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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ZORTRESS (ZORTRESS).
| Breastfeeding | No human data on everolimus in breast milk. Animal studies show excretion in milk. 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. M/P ratio unknown. |
| 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. |
■ 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; severe hepatic impairment (Child-Pugh class C); pregnancy.
| 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. |
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| 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. |