Brand name: Torisel
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Feb 10, 2024. Written by ASHP.

Introduction

Antineoplastic agent; inhibitor of mammalian target of rapamycin (mTOR) kinase.

Uses for Temsirolimus

Renal Cell Carcinoma

Treatment of advanced renal cell carcinoma (RCC) ; designated an orphan drug by FDA for this use.

Overall survival benefit demonstrated with temsirolimus compared with interferon alfa monotherapy. Combination therapy with interferon alfa and temsirolimus did not result in improved overall survival compared with interferon alfa alone.

Clear-cell histology is the most common subtype of RCC. Guidelines from the American Society of Clinical Oncology (ASCO) on management of metastatic clear cell RCC do not include temsirolimus in their treatment recommendations for first-, second-, or later-line treatment.

National Cancer Institute (NCI) includes temsirolimus as one of several treatment options for first-line therapy of stage IV renal cell cancer.

Temsirolimus Dosage and Administration

General

Pretreatment Screening

• Assess patient for hypersensitivity to temsirolimus or its metabolites, polysorbate 80, or any other component in the product.

• Assess serum cholesterol and triglycerides, serum glucose, and urine protein.

• Perform baseline lung radiographic assessment by computed tomography (CT) scan or chest radiograph.

• Verify pregnancy status in females of childbearing potential.

• Assess AST and bilirubin levels prior to initiating therapy.

Patient Monitoring

• Monitor for hypersensitivity reactions throughout the infusion. Interrupt the infusion for severe reactions and administer appropriate supportive therapy.

• Monitor hematologic parameters (absolute neutrophil count [ANC] and platelets), serum cholesterol and triglycerides, serum glucose, and urine protein during treatment.

• Perform periodic radiographic assessment by lung CT scan or chest radiograph and monitor for clinical respiratory symptoms.

• Monitor for signs and symptoms of infections.

• Assess AST and bilirubin levels periodically during therapy.

Premedication and Prophylaxis

• Initiate prophylaxis with IV diphenhydramine 25–50 mg (or similar antihistamine) approximately 30 minutes prior to each dose of temsirolimus to minimize risk of hypersensitivity reactions.

Dispensing and Administration Precautions

• Handling and Disposal:Temsirolimus is a cytotoxic drug; follow applicable special handling and disposal procedures.

Administration

Administer by IV infusion.

IV Administration

Administer by IV infusion. Use of an infusion pump is recommended to ensure accurate drug delivery.

Temsirolimus injection concentrate contains polysorbate 80, which can cause leaching of diethylhexylphthalate (DEHP) from polyvinyl chloride (PVC) infusion bags and administration sets. To minimize exposure to leached DEHP, appropriate administration materials should be composed of glass, polyolefin, or polyethylene.

An in-line polyethersulfone filter with a pore size ≤5 μm should be used.

Commercially available injection must be diluted with the supplied diluent and then further diluted with 0.9% sodium chloride injection. (See Dilution under Dosage and Administration.)

Protect drug from excessive room light and sunlight during handling and preparation.

Dilution

To avoid precipitation, temsirolimus for injection concentrate must be diluted in a 2-step process prior to administration.

First dilution step: Add 1.8 mL of the nonaqueous diluent provided by the manufacturer to vial containing 25 mg/mL of temsirolimus; the resultant solution contains approximately 10 mg/mL of the drug in a total volume of 3 mL. Mix contents well via inversion of the vial and allow sufficient time for air bubbles to subside.

Second dilution step: Withdraw the appropriate dose of temsirolimus from the vial, then rapidly dilute in 250 mL of 0.9% sodium chloride injection in a suitable container (polypropylene, polyolefin, polyethylene, or glass). Mix the final diluted solution by gently inverting the bag or bottle; avoid shaking to prevent excessive foaming of the solution.

Precipitation will occur if undiluted temsirolimus injection concentrate is added directly to an aqueous infusion solution (e.g., 0.9% sodium chloride injection). Always combine commercially available injection concentrate with the manufacturer-supplied diluent before adding to infusion solutions.

Rate of Administration

Infuse over 30 to 60 minutes.

Dosage

Adults

Renal Cell Carcinoma

IV

25 mg once weekly.

Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Temporarily interrupt therapy if hematologic toxicities (e.g., ANC <1000/mm³, platelet count <75,000/mm³) or National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or greater occur.

Following resolution of toxicity to grade 2 or less, consider resuming temsirolimus at a reduced weekly dosage that is 5 mg less than the previous dosage, but not less than 15 mg weekly.

Dosage Modification for Concomitant Use with Strong CYP3A4 Inhibitors or Inducers

Avoid concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice). If concomitant use cannot be avoided, consider a dosage reduction of temsirolimus to 12.5 mg weekly. If the strong CYP3A4 inhibitor is discontinued, allow a washout period of approximately 1 week before resuming the temsirolimus dosage used prior to initiation of the strong CYP3A4 inhibitor.

Avoid concomitant use with strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampicin, phenobarbital). If concomitant use cannot be avoided, consider a dosage increase of temsirolimus from 25 mg weekly to 50 mg weekly. If the strong CYP3A4 inducer is discontinued, return to the temsirolimus dose used prior to initiation of the strong CYP3A4 inducer.

Special Populations

Hepatic Impairment

In patients with mild hepatic impairment (bilirubin >1–1.5 times ULN or AST>ULN but bilirubin ≤ULN), reduce dosage of temsirolimus to 15 mg weekly. Temsirolimus is contraindicated in patients with bilirubin >1.5 times ULN.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Temsirolimus

Contraindications

• Patients with bilirubin >1.5 times ULN.

Warnings/Precautions

Hypersensitivity/Infusion Reactions

Hypersensitivity or infusion reactions (e.g., anaphylaxis, dyspnea, flushing, hypotension, apnea, loss of consciousness, and chest pain) reported. Reactions can occur early with first infusion or with subsequent infusions.

Use with caution in patients with known hypersensitivity to temsirolimus or its metabolites (e.g., sirolimus), polysorbate 80, or any other ingredient in the formulation.

Pretreatment with an H₁antihistamine prior to each dose of temsirolimus is recommended to prevent hypersensitivity reactions. Use temsirolimus with caution in patients with known hypersensitivity to antihistamines or with conditions requiring avoidance of antihistamines.

If a hypersensitivity reaction develops, discontinue infusion and observe patient for at least 30–60 minutes. Treatment may be resumed with administration of an H₁-receptor antagonist (e.g., diphenhydramine), if not previously used, and/or with an H₂-receptor antagonist (e.g., famotidine 20 mg, ranitidine 50 mg) administered IV approximately 30 minutes before restarting the temsirolimus infusion. Resume IV infusion at a slower rate (up to 60 minutes).

Assess risk versus benefit of continuing therapy in patients who develop severe or life-threatening reactions.

Hyperglycemia/Glucose Intolerance

Hyperglycemia is likely to develop. May require initiation or increased dosage of insulin and/or an oral hypoglycemic agent.

Monitor glucose levels prior to and during therapy.

Advise patients to report excessive thirst or any increase in the volume or frequency of urination.

Infections

Immunosuppression may occur. Monitor patients for infections, including opportunistic infections.

Pneumocystis jiroveci pneumonia (PJP), including fatalities, reported and may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Consider prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents is required during temsirolimus treatment.

Interstitial Lung Disease

Interstitial lung disease, sometimes fatal, has occurred.

Monitor patients for symptoms (e.g., dyspnea, cough, hypoxia, fever) and radiographic changes.

Baseline radiographic assessment by lung CT scan or chest radiograph recommended prior to initiation of therapy and periodically perform such assessments even in the absence of clinical symptoms.

If clinically significant respiratory symptoms develop, consider withholding temsirolimus until recovery of symptoms and improvement of radiographic findings related to pneumonitis. Consider use of corticosteroids and/or antibiotics.

Hyperlipemia

Hyperlipemia with increased triglycerides and cholesterol is likely to develop. May require initiation or increased dosage of a lipid-lowering agent.

Monitor serum cholesterol and triglycerides prior to and during therapy.

Bowel Perforation

Bowel perforations, sometimes fatal, reported.

Promptly evaluate patients with metabolic acidosis, fever, abdominal pain, bloody stools, diarrhea, and/or acute abdomen.

Acute Renal Failure

Acute renal failure that is rapidly progressive and sometimes fatal has occurred; was not clearly related to disease progression.

Monitor renal function prior to and during therapy.

Wound Healing Complications

Abnormal wound healing reported. Use caution in patients during the perioperative period.

Intracerebral Hemorrhage

Increased risk of intracerebral bleeding, sometimes fatal, reported in patients with primary CNS tumors or metastases and/or in those receiving anticoagulation therapy.

Proteinuria and Nephrotic Syndrome

Proteinura, including cases of nephrotic syndrome, reported.

Monitor urine protein prior to initiation of treatment and periodically thereafter. Discontinue temsirolimus if patients develop nephrotic syndrome.

Drug Interactions

Avoid concomitant use with strong inhibitors or inducers of CYP3A4; if alternative treatment cannot be given, adjustment of temsirolimus dosage is recommended.

Concomitant use of temsirolimus and sunitinib has resulted in dose-limiting toxicity.

Immunizations and Risks Associated with Live Vaccines

Avoid use of live vaccines and close contact with those who have received live vaccines during treatment. Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on animal findings and mechanism of action.

Geriatric Patients

Older adults are more likely to experience certain adverse reactions (e.g., diarrhea, edema, pneumonia).

Specific Populations

Pregnancy

Temsirolimus may cause fetal harm. Animal studies indicate adverse effects on embryofetal development. Advise pregnant women and females of reproductive potential of the potential risk to the fetus.

Lactation

Not known whether temsirolimus is distributed into milk or the effects on the breastfed child or milk production.

Advise lactating females not to breastfeed during treatment with temsirolimus and for 3 weeks after the final dose.

Females and Males of Reproductive Potential

Can cause fetal harm when administered to pregnant females.

Females of reproductive potential should use effective birth control during and for 3 months after completion of treatment. Male patients with partners of childbearing potential also should use reliable contraception during treatment and for 3 months after the last dose.

Based on animal studies, male and female fertility may be compromised. It is not known if the results are reversible.

Pediatric Use

There is limited information on use in pediatric patients. Effectiveness in pediatric patients with advanced recurrent/refractory solid tumors has not been established.

Adverse reactions in this population were similar to adults.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. Elderly patients may be more likely to experience adverse reactions such as diarrhea, edema, and pneumonia.

Hepatic Impairment

Increased risk of toxicity observed in patients with baseline bilirubin >1.5 times ULN compared with those with bilirubin ≤1.5 times ULN.

Use caution in patients with mild hepatic impairment. Reduce dosage of temsirolimus to 15 mg weekly in patients with mild hepatic impairment (bilirubin >1–1.5 times ULN or AST>ULN but bilirubin ≤ULN). Contraindicated in patients with bilirubin >1.5 times ULN.

Assess AST and bilirubin levels before initiation and periodically thereafter to manage dosage adjustments.

Renal Impairment

Safety and efficacy in patients with renal impairment not studied specifically to date.

Common Adverse Effects

Most common adverse reactions (≥30%): rash, asthenia, mucositis, nausea, edema, anorexia.

Most common laboratory abnormalities (≥30%): anemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, elevated alkaline phosphatase, elevated serum creatinine, lymphopenia, hypophosphatemia, thrombocytopenia, elevated AST, leukopenia.

Drug Interactions

Both temsirolimus and its principal active metabolite, sirolimus, metabolized principally by CYP3A4. . Temsirolimus inhibits CYP isoenzymes 2D6 and 3A4 in vitro.

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma concentrations of the principal active metabolite sirolimus). Avoid concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice); if concomitant use cannot be avoided, consider temsirolimus dosage reduction to 12.5 mg weekly. If the strong CYP3A4 inhibitor is discontinued, allow a washout period of approximately 1 week before temsirolimus is adjusted back to the dosage used prior to initiation of the strong CYP3A4 inhibitor.

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma concentrations of the principal active metabolite sirolimus). Avoid concomitant use with strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampicin, phenobarbital); if concomitant use cannot be avoided, consider a dosage increase of temsirolimus from 25 mg weekly to 50 mg weekly. If the strong CYP3A4 inducer is discontinued, adjust temsirolimus dosage back to the dosage used prior to initiation of the strong CYP3A4 inducer.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6 and CYP3A: No evidence of clinically important effects in drug interaction studies with substrates of CYP2D6; no effect anticipated when temsirolimus is used concomitantly with substrates of CYP3A or CYP2D6.

Drugs Affecting or Affected by Transport Systems

Substrate of P-glycoprotein (P-gp). If coadministered with drugs that inhibit P-gp, increased concentrations of temsirolimus are likely; caution advised.

Inhibitor of P-gp. If coadministered with P-gp substrates, increased concentrations of the substrate drug are likely; caution advised.

Specific Drugs and Foods

Temsirolimus Pharmacokinetics

Absorption

Bioavailability

100% bioavailable after IV administration. Peak temsirolimus blood concentration occurred at the end of the IV infusion. Sirolimus was evident in blood within 15 minutes after the temsirolimus infusion, and peak sirolimus blood concentration occurred at a median of 2 hours.

Distribution

Extent

Extensively distributed into blood cells and peripheral tissues.

Plasma Protein Binding

Approximately 85 and 87% at in vitro concentrations of 10 and 100 ng/mL, respectively.

Elimination

Metabolism

Temsirolimus metabolized by hydrolysis to sirolimus, the principal active metabolite. Temsirolimus and sirolimus both also are metabolized by CYP3A4.

Elimination Route

Excreted in feces (78%) and urine (5%) following IV dosing within 14 days.

Half-life

Temsirolimus: 17.3 hours. Sirolimus: 54.6 hours.

Stability

Storage

Parenteral

Concentrate for Injection

2–8°C; protect from light. Protect from excessive room light and sunlight during handling and preparation.

Temsirolimus solutions that have been diluted to 10 mg/mL (initial dilution) may be stored for ≤24 hours at room temperature (<25°C).

The final diluted solution of temsirolimus (i.e., after the second dilution) for infusion should be administered ≤6 hours from the time that the diluted temsirolimus mixture is added to the sodium chloride injection.

Polysorbate 80 (in the diluent supplied by the manufacturer) can cause leaching of diethylhexyl phthalate (DEHP) from PVC containers or administration sets. Store the final temsirolimus diluted solution (i.e., after the second dilution) in glass or polypropylene bottles or in plastic (polypropylene or polyolefin) bags and administer through polyethylene-lined administration sets.

Actions

• Inhibits mammalian target of rapamycin (mTOR) kinase.

• Temsirolimus binds to the intracellular protein FK506 binding protein-12, forming a drug-protein complex that inhibits activation of mTOR signaling (which regulates cell division). Proteins that regulate cell-cycle progression are suppressed, and G₁phase of the cell cycle is blocked.

• Temsirolimus also reduces expression of hypoxia inducible factor 1α and 2α (HIF-1α and HIF-1β) in vitro, resulting in reduced expression of vascular endothelial growth factor (VEGF) and a potential antiangiogenic effect .

• Although temsirolimus is metabolized to sirolimus, temsirolimus itself exhibits antitumor activity and is not considered a prodrug.

• Temsirolimus inhibited T lymphocyte activity in mice, but effects were reversible and T lymphocyte activity returned to normal within 24 hours of discontinuance. No consistent effect demonstrated on lymphocyte population or activation in humans. However, infections may result from immunosuppression.

Advice to Patients

• Advise patients of the risk of serious allergic reactions, including anaphylaxis; importance of immediately reporting any facial swelling or difficulty breathing.

• Advise patients of the risk of increased blood glucose levels. Instruct them of the need for initiation of, or increase in dosage of insulin or hypoglycemic therapy. Inform patients to contact their healthcare provider to report excessive thirst or any increase in volume or frequency of urination.

• Advise patients of the risk of increased susceptibility to infection. Inform patients to report signs and symptoms of infection.

• Advise patients of the risk of interstitial lung disease, which may be fatal; importance of reporting any new or worsening respiratory symptoms.

• Advise patients of the risk of increased triglyceride and/or cholesterol levels and the need to monitor periodically.

• Advise patients of the risk of bowel perforation, which may be fatal; importance of reporting any new or worsening abdominal pain or blood in stools.

• Advise patients of the risk of renal failure unrelated to disease progression.

• Advise patients of the risk of abnormal wound healing in the event that surgery is performed within a few weeks of therapy initiation or during therapy.

• Importance of advising patients with CNS tumors and/or receiving anticoagulant therapy of the potential for increased risk of intracerebral bleeding, which may be fatal.

• Inform patients of the risk of proteinuria and nephrotic syndrome.

• Advise patients that vaccinations may be less effective during treatment with temsirolimus. Avoid the use of live vaccines and close contact with those who have received live vaccines while receiving temsirolimus.

• Advise patient to inform their healthcare provider if they are or plan to become pregnant. Advise females of childbearing potential and men with partners of childbearing potential to avoid pregnancy and to use effective contraceptive methods during therapy and for 3 months following discontinuance of therapy.

• Advise women not to breastfeed during treatment with temsirolimus and for 3 weeks after the final dose.

• Advise male and female patients that fertility may be compromised.

• Advise geriatric patients that they may be more likely to experience adverse reactions.

• Advise patients to inform their healthcare provider about all concomitant medications, including prescription medicine, over the counter drugs, vitamins, and herbal products.

• Advise patients of other important precautionary information.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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