Usage
- Temsirolimus is prescribed for the treatment of advanced renal cell carcinoma (RCC), a type of kidney cancer. It is also used in some cases for other cancers like mantle cell lymphoma (MCL).
- Pharmacological classification: Temsirolimus is an antineoplastic agent, specifically a kinase inhibitor targeting the mammalian target of rapamycin (mTOR).
- Mechanism of Action: Temsirolimus inhibits mTOR, a key protein kinase regulating cell growth, proliferation, and angiogenesis. By blocking mTOR, temsirolimus disrupts crucial cellular processes necessary for cancer cell survival and tumor growth.
Alternate Names
- International Nonproprietary Name (INN): temsirolimus.
- Brand Name: Torisel.
How It Works
- Pharmacodynamics: Temsirolimus binds to an intracellular protein (FKBP-12), forming a complex that inhibits mTOR. This leads to downstream effects, suppressing cell growth, proliferation, and angiogenesis, ultimately reducing tumor size and progression.
- Pharmacokinetics:
- Absorption: Administered intravenously, achieving peak plasma concentration at the end of infusion.
- Metabolism: Primarily metabolized by CYP3A4 in the liver to sirolimus, its major active metabolite. Temsirolimus also inhibits CYP3A4/5 and CYP2D6.
- Elimination: Predominantly eliminated via feces (78%), with minor renal excretion (4.6%).
Dosage
Standard Dosage
Adults:
- Renal Cell Carcinoma: 25 mg IV infusion once weekly over 30-60 minutes. Continue treatment until disease progression or unacceptable toxicity. Premedication with an antihistamine like diphenhydramine (25-50mg IV) is recommended 30 minutes prior to each infusion to minimize the risk of hypersensitivity reactions.
- Mantle Cell Lymphoma: 175 mg IV infusion once weekly for 3 weeks, followed by 75 mg IV infusion weekly.
Children:
- Efficacy and safety not fully established. Limited data suggests 75 mg/m² weekly IV infusion has shown some efficacy in certain childhood cancers like neuroblastoma and rhabdomyosarcoma, but further research is needed.
Special Cases:
- Elderly Patients: No dose adjustment is typically necessary, but they might be more susceptible to certain side effects like edema, diarrhea, and pneumonia.
- Patients with Renal Impairment: No dose adjustment is usually needed. Caution is advised in severe renal impairment.
- Patients with Hepatic Dysfunction:
- Mild to moderate hepatic impairment (RCC): Reduce dose to 15 mg weekly.
- Severe hepatic impairment (RCC): Reduce dose to 10 mg weekly.
- Mild hepatic impairment (MCL): No dose adjustment.
- Moderate to severe hepatic impairment (MCL): Contraindicated.
- Patients with Comorbid Conditions: Close monitoring and dose adjustments may be necessary for patients with diabetes, hyperlipidemia, and other relevant conditions.
Clinical Use Cases
Temsirolimus is primarily used in oncology settings and has no established role in scenarios like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Dose adjustments are primarily based on hepatic function, adverse effects, and drug interactions. Dose reduction is necessary when co-administered with strong CYP3A4 inhibitors. If strong CYP3A4 inducers are used, a higher dose of Temsirolimus might be required.
Side Effects
Common Side Effects:
- Anemia, hyperglycemia, hyperlipidemia, infections, fatigue, rash, mucositis (mouth sores), edema, diarrhea, nausea, vomiting, constipation, headache, insomnia, dyspnea.
Rare but Serious Side Effects:
- Hypersensitivity/infusion reactions (including anaphylaxis), interstitial lung disease, bowel perforation, renal failure, pancreatitis, cholecystitis, cholelithiasis, Stevens-Johnson syndrome, rhabdomyolysis, angioedema.
Long-Term Effects:
- Impaired fertility, secondary malignancies (due to immunosuppression), metabolic abnormalities.
Adverse Drug Reactions (ADR):
- Anaphylaxis, severe infections, acute renal failure, interstitial lung disease exacerbations, bowel perforation, severe hyperglycemia/hyperlipidemia.
Contraindications
- Bilirubin > 1.5 x ULN.
- Hypersensitivity to temsirolimus, sirolimus, or polysorbate 80.
- Moderate to severe hepatic impairment for MCL patients.
Drug Interactions
- CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin): Increase temsirolimus levels. Avoid concomitant use or reduce temsirolimus dose.
- CYP3A4 inducers (e.g., rifampin, phenytoin, St. John’s Wort): Decrease temsirolimus levels. Avoid concomitant use or adjust dose.
- Immunosuppressants (e.g., cyclosporine, tacrolimus): Increase risk of infection. Close monitoring is warranted.
- Live vaccines: Avoid concomitant use due to increased risk of infection.
- Anticoagulants: May increase bleeding risk.
- Grapefruit juice: May increase temsirolimus levels. Avoid consumption.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Temsirolimus can cause fetal harm and should be avoided during pregnancy. Effective contraception should be used by both male and female patients during treatment and for 3 months after the last dose.
- Breastfeeding: Temsirolimus may be excreted in breast milk and can potentially cause harm to nursing infants. Breastfeeding should be avoided during treatment and for 3 weeks after the last dose.
Drug Profile Summary
- Mechanism of Action: mTOR inhibitor, suppressing cell growth, proliferation, and angiogenesis.
- Side Effects: Anemia, hyperglycemia, infections, fatigue, rash, mucositis, edema. Serious side effects include hypersensitivity reactions, interstitial lung disease, and renal failure.
- Contraindications: Bilirubin >1.5 x ULN, hypersensitivity to temsirolimus or sirolimus.
- Drug Interactions: CYP3A4 inhibitors/inducers, immunosuppressants, live vaccines.
- Pregnancy & Breastfeeding: Avoid use during pregnancy and breastfeeding.
- Dosage: 25 mg IV weekly for RCC; 175mg IV weekly for 3 weeks followed by 75 mg IV weekly for MCL.
- Monitoring Parameters: Blood counts, glucose and lipid profiles, renal and liver function tests, signs of infection, respiratory symptoms.
Popular Combinations
- No established “popular combinations” for routine use. Combination regimens are often specific to certain cancers and clinical trials.
Precautions
- Pre-screening for hepatic and renal function, hypersensitivity to temsirolimus or sirolimus. Monitor for infections, hyperglycemia, hyperlipidemia, respiratory symptoms.
- Pregnant Women: Avoid use.
- Breastfeeding Mothers: Avoid use.
- Children & Elderly: Monitor closely for side effects.
- Lifestyle Considerations: Avoid grapefruit juice. Caution with alcohol consumption.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Temsirolimus?
A: For advanced RCC, the standard dose is 25 mg IV once weekly. For MCL, the recommended regimen is 175 mg IV weekly for 3 weeks, followed by 75 mg IV weekly.
Q2: What are the most common side effects of Temsirolimus?
A: Common side effects include anemia, hyperglycemia, hyperlipidemia, infections, fatigue, rash, and mouth sores.
A: Primarily metabolized by CYP3A4 in the liver to sirolimus, its major active metabolite.
Q4: What are the contraindications for using Temsirolimus?
A: Contraindications include bilirubin > 1.5 x ULN and hypersensitivity to temsirolimus, sirolimus, or polysorbate 80.
Q5: Can Temsirolimus be used in patients with renal impairment?
A: Generally, no dose adjustment is needed for renal impairment, but caution should be exercised in severe cases.
Q6: What are the potential drug interactions with Temsirolimus?
A: Clinically significant interactions can occur with CYP3A4 inhibitors/inducers, immunosuppressants, and live vaccines.
Q7: Can Temsirolimus be used during pregnancy or breastfeeding?
A: Temsirolimus can cause fetal harm and should be avoided during pregnancy and breastfeeding.
Q8: What are the key monitoring parameters for patients on Temsirolimus?
A: Monitor blood counts, glucose and lipid levels, renal and liver function, signs of infection, and respiratory symptoms.
Q9: How should hypersensitivity reactions to Temsirolimus be managed?
A: Stop the infusion immediately and administer an antihistamine. The infusion may be restarted at a slower rate at the physician’s discretion.
