (time fromrandomization to disease progression or death) and ORR,were based on blinded independent radiologic assessment oftumor response. Efficacy results are summarized in Table 3.Table 3: Summary of Efficacy Results of TORISEL vs. IFN-αTORISEL IFN-α P-value a Hazard RatioParameter(95% CI) bn = 209 n = 207Median OverallSurvivalMonths (95% CI)MedianProgression-FreeSurvivalMonths (95% CI)Overall ResponseRate% (95% CI)10.9 7.3 0.0078* 0.73(8.6, 12.7) (6.1, 8.8) (0.58, 0.92)5.5 3.1 0.0001** 0.66(3.9, 7.0) (2.2, 3.8) (0.53, 0.81)8.6 4.8 0.1232** c NA(4.8, 12.4) (1.9, 7.8)CI = confidence interval; NA = not applicable* A comparison is considered statistically significant if thep-value is

TORISEL ® Kit(temsirolimus)injection15 REFERENCES1. NIOSH Alert: Preventing occupational exposures toantineoplastic and other hazardous drugs in healthcaresettings. 2004. U.S. Department of Health and HumanServices, Public Health Service, Centers for DiseaseControl and Prevention, National Institute forOccupational Safety and Health, DHHS (NIOSH)Publication No. 2004-165.2. OSHA Technical Manual, TED 1-0.15A, Section VI:Chapter 2. Controlling Occupational Exposure toHazardous Drugs. OSHA, 1999.http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html3. NIH [2002]. 1999 recommendations for the safe handlingof cytotoxic drugs. U.S. Department of Health and HumanServices, Public Health Service, National Institutes ofHealth, NIH Publication No. 92-2621.4. American Society of Health-System Pharmacists. (2006)ASHP Guidelines on Handling Hazardous Drugs.5. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005.Chemotherapy and biotherapy guidelines andrecommendations for practice (2nd. ed.) Pittsburgh, PA:Oncology Nursing Society.16 HOW SUPPLIED/STORAGE AND HANDLINGNDC 0008-1179-01 TORISEL ® (temsirolimus) injection, 25 mg/mL.NDC 0008-1125-01 DILUENT for TORISEL ® , 1.8 mL(deliverable volume) per vial.These two vials are supplied as a kit in a single carton, andmust be stored at 2º-8ºC (36º-46ºF). Protect from light.U.S. Patent No. 5,362,71817 PATIENT COUNSELING INFORMATION• Allergic (Hypersensitivity) ReactionsPatients should be informed of the possibility of seriousallergic reactions, including anaphylaxis, despitepremedication with antihistamines, and to immediatelyreport any facial swelling or difficulty breathing [seeWarnings and Precautions (5.1)].• Increased Blood Glucose LevelsPatients are likely to experience increased blood glucoselevels while taking TORISEL. This may result in the needfor initiation of, or increase in the dose of, insulin and/orhypoglycemic agents. Patients should be directed toreport any excessive thirst or frequency of urination totheir physician [see Warnings and Precautions (5.2)].• InfectionsPatients should be informed that they may be moresusceptible to infections while being treated withTORISEL [see Warnings and Precautions (5.3)].• Interstitial Lung DiseasePatients should be warned of the possibility of developinginterstitial lung disease, a chronic inflammation of thelungs, which may rarely result in death [see Warnings andPrecautions (5.4)]. Patients should be directed to reportpromptly any new or worsening respiratory symptoms totheir physician.• Increased Blood Triglycerides and/or CholesterolPatients are likely to experience elevated triglyceridesand/or cholesterol during TORISEL treatment. This mayrequire initiation of, or increase in the dose of, lipidloweringagents [see Warnings and Precautions (5.5)].• Bowel PerforationPatients should be warned of the possibility of bowelperforation. Patients should be directed to reportpromptly any new or worsening abdominal pain or bloodin their stools [see Warnings and Precautions (5.6)].• Renal FailurePatients should be informed of the risk of renal failure[see Warnings and Precautions (5.7)].• Wound Healing ComplicationsPatients should be advised of the possibility of abnormalwound healing if they have surgery within a few weeks ofinitiating therapy or during therapy [see Warnings andPrecautions (5.8)].• Intracerebral BleedingPatients with CNS tumors and/or receivinganticoagulants should be informed of the increased riskof developing intracerebral bleeding (including fataloutcomes) while on TORISEL [see Warnings andPrecautions (5.9)].• Medications that can interfere with TORISELSome medicines can interfere with the breakdown ormetabolism of TORISEL. In particular, patients should bedirected to inform their physician if they are taking any ofthe following: Protease inhibitors, anti-epileptic medicinesincluding carbamazepine, phenytoin, and barbiturates,St. John’s Wort, rifampicin, rifabutin, nefazodone orselective serotonin re-uptake inhibitors used to treatdepression, antibiotics or antifungal medicines used totreat infections [see Warnings and Precautions (5.10)].• VaccinationsPatients should be advised that vaccinations may beless effective while being treated with TORISEL. Inaddition, the use of live vaccines, and close contact withthose who have received live vaccines, while onTORISEL should be avoided. [see Warnings andPrecautions (5.12)].• PregnancyTORISEL can cause fetal harm. Women of childbearingpotential should be advised to avoid becoming pregnantthroughout treatment and for 3 months after TORISELtherapy has stopped. Men with partners of childbearingpotential should use reliable contraception throughouttreatment and are recommended to continue this for 3months after the last dose of TORISEL. [see Warningsand Precautions (5.13)].Wyeth Pharmaceuticals Inc.Philadelphia, PA 19101Manufactured for: Wyeth Pharmaceuticals Inc. Philadelphia,PA 19101TORISEL ® (temsirolimus) injection is manufactured by: PierreFabre Medicament Production, Aquitaine Pharm International,Avenue du Bearn, F64320 Idron, FranceDILUENT for TORISEL ® is manufactured by: Ben VenueLaboratories, Inc., Bedford, Ohio 44146-0568W10524C004ET01Rev 09/088

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