Torisel

TORISEL is indicated for the treatment of advanced renal cell carcinoma.

• •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 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.
  )
• •Antihistamine pre-treatment is recommended. (
  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)]

  .
  )
• •Dose reduction is required in patients with mild hepatic impairment. (
  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)]

  .
  )
• •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 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. The admixture of TORISEL in 0.9% Sodium Chloride Injection, USP should be protected from excessive room light and sunlight.
  )

TORISEL (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.

Lactation: Do not breastfeed. (

• •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 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 H₁antihistamine 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).

  A benefit-risk assessment should be done prior to the continuation of temsirolimus therapy in patients with severe or life-threatening reactions.
  )
• •To treat hypersensitivity reactions, stop TORISEL and treat with an antihistamine. TORISEL may be restarted at physician discretion at a slower rate. (
  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 H₁antihistamine 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).

  A benefit-risk assessment should be done prior to the continuation of temsirolimus therapy in patients with severe or life-threatening reactions.
  )
• •Hepatic Impairment: Use caution when treating patients with mild hepatic impairment and reduce dose. (
  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)]

  .
  ,
  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)]

  .
  )
• •Hyperglycemia and hyperlipidemia are likely and may require treatment. Monitor glucose and lipid profiles. (
  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.
  ,
  5.6 Hyperlipidemia

  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.
  )
• •Infections may result from immunosuppression. (
  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.
  )
• •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 Interstitial Lung Disease

  Cases of interstitial lung disease, some resulting in death, occurred in patients who received TORISEL. Some patients were asymptomatic, or had minimal symptoms, 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.

  It is recommended that patients undergo baseline radiographic assessment by lung computed tomography scan or chest radiograph prior to the initiation of TORISEL therapy. Follow such assessments periodically, even in the absence of clinical respiratory symptoms.

  It is recommended that patients be followed closely for occurrence of clinical respiratory symptoms. If clinically significant respiratory symptoms develop, consider withholding TORISEL administration until after recovery of symptoms and improvement of radiographic findings related to pneumonitis. Empiric treatment with corticosteroids and/or antibiotics may be considered. Opportunistic infections such as PJP should be considered in the differential diagnosis. For patients who require use of corticosteroids, prophylaxis of PJP may be considered.
  )
• •Bowel perforation may occur. Evaluate fever, abdominal pain, bloody stools, and/or acute abdomen promptly. (
  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.
  )
• •Renal failure, sometimes fatal, has occurred. Monitor renal function at baseline and while on TORISEL. (
  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.
  )
• •Due to abnormal wound healing, use TORISEL with caution in the perioperative period. (
  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.
  )
• •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 Proteinuria and Nephrotic syndrome

  Proteinuria (including cases of nephrotic syndrome) has occurred in patients treated with TORISEL. Monitor urine protein prior to the start of TORISEL therapy and periodically thereafter. Discontinue TORISEL in patients who develop nephrotic syndrome.
  )
• •Live vaccinations and close contact with those who received live vaccines should be avoided. (
  5.14 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.
  )
• •Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential hazard to the fetus and to use effective contraception. (
  5.15 Embryo-Fetal Toxicity

  Based on findings in animal studies and its mechanism of action, TORISEL can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, daily oral administration of temsirolimus to pregnant animals during organogenesis caused adverse embryo-fetal effects in rats and rabbits at approximately 0.04 and 0.12 times the AUC in patients at the recommended human dose, respectively. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TORISEL and for 3 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TORISEL and for 3 months after the last dose [see

  Clinical Pharmacology (12.1)

  and

  Use in Specific Populations (8.1

  ,

  8.3)

  ].
  ,
  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/m²/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/m²/day (approximately 0.12-fold the AUC in patients with cancer at the recommended human 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)].
  )
• •Elderly patients may be more likely to experience certain adverse reactions, including diarrhea, edema and pneumonia. (
  5.16 Elderly Patients

  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 Use in Specific Populations (8.5)].
  )