HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`TORISEL® safely and effectively. See full prescribing information for
`TORISEL.
`TORISEL Kit (temsirolimus) injection, for intravenous infusion only
`Initial U.S. Approval: 2007
`———————— RECENT MAJOR CHANGES ————————
`
`
`Dosage and Administration, Dose Modification Guidelines (2.4)
`
`7/2010
`
`
`
`
`
`
`7/2010
`Contraindications (4)
`
`
`
`
`7/2010
`Warnings and Precautions, Hepatic Impairment (5.2)
`
`———————— INDICATIONS AND USAGE ————————
`
`TORISEL® is a kinase inhibitor indicated for the treatment of advanced
`renal cell carcinoma. (1)
`
`
`——————— DOSAGE AND ADMINISTRATION ——————
`
`• The recommended dose of TORISEL is 25 mg infused 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)
`
`
`—————— DOSAGE FORMS AND STRENGTHS ——————
`TORISEL injection, 25 mg/mL supplied with DILUENT for TORISEL®.
`(3)
`————————— CONTRAINDICATIONS ————————
`TORISEL is contraindicated in patients with bilirubin >1.5 x ULN. (4)
`
`
`——————— WARNINGS AND PRECAUTIONS ——————
`
`• To treat hypersensitivity reactions stop TORISEL and treat with
`an antihistamine. TORISEL may be restarted at physician
`discretion at a slower rate. (5.1)
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS *
`
`
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Advanced Renal Cell Carcinoma
`
`2.2 Premedication
`
`2.3 Dosage Interruption/Adjustment
`
`2.4 Dose Modification Guidelines
`
`2.5 Instructions for Preparation and Administration
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Hypersensitivity Reactions
`5.2 Hepatic Impairment
`
`5.3 Hyperglycemia/Glucose Intolerance
`
`5.4 Infections
`
`5.5 Interstitial Lung Disease
`
`5.6 Hyperlipemia
`
`5.7 Bowel Perforation
`
`5.8 Renal Failure
`
`5.9 Wound Healing Complications
`
`5.10 Intracerebral Hemorrhage
`
`5.11 Co-administration with Inducers or Inhibitors of CYP3A Metabolism
`
`5.12 Concomitant use of TORISEL with sunitinib
`
`5.13 Vaccinations
`
`5.14 Pregnancy
`
`5.15 Monitoring Laboratory Tests
`
`* Sections or subsections omitted from the full prescribing information are not listed
`
`
`
`• Hepatic Impairment: Use caution when treating patients with
`mild hepatic impairment and reduce dose (2.4, 5.2)
`
`
`• Hyperglycemia and hyperlipemia 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)
`
`• Live vaccinations and close contact with those who received live
`vaccines should be avoided. (5.13)
`
`• Women of childbearing potential should be advised of the
`potential hazard to the fetus and to avoid becoming pregnant.
`(5.14)
`
`————————— ADVERSE REACTIONS —————————
`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, hyperlipemia,
`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
`
`————————— 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)
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`Revised: 7/2010
`
`
`
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`6.2 Post-marketing and Other Clinical Experience
`
`7 DRUG INTERACTIONS
`
`7.1 Agents Inducing CYP3A Metabolism
`
`7.2 Agents Inhibiting CYP3A Metabolism
`
`7.3 Interactions with Drugs Metabolized by CYP2D6
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Renal Impairment
`
`8.7 Hepatic Impairment
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`14 CLINICAL STUDIES
`
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`
`1
`
`
`
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`TORISEL is indicated for the treatment of advanced renal cell carcinoma.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Advanced Renal Cell Carcinoma
`
`The recommended dose of TORISEL for advanced renal cell carcinoma is 25 mg infused 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
`Hypersensitivity Reactions (5.1)].
`
`2.3 Dosage Interruption/Adjustment
`
`TORISEL should be held for absolute neutrophil count (ANC) < 1,000/mm3, platelet count
`< 75,000/mm3, 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 x 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 x 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 Drug Interactions (7.2)]
`
`
`
`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 Drug Interactions (7.1)]
`
`2.5 Instructions for Preparation and Administration
`
`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 should be inspected visually for particulate
`matter and discoloration prior to administration, whenever solution and container permit.
`
`In order to minimize the patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate),
`which may be leached from PVC infusion bags or sets, the final TORISEL dilution for infusion
`should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin)
`and administered through polyethylene-lined administration sets.
`
`Dilution:
`
`
`In preparing the TORISEL administration solution, follow this two-step dilution process in an
`aseptic manner.
`
`Step 1:
`
`Inject 1.8 mL of DILUENT for TORISEL® into the vial of TORISEL (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 TORISEL injection vial, the drug concentration of the
`resulting solution will be 10 mg/mL. A total volume of 3 mL will be obtained including the
`overfill. Mix well by inversion of the vial. Allow sufficient time for air bubbles to subside. This
`10 mg/mL drug solution/diluent mixture must be further diluted as described in Step 2 below.
`
`The solution is clear to slightly turbid, colorless to yellow, and free from visual particulates.
`
`The 10 mg/mL drug solution/diluent mixture is stable for up to 24 hours at controlled room
`
`temperature.
`
`Step 2:
`
`Withdraw the required amount of temsirolimus from the 10 mg/mL drug solution/diluent
`mixture prepared in Step 1. Inject rapidly into a 250 mL container (glass, polyolefin, or
`polyethylene) of 0.9% sodium chloride injection. Mix the admixture by inversion of the bag or
`bottle. Avoid excessive shaking as this may cause foaming.
`
`
`
`3
`
`
`

`

`Administration:
`
`• The sodium chloride injection container should be composed of non-DEHP containing
`
`materials, such as glass, polyolefin or polyethylene, and the administration set should
`consist of non-DEHP tubing to avoid extraction of di-(2-ethylhexyl) phthalate (DEHP).
`TORISEL contains polysorbate 80, which is known to increase the rate of di-(2­
`ethylhexyl) phthalate (DEHP) extraction from PVC.
`• An in line polyethersulfone filter with a pore size of not greater than 5 microns is
`
`
`recommended for administration.
`
`• The final diluted solution of TORISEL is intravenously infused over a 30-60 minute
`
`period once a week. The use of an infusion pump is the preferred method of
`administration to ensure accurate delivery of the drug.
`• Administration of the final diluted infusion solution should be completed within six
`
`
` hours from the time that the drug solution/diluent mixture is added to the sodium
`chloride injection.
`
`
`
` Compatibilities and Incompatibilities
`
`Undiluted TORISEL injection should not be added directly to aqueous infusion solutions.
`Direct addition of TORISEL injection to aqueous solutions will result in precipitation of drug.
`Always combine TORISEL injection with DILUENT for TORISEL® before adding to infusion
`solutions. It is recommended that TORISEL be administered in 0.9% sodium chloride injection
`
` after combining with diluent. The stability of TORISEL in other infusion solutions has not been
` evaluated. Addition of other drugs or nutritional agents to admixtures of TORISEL in sodium
`
`chloride injection has not been evaluated and should be avoided. Temsirolimus is degraded by
`both acids and bases, and thus combinations of temsirolimus with agents capable of modifying
`solution pH should be avoided.
`
`3 DOSAGE FORMS AND STRENGTHS
`
`TORISEL (temsirolimus) is supplied as a kit consisting of the following:
`
`
`TORISEL (temsirolimus) injection (25 mg/ml). The TORISEL vial includes an overfill of
`0.2 mL.
`
`DILUENT for TORISEL®. The DILUENT vial includes a deliverable volume of 1.8 mL.
`
`4 CONTRAINDICATIONS
`
`TORISEL is contraindicated in patients with bilirubin >1.5 x ULN [see Warnings and
`Precautions (5.2)].
`
`
`
`4
`
`
`

`

`5 WARNINGS AND PRECAUTIONS
`
`5.1 Hypersensitivity Reactions
`
`Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis,
`dyspnea, flushing, and chest pain have been observed with TORISEL.
`
`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 H1 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 H1-receptor antagonist (such as diphenhydramine), if not
`previously administered [see Dosage and Administration (2.2)], and/or an H2-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).
`
`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 x ULN experienced greater toxicity than patients with baseline bilirubin
`≤ 1.5 x ULN when treated with TORISEL. The overall frequency of ≥ grade 3 adverse
`reactions and deaths, including deaths due to progressive disease, were greater in patients with
`baseline bilirubin > 1.5 x ULN. TORISEL is contraindicated in patients with bilirubin >1.5 x
`ULN due to increased risk of death [see Contraindications (4)].
`
`Use caution when treating patients with mild hepatic impairment. Concentrations of
`temsirolimus and its metabolite sirolimus were increased in patients with elevated AST or
`
`
`bilirubin levels. If TORISEL must be given in patients with mild hepatic impairment
`(bilirubin >1 – 1.5 x ULN or AST >ULN but bilirubin ≤ULN), reduce the dose of TORISEL to
`15 mg/week [see Dosage and Administration (2.4)].
`
`5.3 Hyperglycemia/Glucose Intolerance
`
`The use of TORISEL is likely to result in increases in serum glucose. In the phase 3 trial, 89%
`of patients receiving TORISEL had at least one elevated serum glucose while on treatment, and
`26% of patients reported hyperglycemia as an adverse event. This may result in the need for an
`
`increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy. Serum
`
`
`
`5
`
`
`

`

`glucose should be tested before and during treatment with TORISEL. Patients should be
`advised to report excessive thirst or any increase in the volume or frequency of urination.
`
`5.4 Infections
`
`The use of TORISEL may result in immunosuppression. Patients should be carefully observed
`for the occurrence of infections, including opportunistic infections [see Adverse Reactions
`(6.1)].
`
`5.5 Interstitial Lung Disease
`
`Cases of interstitial lung disease, some resulting in death, occurred in patients who received
`TORISEL. Some patients were asymptomatic with infiltrates detected on computed
`
`tomography scan or chest radiograph. Others presented with symptoms such as dyspnea, cough,
`hypoxia, and fever. Some patients required discontinuation of TORISEL and/or treatment with
`corticosteroids and/or antibiotics, while some patients continued treatment without additional
`
`intervention. Patients should be advised to report promptly any new or worsening respiratory
`symptoms.
`
`
`5.6 Hyperlipemia
`
`The use of TORISEL is likely to result in increases in serum triglycerides and cholesterol. In
`the phase 3 trial, 87% of patients receiving TORISEL had at least one elevated serum
`
`cholesterol value and 83% had at least one elevated serum triglyceride value. This may require
`initiation, or increase in the dose, of lipid-lowering agents. Serum cholesterol and triglycerides
`should be tested before and during treatment with TORISEL.
`
`5.7 Bowel Perforation
`
`Cases of fatal bowel perforation occurred in patients who received TORISEL. These patients
`presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute
`abdomen. Patients should be advised to report promptly any new or worsening abdominal pain
`or blood in their stools.
`
`5.8 Renal Failure
`
`Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to
`disease progression occurred in patients who received TORISEL. Some of these cases were not
`responsive to dialysis.
`
`5.9 Wound Healing Complications
`
`Use of TORISEL has been associated with abnormal wound healing. Therefore, caution should
`be exercised with the use of TORISEL in the perioperative period.
`
`
`
`6
`
`
`

`

`5.10 Intracerebral Hemorrhage
`
`Patients with central nervous system tumors (primary CNS tumor or metastases) and/or
`receiving anticoagulation therapy may be at an increased risk of developing intracerebral
`bleeding (including fatal outcomes) while receiving TORISEL.
`
`5.11 Co-administration with Inducers or Inhibitors of CYP3A Metabolism
`
`Agents Inducing CYP3A Metabolism:
`
`
`Strong inducers of CYP3A4/5 such as dexamethasone, carbamazepine, phenytoin,
`phenobarbital, rifampin, rifabutin, and rifampacin may decrease exposure of the active
`metabolite, sirolimus. If alternative treatment cannot be administered, a dose adjustment should
`be considered. St. John’s Wort may decrease TORISEL plasma concentrations unpredictably.
`
`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
`blood concentrations of the active metabolite sirolimus. If alternative treatments cannot be
`administered, a dose adjustment should be considered. [see Dosage and Administration (2.4)
`
`and Drug Interactions (7.2)].
`
`5.12 Concomitant use of TORISEL with sunitinib
`
`The combination of TORISEL and sunitinib resulted in dose-limiting toxicity. Dose-limiting
`toxicities (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring
`hospitalization) were observed in two out of three patients treated in the first cohort of a
`phase 1 study at doses of TORISEL 15 mg IV per week and sunitinib 25 mg oral per day (Days
`1-28 followed by a 2-week rest).
`
`5.13 Vaccinations
`
`The use of live vaccines and close contact with those who have received live vaccines should
`be avoided during treatment with TORISEL. Examples of live vaccines are: intranasal
`influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a
`typhoid vaccines.
`
`5.14 Pregnancy
`
`Pregnancy Category D
`
`Temsirolimus administered daily as an oral formulation caused embryo-fetal and intrauterine
`toxicities 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
`
`
`
`7
`
`
`

`

`reduced fetal weight, omphalocele, bifurcated sternabrae, notched ribs, and incomplete
`ossifications.
`
`In rats, the intrauterine and embryo-fetal adverse effects were observed at the oral dose of
`2.7 mg/m2/day (approximately 0.04-fold the AUC in cancer patients at the human
`recommended dose). In rabbits, the intrauterine and embryo-fetal adverse effects were observed
`at the oral dose of ≥7.2 mg/m2/day (approximately 0.12-fold the AUC in cancer patients at the
`recommended human dose).
`
`Women of childbearing potential should be advised to avoid becoming pregnant throughout
`treatment and for 3 months after TORISEL therapy has stopped. Temsirolimus can cause fetal
`harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the
`patient becomes pregnant while taking this drug, the patient should be apprised of the potential
`hazard to the fetus.
`
`Men should be counseled regarding the effects of TORISEL on the fetus and sperm prior to
`starting treatment [see Nonclinical Toxicology (13.1)]. Men with partners of childbearing
`potential should use reliable contraception throughout treatment and are recommended to
`continue this for 3 months after the last dose of TORISEL.
`
`5.15 Monitoring Laboratory Tests
`
`In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and
`chemistry panels were checked every two weeks. Laboratory monitoring for patients receiving
`TORISEL may need to be performed more or less frequently at the physician’s discretion.
`
`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 Reactions [see Warnings and Precautions (5.1)]
`
`Hyperglycemia/Glucose Intolerance [see Warnings and Precautions (5.3)]
`
`Interstitial Lung Disease [see Warnings and Precautions (5.5)]
`
`Hyperlipemia [see Warnings and Precautions (5.6)]
`
`Bowel Perforation [see Warnings and Precautions (5.7)]
`
`Renal Failure [see Warnings and Precautions (5.8)]
`
`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, hyperlipemia, hypertriglyceridemia,
`
`
`
`8
`
`
`

`

`lymphopenia, elevated alkaline phosphatase, elevated serum creatinine, hypophosphatemia,
`thrombocytopenia, elevated AST, and leukopenia.
`
`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
`
`TORISEL 25 mg
`n=208
`
`
`
`IFN-α
`n=200
`
`
`
`
` Adverse Reaction
`
`
`
`Any
`
` General disorders
` Asthenia
` Edemaa
`
`Pain
`Pyrexia
` Weight Loss
` Headache
`Chest Pain
`Chills
`Gastrointestinal disorders
` Mucositisb
`
`Anorexia
`Nausea
`Diarrhea
`
`
`
`
`
`All
`
` Grades*
`
` n (%)
`199 (100)
`
`127 (64)
`21 (11)
`31 (16)
`99 (50)
`50 (25)
`30 (15)
`18 (9)
`59 (30)
`
`19 (10)
`87 (44)
`82 (41)
`40 (20)
`
`
` All Grades*
`
` n (%)
`208 (100)
`
`106 (51)
` 73 (35)
`59 (28)
`50 (24)
`39 (19)
`31 (15)
`34 (16)
`17 (8)
`
` 86 (41)
`66 (32)
`77 (37)
`56 (27)
`
`
`
` Grades 3&4*
`
` n (%)
`139 (67)
`
`23 (11)
`7 (3)
`10 (5)
`1 (1)
`3 (1)
`1 (1)
`2 (1)
`1 (1)
`
`6 (3)
`6 (3)
`5 (2)
`3 (1)
`
`9
`
`
`
` Grades 3&4*
`
` n (%)
`155 (78)
`
`52 (26)
`1 (1)
`4 (2)
`7 (4)
`4 (2)
`0 (0)
`2 (1)
`3 (2)
`
`0 (0)
`8 (4)
`9 (5)
`4 (2)
`
`

`

`
` IFN-α
`
` n=200
`
`
`
`Grades 3&4*
`
`n (%)
`
`3 (2)
`1 (1)
`5 (3)
`
`4 (2)
`3 (2)
`0 (0)
`0 (0)
`
`
`7 (4)
`2 (1)
`2 (1)
`
`
`11 (6)
`0 (0)
`0 (0)
`
`
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`
`0 (0)
`0 (0)
`4 (2)
`
`All
`Grades*
`
` Grades 3&4*
`
` All Grades*
`n (%)
`
` n (%)
`
` n (%)
`
`34 (17)
`9 (4)
`44 (21)
` Abdominal Pain
`36 (18)
`0 (0)
`42 (20)
`Constipation
`57 (29)
`4 (2)
`40 (19)
` Vomiting
`Infections
`
`
`
`
` Infectionsc
`
`19 (10)
`6 (3)
` 42 (20)
`Urinary tract infectiond
`24 (12)
`3 (1)
` 31 (15)
`3 (2)
`0 (0)
`25 (12)
`Pharyngitis
`4 (2)
`0 (0)
`20 (10)
`Rhinitis
`Musculoskeletal and connective
`
`
`
`tissue disorders
`
`
`
`
`28 (14)
`6 (3)
`41 (20)
` Back Pain
`29 (15)
`2 (1)
`37 (18)
`Arthralgia
`29 (15)
`1 (1)
`16 (8)
`Myalgia
`Respiratory, thoracic and
`
`
`
`mediastinal disorders
`
`
`
`
`48 (24)
`18 (9)
`58 (28)
` Dyspnea
`29 (15)
`2 (1)
`53 (26)
`Cough
`7 (4)
`0 (0)
`25 (12)
`Epistaxis
`Skin and subcutaneous tissue
`
`
`
`disorders
`
`
`
`
`
` Rashe
`14 (7)
`10 (5)
` 97 (47)
`16 (8)
`1 (1)
`40 (19)
`Pruritus
`1 (1)
`0 (0)
`28 (14)
`Nail Disorder
`14 (7)
`1 (1)
`22 (11)
`Dry Skin
`2 (1)
`0 (0)
`21 (10)
`Acne
`Nervous system disorders
`
`
`
` Dysgeusiaf
`
`17 (9)
`0 (0)
` 41 (20)
`30 (15)
`1 (1)
`24 (12)
` Insomnia
`27 (14)
`0 (0)
`9 (4)
`Depression
`* Common Toxicity Criteria for Adverse Events (CTCAE), Version 3.0.
`a Includes edema, facial edema, and peripheral edema
`b Includes aphthous stomatitis, glossitis, mouth ulceration, mucositis, and stomatitis
`c Includes infections not otherwise specified (NOS) and the following infections that occurred
`infrequently as distinct entities: abscess, bronchitis, cellulitis, herpes simplex, and herpes zoster
`d Includes cystitis, dysuria, hematuria, urinary frequency, and urinary tract infection
`e Includes eczema, exfoliative dermatitis, maculopapular rash, pruritic rash, pustular rash, rash
`(NOS), and vesiculobullous rash
`f Includes taste loss and taste perversion
`
`Table 1 – Adverse Reactions Reported in at Least 10% of Patients Who Received 25 mg IV
`
`TORISEL or IFN-α in the Randomized Trial
`
`
`TORISEL 25 mg
`
` n=208
`
`
`
` Adverse Reaction
`
`
`
`
`
`
`
`10
`
`
`

`

`
`The following selected adverse reactions were reported less frequently (<10%).
`
`
`Gastrointestinal Disorders - Fatal bowel perforation occurred in 1 patient (1%).
`
`
`Eye Disorders - Conjunctivitis (including lacrimation disorder) occurred in 15 patients (7%).
`
`
`Immune System - Allergic/Hypersensitivity reactions occurred in 18 patients (9%).
`
`
`Angioneurotic edema-type reactions have been observed in some patients who received
`
`TORISEL and ACE inhibitors concomitantly.
`
`
`Infections - Pneumonia occurred in 17 patients (8%); upper respiratory tract infection occurred
`in 14 patients (7%).
`
`General Disorders and Administration Site Conditions - Impaired wound healing occurred in 3
`patients (1%).
`
`Respiratory, Thoracic and Mediastinal Disorders – Interstitial lung disease occurred in 5
`patients (2%), including rare fatalities.
`
`Vascular - Hypertension occurred in 14 patients (7%); venous thromboembolism (including
`deep vein thrombosis and pulmonary embolus) occurred in 5 patients (2%); thrombophlebitis
`occurred in 2 patients (1%).
`
`Table 2 – Incidence of Selected Laboratory Abnormalities in Patients Who Received 25 mg
`
`IV TORISEL or IFN-α in the Randomized Trial
`
`TORISEL 25 mg
`n=208
`
`Grades 3&4*
`All Grades*
`n (%)
`n (%)
`
`
`162 (78)
`208 (100)
`
`
`41 (20)
`195 (94)
`110 (53)
`33 (16)
`39 (19)
`10 (5)
`84 (40)
`3 (1)
`67 (32)
`1 (1)
`
`
`141 (68)
`7 (3)
`79 (38)
`5 (2)
`119 (57)
`7 (3)
`186 (89)
`33 (16)
`102 (49)
`38 (18)
`16 (8)
`2 (1)
`181 (87)
`5 (2)
`173 (83)
`92 (44)
`
`
`IFN-α
`n=200
`
`Grades 3&4*
`All Grades*
`n (%)
` n (%)
`
`
`144 (72)
`195 (98)
`
`
`43 (22)
`180 (90)
`106 (53)
`48 (24)
`58 (29)
`19 (10)
`51 (26)
`0 (0)
`93 (47)
`11 (6)
`
`
`111 (56)
`13 (7)
`103 (52)
`14 (7)
`97 (49)
`2 (1)
`128 (64)
`6 (3)
`61 (31)
`17 (9)
`25 (13)
`4 (2)
`95 (48)
`2 (1)
`144 (72)
`69 (35)
`
`
`
` Laboratory Abnormality
`Any
`
`Hematology
`
` Hemoglobin Decreased
` Lymphocytes Decreased**
`Neutrophils Decreased**
`
` Platelets Decreased
`Leukocytes Decreased
`Chemistry
`
` Alkaline Phosphatase Increased
`AST Increased
` Creatinine Increased
` Glucose Increased
`Phosphorus Decreased
`Total Bilirubin Increased
` Total Cholesterol Increased
`Triglycerides Increased
`
`
`
`11
`
`
`

`

`
`
` Table 2 – Incidence of Selected Laboratory Abnormalities in Patients Who Received 25 mg
`
`IV TORISEL or IFN-α in the Randomized Trial
`
`
`TORISEL 25 mg
`
` n=208
`Grades 3&4*
`All Grades*
`n (%)
`n (%)
`
`
`11 (5)
`43 (21)
`
`
` IFN-α
`
` n=200
`Grades 3&4*
`All Grades*
` n (%)
`n (%)
`
`
`15 (8)
`0 (0)
`
`
`
` Laboratory Abnormality
` Potassium Decreased
`*NCI CTC version 3.0
`**Grade 1 toxicity may be under-reported for lymphocytes and neutrophils
`
`6.2 Post-marketing and Other Clinical Experience
`
`The following adverse reactions have been identified during postapproval use of TORISEL.
`Because these reactions are reported voluntarily from a population of uncertain size, it is not
`possible to readily estimate their frequency or establish a causal relationship to drug exposure.
`
`There have been reports of rhabdomyolysis in patients who received TORISEL.
`
`7 DRUG INTERACTIONS
`
`7.1 Agents Inducing CYP3A Metabolism
`
`Co-administration of TORISEL with rifampin, a potent CYP3A4/5 inducer, had no significant
`effect on temsirolimus Cmax (maximum concentration) and AUC (area under the concentration
`versus the time curve) after intravenous administration, but decreased sirolimus Cmax 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 Cmax or AUC; however, sirolimus AUC increased 3.1-fold,
`and Cmax 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 Interactions with Drugs Metabolized by CYP2D6
`
`The concentration of desipramine, a CYP2D6 substrate, was unaffected when 25 mg of
`TORISEL was co-administered. No clinically significant effect is anticipated when
`temsirolimus is co-administered with agents that are metabolized by CYP2D6 or CYP3A4.
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`Pregnancy Category D [see Warnings and Precautions (5.14)].
`
`
`
`12
`
`
`

`

`8.3 Nursing Mothers
`
`It is not known whether TORISEL is excreted into human milk, and due to the potential for
`tumorigenicity shown for sirolimus (active metabolite of TORISEL) in animal studies, a
`decision should be made whether to discontinue nursing or discontinue TORISEL, taking into
`account the importance of the drug to the mother.
`
`8.4 Pediatric Use
`
`The safety and effectiveness of TORISEL in pediatric patients have not been established.
`
`8.5 Geriatric Use
`
`Clinical studies of TORISEL did not include sufficient numbers of subjects aged 65 and older
`to determine whether they respond differently from younger subjects.
`
`8.6 Renal Impairment
`
`
`No clinical studies were conducted with TORISEL in patients with decreased renal function.
`Less than 5% of total radioactivity was excreted in the urine following a 25 mg intravenous
`dose of [14C]-labeled temsirolimus in healthy subjects. Renal impairment is not expected to
`markedly influence drug exposure, and no dosage adjus