Temsirolimus

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Torisel: 25 mg/mL (1 mL) [contains alcohol, usp, polyethylene glycol, polysorbate 80, propylene glycol]

Generic: 25 mg/mL (1 mL)

Pharmacology

Mechanism of Action

Temsirolimus and its active metabolite, sirolimus, are targeted inhibitors of mTOR (mechanistic target of rapamycin) kinase activity. Temsirolimus (and sirolimus) bind to FKBP-12, an intracellular protein, to form a complex which inhibits mTOR signaling, halting the cell cycle at the G1 phase in tumor cells. Inhibition of mTOR blocks downstream phosphorylation of p70S6k and S6 ribosomal proteins. In renal cell carcinoma, mTOR inhibition also exhibits anti-angiogenesis activity by reducing levels of HIF-1 and HIF-2 alpha (hypoxia inducible factors) and vascular endothelial growth factor (VEGF).

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: 172 L

Metabolism

Hepatic; via CYP3A4 to sirolimus (primary active metabolite) and 4 minor metabolites

Excretion

Feces (78%); urine (<5%)

Time to Peak

Temsirolimus: At end of infusion; Sirolimus: 0.5 to 2 hours after temsirolimus infusion

Half-Life Elimination

Temsirolimus: ~17 hours; Sirolimus: ~55 hours

Use: Labeled Indications

Renal cell carcinoma, advanced: Treatment of advanced renal cell carcinoma (RCC)

Use: Off Label

Endometrial cancer (locally advanced, recurrent, and/or metastatic)b

Data from a small phase II study supports the use of temsirolimus in the treatment of locally advanced, recurrent, and/or metastatic endometrial cancer which is considered incurable by standard therapies Oza 2011. Additional trials may be necessary to further define the role of temsirolimus in this condition.

Contraindications

Bilirubin >1.5 times the upper limit of normal (ULN)

Canadian labeling: Additional contraindications (not in the US labeling): History of anaphylaxis after exposure to temsirolimus, sirolimus, or any component of the formulation

Dosage and Administration

Dosing: Adult

Note: For infusion reaction prophylaxis, premedicate with an H₁ antagonist (eg, diphenhydramine 25 to 50 mg IV) ~30 minutes prior to infusion.

Renal cell cancer (RCC), advanced: IV: 25 mg once weekly; continue until disease progression or unacceptable toxicity

Dosage adjustment for concomitant CYP3A4 inhibitors/inducers:

CYP3A4 inhibitors: Avoid concomitant administration with strong CYP3A4 inhibitors (eg, clarithromycin, itraconazole, ketoconazole, nefazodone, protease inhibitors, telithromycin, voriconazole); if concomitant administration with a strong CYP3A4 inhibitor cannot be avoided, consider a dose reduction to 12.5 mg once weekly. When a strong CYP3A4 inhibitor is discontinued; allow ~1 week to elapse prior to adjusting the temsirolimus upward to the dose used prior to initiation of the CYP3A4 inhibitor.

CYP3A4 inducers: Avoid concomitant administration with strong CYP3A4 inducers (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin); if concomitant administration with a strong CYP3A4 inducer cannot be avoided, consider adjusting temsirolimus dose up to 50 mg once weekly. If the strong CYP3A4 enzyme inducer is discontinued, reduce the temsirolimus to the dose used prior to initiation of the CYP3A4 inducer.

Endometrial cancer (locally advanced, recurrent, and/or metastatic) (off-label use): IV: 25 mg once weekly; continue until disease progression or unacceptable toxicity (Oza 2011).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Hematologic toxicity: ANC <1,000/mm³ or platelets <75,000/mm³: Withhold treatment until resolves and reinitiate treatment with the dose reduced by 5 mg weekly; minimum dose: 15 mg weekly if adjustment for toxicity is needed.

Nonhematologic toxicity: Any toxicity ≥grade 3: Withhold treatment until resolves to ≤grade 2; reinitiate treatment with the dose reduced by 5 mg weekly; minimum dose: 15 mg weekly if adjustment for toxicity is needed.

Infusion/hypersensitivity reaction: Interrupt infusion and observe for 30 to 60 minutes (depending on the severity); treatment may be resumed with discretion at a slower infusion rate (up to 60 minutes); administer an H₁ antagonist (if not given as premedication) and/or an IV H₂ antagonist ~30 minutes prior to resuming infusion.

Interstitial lung disease: Consider withholding treatment for clinically significant respiratory symptoms until after recovery of symptoms or radiographic improvement.

Nephrotic syndrome: Discontinue treatment.

Reconstitution

Preparation requires a two-step dilution process (do not add undiluted temsirolimus to aqueous solution; addition to aqueous solution prior to step 1 will result in precipitation). Step 1: Total amount in undiluted vial is 30 mg/1.2 mL (25 mg/mL concentration); contains overfill. Vials should initially be diluted with 1.8 mL of provided diluent to a concentration of 10 mg/mL. Once diluted with provided diluent, mix by inverting vial. Step 2: After allowing air bubbles to subside, the intended dose should be withdrawn from the 10 mg/mL diluted vial (ie, 2.5 mL for a 25 mg dose) and further diluted in 250 mL of NS in a non-DEHP/non-PVC container (glass, polyolefin, or polypropylene). Mix by inverting bottle or bag; avoid excessive shaking (may result in foaming).

Administration

IV: Infuse over 30 to 60 minutes via an infusion pump (preferred). Use polyethylene-lined non-DEHP, non-PVC administration tubing (if PVC-containing administration set must be used, it should not contain DEHP). Administer through an inline polyethersulfone filter ≤5 micron; if set does not contain an inline filter, a polyethersulfone end filter (0.2 to 5 micron) should be added (do not use both an inline and an end filter).

Premedicate with an H₁ antagonist (eg, diphenhydramine 25 to 50 mg IV) ~30 minutes prior to infusion. Monitor during infusion; interrupt infusion for hypersensitivity/infusion reaction; monitor for 30 to 60 minutes; may reinitiate at a reduced infusion rate (over 60 minutes) with discretion, 30 minutes after administration of a histamine H₁ antagonist and/or a histamine H₂ antagonist (eg, famotidine or ranitidine). Administration should be completed within 6 hours of admixture.

Dietary Considerations

Avoid grapefruit juice (may increase the levels of the major metabolite, sirolimus).

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F). Diluted solution in the vial (10 mg/mL) is stable for 24 hours at room temperature (below 25°C [77°F]). Solutions diluted for infusion (in NS) must be infused within 6 hours of preparation. Protect from light during storage, preparation, and handling.

Drug Interactions

Angiotensin-Converting Enzyme Inhibitors: Temsirolimus may enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CarBAMazepine: May decrease the serum concentration of Temsirolimus. Concentrations of the active metabolite, sirolimus, are also likely to be decreased (and maybe to an even greater degree). Management: Temsirolimus prescribing information recommends against coadministration with strong CYP3A4 inducers such as carbamazepine; however, if concurrent therapy is necessary, an increase in temsirolimus adult dose to 50 mg/week should be considered. Consider therapy modification

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CycloSPORINE (Systemic): Temsirolimus may enhance the adverse/toxic effect of CycloSPORINE (Systemic). An increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) has been described with concomitant sirolimus use. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Temsirolimus. Management: Consider increasing the dose of temsirolimus to 50 mg IV/week (from 25 mg IV/week) if a concomitant CYP3A4 strong inducer is necessary. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Temsirolimus. Management: Avoid concomitant use of temsirolimus and strong CYP3A4 inhibitors whenever possible. If combined, decrease temsirolimus dose to 12.5 mg per week and monitor patients for increased temsirolimus effects and toxicities. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

DexAMETHasone (Systemic): May decrease serum concentrations of the active metabolite(s) of Temsirolimus. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fluconazole: May increase serum concentrations of the active metabolite(s) of Temsirolimus. Management: Consider temsirolimus dose reductions or alternatives to fluconazole. Monitor sirolimus concentrations in all patients receiving fluconazole or any systemic azole antifungal. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosphenytoin: May decrease the serum concentration of Temsirolimus. Concentrations of the active metabolite, sirolimus, are also likely to be decreased (and maybe to an even greater degree). Management: Temsirolimus prescribing information recommends against coadministration with strong CYP3A4 inducers such as phenytoin; however, if concurrent therapy is necessary, an increase in temsirolimus adult dose to 50 mg/week should be considered. Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Grapefruit Juice: May increase the serum concentration of Temsirolimus. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Itraconazole: May increase serum concentrations of the active metabolite(s) of Temsirolimus. Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ketoconazole (Systemic): May increase serum concentrations of the active metabolite(s) of Temsirolimus. Management: Temsirolimus dose adjustments will likely be needed when starting/stopping/changing ketoconazole. Clinical data suggest temsirolimus (adult) dose reductions of around 50% should be considered, but specific guidelines are lacking. Consider therapy modification

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Phenytoin: May decrease the serum concentration of Temsirolimus. Concentrations of the active metabolite, sirolimus, are also likely to be decreased (and maybe to an even greater degree). Management: Temsirolimus prescribing information recommends against coadministration with strong CYP3A4 inducers such as phenytoin; however, if concurrent therapy is necessary, an increase in temsirolimus adult dose to 50 mg/week should be considered. Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Posaconazole: May increase serum concentrations of the active metabolite(s) of Temsirolimus. Management: Consider temsirolimus dose reductions or alternatives to posaconazole. Monitor sirolimus concentrations in all patients receiving posaconazole or any systemic azole antifungal. Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Protease Inhibitors: May enhance the adverse/toxic effect of Temsirolimus. Levels of sirolimus, the active metabolite, may be increased, likely due to inhibition of CYP-mediated metabolism. Consider therapy modification

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of Temsirolimus. Rifamycins will likely cause an even greater decrease in the concentration of the active metabolite sirolimus. Management: Temsirolimus prescribing information recommends against coadministration with strong CYP3A4 inducers such as rifampin; however, if concurrent therapy is necessary, an increase in temsirolimus adult dose to 50 mg/week should be considered. Consider therapy modification

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

SUNItinib: Temsirolimus may enhance the adverse/toxic effect of SUNItinib. Avoid combination

Tacrolimus (Systemic): May enhance the adverse/toxic effect of Temsirolimus. Temsirolimus may enhance the adverse/toxic effect of Tacrolimus (Systemic). Temsirolimus may decrease the serum concentration of Tacrolimus (Systemic). Avoid combination

Tacrolimus (Topical): May enhance the adverse/toxic effect of Temsirolimus. Temsirolimus may enhance the adverse/toxic effect of Tacrolimus (Topical). Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Edema (35%), chest pain (16%)

Central nervous system: Pain (28%), headache (15%), insomnia (12%)

Dermatologic: Skin rash (47%), pruritus (19%), nail disease (14%), xeroderma (11%)

Endocrine & metabolic: Increased serum glucose (89%; grades 3/4: 16%), increased serum cholesterol (87%; grades 3/4: 2%), hypertriglyceridemia (83%; grades 3/4: 44%), hypophosphatemia (49%; grades 3/4: 18%), hyperglycemia (26%), hyperlipidemia (≥30%), hypokalemia (21%; grades 3/4: 5%), weight loss (19%)

Gastrointestinal: Mucositis (41%), nausea (37%), anorexia (32%), diarrhea (27%), abdominal pain (21%; grades 3/4: 4%), constipation (20%), dysgeusia (20%), stomatitis (20%), vomiting (19%)

Genitourinary: Urinary tract infection (15%)

Hematologic & oncologic: Decreased hemoglobin (94%; grades 3/4: 20%), lymphocytopenia (53%; grades 3/4: 16%), thrombocytopenia (40%; grades 3/4: 1%; dose-limiting toxicity), decreased white blood cell count (32%; grades 3/4: 1%), anemia (≥30%), decreased neutrophils (19%; grades 3/4: 5%)

Hepatic: Increased serum alkaline phosphatase (68%; grades 3/4: 3%), increased serum AST (38%; grades 3/4: 2%)

Infection: Infection (20%; grades 3/4: 3%; includes abscess, bronchitis, cellulitis, herpes simplex, herpes zoster)

Neuromuscular & skeletal: Weakness (51%), back pain (20%), arthralgia (18%)

Renal: Increased serum creatinine (57%; grades 3/4: 3%)

Respiratory: Dyspnea (28%), cough (26%), epistaxis (12%), pharyngitis (12%)

Miscellaneous: Fever (24%; grades 3/4: 1%)

1% to 10%:

Cardiovascular: Hypertension (7%), venous thromboembolism (2%; includes deep vein thrombosis and pulmonary embolism), pericardial effusion (1%), thrombophlebitis (1%)

Central nervous system: Chills (8%), depression (4%), convulsions (1%)

Dermatologic: Acne vulgaris (10%)

Endocrine & metabolic: Diabetes mellitus (5%)

Gastrointestinal: Gastrointestinal hemorrhage (1%)

Hematologic & oncologic: Rectal hemorrhage (1%)

Hepatic: Hyperbilirubinemia (8%)

Infection: Sepsis (1%), wound infection (1%)

Neuromuscular & skeletal: Myalgia (8%)

Ophthalmic: Conjunctivitis (8%; including lacrimation disorder)

Respiratory: Rhinitis (10%), pneumonia (8%), upper respiratory tract infection (7%), pleural effusion (4%)

Miscellaneous: Wound healing impairment (1%)

<1%, postmarketing, and/or case reports: Acute renal failure, angioedema, causalgia, cholecystitis, cholelithiasis, decreased glucose tolerance, extravasation reactions (with pain, swelling, warmth, erythema), hypersensitivity reaction, interstitial pulmonary disease, intestinal perforation, pancreatitis, pneumonitis, rhabdomyolysis, seizure, Stevens-Johnson syndrome

Warnings/Precautions

Concerns related to adverse effects:

• Angioedema: Angioedema has been reported in patients taking mTOR inhibitors in combination with ramipril and/or amlodipine; monitor for signs/symptoms of angioedema in patients receiving temsirolimus concurrently with ACE inhibitors or calcium channel blockers.
• Bone marrow suppression: Anemia, neutropenia, thrombocytopenia, and lymphocytopenia may commonly occur; grades 3 and 4 hematologic toxicity have been observed.
• Bowel perforation: Cases of bowel perforation (fatal) have occurred, usually presenting with abdominal pain, bloody stools, diarrhea, fever, or metabolic acidosis; promptly evaluate any new or worsening abdominal pain or bloody stools.
• Hyperglycemia: Increases in serum glucose commonly occur during treatment. Initiation or alteration of insulin and/or oral hypoglycemic therapy may be required. Monitor serum glucose before and during treatment. Use with caution in patients with diabetes.
• Hyperlipidemia: Use with caution in patients with hyperlipidemia; may increase serum lipids (cholesterol and triglycerides). Initiation or dosage adjustment of antihyperlipidemic agents may be required. Monitor cholesterol/triglyceride panel at baseline and periodically during treatment.
• Hypersensitivity/infusion reactions: Hypersensitivity/infusion reactions (eg, anaphylaxis, apnea, dyspnea, flushing, loss of consciousness, hypotension, and/or chest pain) have been reported. Infusion reaction may occur during the initial infusion (early in the infusion) or with subsequent infusions. Premedicate with an antihistamine (H₁ antagonist) prior to infusion (use with caution in patients unable to receive antihistamine premedication); monitor throughout infusion (appropriate supportive care should be available); interrupt infusion for hypersensitivity reaction and observe patient for 30 to 60 minutes. With discretion, treatment may be resumed at a slower infusion rate; administer an H₁ antagonist (if not given as premedication) and/or an IV H₂ antagonist (eg, famotidine or ranitidine) ~30 minutes prior to resuming infusion. For severe infusion reactions, assess risk versus benefit of continued treatment. Use with caution in patients with hypersensitivity to temsirolimus, sirolimus (a metabolite), or polysorbate 80.
• Infection: Treatment may result in immunosuppression, may increase risk of opportunistic infections and/or sepsis. Pneumocystis jirovecii pneumonia (PCP) has been reported; some cases were fatal. Development of PCP may be associated with the use of concomitant corticosteroids or other immunosuppressive agents; consider PCP prophylaxis in patients receiving concomitant immunosuppressive or corticosteroid therapy.
• Proteinuria: Proteinuria, including nephrotic syndrome, is associated with temsirolimus. Monitor for proteinuria at baseline and periodically throughout therapy; discontinue use if nephrotic syndrome occurs.
• Pulmonary toxicity: Interstitial lung disease (ILD), sometimes fatal, has been reported; symptoms include dyspnea, cough, hypoxia and/or fever, although asymptomatic or mild cases may present; promptly evaluate worsening respiratory symptoms. If symptoms develop, consider withholding temsirolimus until symptom recovery and radiographic improvement occur. Consider empiric treatment with corticosteroids and/or antibiotic therapy. Baseline chest radiographic assessment (CT scan or x-ray) is recommended; follow periodically, even in the absence of clinical pulmonary symptoms.
• Renal failure: Acute renal failure with rapid progression (unrelated to disease progression) has been reported, including cases unresponsive to dialysis. An increased incidence of rash, infection and dose interruptions have been reported in patients with renal insufficiency (CrCl ≤60 mL/minute) who received mTOR inhibitors for the treatment of renal cell cancer (Gupta, 2011).
• Wound healing: May be associated with impaired wound healing; use caution in the perioperative period.

Disease-related concerns:

• CNS metastases/tumors: May be at increased risk for developing intracerebral bleeding (may be fatal).
• Hepatic impairment: Use with caution and reduce the dose in patients with mild hepatic impairment (bilirubin >1 to 1.5 x ULN or AST >ULN with bilirubin ≤ULN). Use is contraindicated in patients with moderate-to-severe hepatic impairment (bilirubin >1.5 x ULN). Temsirolimus is predominantly cleared by the liver. Toxicities were increased in patients with baseline bilirubin >1.5 x ULN.

Concurrent drug therapy issues:

• Anticoagulants: Patients who are receiving anticoagulant therapy may be at increased risk for developing intracerebral bleeding (may be fatal).
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Avoid concomitant use with strong CYP3A4 inhibitors and strong CYP3A4 inducers; consider alternative agents that avoid or lessen the potential for CYP-mediated interactions.
• Sunitinib: Combination therapy with temsirolimus and sunitinib has resulted in dose-limiting toxicities, including grade 3 or 4 rash, gout, and/or cellulitis.

Special populations:

• Elderly: Elderly patients may be more likely to experience adverse reactions, including diarrhea, edema, and pneumonia.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer's labeling.

Other warnings/precautions:

• Immunizations: Patients should not be immunized with live viral vaccines during or shortly after treatment and should avoid close contact with recently vaccinated (live vaccine) individuals.

Monitoring Parameters

CBC with differential and platelets (weekly), serum chemistries including glucose (baseline and every other week), serum cholesterol and triglycerides (baseline and periodic), liver function (baseline and periodic), renal function tests (baseline and periodic), urine protein (baseline and periodic)

Monitor for infusion reactions; signs/symptoms of infection, interstitial lung disease (or radiographic changes), hyperglycemia (excessive thirst, polyuria), bowel perforation, nephrotic syndrome, angioedema (if receiving ACE inhibitors or calcium channel blockers)

Pregnancy

Pregnancy Considerations

Based on findings in animal reproduction studies and on the mechanism of action, temsirolimus may cause fetal harm if administered to a pregnant woman. Females of reproductive potential should be advised to avoid pregnancy and use effective contraception during treatment and for 3 months after the last temsirolimus dose. Male patients with female partners of reproductive potential should also use effective birth control during treatment and for 3 months after the last temsirolimus dose.

Patient Education

What is this drug used for?

• It is used to treat kidney cancer.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Acne
• Nausea
• Vomiting
• Mouth irritation
• Throat irritation
• Mouth sores
• Constipation
• Back pain
• Joint pain
• Trouble sleeping
• Dry skin
• Nail changes
• Muscle pain
• Nosebleed
• Runny nose
• Lack of appetite
• Change in taste
• Weight loss

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infusion reaction
• Infection
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit
• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood
• Acidosis like confusion, fast breathing, fast heartbeat, abnormal heartbeat, severe abdominal pain, nausea, vomiting, fatigue, shortness of breath, or loss of strength and energy
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Severe pulmonary disorder like lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse
• Severe headache
• Severe dizziness
• Passing out
• Vision changes
• Severe loss of strength and energy
• Abdominal pain
• Bruising
• Bleeding
• Diarrhea
• Swelling
• Black, tarry, or bloody stools
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.