AFINITOR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for AFINITOR (AFINITOR).
Inhibitor of mammalian target of rapamycin (mTOR), specifically the mTORC1 complex, by binding to the FKBP-12 protein, reducing cell proliferation, angiogenesis, and glucose uptake.
| Metabolism | Substrate of CYP3A4; metabolized primarily by CYP3A4; also a substrate of P-glycoprotein (P-gp). |
| Excretion | Primarily fecal (80%) and renal (5%) as unchanged drug and metabolites. Biliary excretion is significant. |
| Half-life | Terminal elimination half-life: 30 hours (range 15–40 hours) in healthy subjects; increases to 40–70 hours in moderate hepatic impairment. |
| Protein binding | 74% bound to plasma proteins (primarily albumin and α1-acid glycoprotein). |
| Volume of Distribution | Mean steady-state Vd: 342 L (approx. 4.9 L/kg in a 70 kg adult), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability: approximately 16% (low due to P-glycoprotein efflux and first-pass metabolism); food reduces variability but does not alter AUC significantly. |
| Onset of Action | Oral: Peak concentration at 1–2 hours; clinical effect (e.g., mTOR inhibition) occurs within hours; tumor response may take weeks. |
| Duration of Action | Therapeutic effect persists throughout the dosing interval (once daily) due to sustained mTORC1 inhibition; pharmacodynamic effect lasts >24 hours. |
| Action Class | Immunosuppressant- mTOR inhibitors |
| Brand Substitutes | Evermil 5 Tablet, Everbliss 5mg Tablet, Rolimus 5 Tablet, Volantis 5mg Tablet, Evertor 5mg Tablet, Evermil 10 Tablet, Rolimus 10 Tablet, Everbliss 10mg Tablet, Volantis 10mg Tablet, Evertor 10mg Tablet |
10 mg orally once daily for advanced breast cancer, neuroendocrine tumors, and renal cell carcinoma; 10 mg orally once daily for subependymal giant cell astrocytoma (SEGA) in adults; 5 mg/m^2 orally once daily for SEGA in pediatric patients (titrated to trough levels 5-15 ng/mL).
| Dosage form | TABLET |
| Renal impairment | No dose adjustment for mild to moderate renal impairment (CrCl >=30 mL/min). For severe renal impairment (CrCl <30 mL/min): reduce dose to 5 mg once daily. End-stage renal disease (CrCl <15 mL/min): use with caution, no specific recommendation. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose to 5 mg daily; Child-Pugh C: reduce dose to 2.5 mg daily, or consider alternate therapy. |
| Pediatric use | For SEGA: 5 mg/m^2 orally once daily, adjusted to achieve everolimus trough concentrations of 5-15 ng/mL. Dose adjustments per AUC or tolerability. Not approved for other indications in children. |
| Geriatric use | No specific dose adjustment; start at recommended adult dose. Monitor for increased risk of infections, stomatitis, and metabolic effects due to age-related decline in organ function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for AFINITOR (AFINITOR).
| Breastfeeding | No data on presence in human milk, effects on breastfed infant, or milk production. M/P ratio unknown. Breastfeeding is not recommended due to potential adverse effects on the developing immune system and growth. |
| Teratogenic Risk | Pregnancy Category D. Positive evidence of human fetal risk. Based on its mechanism of action (mTOR inhibitor) and animal studies, AFINITOR (everolimus) is embryotoxic and fetotoxic. First trimester exposure carries risk of structural anomalies; second and third trimester exposure may cause fetal growth restriction, oligohydramnios, and renal impairment. Use only if benefit outweighs risk. |
■ FDA Black Box Warning
No black box warnings.
| Serious Effects |
["Hypersensitivity to everolimus, sirolimus, or any component of the formulation"]
| Precautions | ["Non-infectious pneumonitis","Infections (including opportunistic infections)","Hypersensitivity reactions including anaphylaxis","Angioedema","Renal failure","Impaired wound healing","Metabolic effects (hyperglycemia, dyslipidemia)","Myelosuppression","Immunosuppression leading to increased risk of infections","Cases of fatal hemorrhage in patients with history of bleeding","Radiation sensitization and recall reactions, especially in patients with previous radiation therapy","Increased risk of pneumocystis jirovecii pneumonia (PJP) and other opportunistic infections; consider prophylaxis","Avoid live vaccines"] |
| Food/Dietary | Avoid grapefruit, grapefruit juice, and Seville oranges (including marmalade) due to CYP3A4 inhibition increasing everolimus levels. Take consistently with or without food, but high-fat meals reduce absorption. Avoid St. John's wort. |
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| Fetal Monitoring | Monitor maternal blood pressure, renal function, blood glucose, and lipid profile. Monitor fetal growth by ultrasound every 4 weeks after viability. Assess amniotic fluid volume. Monitor for signs of mTOR inhibitor toxicity in the mother (e.g., pneumonitis, infections, stomatitis). |
| Fertility Effects | May impair fertility in females and males based on animal studies. In females, everolimus may cause menstrual irregularities, anovulation, and ovarian failure. In males, may cause azoospermia or oligospermia. Reversibility uncertain. |
| Clinical Pearls | Monitor renal function and blood glucose regularly; Afinitor (everolimus) can cause non-infectious pneumonitis, so obtain baseline chest imaging and assess for new or worsening respiratory symptoms. Adjust dose for moderate hepatic impairment (Child-Pugh B). Avoid live vaccines during treatment. |
| Patient Advice | Take Afinitor at the same time each day, consistently either with or without food. · Avoid grapefruit, grapefruit juice, and Seville oranges during treatment. · Report any new or worsening cough, chest pain, or difficulty breathing immediately. · Monitor for signs of infection such as fever, chills, or sore throat; avoid large crowds and sick individuals. · Use effective contraception during treatment and for 8 weeks after stopping. · Do not crush or chew tablets; swallow whole with a glass of water. |