GENGRAF
Clinical safety rating: caution
Comprehensive clinical and safety monograph for GENGRAF (GENGRAF).
Calcineurin inhibitor; binds to cyclophilin, inhibits calcineurin-dependent T-cell activation, preventing nuclear factor of activated T-cells (NF-AT) dephosphorylation and translocation, thereby reducing IL-2 and other cytokine gene transcription.
| Metabolism | Hepatic metabolism primarily via CYP3A4 enzyme; also substrate for CYP3A5. Metabolized to multiple metabolites with variable activity, including AM1 (hydroxylated), AM9 (N-demethylated), and AM4N (cyclized). Undergoes extensive first-pass metabolism. |
| Excretion | Primarily biliary/fecal (94%); renal excretion accounts for 6% (0.1% unchanged). |
| Half-life | Terminal half-life is approximately 8.4 hours (range 5-18 hours) in adult volunteers; prolonged in hepatic impairment. |
| Protein binding | 90-98% bound to plasma proteins, primarily lipoproteins, albumin, and alpha-1-acid glycoprotein. |
| Volume of Distribution | 3.5 L/kg (range 1.2-4.8 L/kg) in renal transplant recipients; distribution is extensive and variable. |
| Bioavailability | Oral bioavailability is 30% (range 10-60%), variable due to first-pass metabolism and food effects. |
| Onset of Action | Oral: 2-6 hours to peak blood concentration; clinical immunosuppressive effect correlates with trough levels. |
| Duration of Action | Dosing interval is typically every 12 hours; sustained trough levels required for continuous immunosuppression. |
5-15 mg/kg/day orally in divided doses every 12 hours.
| Dosage form | CAPSULE |
| Renal impairment | GFR <30 mL/min: reduce dose by 50%. |
| Liver impairment | Child-Pugh Class A: no adjustment; Class B: reduce dose by 50%; Class C: avoid use. |
| Pediatric use | 4-10 mg/kg/day orally in divided doses every 12 hours; adjusted to target trough levels. |
| Geriatric use | Initiate at lower end of dosing range and titrate based on renal function and drug levels. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for GENGRAF (GENGRAF).
| Breastfeeding | Cyclosporine is excreted into breast milk. Milk-to-plasma ratio approximately 0.3-0.6. Potential for infant immunosuppression and growth inhibition. Weigh benefits against risks; monitor infant for adverse effects. |
| Teratogenic Risk | First trimester: Cyclosporine crosses the placenta. Limited human data, but no major malformations attributed. Second and third trimesters: Risk of intrauterine growth restriction, prematurity, and low birth weight. Consider risk-benefit; avoid if possible, but may be used if essential. |
■ FDA Black Box Warning
Increased susceptibility to infection and development of lymphoma and other malignancies, particularly of the skin. Only physicians experienced in immunosuppressive therapy and management of transplant patients should prescribe cyclosporine.
| Serious Effects |
["Hypersensitivity to cyclosporine or any component of the formulation (including Cremophor EL for IV)","Uncontrolled hypertension","Malignancy (except non-melanoma skin cancer) in patients with rheumatoid arthritis or psoriasis","Concomitant use with PUVA or UVB therapy, methotrexate, other immunosuppressive agents, or coal tar (for psoriasis patients)","Abnormal renal function with uncontrolled hypertension (for psoriasis patients)","Pregnancy (category C; additional risk of premature birth and low birth weight)"]
| Precautions | ["Nephrotoxicity: Monitor renal function regularly; risk increased with high doses, other nephrotoxic drugs, or prolonged use.","Hepatotoxicity: Monitor liver function.","Hypertension: Common; require blood pressure control.","Neurotoxicity: Including tremor, convulsions, headache, and paresthesias.","Hyperkalemia: Monitor serum potassium, especially with potassium-sparing diuretics or ACE inhibitors.","Hypomagnesemia: Supplementation may be required.","Increased risk of infections and lymphoproliferative disorders.","Potential for anaphylactic reactions with IV formulation (due to Cremophor EL).","Carcinogenesis: Especially skin malignancies; minimize UV exposure."] |
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| Fetal Monitoring |
| Monitor cyclosporine trough levels: target same as non-pregnant (100-400 ng/mL depending on indication). Monitor renal function, blood pressure, liver function tests. Serial fetal ultrasound for growth assessment. Monitor for maternal hypertension and preeclampsia. |
| Fertility Effects | No known negative impact on fertility in males or females. Cyclosporine does not appear to impair reproductive capacity. |