Usage
Everolimus is prescribed for various medical conditions, including:
- Advanced renal cell carcinoma (RCC): After treatment with sunitinib or sorafenib has failed.
- Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS): In patients requiring therapeutic intervention but not suitable for curative surgical resection.
- Advanced hormone receptor-positive, HER2-negative breast cancer: In postmenopausal women, in combination with exemestane, after failure of treatment with letrozole or anastrozole.
- Progressive, well-differentiated, non-functional neuroendocrine tumors (NET): Of gastrointestinal (GI) or lung origin that are unresectable, locally advanced, or metastatic. It is not indicated for functional carcinoid tumors.
- Renal angiomyolipoma associated with TSC: In adults not requiring immediate surgery.
- TSC-associated partial-onset seizures: As adjunctive treatment.
- Prophylaxis of organ rejection: In liver and kidney transplant recipients.
Pharmacological Classification: Everolimus is classified as a kinase inhibitor, specifically an mTOR (mammalian target of rapamycin) inhibitor. It also possesses immunosuppressant properties.
Mechanism of Action: Everolimus inhibits mTOR complex 1 (mTORC1), a key regulator of cell growth, proliferation, and angiogenesis. By binding to mTORC1, everolimus disrupts cellular processes essential for tumor growth and progression. It also inhibits the proliferation of cells involved in immune responses, contributing to its immunosuppressant effects.
Alternate Names
Everolimus is also known internationally by its generic name. Brand names include Afinitor, Afinitor Disperz, Torpenz, and Zortress.
How It Works
Pharmacodynamics: Everolimus exerts its antineoplastic effects by inhibiting mTORC1, leading to decreased cell proliferation, reduced glycolysis, and inhibition of angiogenesis. Its immunosuppressant effects result from inhibiting the proliferation and activation of T-cells and B-cells, reducing antibody production and cytokine release.
Pharmacokinetics:
- Absorption: Everolimus is rapidly absorbed after oral administration, reaching peak concentrations within 1 to 2 hours. High-fat meals can decrease peak concentration (Cmax) by up to 60% and area under the curve (AUC) by about 16%. Bioavailability is approximately 30%.
- Metabolism: Everolimus is extensively metabolized by CYP3A4 in the liver.
- Elimination: Primarily eliminated through biliary/fecal excretion as metabolites, with a small percentage excreted in urine. The terminal half-life is approximately 30 hours.
Mode of Action: Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits mTORC1. This inhibition disrupts downstream signaling pathways involved in cell growth, proliferation, and angiogenesis.
Receptor Binding/Enzyme Inhibition: Everolimus binds to FKBP-12 and inhibits the mTORC1 kinase.
Elimination Pathways: Mainly biliary/fecal excretion; less than 5% excreted unchanged in urine. Metabolized by CYP3A4.
Dosage
Standard Dosage
Adults:
The standard dose for most indications is 10 mg orally once daily.
Children:
Dosing is based on body surface area (BSA) for some indications, such as SEGA associated with TSC (4.5 mg/m² orally once daily) and partial-onset seizures (5 mg/m² orally once daily). For other indications, the dose must be determined by the physician.
Special Cases:
- Elderly Patients: No specific dose adjustment is required, but careful monitoring for adverse events is recommended.
- Patients with Renal Impairment: No dose adjustment is generally necessary.
- Patients with Hepatic Dysfunction: Dose adjustments are required. For Child-Pugh class B, reduce the dose to 5 mg daily. For Child-Pugh class C, everolimus is not recommended unless the potential benefits outweigh the risks, and if used, the dose should not exceed 2.5 mg daily.
- Patients with Comorbid Conditions: Dose adjustments may be needed based on specific comorbid conditions and concomitant medications.
Clinical Use Cases
Everolimus is not indicated for the clinical use cases you mentioned (intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like status epilepticus or cardiac arrest). It is primarily used for the treatment of specific cancers and tumors, as well as for immunosuppression in transplant patients.
Dosage Adjustments
Dose adjustments are required for hepatic impairment and when co-administered with CYP3A4 and/or P-gp inhibitors or inducers.
Side Effects
Common Side Effects:
Stomatitis, infection, rash, fatigue, diarrhea, peripheral edema, anemia, nausea, hyperlipidemia, headache, abdominal pain, fever, cough, constipation, hypertension, urinary tract infection, leukopenia, decreased appetite.
Rare but Serious Side Effects:
Pneumonitis, angioedema, pancreatitis, hypertensive crisis, bleeding events, congestive heart failure, pulmonary embolism, hepatic artery thrombosis (in liver transplant patients), renal impairment.
Long-Term Effects:
Dyslipidemia, impaired glucose tolerance, renal dysfunction, infections, secondary malignancies (rare).
Adverse Drug Reactions (ADR):
Anaphylaxis, angioedema, Stevens-Johnson syndrome (rare), interstitial lung disease.
Contraindications
Hypersensitivity to everolimus, other rapamycin derivatives, or any component of the formulation. Severe chronic obstructive pulmonary disease (COPD) or pulmonary fibrosis.
Drug Interactions
Everolimus interacts with numerous medications, including:
- CYP3A4 Inhibitors: Increase everolimus levels.
- CYP3A4 Inducers: Decrease everolimus levels.
- P-gp Inhibitors: Increase everolimus levels.
- P-gp Inducers: Decrease everolimus levels.
- Immunosuppressants: Increase risk of infection.
- Live vaccines: Should be avoided.
Examples: azole antifungals (ketoconazole, itraconazole), antibiotics (clarithromycin), anticonvulsants (carbamazepine, phenytoin), St. John’s wort, grapefruit juice.
Pregnancy and Breastfeeding
Pregnancy Safety Category: Everolimus is not recommended during pregnancy due to potential fetal harm. Adequate contraception should be used during treatment and for 8 weeks after the last dose.
Fetal Risks: Embryo-fetal toxicity, including increased resorptions, reduced fetal weight, and malformations.
Breastfeeding: Everolimus is not recommended during breastfeeding. It is excreted in animal milk and may pose a risk to nursing infants. Breastfeeding should be avoided during treatment and for 2 weeks after the last dose.
Drug Profile Summary
- Mechanism of Action: mTORC1 inhibitor; immunosuppressant.
- Side Effects: Stomatitis, infection, rash, fatigue, diarrhea, edema, anemia, nausea, hyperlipidemia, cough, constipation, hypertension. Serious: pneumonitis, angioedema, bleeding.
- Contraindications: Hypersensitivity, severe COPD or pulmonary fibrosis.
- Drug Interactions: CYP3A4 and P-gp inhibitors/inducers, immunosuppressants.
- Pregnancy & Breastfeeding: Not recommended.
- Dosage: 10 mg orally once daily (most indications); adjust for hepatic impairment and drug interactions.
- Monitoring Parameters: Blood counts, renal function, liver function, lipid profile, blood glucose.
Popular Combinations
- Everolimus + exemestane (for advanced breast cancer)
- Everolimus + reduced-dose tacrolimus + corticosteroids (for liver transplant rejection prophylaxis)
Precautions
- Resolve existing infections before starting treatment.
- Optimize glycemic and lipid control.
- Monitor for pulmonary toxicity.
- Avoid co-administration with strong CYP3A4 or P-gp inhibitors and inducers.
- Use with caution in patients with lung disease, elderly patients, or those at risk of bleeding.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Everolimus?
A: The recommended dose is 10 mg orally once daily for most adult indications. Pediatric and specific case dosing varies and must be determined by the physician.
Q2: What are the most common side effects?
A: Stomatitis, infections, rash, fatigue, diarrhea, edema, anemia, nausea, hyperlipidemia.
Q3: What are the serious side effects I should watch out for?
A: Pneumonitis, angioedema, severe infections, bleeding events, congestive heart failure.
Q4: Can Everolimus be used during pregnancy or breastfeeding?
A: No, everolimus is not recommended for use during pregnancy or breastfeeding due to potential harm to the fetus or infant.
Q5: What are the important drug interactions I should be aware of?
A: Everolimus interacts with CYP3A4 and P-gp inhibitors and inducers, which can alter its blood levels. Concomitant use of immunosuppressants increases the risk of infections.
Q6: Are there any specific monitoring parameters for patients taking Everolimus?
A: Yes, monitor blood counts, renal and liver function, lipid profile, and blood glucose.
Q7: How should Everolimus be administered?
A: Everolimus tablets should be swallowed whole with water, with or without food, but not after a high-fat meal. Afinitor Disperz tablets should be dispersed in water before administration.
Q8: What should I do if a patient misses a dose?
A: If less than 6 hours have passed since the missed dose, the patient can take it as soon as they remember. If more than 6 hours have passed, they should skip the missed dose and take the next dose at the regular scheduled time.
Q9: What are the contraindications to using Everolimus?
A: Hypersensitivity to everolimus or other rapamycin derivatives, severe COPD or pulmonary fibrosis.
