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Temsirolimus

Pronunciation

(tem sir OH li mus)

Index Terms

  • CCI-779

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]

Brand Names: U.S.

  • Torisel

Pharmacologic Category

  • Antineoplastic Agent, mTOR Kinase Inhibitor

Pharmacology

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).

Distribution

Vdss: 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)

Contraindications

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

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

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, St John’s wort); 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.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

Hemodialysis: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

Mild hepatic impairment (bilirubin >1 to 1.5 x ULN or AST >ULN with bilirubin ≤ULN): Reduce dose to 15 mg once weekly.

Moderate-to-severe hepatic impairment (bilirubin >1.5 x ULN): Use is contraindicated.

Dosing: Adjustment for Toxicity

Hematologic toxicity: ANC <1000/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; 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.

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). 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

Infuse over 30 to 60 minutes via an infusion pump (preferred). Use polyethylene-lined non-DEHP administration tubing. 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.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Dietary Considerations

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

Compatibility

Stable in NS; do not mix with other solutions or medications. Temsirolimus is degraded by acids and bases.

Storage

Store intact vials refrigerated 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

ACE Inhibitors: Temsirolimus may enhance the adverse/toxic effect of ACE 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. Monitor therapy

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. 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

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. 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. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

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

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

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

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

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

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. 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

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. 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. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

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

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. 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

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

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Macrolide Antibiotics: 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. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin; Spiramycin. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. 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. 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. Monitor therapy

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

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. 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

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

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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. 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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. 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. Avoid combination

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

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. 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% (Limited to important or life-threatening): Acute renal failure, angioedema, cholecystitis, cholelithiasis, causalgia, 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:

• Angioneurotic edema: Has been reported; concurrent use with other drugs known to cause angioedema (eg, ACE inhibitors) may increase risk.

• 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 jiroveci 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.

• 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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

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)

Monitor for infusion reactions; infection; symptoms of ILD (or radiographic changes), symptoms of hyperglycemia (excessive thirst, polyuria); symptoms of bowel perforation

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Based on its mechanism of action, temsirolimus may cause fetal harm if administered to a pregnant woman. Women of childbearing potential should be advised to avoid pregnancy. Men and women should use effective birth control during temsirolimus treatment, and continue for 3 months after temsirolimus discontinuation.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience acne, nausea, vomiting, mouth irritation, throat irritation, mouth sores, constipation, back pain, joint pain, insomnia, dry skin, nail changes, muscle pain, nosebleed, rhinorrhea, lack of appetite, change in taste, or weight loss. Have patient report immediately to prescriber signs of infusion reaction, signs of infection, signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), signs of acidosis (confusion, fast breathing, tachycardia, abnormal heartbeat, severe abdominal pain, nausea, vomiting, fatigue, shortness of breath, or loss of strength and energy), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), severe headache, severe loss of strength and energy, abdominal pain, coughing up blood, bruising, bleeding, diarrhea, or black, tarry, or bloody stools (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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