Overview of Contraindications, Warnings and Precautions

Hepatic Impairment

• TORISEL is contraindicated in patients with bilirubin >1.5 x ULN due to increased risk of death
• TORISEL should be used with caution when treating patients with mild hepatic impairment, defined as:
  • Bilirubin >1 - 1.5 x ULN
    or
  • AST > ULN but bilirubin ≤ ULN

Dose adjustment for mild hepatic impairment

• If TORISEL must be given to patients with mild hepatic impairment, reduce the dose to 15 mg/week
• 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

Hyperglycemia/glucose intolerance¹

In the phase 3 clinical study, the use of TORISEL 25 mg IV once weekly was associated with increases in serum glucose.

• The use of TORISEL is likely to result in increases in serum glucose¹
• Hyperglycemia may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy¹
  • During the phase 3 study, the use of insulin or oral hypoglycemic therapies occurred at the physician's discretion²
• Serum glucose should be tested before and during treatment with TORISEL¹
• Patients should be advised to report excessive thirst or any increase in the volume or frequency of urination¹

Patients should be closely monitored for adverse events, and treatment of these events should be based on the physician's medical judgment and discretion considering the needs of each individual patient.

Considerations for the management of hyperglycemia

• Dietary guidance from a nutritionist³
• Treatment option for hyperglycemia may include⁴
  • Increased exercise
• Hyperglycemia may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy¹

Infection¹

In the phase 3 clinical study, the use of TORISEL 25 mg IV once weekly was associated with increases in the occurrence of infection.

• The use of TORISEL may result in immunosuppression.
  • Patients should be carefully observed for the occurrence of infections, including opportunistic infections
• Patients should be informed that they may be more susceptible to infections while being treated with TORISEL

Patients should be closely monitored for adverse events, and treatment of these events should be based on the physician's medical judgment and discretion considering the needs of each individual patient.

Considerations for the management of infection

• Infection control should incorporate standard measures and should not rely exclusively on antimicrobial prophylaxis⁵
• Vigilance for early signs/symptoms of infection and prompt treatment with an anti-infective agent at the discretion of the attending physician may reduce the complications of infection²
• The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with TORISEL¹

Interstitial lung disease¹

In the phase 3 clinical study, the use of TORISEL 25 mg IV once weekly was associated with a 2% occurrence of ILD, including rare fatalities.

• 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

Patients should be closely monitored for adverse events, and treatment of these events should be based on the physician's medical judgment and discretion considering the needs of each individual patient.

Considerations for the management of ILD

• Some patients required discontinuation of TORISEL and/or treatment with corticosteroids and/or antibiotics. Patients should be monitored closely for clinical respiratory symptoms
• Patients should be warned of the possibility of developing ILD during treatment
• Patients should be directed to report promptly any new or worsening respiratory symptoms

Hyperlipidemia¹

In the phase 3 clinical study, the use of TORISEL 25 mg IV once weekly was associated with hyperlipidemia.

Patients should be closely monitored for adverse events, and treatment of these events should be based on the physician's medical judgment and discretion considering the needs of each individual patient.

Considerations for the management of hyperlipidemia

• Serum cholesterol and triglycerides should be tested before and during treatment with TORISEL¹
• Increased blood lipids may require initiation, or increase in the dose, of lipid-lowering agents¹
• In the phase 3 study, the use of serum lipid-lowering agents occurred at the physician's discretion²

Bowel perforation¹

In the phase 3 clinical study, the use of TORISEL 25 mg IV once weekly was associated with bowel perforation.

• In the phase 3 study, fatal bowel perforation occurred in 1 patient
• 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 warned of the possibility of bowel perforation and advised to report promptly any new or worsening abdominal pain or blood in their stools

Patients should be closely monitored for adverse events, and treatment of these events should be based on the physician's medical judgment and discretion considering the needs of each individual patient.

Considerations for the management of bowel perforation

• Watch for potential signs of bowel perforation, including, but not limited to, dehydration, oliguria, and shock⁶
• If bowel perforation occurs, immediate medical or surgical intervention is indicated⁶

Renal failure¹

In the phase 3 clinical study, the use of TORISEL 25 mg IV once weekly was associated with 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
• Patients should be informed of the risk of renal failure

Patients should be closely monitored for adverse events, and treatment of these events should be based on the physician's medical judgment and discretion considering the needs of each individual patient.

Considerations for the management of renal failure

• In the phase 3 study, chemistry panels were checked every 2 weeks and at baseline¹

Wound healing complications¹

In the phase 3 clinical study, the use of TORISEL 25 mg IV once weekly was associated with abnormal wound healing.

Patients should be closely monitored for adverse events, and treatment of these events should be based on the physician's medical judgment and discretion considering the needs of each individual patient.

Considerations for the management of abnormal wound healing

• Caution should be exercised with the use of TORISEL in the perioperative period¹
• Patients should be advised of the possibility of abnormal wound healing if they have surgery within a few weeks of initiating therapy or during therapy¹

Intracerebral hemorrhage¹

In the phase 3 clinical study, the use of TORISEL 25 mg IV once weekly was associated with intracerebral hemorrhage.

• Patients with CNS 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 TORISEL¹

Patients should be closely monitored for adverse events, and treatment of these events should be based on the physician's medical judgment and discretion considering the needs of each individual patient.

Considerations for the management of intracerebral hemorrhage

• Patients with CNS tumors and/or receiving anticoagulants should be informed of the increased risk of developing intracerebral hemorrhage (including fatal outcomes) while on TORISEL¹

Live vaccinations¹

The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with TORISEL.

Consideration for the use of live vaccinations

• Patients should be advised that vaccination may be less effective while being treating with TORISEL
• 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

Pregnancy¹

TORISEL may cause fetal harm when administered to pregnant women (Pregnancy Category D).

• Women of childbearing potential should be advised to avoid becoming pregnant throughout treatment and for 3 months after TORISEL therapy has stopped
• If TORISEL 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 with TORISEL
• 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
• 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
• Pediatric Use: The safety and effectiveness of TORISEL in pediatric patients have not been established

Patients should be closely monitored for adverse events, and treatment of these events should be based on the physician's medical judgment and discretion considering the needs of each individual patient.

Additional considerations

CYP3A interactions

• Strong inducers of CYP3A4/5 (eg, dexamethasone, rifampin) and strong inhibitors of CYP3A4 (eg, ketoconazole, atazanavir) may decrease and increase concentrations of the major metabolite of TORISEL, respectively. If alternatives cannot be used, dose modifications of TORISEL are recommended.¹ Learn more about Drug Interactions
• St. John's Wort may decrease TORISEL plasma concentrations, and grapefruit juice may increase plasma concentrations of the major metabolite of TORISEL, and therefore both should be avoided.¹
• If TORISEL is administered with drugs that inhibit or are substrates of P-glycoprotein (Pgp), increased concentrations of TORISEL or the substrate drug are likely and caution should be exercised.¹

Concomitant use with sunitinib

• The combination of TORISEL and sunitinib resulted in dose-limiting toxicity (grade ¾ erythematous maculopapular rash, and gout/cellulitis requiring hospitalization)¹

Monitoring laboratory tests

• In the randomized, phase 3 trial, CBCs were checked weekly, and chemistry panels were checked every 2 weeks. Laboratory monitoring for patients receiving TORISEL may need to be performed more or less frequently at the physician's discretion¹
• 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 thereafter¹

Hypersensitivity reactions¹

In the phase 3 clinical study, the use of TORISEL 25 mg IV once weekly was associated with hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, and chest pain.

• In the phase 3 study, all hypersensitivity reactions experienced by patients receiving TORISEL alone were of grade 1 or 2 severity⁶
  • 5% of patients experienced a hypersensitivity reaction(s) on the same day as dosing, despite receiving premedication with an antihistamine⁶
  • A total of 9% of patients experienced allergic or hypersensitivity reactions¹
• If a patient develops a hypersensitivity reaction, stop the infusion and observe for at least 30 to 60 minutes. At the physician’s discretion, treat with an H1 antagonist, if not previously administered, and/or an H2 antagonist. The infusion may then be resumed at a slower rate (up to 60 minutes)¹
• Hypersensitivity/infusion reactions, including flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, hypersensitivity and anaphylaxis, may occur very early in the first infusion or with subsequent infusions. Pretreat with an H1 antihistamine. TORISEL infusion should be interrupted in patients with infusion reactions and appropriate therapy given
• A benefit-risk assessment should be done prior to the continuation of TORISEL therapy in patients with severe or life-threatening reactions

Patients should be closely monitored for adverse events, and treatment of these events should be based on the physician's medical judgment and discretion considering the needs of each individual patient.

Precautions regarding hypersensitivity¹

• 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
• 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
• Pretreatment with an antihistamine is recommended with the administration of TORISEL
• Patients should be informed of the possibility of serious allergic reactions, including anaphylaxis, despite premedication with antihistamines, and to immediately report any facial swelling or difficulty breathing

If a patient develops a hypersensitivity reaction during the TORISEL infusion¹

1. Stop the infusion
2. Observe the patient for at least 30 to 60 minutes (depending on the severity of the reaction)
3. At the discretion of the physician, treatment may be resumed with the administration of one or both of the following agents approximately 30 minutes before restarting the infusion:
   • H1-receptor antagonist (such as diphenhydramine), if not previously administered
   • H2-receptor antagonist (such as IV famotidine 20 mg or IV ranitidine 50 mg)
4. The infusion may then be resumed at a slower rate (up to 60 minutes)

For more details on TORISEL safety, download the Prescribing Information.

Important Safety Information

• TORISEL is contraindicated in patients with bilirubin >1.5 x ULN and should be used with caution when treating patients with mild hepatic impairment (bilirubin >1 - 1.5 x ULN or AST > ULN but bilirubin ≤ ULN). If TORISEL must be given to patients with mild hepatic impairment, reduce the dose of TORISEL to 15 mg/week. In a phase 1 study, the overall frequency of ≥ grade 3 adverse reactions and deaths, including deaths due to progressive disease, was greater in patients with baseline bilirubin > 1.5 x ULN.
• Hypersensitivity/infusion reactions, including flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, hypersensitivity and anaphylaxis, may occur very early in the first infusion or with subsequent infusions. Pretreat with an H1 antihistamine. TORISEL infusion should be interrupted in patients with infusion reactions and appropriate therapy given.
• Serum glucose, serum cholesterol, and triglycerides should be tested before and during TORISEL treatment.
• TORISEL is likely to result in hyperglycemia and hyperlipemia. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy and/or lipid-lowering agents, respectively.
• TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections.
• Cases of interstitial lung disease, some resulting in death, have occurred. Some patients were asymptomatic or had minimal symptoms. Patients should undergo baseline radiography prior to TORISEL therapy and periodically thereafter, even in the absence of clinical respiratory symptoms. Follow patients closely and, if clinically significant respiratory symptoms develop, consider withholding TORISEL until recovery of symptoms and radiographic improvement of pneumonitis findings. Some patients required TORISEL discontinuation and/or treatment with corticosteroids and/or antibiotics.
• Cases of fatal bowel perforation occurred with TORISEL. These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen.
• Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received TORISEL.
• Due to abnormal wound healing, use TORISEL with caution in the perioperative period.
• 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.
• Live vaccinations and close contact with those who received live vaccines should be avoided.
• TORISEL may cause fetal harm. Patients and their partners should be advised to avoid pregnancy throughout treatment and for 3 months after TORISEL therapy has stopped.
• Elderly patients may be more likely to experience certain adverse reactions including diarrhea, edema and pneumonia.
• The most common (incidence ≥30%) adverse reactions observed with TORISEL are: rash (47%), asthenia (51%), mucositis (41%), nausea (37%), edema (35%), and anorexia (32%). The most common laboratory abnormalities (incidence ≥30%) are anemia (94%), hyperglycemia (89%), hyperlipemia (87%), hypertriglyceridemia (83%), elevated alkaline phosphatase (68%), elevated serum creatinine (57%), lymphopenia (53%), hypophosphatemia (49%), thrombocytopenia (40%), elevated AST (38%), and leukopenia (32%).
• Most common grades 3/4 adverse events and laboratory abnormalities included asthenia (11%), dyspnea (9%), hemoglobin decreased (20%), lymphocytes decreased (16%), glucose increased (16%), phosphorus decreased (18%), and triglycerides increased (44%).
• Pleural effusion, hemodynamically significant pericardial effusions requiring intervention, convulsions, rhabdomyolysis, Stevens-Johnson Syndrome, complex regional pain syndrome and extravasations have been reported during postmarketing use.
• Strong inducers of CYP3A4/5 (eg, dexamethasone, rifampin) and strong inhibitors of CYP3A4 (eg, ketoconazole, atazanavir) may decrease and increase concentrations of the major metabolite of TORISEL, respectively. If alternatives cannot be used, dose modifications of TORISEL are recommended.
• Avoid St. John's Wort which may decrease TORISEL plasma concentrations, and grapefruit juice which may increase plasma concentrations of the major metabolite of TORISEL.
• The combination of TORISEL and sunitinib resulted in dose-limiting toxicity (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization).

Please see the full Prescribing Information for TORISEL.