EVEROLIMUS
Clinical safety rating: avoid
Contraindicated (not allowed)
Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase. It binds to FKBP-12, forming a complex that inhibits mTOR complex 1 (mTORC1) signaling, reducing cell proliferation, angiogenesis, and glucose uptake.
| Metabolism | Primarily metabolized by CYP3A4; also a substrate of P-glycoprotein (P-gp). Major metabolites are hydroxy and demethyl derivatives, with the parent drug being the main active moiety. |
| Excretion | Primarily fecal (80%) with 5% renal excretion as metabolites; unchanged drug minimal in urine. |
| Half-life | Terminal half-life ~30 hours (range 26–38 h) in stable renal transplant patients; supports once-daily dosing. |
| Protein binding | ~74% bound to plasma proteins (primarily albumin and α1-acid glycoprotein). |
| Volume of Distribution | Vd/F ~4–6 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability ~30% (range 16–50%) with high interindividual variability; reduced by high-fat meal (Cmax ↓ 60%, AUC ↓ 20%). |
| Onset of Action | Oral: peak effect on mTOR inhibition within 1–2 hours post-dose; clinical immunosuppression onset within days. |
| Duration of Action | Duration of mTOR inhibition ~24 hours with once-daily dosing; continuous exposure required for sustained immunosuppression. |
10 mg orally once daily for advanced RCC or pancreatic NET; 10 mg orally once daily for subependymal giant cell astrocytoma; 5 mg orally once daily for renal angiomyolipoma. For breast cancer: 10 mg orally once daily with exemestane 25 mg orally daily. For renal transplant rejection prophylaxis: 0.75 mg (maximum 1.5 mg) orally twice daily with cyclosporine and corticosteroids, with therapeutic drug monitoring (trough 3-8 ng/mL).
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). For severe renal impairment (CrCl <30 mL/min): initiate at 5 mg orally once daily; titrate based on tolerability. Not studied in ESRD on dialysis; use caution. |
| Liver impairment | Child-Pugh A: 7.5 mg orally once daily. Child-Pugh B: 5 mg orally once daily. Child-Pugh C: not recommended (no dosing data). |
| Pediatric use | For subependymal giant cell astrocytoma (SEGA): 4.5 mg/m² orally once daily, rounded to nearest 2.5 or 5 mg dose. Below 1 year: not established. For other indications: safety and efficacy not established. Dosing based on BSA with titration to target trough 5-15 ng/mL. |
| Geriatric use | No specific dose adjustment based solely on age. Monitor renal function and consider risk of infections, pulmonary toxicity, and metabolic effects (hyperglycemia, hyperlipidemia) more frequently in elderly patients. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Strong CYP3A4 or P-gp inhibitors may increase levels and inducers may decrease levels Can cause non-infectious pneumonitis and immunosuppression.
| Breastfeeding | Excreted in rat milk; unknown in human milk. M/P ratio not established. Due to potential for serious adverse reactions in nursing infants (immunosuppression, growth impairment), breastfeeding is contraindicated during therapy and for 2 weeks after last dose. |
| Teratogenic Risk | FDA Category C. First trimester: Evidence of embryo-fetal toxicity in animal studies (increased resorptions, malformations); human data limited. Second and third trimesters: Potential for fetal growth restriction, oligohydramnios due to mTOR inhibition; avoid unless maternal benefit outweighs risk. |
■ FDA Black Box Warning
None (no FDA black box warning).
| Common Effects | certain cancers |
| Serious Effects |
["Hypersensitivity to everolimus, sirolimus, or any component of the formulation","Severe hepatic impairment (Child-Pugh class C)"]
| Precautions | ["Non-infectious pneumonitis (monitor for respiratory symptoms; manage by dose reduction or interruption)","Infections (increased risk, including opportunistic infections; monitor and treat promptly)","Renal impairment (monitor renal function, especially in transplant patients)","Hyperglycemia, hyperlipidemia, hypertriglyceridemia (monitor serum glucose and lipids)","Stomatitis (oral ulcers; manage with supportive care and dose modifications)","Bone marrow suppression (anemia, leukopenia, thrombocytopenia; monitor blood counts)","Risk of impaired wound healing (caution in perioperative period)","Immunizations (avoid live vaccines during treatment)","Embryo-fetal toxicity (can cause fetal harm; advise effective contraception)"] |
Loading safety data…
| Fetal Monitoring | Monitor fetal growth via serial ultrasound (every 4-6 weeks) for growth restriction and oligohydramnios. Maternal monitoring: trough everolimus levels (target 3-8 ng/mL), renal function, blood pressure, blood glucose, and signs of infection. |
| Fertility Effects | May impair male and female fertility. In males: oligospermia, azoospermia, and testicular atrophy (reversible in animal studies). In females: anovulation, menstrual irregularities; potential for premature ovarian failure. |