ZORTRESS
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ZORTRESS (ZORTRESS).
Inhibits mammalian target of rapamycin (mTOR) by binding to FKBP-12, blocking cell cycle progression from G1 to S phase, thereby suppressing cytokine-driven T-cell proliferation.
| Metabolism | Primarily via CYP3A4; also substrate for P-glycoprotein. Major metabolite is sirolimus. |
| Excretion | Primarily fecal (~78%) with <2.5% excreted unchanged in urine. Small amount via biliary elimination. |
| Half-life | Terminal elimination half-life is approximately 10-15 hours in renal transplant patients. In de novo liver transplant patients, half-life is ~13 hours. The effective half-life supports twice-daily dosing. |
| Protein binding | ~97% bound to human plasma proteins, predominantly to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Volume of distribution (Vd) is approximately 5-6 L/kg, indicating extensive tissue distribution beyond plasma volume. |
| Bioavailability | Absolute oral bioavailability is approximately 16-20% due to extensive first-pass metabolism. Absorption is increased with high-fat meal; therefore, take consistently with or without food. |
| Onset of Action | Oral: immunosuppressive effect detectable within 4-6 hours after first dose due to inhibition of mTOR-mediated signaling. |
| Duration of Action | Duration of therapeutic effect is approximately 12 hours with twice-daily dosing due to sustained mTOR inhibition requiring consistent trough concentrations. |
| Molecular Weight | 1034 |
1.5 mg orally twice daily, administered with cyclosporine and corticosteroids.
| Dosage form | TABLET |
| Renal impairment | No adjustment required for renal impairment; monitor renal function closely due to potential nephrotoxicity from concomitant cyclosporine. |
| Liver impairment | Child-Pugh class A or B: reduce dose to 0.75 mg twice daily. Child-Pugh class C: not recommended. |
| Pediatric use | Not established; safety and efficacy in pediatric patients have not been studied. |
| Geriatric use | No specific dose adjustments; use with caution due to increased risk of infections and renal dysfunction. |
| 1st trimester | Limited human data; animal studies show embryotoxicity and teratogenicity at subtherapeutic doses. Use only if potential benefit justifies risk to fetus. |
| 2nd trimester | Same as T1; may cause fetal harm based on animal data. Monitor for intrauterine growth restriction if used. |
| 3rd trimester | Same as T2; neonatal immunosuppression and lymphopenia possible if used near term. |
Clinical note
Comprehensive clinical and safety monograph for ZORTRESS (ZORTRESS).
| Placental transfer | High; crosses placenta based on animal studies; expected in humans due to low molecular weight. |
| Breastfeeding | Excreted in rat milk; no human data. Due to potential for serious adverse reactions in nursing infants, use is not recommended during breastfeeding. |
■ FDA Black Box Warning
Increased susceptibility to infection and possible development of lymphoma and other malignancies, particularly of the skin. Only use in patients with low immunologic risk.
| Serious Effects |
Hypersensitivity to everolimus or sirolimus derivativesSevere hepatic impairment (Child-Pugh class C)
| Precautions | Lymphomas and other malignancies; increased risk of skin cancer; increased susceptibility to infection; interstitial lung disease; renal function deterioration; wound healing complications; hyperlipidemia; angioedema; interactions with strong CYP3A4 inhibitors/inducers. |
| Food/Dietary | Avoid grapefruit and grapefruit juice due to CYP3A4 inhibition increasing everolimus exposure. Also avoid Seville oranges and their products (e.g., marmalade). High-fat meals may reduce absorption; take consistently with or without food. No other specific dietary restrictions. |
Loading safety data…
| Lactation Rating |
| L5 - Contraindicated |
| Teratogenic Risk | Zortress (everolimus) is an mTOR inhibitor. Animal studies show embryotoxicity and fetotoxicity at maternal toxic doses. There are no adequate human studies. First trimester exposure may increase risk of congenital anomalies; second and third trimester exposure may cause fetal renal dysfunction, oligohydramnios, and growth restriction. Use only if potential benefit justifies risk. |
| Fetal Monitoring | Monitor maternal blood pressure, renal function, serum everolimus trough levels, complete blood count, lipid profile, and blood glucose. Fetal monitoring includes serial ultrasound for growth, amniotic fluid index, and Doppler studies as indicated. Assess for signs of infection. |
| Fertility Effects | Everolimus may impair male and female fertility based on animal studies. In males, it can cause reduced spermatogenesis and testicular atrophy. In females, it may cause irregular menstrual cycles and ovarian dysfunction. Reversibility uncertain. |
| Clinical Pearls | Zortress (everolimus) is an mTOR inhibitor used for prophylaxis of organ rejection in kidney transplant recipients at low-to-moderate immunologic risk. Monitor everolimus trough levels (target 3-8 ng/mL when used with cyclosporine). Avoid coadministration with strong CYP3A4/P-gp inducers or inhibitors. Dose reduction required for hepatic impairment. Regular monitoring of renal function, blood glucose, lipids, and complete blood count is essential due to risks of nephrotoxicity, hyperglycemia, hyperlipidemia, and myelosuppression. Angioedema and non-infectious pneumonitis require immediate attention. Not recommended in heart or liver transplant due to increased mortality and hepatic artery thrombosis risk. |
| Patient Advice | Take Zortress exactly as prescribed, at the same time each day, with or without food. · Do not crush or chew tablets; swallow whole with water. · Avoid grapefruit, grapefruit juice, and Seville oranges (e.g., marmalade) as they can increase drug levels. · Report any signs of infection (fever, chills, sore throat), bleeding or bruising, mouth ulcers, or shortness of breath immediately. · Regular blood tests are required to monitor drug levels, kidney function, blood counts, and cholesterol. · Use effective contraception during treatment and for 8 weeks after stopping; everolimus may harm an unborn baby. · Avoid live vaccines (e.g., MMR, nasal flu, yellow fever) during therapy. · Limit exposure to sunlight; use sunscreen and protective clothing due to increased risk of skin cancer. · Do not stop or change dose without consulting your transplant team. · Keep a list of all medications (including OTC and herbal products) and share with your healthcare provider. |