Temsirolimus
Class: Antineoplastic Agents
- mTOR Inhibitors
VA Class: AN900
Chemical Name: Rapamycin, 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]
Molecular Formula: C56H87NO16
CAS Number: 162635-04-3
Brands: Torisel
Medically reviewed by Drugs.com. Last updated on Jan 22, 2021.
Introduction
Antineoplastic agent; inhibitor of mammalian target of rapamycin (mTOR) kinase.1 2 3 4 5 6 7 8 9 10 11 12
Uses for Temsirolimus
Renal Cell Carcinoma
Treatment of advanced renal cell carcinoma1 2 12 (designated an orphan drug by FDA for this use);17 considered to be a first-line therapy in poor-risk patients.2 10 13 14 20
Also has been studied in combination with interferon alfa to treat advanced renal cell carcinoma†.1 2 19 Results from a randomized study indicate overall survival benefit with temsirolimus alone compared with interferon alfa alone.1 2 Combination therapy with interferon alfa and temsirolimus also did not result in improved overall survival compared with interferon alfa alone.1 2
Temsirolimus Dosage and Administration
General
-
To minimize risk of hypersensitivity reactions, premedicate with IV diphenhydramine hydrochloride 25–50 mg (or a similar antihistamine) administered about 30 minutes before beginning temsirolimus infusion.1 2 6 12 19
Administration
Administer by IV infusion.1
IV Administration
For solution and drug compatibility information, see Compatibility under Stability.
Use infusion pump to administer.1
Use of an inline polyethersulfone filter with a pore size ≤5 μm and polyethylene-lined administration sets is recommended.1 (See Concentrate for Injection under Stability.)
Protect drug from excessive room light and sunlight during handling and preparation.1 6
Dilution
To avoid precipitation, temsirolimus for injection concentrate must be diluted in a 2-step process prior to administration.1
First dilution step: Add 1.8 mL of the nonaqueous diluent supplied by the manufacturer to vial containing 25 mg/mL of temsirolimus (total volume of 1.2 mL); the resultant solution contains approximately 10 mg/mL of the drug in a total volume of 3 mL.1 Mix well by inversion of the vial; allow sufficient time for air bubbles to subside.1
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).1 (See Concentrate for Injection under Stability.) Mix the final diluted solution by gently inverting the bag or bottle; avoid shaking to prevent excessive foaming of the solution.1 Precipitation will occur if undiluted temsirolimus for injection concentrate is added directly to an aqueous infusion solution (e.g., 0.9% sodium chloride injection).1
Rate of Administration
Infuse over 30–60 minutes.1
Dosage
Adults
Renal Cell Carcinoma
General Dosage
IV25 mg once weekly.1
Continue therapy for as long as the patient derives clinical benefit from the drug or until unacceptable toxicity occurs.1 2
Dosage adjustments should be considered when used in conjunction with potent inhibitors or inducers of CYP3A4.1 (See Interactions.)
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.1
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.1
Prescribing Limits
Adults
Renal Cell Carcinoma
IV
Doses >25 mg may increase risk of serious adverse events (e.g., thrombosis, bowel perforation, interstitial lung disease, seizure, psychosis).1
Special Populations
Hepatic Impairment
Temsirolimus is cleared predominantly by the liver.1 20 Dosage reduction or discontinuance may be warranted to reduce potential for toxicity, but no specific dosage recommendations at this time.15 (See Hepatic Impairment under Cautions.)
Renal Impairment
No specific dosage reduction recommended.1 (See Renal Impairment under Cautions.) Not studied in patients undergoing hemodialysis.1 20
Geriatric Patients
No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)
Cautions for Temsirolimus
Contraindications
-
Manufacturer states none known.1
Warnings/Precautions
Sensitivity Reactions
Hypersensitivity Reactions
Anaphylaxis, dyspnea, flushing, and chest pain reported.1
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.1
Pretreatment with an antihistamine prior to each dose of temsirolimus is recommended to prevent hypersensitivity reactions.1 2 6 Use temsirolimus with caution in patients with known hypersensitivity to antihistamines or with conditions requiring avoidance of antihistamines.1
If a hypersensitivity reaction develops, discontinue the infusion, and observe the patient for at least 30–60 minutes.1 Treatment may be resumed with administration of an H1-receptor antagonist (e.g., diphenhydramine hydrochloride), 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.1 Resume IV infusion at a slower rate (up to 60 minutes).1
Hyperglycemia/Glucose Intolerance
Hyperglycemia is likely to develop.1 May require initiation or increased dosage of insulin and/or an oral hypoglycemic agent.1 Monitor glucose levels prior to and during therapy.1
Immunosuppression
Immunosuppression may occur.1 Monitor patients for infections, including opportunistic infections.1
Instruct patient to avoid use of live vaccines and close contact with those who have received live vaccines.1
Interstitial Lung Disease
Interstitial lung disease, sometimes fatal, has occurred.1 Monitor patients for symptoms (e.g., dyspnea, cough, hypoxia, fever) and for radiographic changes.1 If suspected, discontinue temsirolimus and consider use of corticosteroids and/or antibiotics.1
Hyperlipemia
Hyperlipemia with increased triglycerides and cholesterol is likely to develop.1 May require initiation or increased dosage of a lipid-lowering agent.1 Monitor serum cholesterol and triglycerides prior to and during therapy.1
Bowel Perforation
Bowel perforations, sometimes fatal, reported.1 Promptly evaluate patients with metabolic acidosis, fever, abdominal pain, bloody stools, diarrhea, and/or acute abdomen.1
Acute Renal Failure
Acute renal failure that is rapidly progressive and sometimes fatal has occurred; was not clearly related to disease progression.1 Monitor renal function prior to and during therapy.1
Wound Healing Complications
Abnormal wound healing reported.1 Use caution in patients during the perioperative period.1
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.1
Drug and Food Interactions
Avoid concomitant use with certain drugs (e.g., potent inhibitors or inducers of CYP3A4) or foods (e.g., grapefruit juice); if alternative treatment cannot be given, adjustment of temsirolimus dosage is recommended.1 (See Interactions.)
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm.1 Animal studies indicate adverse effects on embryofetal development.1
Women should avoid becoming pregnant during and for 3 months after discontinuing temsirolimus therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1
Male patients with partners of childbearing potential also should use reliable contraception during temsirolimus treatment and for 3 months after the last dose.1
Adequate Patient Evaluation and Monitoring
Periodically monitor CBC and chemistry panels in patients receiving temsirolimus.1 In clinical trials, CBC was assessed prior to and on a weekly basis during therapy; chemistry panels were checked every 2 weeks. 1 2 These tests may be monitored more or less frequently during temsirolimus therapy at the discretion of the clinician.1
Periodically monitor glucose and lipid profiles and renal function tests.1
Specific Populations
Pregnancy
Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Lactation
Not known whether temsirolimus is distributed into milk; discontinue nursing or the drug, taking into account the importance of the drug to the woman.1
Pediatric Use
Safety and efficacy not established in pediatric patients.1
Geriatric Use
Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1
Hepatic Impairment
Safety and efficacy in patients with hepatic impairment not studied specifically to date;1 15 studies in this patient population are ongoing.15 (See Special Populations under Pharmacokinetics.)
Renal Impairment
Safety and efficacy in patients with renal impairment not studied specifically to date.1 (See Special Populations under Pharmacokinetics.)
Common Adverse Effects
Rash,1 2 6 19 asthenia,1 2 6 19 mucositis/stomatitis,1 2 6 19 nausea,1 2 6 19 edema,1 2 anorexia,1 2 19 anemia,1 2 19 hyperglycemia,1 2 hyperlipemia,1 2 hypertriglyceridemia,1 19 lymphopenia,1 increased alkaline phosphatase,1 increased serum creatinine,1 2 hypophosphatemia,1 19 thrombocytopenia,1 2 19 increased AST levels,1 2 leukopenia.1 2 19
Interactions for Temsirolimus
Both temsirolimus and its principal active metabolite, sirolimus, metabolized principally by CYP3A4.1 6 16 18 20 .1 6 16 18 Temsirolimus inhibits CYP isoenzymes 2D6 and 3A4 in vitro.1
Drugs Affecting Hepatic Microsomal Enzymes
CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma concentrations of the principal active metabolite sirolimus).1 Avoid concomitant use with potent CYP3A4 inhibitors; if no alternative is available, consider temsirolimus dosage adjustment.1 (See Specific Drugs and Foods under Interactions.)
CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma concentrations of the principal active metabolite sirolimus).1 Avoid concomitant use with potent CYP3A4 inducers; if no alternative is available, consider temsirolimus dosage adjustment.1 (See Specific Drugs and Foods under Interactions.)
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP2D6 and CYP3A4: No evidence of clinically important effects in drug interaction studies with substrates of CYP2D6; no effect anticipated on substrates of CYP3A4.1
Specific Drugs and Foods
Drug or Food |
Interaction |
Comments |
---|---|---|
ACE inhibitors |
Angioedema-type reactions observed during concomitant therapy1 |
Caution is advised |
Anticoagulants |
Increased risk of intracerebral bleeding1 |
Caution is advised1 |
Anticonvulsants (carbamazepine, phenobarbital, phenytoin) |
Increase temsirolimus dosage from 25 to 50 mg weekly; if potent CYP3A4 inducer is discontinued, resume temsirolimus dosage at previous level1 |
|
Antifungals, azoles (itraconazole, ketoconazole, voriconazole) |
Decrease temsirolimus dosage from 25 to 12.5 mg weekly; if potent CYP3A4 inhibitor is discontinued, allow interval of 1 week before resuming previous level of temsirolimus dosage1 |
|
Antimycobacterials, rifamycins (rifabutin, rifampin) |
Decreased plasma sirolimus concentrations1 |
Increase temsirolimus dosage from 25 to 50 mg weekly; if potent CYP3A4 inducer is discontinued, resume previous level of temsirolimus dosage1 |
Dexamethasone |
Increase temsirolimus dosage from 25 to 50 mg weekly; if potent CYP3A4 inducer is discontinued, resume previous level of temsirolimus dosage1 |
|
Grapefruit juice |
Increased plasma sirolimus concentrations may occur1 |
Avoid concomitant use1 |
HIV protease inhibitors (atazanavir, indinavir, nelfinavir, ritonavir, saquinavir) |
Decrease temsirolimus dosage from 25 to 12.5 mg weekly; if potent CYP3A4 inhibitor is discontinued, allow interval of 1 week before resuming previous level of temsirolimus dosage1 |
|
Macrolides (clarithromycin, telithromycin) |
Decrease temsirolimus dosage from 25 to 12.5 mg weekly; if potent CYP3A4 inhibitor is discontinued, allow interval of 1 week before resuming previous level of temsirolimus dosage1 |
|
Nefazodone |
Increased plasma sirolimus concentrations1 |
Decrease temsirolimus dosage from 25 to 12.5 mg weekly; if potent CYP3A4 inhibitor is discontinued, allow interval of 1 week before resuming previous level of temsirolimus dosage1 |
St. John's wort (Hypericum perforatum) |
Unpredictable decreases in plasma temsirolimus concentrations1 |
Avoid concomitant use 1 |
Sunitinib |
Increased risk of dose-limiting toxicity requiring hospitalization (e.g., grade 3/4 erythematous maculopapular rash, gout/cellulitis) reported with concurrent use 1 |
Temsirolimus Pharmacokinetics
Absorption
Bioavailability
100% bioavailable after IV administration.15 Peak temsirolimus blood concentration occurred at the end of the IV infusion.1 15 18 Sirolimus was evident in blood within 15 minutes after the temsirolimus infusion, and peak sirolimus blood concentration occurred at a median of 2 hours.6 18
Distribution
Extent
Extensively distributed into blood cells and peripheral tissues.1 15 Following IV administration of a single 25-mg dose, mean volume of distribution in whole blood was 172 L.1
Not known if temsirolimus or its metabolites cross the blood-brain barrier in humans.15 However, the drug and its metabolites distribute into brain tissue in rats.15
Not known whether temsirolimus is distributed into milk.1
Plasma Protein Binding
Approximately 85 and 87% at in vitro concentrations of 10 and 100 ng/mL, respectively.15 18
Elimination
Metabolism
Temsirolimus metabolized by hydrolysis to sirolimus, the principal active metabolite.1 15 16 Temsirolimus and sirolimus both also are metabolized by CYP3A4.16 18
Elimination Route
Excreted in feces (78%) and urine (5%) following IV dosing within 14 days.1
Half-life
Temsirolimus: 17.3 hours.1 15 18 Sirolimus: 54.6 hours.1 15 18
Special Populations
Metabolism in patients with hepatic dysfunction under investigation; no data currently available.1 15
Renal impairment is not expected to markedly influence drug exposure.1
Stability
Storage
Parenteral
Concentrate for Injection
2–8°C; protect from light.1 Protect from excessive room light and sunlight during handling and preparation.1 6
Temsirolimus solutions that have been diluted to 10 mg/mL (initial dilution) may be stored for ≤24 hours at room temperature.1
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.1
Polysorbate 80 (in the diluent supplied by the manufacturer) can cause leaching of diethylhexyl phthalate (DEHP) from PVC containers or administration sets.1 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.1
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
Parenteral
Solution Compatibility
Do not add temsirolimus concentrate for injection to the infusion solution without performing the first dilution step; precipitation will occur.1 (See Dilution under Dosage and Administration.)
Compatible1 |
---|
Sodium chloride 0.9% (after first dilution step) |
Drug Compatibility
Avoid addition of other drugs or nutritional agents to admixtures of temsirolimus in 0.9% sodium chloride injection; compatibility not evaluated.1
Temsirolimus concentrate for injection is unstable in the presence of acids or bases; avoid combining with agents capable of modifying pH.1
Actions
-
Inhibits mammalian target of rapamycin (mTOR) kinase.1 2 3 4 5 6 7 8 9 10 11 12
-
Although the mechanism of action has not been fully elucidated, 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).1 2 3 6 12 Proteins that regulate cell-cycle progression are suppressed, and G1phase of the cell cycle is blocked.1 2 3 8 11
-
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 .1 3 6 7 10
-
Although temsirolimus is metabolized to sirolimus, temsirolimus itself exhibits antitumor activity and is not considered a prodrug.15
-
Temsirolimus inhibited T lymphocyte activity in mice, but effects were reversible and T lymphocyte activity returned to normal within 24 hours of discontinuance.6 No consistent effect demonstrated on lymphocyte population or activation in humans.6 However, infections may result from immunosuppression.1
Advice to Patients
-
Risk of serious allergic reactions, including anaphylaxis; importance of immediately reporting any facial swelling or difficulty breathing.1
-
Risk of increased blood glucose levels; importance of reporting excessive thirst or any increase in volume or frequency of urination.1
-
Risk of increased triglyceride and/or cholesterol levels.1
-
Increased susceptibility to infection or renal failure.1
-
Risk of abnormal wound healing in the event that surgery is performed within a few weeks of therapy initiation or during therapy.1
-
Risk of interstitial lung disease, which may be fatal; importance of reporting any new or worsening respiratory symptoms.1
-
Risk of bowel perforation, which may be fatal; importance of reporting any new or worsening abdominal pain or blood in stools.1
-
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.1
-
Risk of decreased efficacy of vaccination; importance of avoiding use of live vaccines and close contact with those who have received live vaccines.1
-
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
-
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women 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.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
-
Importance of informing patients of other important precautionary information.1 (See Cautions.)
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.
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Parenteral |
For injection concentrate, for IV infusion only |
25 mg/mL (30 mg) |
Torisel (with dehydrated alcohol 39.5% w/v and propylene glycol 50.3% w/v and with diluent containing dehydrated alcohol) |
Wyeth |
AHFS DI Essentials™. © Copyright 2021, Selected Revisions February 1, 2010. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
References
1. Wyeth Pharmaceuticals Inc. Torisel (temsirolimus) injection prescribing information. Philadelphia, PA: 2008 Sep.
2. Hudes G, Carducci M, Tomczak P et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med.2007; 356:2271-81. http://www.ncbi.nlm.nih.gov/pubmed/17538086?dopt=AbstractPlus
3. Cho D, Signoretti S, Regan M et al. The role of mammalian target of rapamycin inhibitors in the treatment of advanced renal cancer. Clin Cancer Res. 2007; 13(Suppl 2):758s-63s. http://www.ncbi.nlm.nih.gov/pubmed/17255306?dopt=AbstractPlus
4. Atkins MB, Ernstoff MS, Figlin RA et al. Innovations and challenges in renal cell carcinoma: summary statement from the Second Cambridge Conference. Clin Cancer Res.2007; 13(Suppl 2):667S-70S. http://www.ncbi.nlm.nih.gov/pubmed/17255291?dopt=AbstractPlus
5. Motzer RJ, Bukowski RM. Targeted therapy for metastatic renal carcinoma. J Clin Oncol. 2006; 24:5601-8. http://www.ncbi.nlm.nih.gov/pubmed/17158546?dopt=AbstractPlus
6. Hidalgo M, Buckner JC, Erlichman C et al. A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res.2006; 12:5755-63. http://www.ncbi.nlm.nih.gov/pubmed/17020981?dopt=AbstractPlus
7. Rini BI. Molecularly targeted therapy in renal cell carcinoma: where do we go from here? Expert Rev Anticancer Ther. 2006; 6:1753-60.
8. Pouessel D, Culine S. Targeted therapies in metastatic renal cell carcinoma: the light at the end of the tunnel. Expert Rev Anticancer Ther. 2006; 6:1761-7. http://www.ncbi.nlm.nih.gov/pubmed/17181490?dopt=AbstractPlus
9. Hutson TE, Sonpavde G, Galsky MD. Targeting growth factor and antiangiogenic pathways in clear-cell renal cell carcinoma: rationale and ongoing trials. Clin Genitourin Cancer. 2006; 5(Suppl 1):31S-9S.
10. Escudier B. Advanced renal cell carcinoma: current and emerging management strategies. Drugs. 2007; 67:1257-64. http://www.ncbi.nlm.nih.gov/pubmed/17547470?dopt=AbstractPlus
11. Reddy GK, Mughal TI, Rini BI. Current data with mammalian target of rapamycin inhibitors in advanced-stage renal cell carcinoma. Clin Genitourin Cancer. 2006; 5:110-3. http://www.ncbi.nlm.nih.gov/pubmed/17026798?dopt=AbstractPlus
12. Atkins MB, Hidalgo M, Stadler WM et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol. 2004; 22:909-18. http://www.ncbi.nlm.nih.gov/pubmed/14990647?dopt=AbstractPlus
13. Halbert RJ, Figlin RA, Atkins MB et al. Treatment of patients with metastatic renal cell cancer: a RAND appropriateness panel. Cancer. 2006; 107:2375-83. http://www.ncbi.nlm.nih.gov/pubmed/17048248?dopt=AbstractPlus
14. Ozols RF, Herbst RS, Colson YL et al. Clinical cancer advances 2006: major research advances in cancer treatment, prevention, and screening–a report from the American Society of Clinical Oncology. J Clin Oncol. 2007; 25:146-62. http://www.ncbi.nlm.nih.gov/pubmed/17158528?dopt=AbstractPlus
15. Wyeth Pharmaceuticals Inc. Collegeville, PA: Personal communication. 2007 Jul 2.
16. Boni JP, Leister C, Bender G et al. Population pharmacokinetics of CCI-779: correlations to safety and pharmacogenomic responses in patients with advanced renal cancer. Clin Pharmacol Ther. 2005; 77:76-89. http://www.ncbi.nlm.nih.gov/pubmed/15637533?dopt=AbstractPlus
17. Food and Drug Administration. Orphan designations pursuant to section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97 414). Rockville, MD. From FDA web site (http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/default.htm). Accessed 2007 Jul 25.
18. Office of Clincial Pharmacology, Food and Drug Administration. Clinical pharmacology and biopharmaceutics review section of FDA approval package for temsirolimus. From the FDA website http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022088s000TOC.cfm
19. Motzer RJ, Hudes GR, Curti BD et al. Phase I/II trial of temsirolimus combined with interferon alfa for advanced renal cell carcinoma. J Clin Oncol. 2007: 25:3958-64.
20. Wyeth Pharmaceuticals Inc. Collegeville, PA: Personal communication.
21. Kato M, Chiba K, Horikawa M et al. The quantitative prediction of in vivo enzyme induction caused by drug exposure from in vitro information on human hepatocytes. Drug Metab Pharmocokinet. 2005; 20: 236-43.
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