ENVARSUS XR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ENVARSUS XR (ENVARSUS XR).
Calcineurin inhibitor. Binds to FKBP-12, forming a complex that inhibits calcineurin phosphatase, thereby blocking T-cell activation and IL-2 transcription.
| Metabolism | Primarily hepatic via CYP3A4 and CYP3A5; also metabolized by intestinal CYP3A4. |
| Excretion | Primarily fecal (94%) with minor renal excretion (2.2% as unchanged drug). Biliary excretion is a significant route. |
| Half-life | Terminal half-life approximately 25-30 hours in stable renal transplant patients. Longer half-life (up to 50 hours) in patients with hepatic impairment. |
| Protein binding | Approximately 99% bound to erythrocytes and plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | 0.9-1.4 L/kg in renal transplant patients; large volume indicates extensive tissue distribution, particularly to red blood cells. |
| Bioavailability | Oral bioavailability is approximately 15-25% with the extended-release formulation; reduced by high-fat meal, so should be taken consistently on an empty stomach. |
| Onset of Action | Not applicable for immediate clinical effect; steady-state achieved after 4-5 days of once-daily dosing. |
| Duration of Action | Approximately 24 hours with once-daily dosing, maintained by therapeutic drug monitoring to keep trough levels within target range. |
| Molecular Weight | 1203.6 |
0.2 mg/kg/day orally once daily, with the morning meal, using extended-release tablets. Dose adjustments guided by trough concentrations.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | No specific GFR-based dose adjustment; however, due to nephrotoxicity, monitor renal function closely and reduce dose if renal impairment occurs. For patients with severe renal impairment (CrCl <30 mL/min), consider alternative immunosuppression. |
| Liver impairment | In patients with mild to moderate hepatic impairment (Child-Pugh A or B), reduce dose by 25%. For severe hepatic impairment (Child-Pugh C), reduce dose by 50% and monitor trough levels closely. |
| Pediatric use | For pediatric kidney transplant recipients: 0.2 mg/kg/day orally once daily, with morning meal. Adjust to target trough concentrations. Safety and efficacy not established for other indications in pediatrics. |
| Geriatric use | No specific dose adjustment; however, elderly patients may have increased susceptibility to nephrotoxicity and neurotoxicity. Use lowest effective dose, monitor renal function, and adjust based on trough levels. |
| 1st trimester | Limited human data; animal studies show embryotoxicity at clinically relevant doses. Use only if benefit outweighs risk. |
| 2nd trimester | May cause fetal renal dysfunction, intrauterine growth restriction, and preterm delivery. Monitor fetal growth and amniotic fluid. |
| 3rd trimester | Risk of neonatal nephrotoxicity, hyperkalemia, and low birth weight. Monitor neonate for adverse effects. |
Clinical note
Comprehensive clinical and safety monograph for ENVARSUS XR (ENVARSUS XR).
| Placental transfer | Crosses placenta; fetal concentrations approximately 30-50% of maternal levels. |
| Breastfeeding | Excreted into breast milk; concentrations low but may accumulate in infant. Consider risk of immunosuppression; avoid if possible or monitor infant for signs of infection. |
■ FDA Black Box Warning
Increased susceptibility to infection and possible development of malignancy (e.g., lymphoma, skin cancer).
| Serious Effects |
Hypersensitivity to tacrolimus or any componentConcurrent use with strong CYP3A4 inducers/inhibitors without dose adjustmentSevere hepatic impairment (Child-Pugh C)
| Precautions | Nephrotoxicity, neurotoxicity, hypertension, hyperkalemia, post-transplant diabetes mellitus, monitoring of blood concentrations required. |
| Food/Dietary | Grapefruit and grapefruit juice increase tacrolimus exposure and must be avoided. High-fat meals may decrease absorption; consistency of food intake relative to dosing is recommended. Alcohol should be limited due to potential additive hepatotoxicity. |
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| Lactation Rating |
| L3 (Moderately Safe) |
| Teratogenic Risk | Envarsus XR (tacrolimus) is classified as FDA Pregnancy Category C. In the first trimester, there is an increased risk of congenital anomalies (e.g., cardiac, renal) based on animal studies; human data are limited but suggest a possible small increase. During the second and third trimesters, risks include intrauterine growth restriction, preterm delivery, and transient neonatal hyperkalemia and renal dysfunction. Advise women of childbearing potential to use effective contraception. |
| Fetal Monitoring | Monitor maternal tacrolimus trough concentrations every 2–4 weeks during pregnancy and postpartum. Assess renal function (serum creatinine, BUN), blood pressure, liver function, and blood glucose regularly. Perform serial fetal ultrasound for growth and anatomy. Monitor for maternal hypertension and preeclampsia. Assess neonate for hyperkalemia, renal function, and infections after delivery. |
| Fertility Effects | Tacrolimus may impair male and female fertility based on animal studies. In males, it can reduce sperm count and motility. In females, it may cause ovarian dysfunction (including irregular menstrual cycles) and reduced ovarian reserve. However, successful pregnancies have been reported in transplant recipients on tacrolimus. Preconception counseling is recommended. |
| Clinical Pearls | ENVARSUS XR is an extended-release formulation of tacrolimus; conversion from immediate-release tacrolimus requires close therapeutic drug monitoring due to altered pharmacokinetics. Administer consistently with or without food to minimize variability. Avoid grapefruit products. Monitor renal function, blood pressure, electrolytes, glucose, and trough tacrolimus levels. CYP3A4/5 inducers/inhibitors significantly affect tacrolimus exposure; adjust dose accordingly. Do not crush, chew, or split tablets. |
| Patient Advice | Take exactly as prescribed, at the same time each day, with or without food but consistently. · Swallow whole; do not crush, chew, or break the tablet. · Avoid grapefruit and grapefruit juice. · Do not stop or change dose without consulting your doctor. · Report signs of infection (fever, sore throat), tremor, headache, changes in urination, or unusual bleeding. · Avoid live vaccines and limit sun exposure due to increased skin cancer risk. · Keep all appointments for blood tests to monitor drug levels and organ function. |