ASTAGRAF XL
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ASTAGRAF XL (ASTAGRAF XL).
Calcineurin inhibitor that binds to FKBP-12, forming a complex that inhibits calcineurin, thereby preventing dephosphorylation and nuclear translocation of NFAT, which reduces T-cell activation and cytokine production (e.g., IL-2).
| Metabolism | Primarily hepatic via CYP3A4 and CYP3A5; undergoes extensive first-pass metabolism. Substrate of P-glycoprotein. |
| Excretion | Primarily fecal (94.6%) via biliary elimination. Renal excretion accounts for approximately 2.4% of the dose, mainly as metabolites. Less than 1% is excreted unchanged in urine. |
| Half-life | Terminal elimination half-life is approximately 43 hours (range 15.8–68.6 hours) in adult kidney transplant recipients. This long half-life supports once-daily dosing. In liver transplant patients, half-life ranges from 12 to 42 hours. |
| Protein binding | Approximately 99% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Volume of distribution is 3.5–4.5 L/kg (wide distribution, indicating extensive tissue binding). High Vd reflects distribution into erythrocytes, lymphocytes, and tissues. |
| Bioavailability | Oral bioavailability is highly variable, approximately 20–30% (range 5–89%). Absorption is incomplete and inconsistent; food decreases absorption by up to 33%. The modified-release formulation (Astagraf XL) has a lower peak and more sustained absorption compared to immediate-release. |
| Onset of Action | Oral: Onset of immunosuppression occurs within hours, but maximal effect (e.g., lymphocytic IL-2 production inhibition) is achieved after 3–5 days of therapeutic dosing. Intravenous: Onset more rapid, within 1–2 hours with continuous infusion. |
| Duration of Action | Immunosuppressive effect persists throughout the 24-hour dosing interval with once-daily administration. Serum levels maintained above trough threshold for calcineurin inhibition for the entire day. |
| Molecular Weight | 822.05 |
Initial oral dose of 0.1-0.15 mg/kg/day divided every 12 hours, with subsequent adjustments based on trough levels. Typical maintenance dose 0.05-0.15 mg/kg/day.
| Dosage form | CAPSULE, EXTENDED RELEASE |
| Renal impairment | For GFR <30 mL/min: reduce dose by 50% and monitor trough levels closely. No adjustment for GFR >30 mL/min. |
| Liver impairment | Child-Pugh Class A: no adjustment. Class B: reduce dose by 25%. Class C: reduce dose by 50% and monitor trough levels frequently. |
| Pediatric use | Initial oral dose 0.15-0.2 mg/kg/day divided every 12 hours. Adjust to target trough levels of 5-15 ng/mL. Maximum dose 0.3 mg/kg/day. |
| Geriatric use | Start at lower end of adult dosing range (0.05 mg/kg/day) and titrate slowly due to reduced renal function and increased risk of adverse effects. Monitor trough levels closely. |
| 1st trimester | Tacrolimus crosses the placenta. Data from the Transplant Pregnancy Registry International (TPR) and other studies suggest an increased risk of preterm delivery and low birth weight, but no consistent pattern of major malformations. Exposure during the first trimester may be associated with a slight increase in congenital anomalies, though data are limited. Use only if potential benefit outweighs risk. |
| 2nd trimester | Continued use may be necessary for graft survival. Monitor for maternal hypertension, preeclampsia, and gestational diabetes. Tacrolimus levels can decrease due to increased volume of distribution and clearance; dose adjustments may be required. |
| 3rd trimester | Risk of neonatal hyperkalemia, renal impairment, and transient immunosuppression. Monitor tacrolimus levels closely. Use lowest effective dose. Cases of neonatal toxicity have been reported. |
Clinical note
Comprehensive clinical and safety monograph for ASTAGRAF XL (ASTAGRAF XL).
| Placental transfer | Tacrolimus crosses the placenta. Cord blood concentrations are approximately 30-50% of maternal blood concentrations. Studies demonstrate measurable levels in fetal tissues. The degree of transfer is significant enough to require monitoring of neonatal effects. |
■ FDA Black Box Warning
Increased susceptibility to infection and possible development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression. Increased nephrotoxicity, especially when used with other nephrotoxic drugs.
| Serious Effects |
Hypersensitivity to tacrolimus or any component of the formulationConcurrent use of cyclosporineConcurrent use of sirolimus or everolimus (due to increased risk of renal dysfunction and other adverse effects)
| Precautions | Nephrotoxicity, neurotoxicity (tremor, headache, seizures), hypertension, hyperkalemia, hyperglycemia, increased risk of infections and malignancies (especially skin), and lymphoproliferative disorders. Monitor blood pressure, renal function, electrolytes, and drug levels. |
| Food/Dietary | Grapefruit juice significantly increases tacrolimus AUC and Cmax; avoid concurrent use. High-fat meals may decrease absorption; maintain consistent fat intake with each dose to ensure stable levels. Avoid taking with alcohol or herbal supplements like St. John's wort, which may reduce efficacy. |
Loading safety data…
| Breastfeeding | Tacrolimus is excreted into human breast milk in low concentrations. Relative infant dose is estimated to be <1% of maternal weight-adjusted dose. While limited data suggest minimal risk, monitor infant for potential immunosuppression, diarrhea, or growth retardation. Some guidelines consider breastfeeding acceptable with caution, especially if maternal dose is low and infant levels are not required. |
| Lactation Rating | L3: Limited Data - Probably Compatible |
| Teratogenic Risk | Tacrolimus is classified as FDA Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. In animal studies, tacrolimus caused maternal toxicity and embryotoxicity at doses higher than those used clinically. First trimester exposure is associated with an increased risk of congenital anomalies, including cardiac malformations. Second and third trimester use has been linked with intrauterine growth restriction, preterm delivery, and transient neonatal hyperkalemia and renal dysfunction. Postnatal immunosuppression in the neonate may occur. |
| Fetal Monitoring | Monitor maternal blood pressure, renal function (serum creatinine, BUN), electrolytes (especially potassium, magnesium), blood glucose, liver function tests, and tacrolimus trough levels every 1-2 weeks during pregnancy. Fetal monitoring includes serial ultrasound for growth and anatomy, and nonstress testing biweekly after 32 weeks. Monitor neonatal serum potassium and renal function at birth. |
| Fertility Effects | Tacrolimus has been associated with reversible impairment of spermatogenesis in males and menstrual irregularities in females. In male patients, reduced sperm count and motility have been reported. Fertility effects may be dose-dependent and typically resolve upon dose reduction or discontinuation. Preclinical studies show no direct gonadal toxicity. |
| Clinical Pearls | Monitor trough levels 5-15 ng/mL; avoid using with sirolimus due to increased risk of thrombotic microangiopathy; conversion from tacrolimus immediate-release is 1:1 (mg:mg) but monitor levels closely for 2 weeks; administer consistently with or without food to avoid fluctuations. |
| Patient Advice | Take at the same time every day, consistently with or without food. · Do not crush, chew, or split the extended-release capsules; swallow whole. · Avoid grapefruit and grapefruit juice as they can increase drug levels and toxicity. · Report signs of infection (fever, sore throat), tremors, or changes in urine output immediately. · Minimize sun exposure and use sunscreen due to increased risk of skin cancer. · Do not change brand or formulation without consulting your transplant team. · Keep all appointments for blood level monitoring. |