CYCLOSPORINE
Clinical safety rating: avoid
Positive evidence of fetus risks but benefits may outweigh risks in some cases
Cyclosporine is a calcineurin inhibitor that binds to cyclophilin, forming a complex that inhibits calcineurin, thereby preventing dephosphorylation and nuclear translocation of nuclear factor of activated T-cells (NFAT), which reduces transcription of interleukin-2 and other cytokines, leading to immunosuppression.
| Metabolism | Primarily metabolized by CYP3A4; also a substrate of P-glycoprotein. Major metabolites include AM1, AM4N, and AM9. |
| Excretion | Primarily hepatic metabolism via CYP3A4; eliminated in bile and feces. Renal excretion accounts for <6% of unchanged drug. Approximately 90% of metabolites are excreted in bile and feces. |
| Half-life | Terminal elimination half-life ranges from 8.4 to 27 hours (mean ~19 hours) in adults with normal liver function. In patients with hepatic impairment, half-life may be prolonged. Pediatric patients typically have shorter half-lives (7–19 hours). |
| Protein binding | 90–98% bound primarily to lipoproteins (especially HDL), also to albumins and globulins. Binding is concentration-dependent and saturable. |
| Volume of Distribution | 4–8 L/kg (range 3–13 L/kg) in adults, indicating extensive tissue distribution. Higher Vd in obese patients and children. Distributes into erythrocytes, leukocytes, and various organs. |
| Bioavailability | Oral (microemulsion): 23–43% (mean ~30%). Bioavailability is highly variable and depends on formulation, food intake (decreased by high-fat meal), and liver function. Neoral (microemulsion) has improved bioavailability over Sandimmune. IV: 100%. |
| Onset of Action | Oral: 2–6 hours (microemulsion formulation); IV: within 30 minutes to 2 hours; Topical (ophthalmic): within 2–4 weeks for keratoconjunctivitis sicca. |
| Duration of Action | Oral/IV: Duration depends on dosing interval and therapeutic monitoring; typically 12–24 hours, with trough levels maintained for immunosuppression. Topical ophthalmic: effects persist as long as treatment continues; onset of symptom relief may take weeks. |
Initial oral dose: 3-5 mg/kg/day divided q12h; maintenance: 2-4 mg/kg/day divided q12h. IV dose: 3-5 mg/kg/day as continuous infusion or divided q8-12h.
| Dosage form | EMULSION |
| Renal impairment | No initial dose reduction necessary. Reduce dose by 25-50% if serum creatinine increases >30% from baseline. Avoid use in severe renal impairment (GFR <20 mL/min) unless benefits outweigh risks. |
| Liver impairment | Child-Pugh class A: No adjustment. Child-Pugh class B: Reduce dose by 25-50% due to decreased clearance. Child-Pugh class C: Avoid use or reduce by >50% with close monitoring. |
| Pediatric use | Oral: 5-10 mg/kg/day divided q12h. IV: 5-6 mg/kg/day as continuous infusion or divided q12h. Tirate to achieve therapeutic levels (100-400 ng/mL whole blood). |
| Geriatric use | Use with caution due to age-related renal impairment. Start at low end of dosing range (e.g., 2.5-3 mg/kg/day oral) and adjust based on renal function and cyclosporine trough levels. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Many drugs can increase levels (eg ketoconazole) or decrease levels (eg rifampin) Nephrotoxicity and hypertension are common dose-related toxicities.
| Breastfeeding | Cyclosporine is excreted into breast milk with a milk-to-plasma ratio (M/P) of approximately 0.17 to 0.5. Infant exposure is low (estimated 2-14% of maternal weight-adjusted dose). Limited data show no adverse effects in breastfed infants, but caution is advised due to theoretical risks of immunosuppression and nephrotoxicity. Consider monitoring infant trough levels if breastfeeding is pursued. |
| Teratogenic Risk | Cyclosporine is not a major human teratogen. First trimester exposure: no significant increase in major malformations above baseline. Second and third trimesters: associated with intrauterine growth restriction (IUGR), prematurity, low birth weight, and neonatal complications such as hyperkalemia, hypomagnesemia, and renal dysfunction. Risk of maternal hypertension and preeclampsia is increased. Overall, benefits may outweigh risks in transplant or autoimmune patients. |
■ FDA Black Box Warning
Increased susceptibility to infection and development of lymphoma and other malignancies may occur; only physicians experienced in immunosuppressive therapy should prescribe cyclosporine.
| Common Effects | autoimmune disorders |
| Serious Effects |
Hypersensitivity to cyclosporine or any components; concurrent use with PUVA or UVB therapy in psoriasis; uncontrolled hypertension; active malignancy; severe renal dysfunction (except in transplant setting).
| Precautions | Monitor renal function and blood pressure due to nephrotoxicity and hypertension; risk of hepatotoxicity; increased risk of infections and lymphomas; avoid live vaccines; monitor drug levels due to narrow therapeutic index; potential for hyperkalemia and hypomagnesemia; neurological toxicities including tremor and convulsions. |
| Food/Dietary |
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| Fetal Monitoring | Monitor maternal blood pressure, serum creatinine, blood urea nitrogen, liver function, and trough cyclosporine levels throughout pregnancy. Periodic fetal ultrasound for growth restriction and amniotic fluid assessment. Monitor neonate for hypoglycemia, hyperkalemia, and renal function post-delivery. Screen for maternal infections due to immunosuppression. |
| Fertility Effects | Cyclosporine does not commonly impair fertility, but it may cause reversible ovarian or testicular dysfunction in some patients. It is used in transplant recipients who often have restored fertility after transplantation. No conclusive evidence of direct gonadotoxicity. |
| Grapefruit and grapefruit juice significantly increase cyclosporine concentrations and should be avoided. High-fat meals may alter absorption; take with consistent meals. Avoid excessive potassium intake (e.g., bananas, oranges, salt substitutes). |
| Clinical Pearls | Monitor trough levels 2 hours post-dose (C2) for Neoral; target varies by indication. Avoid concurrent use of nephrotoxic drugs (e.g., NSAIDs, aminoglycosides). Check magnesium and potassium levels regularly; hypomagnesemia can increase cyclosporine toxicity. Use with caution in patients with hypertension or hyperlipidemia. Grapefruit juice increases cyclosporine levels; avoid. |
| Patient Advice | Take cyclosporine exactly as prescribed, at the same time each day with consistent mealtimes. · Do not consume grapefruit or grapefruit juice while on this medication. · Report signs of infection (fever, sore throat), tremors, unusual bleeding/bruising, or changes in urine output. · Avoid live vaccines (e.g., MMR, varicella) during treatment. · Use strict sun protection; cyclosporine increases risk of skin cancer. · Regular blood tests are required to monitor drug levels and organ function. |