Indications
Drug is indicated for the treatment of advanced renal cell cancer.
Mechanism of Action
Drug is a kinase inhibitor that blocks the action of mTOR (mammalian target of rapamycin). mTOR plays an important role in regulating key cellular functions, such as cell proliferation, survival, movement, and angiogenesis. It is part of the P13K (phosphoinositide 3-kinase)/Akt (protein kinase) signaling pathway which is often mutated in cancer. When mTOR is blocked, this leads to cell cycle arrest in the G1 phase of the cell cycle.
Metabolism
Temsirolimus is metabolized by the P450 cytochrome system, principally by CYP3A4, forming five metabolites, including the major active metabolite sirolimus(Drug information on sirolimus). The metabolites are excreted via the feces (82% within 14 days), and via the urine to a lesser degree. The mean half-life of temsirolimus is 17.3 hours, and of sirolimus is 54.6 hours.
Drug Administration
• Assess absolute neutrophil count > 1,000 cells /mm³, platelet count > 75,000 cells/mm³
• Premedicate your patient with diphenhydramine(Drug information on diphenhydramine) 25–50 mg 30 minutes prior to temsirolimus administration.
• Drug is administered as a 25-mg dose in 250 mL 0.9% normal saline IV over 30–60 min weekly via an in-line polyethersulfone filter (≤ 5 microns) until disease progression, or unacceptable toxicity. Use non-DEHP (di(2-ethylhexyl)phthalate) bags (glass, polypropylene) and tubing (polypropylene, polyolefin).
• Dose modification: Hold drug for National Cancer
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade 3–4 toxicity until resolves to grade 2 or less; dose reduce by 5 mg/week to a dose no lower than 15 mg/week.
Patient Education
Teach patient:
• That allergic reaction may rarely occur, and to report swelling in the face, flushing, chest pain, or difficulty breathing right away during drug administration.
• To come to the emergency department right away if s/he develops pain in the abdomen or blood in the stool, which may be accompanied by diarrhea and/or fever, as bowel perforation rarely may occur.
• About the signs and symptoms of infection, and to report them right away (fever ≥ 100.5 F, colored sputum, pain on urination).
• About signs and symptoms of hyperglycemia, and to report them (polyuria, polydipsia, polyphagia).
• To report difficulty breathing at any time, as interstitial lung disease may occur rarely.
• That rarely, renal failure may occur, and that blood tests can identify and treat this problem.
• To discuss any planned surgery with their physician, as problems with wound healing may occur if surgery is performed while the patient is receiving temsirolimus.
• That routine blood tests will be done to check blood counts, blood lipid and triglyceride levels, kidney and liver function, and blood sugar.
About drug interactions:
• Possible CNS bleed if on anticoagulants: Report any change in mental status or onset of bleeding right away.
• Avoid any new over-the-counter or prescription drugs without discussing with his/her physician, nurse practitioner, or physician assistant first, as certain drugs may increase the blood levels of temsirolimus (eg, antiseizure medicines, some antidepressants, some antibiotic medicines, as well as St. John’s Wort.
• To avoid live vaccinations and contact with people who have recently been vaccinated with live vaccinations
• To use effective birth control measures during treatment and for 3 months after drug has been stopped, if of childbearing age.
Interactions
Temsirolimus has interactions with:
• Strong inducers of CYP3A4/5: dexamethasone(Drug information on dexamethasone), phenytoin, carbamazepine(Drug information on carbamazepine), rifampin, rifabutin, rifampacin, phenobarbital, St. John’s Wort. If concomitant administration is essential, consider dose increase of temsirolimus to 50 mg/week.
• Strong inhibitors of CYP3A4: ketoconazole(Drug information on ketoconazole), itraconazole(Drug information on itraconazole), clarithromycin(Drug information on clarithromycin), atazanavir(Drug information on atazanavir), indinavir(Drug information on indinavir), nefazodone(Drug information on nefazodone), nelfinavir, ritonavir(Drug information on ritonavir), saquinavir, telithromycin(Drug information on telithromycin), voriconazole(Drug information on voriconazole), grapefruit juice. If concomitant administration is essential, dose reduce temsirolimus to 12.5 mg/week.
• Sunitinib: increased risk of grade 3/4 toxicity (rash, gout/cellulitis); use together cautiously and at reduced dosage, if at all.
• Live vaccines (intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines): increased risk of infection.
• Acids, bases: degrade drug, avoid combination with drugs which can change pH.
Special Considerations
• If hypersensitivity occurs, stop drug and administer an antihistamine as ordered.
• Monitor blood sugar and lipid profiles (cholesterol, triglycerides) at baseline and during treatment, as hyperglycemia and hyperlipidemia are likely and may require treatment.
• Drug is a potent immunosuppressant. Monitor patient closely for signs/symptoms of infection.
• Monitor renal function baseline and prior to each treatment, as drug may cause renal failure rarely.
• Drug should be used cautiously in the perioperative period, as the drug is associated with abnormal wound healing.
• Drug may cause interstitial lung disease rarely. Assess for pulmonary symptoms (dyspnea, cough, hypoxia, fever) and if they occur, stop drug until ILD can be ruled out. If ILD occurs, treat with corticosteroids and/or antibiotics as ordered.
• In clinical studies with patients having primary or metastatic brain tumors, the risk for CNS bleeding was increased, especially if on an anticoagulant. Use with caution; patients with CNS tumors and/or those receiving anticoagulant therapy are at risk for CNS bleeding.
Contraindications/Precautions
None; use cautiously, if at all, in patients with hypersensitivity to sirolimus, polysorbate 80.
This series of case presentations (five individual cases) will provide oncologists and other healthcare professionals with strategies for evaluating evidence-based data on the latest treatments in metastatic breast cancer (MBC) and the application of that data into the development of individualized approaches to care, including overcoming resistance, in order to optimize management and outcomes for patients.
