TACROLIMUS
Clinical safety rating: avoid
Positive evidence of fetus risks but benefits may outweigh risks in some cases
Tacrolimus is a calcineurin inhibitor. It binds to FK506-binding protein 12 (FKBP12), forming a complex that inhibits calcineurin phosphatase activity. This prevents dephosphorylation and nuclear translocation of nuclear factor of activated T-cells (NFAT), thereby inhibiting transcription of interleukin-2 (IL-2) and other cytokines, leading to suppressed T-cell activation and proliferation.
| Metabolism | Primarily metabolized by cytochrome P450 3A4 (CYP3A4) and to a lesser extent by CYP3A5 in the liver and intestinal wall. It is a substrate of P-glycoprotein (ABCB1). |
| Excretion | Primarily fecal (approximately 93%), with renal excretion accounting for about 2.4% of the unchanged drug. Biliary excretion is a minor route for metabolites. |
| Half-life | Terminal elimination half-life is approximately 8.7-21.7 hours in healthy volunteers and 18-41 hours in liver transplant recipients. Prolonged half-life in hepatic impairment requires dose adjustments. |
| Protein binding | Approximately 99% bound, primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Approximately 0.85-1.5 L/kg, reflecting extensive tissue distribution and binding to lymphocytes. |
| Bioavailability | Oral: about 17-25% (variable due to first-pass metabolism and food effects); topical: minimal systemic absorption (less than 5% in healthy skin). |
| Onset of Action | Intravenous: immediate (within minutes); oral: 1-3 hours; topical: within days for psoriasis, longer for atopic dermatitis. |
| Duration of Action | Immunosuppressive effects persist for 12-24 hours post-dose, requiring twice-daily dosing. Topical duration varies; application once or twice daily is typical. |
0.1-0.2 mg/kg/day orally in two divided doses (immediate-release); 0.05-0.15 mg/kg/day orally once daily (extended-release); 0.01-0.05 mg/kg/day continuous IV infusion.
| Dosage form | CAPSULE |
| Renal impairment | No standard dose adjustment for renal impairment; monitor renal function closely and reduce dose if nephrotoxicity occurs. For GFR < 30 mL/min, consider dose reduction by 50% and close monitoring. |
| Liver impairment | Child-Pugh Class A: no adjustment; Child-Pugh Class B: reduce dose by 50%; Child-Pugh Class C: reduce dose by 75%; monitor trough levels. |
| Pediatric use | 0.15-0.3 mg/kg/day orally in two divided doses (immediate-release); 0.03-0.1 mg/kg/day continuous IV infusion; titrate to target trough levels. |
| Geriatric use | Start at lower end of dosing range (0.05-0.1 mg/kg/day orally); monitor renal function and trough levels closely due to age-related decline in renal function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Strong CYP3A4 inhibitors may increase levels and inducers may decrease levels Can cause nephrotoxicity and neurotoxicity.
| Breastfeeding | Tacrolimus is excreted into breast milk. M/P ratio (concentration in milk:plasma) is approximately 0.3-0.9. It is recommended to use with caution; monitor infant for immunosuppression and tacrolimus trough levels. |
| Teratogenic Risk | First trimester: Increased risk of congenital malformations including cardiac anomalies. Second and third trimesters: Risk of fetal growth restriction, preterm delivery, and neonatal hyperkalemia. Tacrolimus crosses the placenta. |
■ FDA Black Box Warning
Increased susceptibility to infection and the possible development of lymphoma. Only physicians experienced in immunosuppressive therapy and management of transplant patients should prescribe tacrolimus. Patients receiving tacrolimus should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources.
| Common Effects | immunosuppression |
| Serious Effects |
["Hypersensitivity to tacrolimus or any component of the formulation","Hypersensitivity to hydrogenated castor oil (present in some intravenous formulations)"]
| Precautions | ["Increased risk of lymphomas and other malignancies, particularly skin cancer","Increased susceptibility to infections, including opportunistic infections and reactivation of latent viruses (e.g., BK virus, CMV, EBV)","Nephrotoxicity: acute and chronic renal impairment, monitor renal function closely","Neurotoxicity: tremors, headache, seizures, posterior reversible encephalopathy syndrome (PRES)","Hyperkalemia: monitor serum potassium levels","Hypertension: monitor blood pressure and manage accordingly","Post-transplant diabetes mellitus: monitor blood glucose levels","Anaphylactic reactions: risk with intravenous formulation due to castor oil derivative (polyoxyl 60 hydrogenated castor oil) in some formulations","QT prolongation: caution in patients with risk factors or with drugs that prolong QT interval"] |
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| Fetal Monitoring |
| Maternal: Trough tacrolimus blood levels, renal function, blood pressure, blood glucose, and signs of infection. Fetal/neonatal: Growth ultrasound, neonatal monitoring for hyperkalemia, renal function, and tacrolimus levels. |
| Fertility Effects | Tacrolimus may restore fertility in patients with chronic kidney disease or post-transplant. No direct adverse effects on fertility; however, risk of fetal exposure during pregnancy requires careful planning. |