Dosing and Administration of TORISEL

• The recommended dose of TORISEL is 25 mg IV infused over a 30-60 minute period once a week¹
• Treatment should continue until disease progression or unacceptable toxicity occurs ¹
• Patients should receive prophylactic intravenous diphenhydramine 25 to 50 mg (or similar antihistamine) approximately 30 minutes before the start of each dose of TORISEL¹

How TORISEL is supplied¹

Each carton contains 1 vial of each of the following:

• TORISEL (temsirolimus) injection, 25 mg/mL (NDC 0008-1179-01)
• DILUENT for TORISEL (temsirolimus), 1.8 mL (deliverable volume) per vial (NDC 0008-1125-01)

Storage and handling¹

• Keep vials together
• USE ONLY PROVIDED DILUENT
• Store under refrigeration (2°C-8°C; 36°F -46°F)
• Protect from light

TORISEL premedication¹

• Prophylactic premedication
  • Diphenhydramine 25-50 mg IV approximately 30 minutes before each dose of TORISEL is recommended
• Hypersensitivity reactions have been observed
  • Symptoms include, but are not limited to, anaphylaxis, dyspnea, flushing, and chest pain
  • Allergic/hypersensitivity reactions occurred in 9% of patients receiving TORISEL

TORISEL preparation and administration¹

• Recommended dose: 25 mg weekly 30-60 minute infusion, diluted in an aseptic manner
• Step 1: Inject 1.8 mL provided diluent into TORISEL vial
  • Mix by inverting vial – allow time for air bubbles to subside
  • Reconstituted vial: 30 mg in 3 mL (10 mg/mL)
    • Intentional overfill of 0.2 mL
  • 25 mg fixed dose = 2.5 mL reconstituted drug
  • Concentrate-diluent mixture is stable for 24 hours at controlled room temperature
• Step 2: Inject 2.5 mL of concentrate-diluent mixture rapidly into 250 mL 0.9% normal saline
  • Mix by inversion of the bag or bottle; avoid shaking to minimize foaming
  • Complete infusion within 6 hours of reconstitution

TORISEL administration considerations¹

• During preparation and handling, TORISEL should be protected from excessive room light and sunlight
• The sodium chloride injection container should be of non-DEHP-containing materials
  • Glass, polyolefin, polyethylene, or polypropylene
  • TORISEL concentrate contains polysorbate 80
• In-line polyethersulfone filter with pore size ≤ 5 microns
• Infusion pump is preferred method
• Inspect visually for particulate matter and discoloration prior to administration

Dosage interruption/adjustment¹

• Hold for the following:
  • Absolute neutrophil count (ANC) < 1,000/mm³
  • Platelet count < 75,000/mm³
  • NCI CTCAE* grade 3 or greater adverse reactions
• Once toxicities resolve to grade 2 or less
  • Restart with dose reduced by 5 mg/week to dose no lower than 15 mg/week

*Common Terminology Criteria for Adverse Events

Hepatic Impairment¹

• Use caution when treating patients with hepatic impairment
• If TORISEL must be given in patients with mild hepatic impairment (bilirubin >1 – 1.5 x ULN or AST > ULN but bilirubin ≤ ULN), reduce the dose of TORISEL to 15 mg/week. TORISEL is contraindicated in patients with bilirubin > 1.5 x ULN

Hypersensitivity reaction management¹

• Stop infusion
• Observe patient for 30 to 60 minutes
• At the discretion of the physician, treatment may be resumed
  • Consider administration of
    • H₁-receptor antagonist (such as diphenhydramine), if not previously administered and/or H₂-receptor antagonist (such as IV famotidine or IV ranitidine) approximately 30 minutes prior to restarting TORISEL infusion)
• Resume infusion at slower rate
• Up to 60-minute infusion

Laboratory monitoring

• In the randomized, phase 3 clinical trial, complete blood counts (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 discretion.
• 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.

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Important Safety 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 reactions manifested by symptoms, including, but not limited to anaphylaxis, dyspnea, flushing, and chest pain have been observed with TORISEL.
• Serum glucose, serum cholesterol, and triglycerides should be tested before and during treatment with TORISEL.
  • The use of 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.
• The use of 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 and others presented with symptoms. Some patients required discontinuation of TORISEL 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.
• Patients and their partners should be advised to avoid pregnancy throughout treatment and for 3 months after TORISEL therapy has stopped.
• 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%).
• 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.
• 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.
• 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.

TRS00099