TACROLIMUS
Clinical safety rating
avoidPositive 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. |
| Molecular Weight | 822.05 |
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 | Tacrolimus is not known to be teratogenic in humans; however, cases of neonatal hyperkalemia and renal dysfunction have been reported. Use only if benefit outweighs risk. |
| 2nd trimester | Monitor maternal blood pressure, renal function, and drug levels. Risk of gestational diabetes and hypertension. Adjust dose as needed. |
| 3rd trimester | Continue therapy with careful monitoring. May be associated with preterm delivery and low birth weight. monitor neonatal drug levels and renal function at birth. |
Clinical note
Strong CYP3A4 inhibitors may increase levels and inducers may decrease levels Can cause nephrotoxicity and neurotoxicity.
| Placental transfer | Tacrolimus crosses the placenta; cord blood concentrations are about 50% of maternal blood concentrations. |
| Breastfeeding | Tacrolimus is excreted into breast milk in low amounts; relative infant dose estimated <1% of maternal weight-adjusted dose. Limited data suggest no adverse effects in breastfed infants. Caution with preterm or ill infants. Monitor infant for signs of immunosuppression, weight gain, renal function. |
| Lactation Rating | L2 (Possibly Compatible) |
| 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. |
| 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. |
■ 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 formulationUse with bosentan or sirolimus in renal transplant patients (increased risk of nephrotoxicity and wound healing complications)Concurrent administration with live vaccines
| 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 |
| Food/Dietary | Grapefruit and grapefruit juice increase tacrolimus levels by inhibiting CYP3A4 and must be avoided. High-fat meals decrease absorption; consistent timing relative to meals recommended. |
| Clinical Pearls | Monitor trough levels 2-3 days after dose changes; target 5-15 ng/mL for most indications. Use with caution in renal impairment due to nephrotoxicity. Strong CYP3A4 interaction potential; avoid grapefruit and adjust azole antifungals. Hypomagnesemia common; supplement as needed. |
| Patient Advice | Take consistently with or without food, but do not switch between. · Avoid grapefruit and grapefruit juice. · Report signs of infection, tremors, or kidney issues (swelling, decreased urine). · Do not take any new medications without consulting your doctor. · Use sun protection due to increased skin cancer risk. · Do not miss doses; if you do, take as soon as remembered unless near next dose. |
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