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. |
| Molecular Weight | 1202.61 |
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 | Use only if potential benefit justifies risk; may be associated with increased risk of congenital malformations (e.g., cleft palate) based on animal studies and limited human data. |
| 2nd trimester | Use with caution; monitor maternal renal function and blood pressure; risk of fetal growth restriction and premature birth. |
| 3rd trimester | Use with caution; may cause neonatal immunosuppression and increased risk of infection; monitor for renal toxicity in newborn. |
Clinical note
Comprehensive clinical and safety monograph for GENGRAF (GENGRAF).
| Placental transfer | Cyclosporine crosses the placenta. Cord blood concentrations are approximately 50-60% of maternal levels. |
| Breastfeeding | Cyclosporine is excreted into breast milk in low concentrations; however, due to potential for immunosuppression and growth retardation in the nursing infant, breastfeeding is generally not recommended during treatment. Weigh benefits against risks. |
■ 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 formulationConcurrent use with PUVA or UVB radiation (psoralen plus ultraviolet A or B) due to increased risk of skin cancer
| 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. |
| Food/Dietary |
Loading safety data…
| Lactation Rating | L4 (Possibly Hazardous) |
| 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. |
| 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. |
| Grapefruit and grapefruit juice increase cyclosporine levels and must be avoided. High-potassium foods (e.g., bananas, oranges, potatoes) may increase hyperkalemia risk; monitor intake. Avoid St. John's wort as it reduces drug levels. |
| Clinical Pearls | Monitor trough levels (target 100-400 ng/mL) and renal function closely. Calcineurin inhibitors cause nephrotoxicity; dose reduction may be necessary. Avoid use with potassium-sparing diuretics or ACE inhibitors due to hyperkalemia risk. Grapefruit increases levels; avoid coadministration. Remember to adjust dose for hepatic impairment. |
| Patient Advice | Take with or without food consistently at the same times each day. · Do not consume grapefruit or grapefruit juice while on this medication. · Report signs of infection, tremors, or changes in urine output immediately. · Avoid live vaccinations and limit sun exposure due to increased skin cancer risk. · Do not stop or change dose without consulting your doctor. |