PROGRAF
Clinical safety rating
cautionComprehensive clinical and safety monograph for PROGRAF (PROGRAF).
Calcineurin inhibitor; binds to FKBP-12, inhibits calcineurin, preventing dephosphorylation and nuclear translocation of NF-AT, thereby inhibiting T-cell activation and cytokine gene transcription.
| Metabolism | Primarily hepatic via CYP3A4 and CYP3A5; intestinal metabolism contributes. P-glycoprotein substrate. |
| Excretion | Primarily fecal (approximately 92%) with biliary excretion as the major route; renal excretion accounts for about 2.4% of the dose as unchanged drug and metabolites. |
| Half-life | Terminal elimination half-life is approximately 8.7 hours (range 4-41 hours) in healthy volunteers; in liver transplant patients, half-life is approximately 11.7 hours (range 3.9-56 hours); prolonged in patients with hepatic impairment. |
| Protein binding | 99% bound primarily to albumin and alpha-1-acid glycoprotein; also binds to erythrocytes and lipoproteins. |
| Volume of Distribution | Volume of distribution is approximately 0.99 L/kg (range 0.6-1.9 L/kg) in healthy subjects; higher values indicate extensive tissue distribution and binding to erythrocytes. |
| Bioavailability | Oral bioavailability is approximately 17-25% (range 4-89%) in transplant patients, with high inter- and intra-subject variability; absorption is influenced by food. |
| Onset of Action | Oral: Onset of immunosuppression occurs within 1-2 hours after a single oral dose; IV: Immediate action upon administration. |
| Duration of Action | Duration of immunosuppressive effect persists for 12-24 hours; dosing is typically every 12 hours to maintain therapeutic levels. |
| Molecular Weight | 822.05 |
Initial oral dose: 0.1-0.15 mg/kg/day divided into 2 doses (every 12 hours). IV dose: 0.03-0.05 mg/kg/day as continuous infusion. Adjunct with corticosteroids.
| Dosage form | INJECTABLE |
| Renal impairment | No specific GFR-based dose adjustment required, but monitor renal function closely due to nephrotoxicity. For severe renal impairment (CrCl <30 mL/min), reduce dose by 25-50% and monitor levels. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 25%. Child-Pugh C: reduce dose by 50% and titrate based on trough levels. |
| Pediatric use | Oral: 0.1-0.3 mg/kg/day divided every 12 hours. IV: 0.03-0.05 mg/kg/day continuous infusion. Monitor trough concentrations. |
| Geriatric use | Start at lower end of dosing range due to potential age-related decline in renal function. Monitor renal function and tacrolimus levels closely. |
| 1st trimester | Tacrolimus (PROGRAF) crosses the placenta. There are no adequate and well-controlled studies in pregnant women. However, based on published data, the risk of major birth defects is not significantly increased with use of tacrolimus during the first trimester. It may be associated with an increased risk of preterm delivery and low birth weight. Maternal immunosuppression may increase risk of infections. Use only if potential benefit justifies potential risk to the fetus. |
| 2nd trimester | Continued use of tacrolimus during the second trimester is often necessary for maternal health in transplant recipients. There is a risk of maternal hypertension, preeclampsia, and gestational diabetes. Fetal risks include preterm birth, low birth weight, and transient neonatal renal dysfunction. Close monitoring of maternal tacrolimus levels and fetal growth is recommended. |
| 3rd trimester | Use of tacrolimus in the third trimester may be associated with neonatal adverse effects including transient hyperkalemia, renal impairment, and immunosuppression. There is a risk of preterm labor and low birth weight. Tacrolimus levels may decrease during pregnancy, requiring dose adjustments. Postnatally, infants should be monitored for signs of tacrolimus toxicity and infections. |
Clinical note
Comprehensive clinical and safety monograph for PROGRAF (PROGRAF).
| Placental transfer | Tacrolimus crosses the placenta. In ex vivo human placental perfusion studies, tacrolimus crosses the placenta with a transfer rate of approximately 25% of maternal concentration found in fetal circulation. In pregnant transplant recipients, cord blood concentrations are about 50-70% of maternal blood concentrations. The drug accumulates in fetal tissues, with higher concentrations in fetal plasma than in amniotic fluid. |
| Breastfeeding | Tacrolimus is excreted into human breast milk in low concentrations. In breastfed infants of mothers taking tacrolimus, the estimated daily dose received by the infant is less than 0.5% of the maternal weight-adjusted dose. Based on limited data, adverse effects in breastfed infants are not commonly reported. However, because of the potential for serious adverse reactions, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for tacrolimus and any potential adverse effects on the breastfed child from the drug or underlying maternal condition. Monitor breastfed infants for signs of immunosuppression and tacrolimus toxicity (e.g., infection, renal impairment). |
| Lactation Rating | L3 - Limited Data, Probably Compatible |
| Teratogenic Risk | Pregnancy Category C. Risk in first trimester: increased risk of congenital malformations (animal studies); human data limited. Second and third trimester: potential for fetal growth restriction, prematurity, and neonatal toxicity (hyperkalemia, renal dysfunction). Use only if benefit outweighs risk. |
| Fetal Monitoring | Maternal: blood pressure, renal function (serum creatinine, BUN), liver function tests, blood glucose, potassium levels, tacrolimus trough concentrations. Fetal: serial ultrasound for growth, amniotic fluid volume, and Doppler studies; consider fetal echocardiography with maternal use in first trimester. |
| Fertility Effects | Tacrolimus may affect fertility in females (menstrual disorders) and males (decreased spermatogenesis). Effects are typically reversible upon discontinuation. |
■ FDA Black Box Warning
Increased risk of lymphomas and other malignancies, particularly skin cancer; increased susceptibility to infections. Only should be prescribed by physicians experienced in immunosuppressive therapy.
| Common Effects | Increased glucose level in blood Kidney damage Insomnia difficulty in sleeping Tremors High blood pressure Infection |
| Serious Effects |
Hypersensitivity to tacrolimus or any component of the formulationConcomitant use with cyclosporine (increased risk of nephrotoxicity and neurotoxicity)Use of Prograf extended-release capsules in patients with hereditary fructose intolerance (due to sorbitol content)
| Precautions | Nephrotoxicity, neurotoxicity (tremor, headache, seizures), hypertension, hyperkalemia, hyperglycemia, thrombotic microangiopathy, risk of BK virus infection, increased risk of EBV-associated post-transplant lymphoproliferative disorder. |
| Food/Dietary | Grapefruit and grapefruit juice increase tacrolimus levels, avoid. High-fat meals may decrease absorption; take consistently with or without food. Avoid potassium-rich foods if hyperkalemia risk. |
| Clinical Pearls | Monitor trough levels 12 hours post-dose; target 5-20 ng/mL depending on organ. Avoid with live vaccines. Adjust dose for hepatic impairment. Cautious co-administration with nephrotoxic drugs. Grapefruit juice increases tacrolimus levels. |
| Patient Advice | Take at the same time every day, 12 hours apart. · Do not eat grapefruit or drink grapefruit juice. · Report signs of infection, tremors, or changes in urine output. · Avoid live vaccines and limit sun exposure. · Do not stop abruptly; taper under medical supervision. |
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