Everolimus

• Oncology:
• Advanced renal cell carcinoma (RCC) after failure of treatment with VEGF-targeted therapy.
• Progressive neuroendocrine tumors of pancreatic origin (PNET) in adults with unresectable, locally advanced or metastatic disease.
• Advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane following failure of letrozole or anastrozole.
• Advanced or metastatic non-small cell lung cancer (NSCLC) in patients with specific molecular characteristics.
• Treatment of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) in patients not requiring immediate surgery.
• Treatment of renal angiomyolipoma and other TSC-associated tumors.
• Advanced gastrointestinal neuroendocrine tumors.
• Immunosuppression:
• Prevention of organ rejection in adult patients receiving renal or cardiac transplants.
• Off-label/Clinically accepted uses:
• Treatment of certain types of lymphangioleiomyomatosis (LAM).
• Investigational uses in various other cancers and TSC manifestations.

• Route: Oral administration.
• Oncology:
• Typical starting dose: 10 mg once daily.
• Dose adjustments based on tolerability and adverse effects.
• Continue until disease progression or unacceptable toxicity.
• Immunosuppression:
• Initial dose: varies based on organ transplanted and concomitant medications.
• Typical maintenance dose: 0.75 to 2 mg twice daily, adjusted according to trough blood levels.
• Special Populations:
• Elderly: No initial dose adjustment; monitor for toxicity.
• Hepatic impairment: Dose reduction recommended for moderate to severe impairment.
• Renal impairment: No dose adjustment typically needed; monitor renal function closely.
• Monitoring:
• Therapeutic drug monitoring recommended to maintain plasma trough levels within target range.
• Administration Instructions:
• Take consistently with or without food.
• Swallow tablets whole with water; do not crush or chew.
• Avoid grapefruit and grapefruit juice due to interaction risk.

Everolimus is a selective inhibitor of the mammalian target of rapamycin (mTOR), a serine/threonine kinase involved in regulating cell growth, proliferation, metabolism, and angiogenesis. Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits mTOR Complex 1 (mTORC1). This inhibition results in decreased protein synthesis and cell cycle arrest in the G1 phase, leading to reduced tumor cell proliferation and angiogenesis. In transplant patients, mTOR inhibition suppresses T-cell activation and proliferation, contributing to immunosuppression.

• Absorption: Oral bioavailability approximately 30%; peak plasma concentration achieved 1–2 hours post-dose.
• Distribution: Widely distributed with volume of distribution around 150 L; extensively bound to plasma proteins (~74%).
• Metabolism: Primarily metabolized by CYP3A4 and substrate of P-glycoprotein.
• Active Metabolites: Minor active metabolites present.
• Elimination: Mainly eliminated via feces (80%) and urine (5%).
• Half-life: Approximately 30 hours.
• Onset: Pharmacodynamic effects observed within days.

• Pregnancy: Category D — Positive evidence of human fetal risk. Everolimus may cause fetal harm based on animal studies and limited human data. Use only if potential benefits justify risks.
• Lactation: Unknown if excreted in human milk. Breastfeeding is not recommended during treatment due to potential toxicity.

• Primary Class: Antineoplastic agent / Immunosuppressant.
• Subclass: mTOR inhibitor.

• Hypersensitivity to everolimus, sirolimus, or any excipients.
• Severe hepatic impairment without dose adjustment.
• Concomitant use with strong CYP3A4 inhibitors or inducers without careful monitoring.
• Active serious infections due to immunosuppressive effects.

• High-risk groups: Immunocompromised patients, elderly, hepatic impairment.
• Black box warnings: Increased risk of infection and malignancies.
• Monitor for pneumonitis, renal failure, hepatic failure, and metabolic disturbances (hyperglycemia, hyperlipidemia).
• Caution in patients with delayed wound healing; avoid surgery during treatment when possible.
• Monitor hematologic parameters for anemia, thrombocytopenia, and leukopenia.
• Watch for early signs of severe adverse events such as respiratory symptoms indicating pneumonitis.

• Common:
• Stomatitis/mouth ulcers
• Infections (respiratory, urinary tract)
• Diarrhea, nausea, vomiting
• Fatigue
• Rash and acneiform dermatitis
• Hyperglycemia and hyperlipidemia
• Serious:
• Non-infectious pneumonitis
• Renal dysfunction
• Hepatic impairment
• Severe infections, sepsis
• Thrombotic microangiopathy
• Onset varies; stomatitis often early within weeks, pneumonitis may occur later.

• CYP3A4 and P-glycoprotein:
• Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) increase everolimus plasma levels → risk of toxicity.
• CYP3A4 inducers (e.g., rifampin, carbamazepine) decrease levels → reduced efficacy.
• Drug-food: Avoid grapefruit and grapefruit juice.
• Other interactions: Immunosuppressants and other nephrotoxic drugs may increase toxicity risk.

• Updated guidelines recommend therapeutic drug monitoring for optimal dosing.
• Recent studies emphasize managing stomatitis proactively.
• New warnings about pneumonitis and metabolic effects added to prescribing information.
• EMA and FDA continue to monitor post-marketing safety data; no major changes in indications recently.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep tablets in original packaging until use.
• Do not freeze.
• Keep out of reach of children.