Data from FDA - Curated by Toby Galbraith - Last updated 07 August 2017

Indication(s)

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)

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Advisory information

contraindications
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)
Adverse reactions
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 GradesCommon 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) EdemaIncludes 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 MucositisIncludes 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) Vomiting 40 (19) 4 (2) 57 (29) 5 (3) Infections InfectionsIncludes infections not otherwise specified (NOS) and the following infections that occurred infrequently as distinct entities: abscess, bronchitis, cellulitis, herpes simplex, and herpes zoster 42 (20) 6 (3) 19 (10) 4 (2) Urinary tract infectionIncludes cystitis, dysuria, hematuria, urinary frequency, and urinary tract infection 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 and connective tissue disorders Back 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) Respiratory, thoracic and mediastinal disorders Dyspnea 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 and subcutaneous tissue disorders RashIncludes eczema, exfoliative dermatitis, maculopapular rash, pruritic rash, pustular rash, rash (NOS), and vesiculobullous rash 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 system disorders DysgeusiaIncludes taste loss and taste perversion 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) The following selected adverse reactions were reported less frequently (<10%). Gastrointestinal Disorders – Gastrointestinal hemorrhage (1%), rectal hemorrhage (1%). Eye Disorders – Conjunctivitis (including lacrimation disorder) (8%). Immune System – Angioneurotic edema-type reactions (including delayed reactions occurring two months following initiation of therapy) have been observed in some patients who received TORISEL and ACE inhibitors concomitantly. Infections – Pneumonia (8%), upper respiratory tract infection (7%), wound infection/post-operative wound infection (1%), sepsis (1%). General Disorders and Administration Site Conditions - Diabetes mellitus (5%). Respiratory, Thoracic and Mediastinal Disorders – Pleural effusion (4%). Vascular – Hypertension (7%), venous thromboembolism (including deep vein thrombosis and pulmonary embolus [including fatal outcomes]) (2%), thrombophlebitis (1%), pericardial effusion (1%). Nervous System Disorders – Convulsion (1%). Table 2 – Incidence of Selected Laboratory Abnormalities in Patients Who Received 25 mg IV TORISEL or IFN-α in the Randomized Trial Laboratory Abnormality TORISEL 25 mg n = 208 IFN-α n = 200 All GradesNCI CTC version 3.0 n (%) Grades 3&4 n (%) All Grades n (%) Grades 3&4 n (%) Any 208 (100) 162 (78) 195 (98) 144 (72) Hematology Hemoglobin Decreased 195 (94) 41 (20) 180 (90) 43 (22) Lymphocytes DecreasedGrade 1 toxicity may be under-reported for lymphocytes and neutrophils 110 (53) 33 (16) 106 (53) 48 (24) Neutrophils Decreased 39 (19) 10 (5) 58 (29) 19 (10) Platelets Decreased 84 (40) 3 (1) 51 (26) 0 (0) Leukocytes Decreased 67 (32) 1 (1) 93 (47) 11 (6) Chemistry Alkaline Phosphatase Increased 141 (68) 7 (3) 111 (56) 13 (7) AST Increased 79 (38) 5 (2) 103 (52) 14 (7) Creatinine Increased 119 (57) 7 (3) 97 (49) 2 (1) Glucose Increased 186 (89) 33 (16) 128 (64) 6 (3) Phosphorus Decreased 102 (49) 38 (18) 61 (31) 17 (9) Total Bilirubin Increased 16 (8) 2 (1) 25 (13) 4 (2) Total Cholesterol Increased 181 (87) 5 (2) 95 (48) 2 (1) Triglycerides Increased 173 (83) 92 (44) 144 (72) 69 (35) Potassium Decreased 43 (21) 11 (5) 15 (8) 0 (0) 6.2 Post-marketing and Other Clinical Experience The following adverse reactions have been identified during post approval use of TORISEL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to readily estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been observed in patients receiving temsirolimus: angioedema, rhabdomyolysis, Stevens-Johnson Syndrome, complex regional pain syndrome (reflex sympathetic dystrophy), pancreatitis, cholecystitis, and cholelithiasis. There are also post-marketing reports of temsirolimus extravasations resulting in swelling, pain, warmth, and erythema.

Usage information

Dosing and administration
2 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) 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 Warnings and Precautions (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×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 (5.11) 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 (5.11) and Drug Interactions (7.1)]. 2.5 Instructions for Preparation 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. TORISEL 25 mg/mL injection must be diluted with the supplied diluent before further dilution in 0.9% Sodium Chloride Injection, USP. Please note that both the TORISEL injection and diluent vials contain an overfill to ensure the recommended volume can be withdrawn. Follow this two-step dilution process in an aseptic manner. Step 1: DILUTION OF TORISEL INJECTION 25 MG/ML WITH SUPPLIED DILUENT Each Vial of Torisel (temsirolimus) must first be mixed with 1.8 mL of the enclosed diluent. The resultant solution contains 30 mg/3 mL (10 mg/mL). Mix well by inversion of the vial. Allow sufficient time for the air bubbles to subside. The solution should be clear to slightly turbid, colorless to light-yellow solution, essentially free from visual particulates. The concentrate-diluent mixture is stable below 25ºC for up to 24 hours. Step 2: DILUTION OF CONCENTRATE-DILUENT MIXTURE WITH 0.9% SODIUM CHLORIDE INJECTION, USP Withdraw precisely the required amount of concentrate-diluent mixture containing temsirolimus 10 mg/mL as prepared in Step 1 from the vial (i.e., 2.5 mL for a temsirolimus dose of 25 mg) and further dilute into an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. Mix by inversion of the bag or bottle, avoiding excessive shaking, as this may cause foaming. The resulting solution should be inspected visually for particulate matter and discoloration prior to administration. The admixture of TORISEL in 0.9% Sodium Chloride Injection, USP should be protected from excessive room light and sunlight. 2.6 Administration Administration of the final diluted solution should be completed within six hours from the time that TORISEL is first added to 0.9% Solution Chloride Injection, USP. TORISEL is infused over a 30- to 60-minute period once weekly. The use of an infusion pump is the preferred method of administration to ensure accurate delivery of the product. Appropriate administration materials should be composed of glass, polyolefin, or polyethylene to avoid excessive loss of product and diethylhexylpthalate (DEHP) extraction. The administration materials should consist of non-DEHP, non-polyvinylchloride (PVC) tubing with appropriate filter. In the case when a PVC administration set has to be used, it should not contain DEHP. An in-line polyethersulfone filter with a pore size of not greater than 5 microns is recommended for administration to avoid the possibility of particles bigger than 5 microns being infused. If the administration set available does not have an in-line filter incorporated, a polyethersulfone filter should be added at the set (i.e., an end-filter) before the admixture reaches the vein of the patient. Different end-filters can be used, ranging in filter pore size from 0.2 microns up to 5 microns. The use of both an in-line and end-filter is not recommended. TORISEL, when diluted, contains polysorbate 80, which is known to increase the rate of DEHP extraction from PVC. This should be considered during the preparation and administration of TORISEL, including storage time elapsed when in direct contact with PVC following constitution. 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 0.9% 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.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.14)]. 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. 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 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 patients with cancer 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 patients with cancer at the recommended human dose). 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 Limited data are available on the use of temsirolimus in pediatric patients. The effectiveness of temsirolimus in pediatric patients with advanced recurrent/refractory solid tumors has not been established. TORISEL was studied in 71 patients (59 patients ages 1 to 17 years and 12 patients ages 18 to 21 years) with relapsed/refractory solid tumors in a phase 1–2 safety and exploratory pharmacodynamic study. In phase 1, 19 pediatric patients with advanced recurrent/refractory solid tumors received TORISEL at doses ranging from 10 mg/m2 to 150 mg/m2 as a 60-minute intravenous infusion once weekly in three-week cycles. In phase 2, 52 pediatric patients with recurrent/relapsed neuroblastoma, rhabdomyosarcoma, or high grade glioma received TORISEL at a weekly dose of 75 mg/m2. One of 19 patients with neuroblastoma achieved a partial response. There were no objective responses in pediatric patients with recurrent/relapsed rhabdomyosarcoma or high grade glioma. Adverse reactions associated with TORISEL were similar to those observed in adults. The most common adverse reactions (≥20%) in pediatric patients receiving the 75 mg/m2 dose included thrombocytopenia, infections, asthenia/fatigue, fever, pain, leukopenia, rash, anemia, hyperlipidemia, increased cough, stomatitis, anorexia, increased plasma levels of alanine aminotransferase and aspartate aminotransferase, hypercholesterolemia, hyperglycemia, abdominal pain, headache, arthralgia, upper respiratory infection, nausea and vomiting, neutropenia, hypokalemia, and hypophosphatemia. Pharmacokinetics: In phase 1 of the above mentioned pediatric trial, the single dose and multiple dose total systemic exposure (AUC) of temsirolimus and sirolimus were less than dose-proportional over the dose range of 10 to 150 mg/m2. In the phase 2 portion, the multiple dose (Day 1, Cycle 2) pharmacokinetics of TORISEL 75 mg/m2 were characterized in an additional 35 patients ages 28 days to 21 years (median age of 8 years). The geometric mean body surface adjusted clearance of temsirolimus and sirolimus was 9.45 L/h/m2 and 9.26 L/h/m2, respectively. The mean elimination half-life of temsirolimus and sirolimus was 31 hours and 44 hours, respectively. The exposure (AUCss) to temsirolimus and sirolimus was approximately 6-fold and 2-fold higher, respectively than the exposure in adult patients receiving a 25 mg intravenous infusion. 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. Based on the results of a phase 3 study, elderly patients may be more likely to experience certain adverse reactions including diarrhea, edema, and pneumonia [see Warnings and Precautions (5.15)]. 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 adjustment of TORISEL is recommended in patients with renal impairment. TORISEL has not been studied in patients undergoing hemodialysis. 8.7 Hepatic Impairment TORISEL was evaluated in a dose escalation phase 1 study in 110 patients with normal or varying degrees of hepatic impairment as defined by AST and bilirubin levels and patients with liver transplant (Table 3). Patients with moderate and severe hepatic impairment had increased rates of adverse reactions and deaths, including deaths due to progressive disease, during the study (Table 3). Table 3 – Adverse Reactions in Patients with Advanced Malignancies Plus Normal or Impaired Hepatic Function Hepatic FunctionHepatic Function Groups: normal = bilirubin and AST ≤ULN; mild = bilirubin >1 – 1.5×ULN or AST >ULN but bilirubin ≤ULN; moderate = bilirubin >1.5 – 3×ULN; severe = bilirubin >3×ULN; liver transplant = any bilirubin and AST. TORISEL Dose Range Adverse Reactions Grade ≥ 3Common Terminology Criteria for Adverse Events, version 3.0, including all causality. n (%) DeathIncludes deaths due to progressive disease and adverse reactions. n (%) Normal (n = 25) 25 – 175 20 (80.0) 2 (8.0) Mild (n = 39) 10 – 25 32 (82.1) 5 (12.8) Moderate (n = 20) 10 – 25 19 (95.0) 8 (40.0) Severe (n = 24) 7.5 – 15 23 (95.8) 13 (54.2) Liver Transplant (n = 2) 10 1 (50.0) 0 (0) TORISEL is contraindicated in patients with bilirubin >1.5×ULN [see Contraindications (4), and Warnings and Precautions (5.2)]. Use caution when treating patients with mild 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 [see Dosage and Administration (2.4)]. Because there is a need for dosage adjustment based upon hepatic function, assessment of AST and bilirubin levels is recommended before initiation of TORISEL and periodically thereafter.
Pregnancy and lactation
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.

Interactions

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 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 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).

More information

Category Value
Authorisation number NDA022088
Orphan designation No
Product NDC 0008-1179
Date Last Revised 12-07-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 722289
Storage and handling Each kit is supplied in a single carton containing one single-use vial of 25 mg/mL of temsirolimus and one DILUENT vial which includes a deliverable volume of 1.8 mL, and must be stored at 2º–8º C (36º–46º F). Protect from light.
Marketing authorisation holder Wyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.