Torisel

temsirolimus · Kit

Prescription (Rx) 2 recalls

Uses

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 )

Dosage and administration

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

Dosage forms and strengths

(temsirolimus) is supplied as a kit consisting of the following: TORISEL (temsirolimus) injection (25 mg/mL). The TORISEL vial contains temsirolimus at a concentration of 25 mg/mL. The vial contains an overfill of 0.2 mL to ensure the ability to withdraw the recommended dose. DILUENT for TORISEL. The DILUENT vial includes a deliverable volume of 1.8 mL. This vial contains an overfill in order to ensure that the appropriate volume can be withdrawn. TORISEL injection, 25 mg/mL supplied with DILUENT for TORISEL. ( 3 )

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 )

Warnings and precautions

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

Side effects

The following serious adverse reactions have been associated with TORISEL in clinical trials and are discussed in greater detail in other sections of the label [see Warnings and Precautions (5) ] .
• Hypersensitivity/Infusion Reactions [see Warnings and Precautions (5.1) ]
• Hepatic Impairment [see Warnings and Precautions (5.2) ]
• Hyperglycemia/Glucose Intolerance [see Warnings and Precautions (5.3) ]
• Infections [see Warnings and Precautions (5.4) ]
• Interstitial Lung Disease [see Warnings and Precautions (5.5) ]
• Hyperlipidemia [see Warnings and Precautions (5.6) ]
• Bowel Perforation [see Warnings and Precautions (5.7) ]
• Renal Failure [see Warnings and Precautions (5.8) ]
• Wound Healing Complications [see Warnings and Precautions (5.9) ]
• Intracerebral Hemorrhage [see Warnings and Precautions (5.10) ] The most common (≥30%) adverse reactions observed with TORISEL are rash, asthenia, mucositis, nausea, edema, and anorexia. The most common (≥30%) laboratory abnormalities observed with TORISEL are anemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, lymphopenia, elevated alkaline phosphatase, elevated serum creatinine, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia. The most common adverse reactions (incidence ≥30%) are rash, asthenia, mucositis, nausea, edema, and anorexia. The most common laboratory abnormalities (incidence ≥30%) are anemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, elevated alkaline phosphatase, elevated serum creatinine, lymphopenia, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia. ( 6 )To report SUSPECTED ADVERSE REACTIONS, contact Wyeth Pharmaceuticals Inc. at 1-800-934-5556 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. In the phase 3 randomized, open-label study of interferon alfa (IFN-α) alone, TORISEL alone, and TORISEL and IFN-α, a total of 616 patients were treated. Two hundred patients received IFN-α weekly, 208 received TORISEL 25 mg weekly, and 208 patients received a combination of TORISEL and IFN-α weekly [see Clinical Studies (14) ] . Treatment with the combination of TORISEL 15 mg and IFN-α was associated with an increased incidence of multiple adverse reactions and did not result in a significant increase in overall survival when compared with IFN-α alone. Table 1 shows the percentage of patients experiencing treatment emergent adverse reactions. Reactions reported in at least 10% of patients who received TORISEL 25 mg alone or IFN-α alone are listed. Table 2 shows the percentage of patients experiencing selected laboratory abnormalities. Data for the same adverse reactions and laboratory abnormalities in the IFN-α alone arm are shown for comparison : Table 1 – Adverse Reactions Reported in at Least 10% of Patients Who Received 25 mg IV TORISEL or IFN-α in the Randomized Trial Adverse Reaction TORISEL 25 mg n = 208 IFN-α n = 200 All Grades Common Toxicity Criteria for Adverse Events (CTCAE), Version 3.0. n (%) Grades 3&4 n (%) All Grades n (%) Grades 3&4 n (%) General disorders Asthenia 106 (51) 23 (11) 127 (64) 52 (26) Edema Includes edema, facial edema, and peripheral edema 73 (35) 7 (3) 21 (11) 1 (1) Pain 59 (28) 10 (5) 31 (16) 4 (2) Pyrexia 50 (24) 1 (1) 99 (50) 7 (4) Weight Loss 39 (19) 3 (1) 50 (25) 4 (2) Headache 31 (15) 1 (1) 30 (15) 0 (0) Chest Pain 34 (16) 2 (1) 18 (9) 2 (1) Chills 17 (8) 1 (1) 59 (30) 3 (2) Gastrointestinal disorders Mucositis Includes aphthous stomatitis, glossitis, mouth ulceration, mucositis, and stomatitis 86 (41) 6 (3) 19 (10) 0 (0) Anorexia 66 (32) 6 (3) 87 (44) 8 (4) Nausea 77 (37) 5 (2) 82 (41) 9 (5) Diarrhea 56 (27) 3 (1) 40 (20) 4 (2) Abdominal Pain 44 (21) 9 (4) 34 (17) 3 (2) Constipation 42 (20) 0 (0) 36 (18) 1 (1) Vomiting 40 (19) 4 (2) 57 (29) 5 (3) Infections Infections Includes 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 infection Includes 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 Rash Includes 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 Dysgeusia Includes 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%).

Drug interactions

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

Use in specific populations

Lactation: Do not breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings in animal studies and its mechanism of action, temsirolimus can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . Although there are no data on the use of TORISEL in pregnant women, there are limited data on the use of sirolimus, the active metabolite of temsirolimus, during pregnancy; however, these data are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal reproductive studies, oral daily administration of temsirolimus to pregnant rats and rabbits during organogenesis caused adverse embryo-fetal effects at approximately 0.04 and 0.12 times the AUC in patients at the recommended dose, respectively (see Data ) . Advise pregnant women of the potential hazard to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data Temsirolimus administered daily as an oral formulation throughout organogenesis caused adverse embryo-fetal effects in rats and rabbits at human sub-therapeutic exposures. Embryo-fetal adverse effects in rats consisted of reduced fetal weight and reduced ossifications, and in rabbits included reduced fetal weight, omphalocele, bifurcated sternabrae, notched ribs, and incomplete ossifications. In rats, the adverse embryo-fetal effects were observed at the oral dose of 2.7 mg/m 2 /day (approximately 0.04-fold the AUC in patients with cancer at the human recommended dose). In rabbits, the adverse embryo-fetal effects were observed at the oral dose of ≥7.2 mg/m 2 /day (approximately 0.12-fold the AUC in patients with cancer at the recommended human dose). 8.2 Lactation Risk Summary There is no information regarding the presence of TORISEL or its metabolites in human milk, or their effects on the breastfed child or milk production. Trace amounts of sirolimus, the active metabolite of temsirolimus, were present in milk from lactating rats administered sirolimus. Because of the potential for serious adverse reactions in a breastfed child from TORISEL, advise a lactating woman not to breastfeed during treatment with TORISEL and for 3 weeks after the final dose. 8.3 Females and Males of Reproductive Potential Contraception Females TORISEL can cause fetal harm when administered to a pregnant woman [see Use in Specific Population (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with TORISEL and for 3 months after the last dose. Males Advise males with partners of reproductive potential to use effective contraception during treatment with TORISEL and for 3 months after the last dose [see Nonclinical Toxicology (13.1) ] . Infertility Based on the findings in animal fertility studies, male and female fertility may be compromised by the treatment with Torisel. It is not known if the effects on fertility in animal studies were reversible [see Nonclinical Toxicology (13.1) ]. 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/m 2 to 150 mg/m 2 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/m 2 . 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/m 2 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/m 2 . In the phase 2 portion, the multiple dose (Day 1, Cycle 2) pharmacokinetics of TORISEL 75 mg/m 2 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/m 2 and 9.26 L/h/m 2 , 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.

Pregnancy

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

Pediatric use

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/m 2 to 150 mg/m 2 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/m 2 . 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/m 2 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/m 2 . In the phase 2 portion, the multiple dose (Day 1, Cycle 2) pharmacokinetics of TORISEL 75 mg/m 2 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/m 2 and 9.26 L/h/m 2 , 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.

Geriatric use

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 (5.16) ] .

Overdosage

There is no specific treatment for TORISEL intravenous overdose. TORISEL has been administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as high as 220 mg/m 2 . The risk of several serious adverse events, including thrombosis, bowel perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of TORISEL greater than 25 mg.

Description

Temsirolimus, an inhibitor of mTOR, is an antineoplastic agent. Temsirolimus is a white to off-white powder with a molecular formula of C 56 H 87 NO 16 and a molecular weight of 1030.30. It is non-hygroscopic. Temsirolimus is practically insoluble in water and soluble in alcohol. It has no ionizable functional groups, and its solubility is independent of pH. The chemical name of temsirolimus is (3 S ,6 R ,7 E ,9 R ,10 R ,12 R ,14 S ,15 E ,17 E ,19 E ,21 S ,23 S ,26 R ,27 R ,34a S )-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1 R )-2-[(1 S ,3 R ,4 R )-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23, 27-epoxy-3 H -pyrido[2,1- c ][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4 H ,6 H ,31 H )-pentone 4'-[2,2-bis(hydroxymethyl)propionate]; or Rapamycin, 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]. TORISEL (temsirolimus) injection, 25 mg/mL, is a clear, colorless to light yellow, non-aqueous, ethanolic, sterile solution. TORISEL (temsirolimus) injection requires two dilutions prior to intravenous infusion. TORISEL (temsirolimus) injection should be diluted only with the supplied DILUENT for TORISEL. DILUENT for TORISEL is a sterile, non-aqueous solution that 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 -alpha-tocopherol (0.075% w/v), propylene glycol (50.3% w/v), and anhydrous citric acid (0.0025% w/v). DILUENT for TORISEL: Inactive ingredients: polysorbate 80 (40.0% w/v), polyethylene glycol 400 (42.8% w/v) and dehydrated alcohol (19.9% w/v). After the TORISEL (temsirolimus) injection vial has been diluted with DILUENT for TORISEL, in accordance with the instructions in section 2.5, the solution contains 35.2% alcohol. TORISEL (temsirolimus) injection and DILUENT for TORISEL are filled in clear glass vials with butyl rubber stoppers. Chemical Structure

Mechanism of action

12.1 Mechanism of Action Temsirolimus is an inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity resulted in a G1 growth arrest in treated tumor cells. When mTOR was inhibited, its ability to phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the PI3 kinase/AKT pathway was blocked. In in vitro studies using renal cell carcinoma cell lines, temsirolimus inhibited the activity of mTOR and resulted in reduced levels of the hypoxia-inducible factors HIF-1 and HIF-2 alpha, and the vascular endothelial growth factor.

How supplied

0008-1179-01 TORISEL (temsirolimus) injection, 25 mg/mL. 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. TORISEL is a cytotoxic drug. Follow applicable special handling and disposal procedures 1 .

Storage

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. TORISEL is a cytotoxic drug. Follow applicable special handling and disposal procedures 1 .

Patient information

Allergic (Hypersensitivity/Infusion) Reactions Patients should be informed of the possibility of serious allergic reactions, including anaphylaxis (including life threatening and fatal reactions), despite premedication with antihistamines, and to immediately report any facial swelling or difficulty breathing [see Warnings and Precautions (5.1) ] . Increased Blood Glucose Levels Patients are likely to experience increased blood glucose levels while taking TORISEL. This may result in the need for initiation of, or increase in the dose of, insulin and/or hypoglycemic agents. Patients should be directed to report any excessive thirst or frequency of urination to their physician [see Warnings and Precautions (5.3) ] . Infections Patients should be informed that they may be more susceptible to infections while being treated with TORISEL [see Warnings and Precautions (5.4) ] . Interstitial Lung Disease Patients should be warned of the possibility of developing interstitial lung disease, a chronic inflammation of the lungs, which may rarely result in death [see Warnings and Precautions (5.5) ] . Patients, including those who are taking or have taken corticosteroids or immunosuppressive agents, should be directed to report promptly any new or worsening respiratory symptoms to their physician. Increased Blood Triglycerides and/or Cholesterol Patients are likely to experience elevated triglycerides and/or cholesterol during TORISEL treatment. This may require initiation of, or increase in the dose of, lipid-lowering agents [see Warnings and Precautions (5.6) ] . Bowel Perforation Patients should be warned of the possibility of bowel perforation. Patients should be directed to report promptly any new or worsening abdominal pain or blood in their stools [see Warnings and Precautions (5.7) ] . Renal Failure Patients should be informed of the risk of renal failure [see Warnings and Precautions (5.8) ] . Wound Healing Complications Patients should be advised of the possibility of abnormal wound healing if they have surgery within a few weeks of initiating therapy or during therapy [see Warnings and Precautions (5.9) ] . Intracerebral Bleeding Patients with CNS tumors and/or receiving anticoagulants should be informed of the increased risk of developing intracerebral bleeding (including fatal outcomes) while on TORISEL [see Warnings and Precautions (5.10) ] . Proteinuria and Nephrotic Syndrome Advise patients that treatment with TORISEL may require monitoring for proteinuria and nephrotic syndrome and to contact their health care provider for signs and symptoms of nephrotic syndrome [see Warnings and Precautions (5.11) ] . Medications that can interfere with TORISEL Some medicines can interfere with the breakdown or metabolism of TORISEL. In particular, patients should be directed to inform their physician if they are taking any of the following: Protease inhibitors, anti-epileptic medicines including carbamazepine, phenytoin, and barbiturates, St. John's Wort, rifampicin, rifabutin, nefazodone or selective serotonin re-uptake inhibitors used to treat depression, antibiotics or antifungal medicines used to treat infections [see Warnings and Precautions (5.12) ] . Vaccinations Patients should be advised that vaccinations may be less effective while being treated with TORISEL. In addition, the use of live vaccines, and close contact with those who have received live vaccines, while on TORISEL should be avoided [see Warnings and Precautions (5.14) ] . Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential that TORISEL can cause fetal harm. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.15) and Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with TORISEL and for 3 months after receiving the last dose [see Use in Specific Populations (8.3) ] . Advise males with female partners of reproductive potential to use effective contraception during treatment with TORISEL and for 3 months after receiving the last dose [see Use in Specific Populations (8.3) ] . Lactation Advise lactating women not to breastfeed during treatment with TORISEL and for 3 weeks after the last dose [see Use in Specific Populations (8.2) ] . Infertility Advise patients that male and female fertility may be compromised by treatment with TORISEL [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1) ] . Elderly Patients Elderly patients should be advised that they may be more likely to experience certain adverse reactions including diarrhea, edema, and pneumonia [see Warnings and Precautions (5.16) ] .

Label text from the FDA structured product label by Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc. (revised Dec 26, 2025). Long sections are shortened; the complete label is on DailyMed.

Torisel NDC products (1)

NDCStrength & formLabelerType
0008-1179
Kit		Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc.NDA

Torisel recalls

Frequently asked questions

What is Torisel used for?

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 )

What are the side effects of Torisel?

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… See the full label for the complete list.

Who makes Torisel?

Torisel is listed by 1 labeler in the FDA NDC directory, including Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc..

Has Torisel been recalled?

The FDA enforcement database lists 2 recalls for Torisel, most recently D-0235-2015 (class iii): Crystallization: Impurities in a raw material used to manufacture the diluent can cause the formation of crystals in the diluent vials after cold storage. The…