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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ASTAGRAF XL (ASTAGRAF XL).
| Breastfeeding | Tacrolimus is excreted into human breast milk with a milk-to-plasma (M/P) ratio of approximately 0.3. Limited data suggest low infant exposure (relative infant dose 0.5% of maternal weight-adjusted dose). However, because of potential for infant immunosuppression and growth effects, breastfeeding is generally not recommended unless benefits outweigh risks. Monitor infant for trough levels if breastfeeding. |
| 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. |
■ 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 formulation; concurrent use with cyclosporine or other calcineurin inhibitors.
| 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. |
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| 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. |