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Once-Daily Extended-Release Tacrolimus

ENVARSUS XR may overcome the limitations of other tacrolimus formulations, improving tacrolimus release and absorption over 24 hours.1-3 As a result of the advanced technology of ENVARSUS XR, with available strengths including 0.75 mg, 1 mg, and 4 mg, ENVARSUS XR is suitable for both de novo and conversion kidney transplant patients.1

ENVARSUS XR is available in 3 strengths1

  • There is no generic equivalent for ENVARSUS XR4
  • ENVARSUS XR cannot be automatically substituted at the pharmacy with any other tacrolimus brand or generic product1
Download Patient Dosing Information
0.75 mg tablet, debossed with “TCS” on one side and “0.75” on the other
1 mg tablet, debossed with “TCS” on one side and “1” on the other
4 mg tablet, debossed with “TCS” on one side and “4” on the other
0.75-mg tablet, 1-mg tablet, and 4-mg tablet of ENVARSUS XR.*
*Tablets not shown at actual size.

Important administration instructions1

  • ENVARSUS XR (tacrolimus extended-release tablets) is not interchangeable or substitutable with tacrolimus extended-release capsules, tacrolimus capsules, and tacrolimus for oral suspension. Under- or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions
    • ENVARSUS XR should not be used without the supervision of a physician with experience in immunosuppressive therapy
  • ENVARSUS XR should be taken on an empty stomach consistently at the same time of the day, preferably in the morning to ensure consistent and maximum possible drug exposure, at least 1 hour before a meal or at least 2 hours after a meal
  • Advise patients to swallow ENVARSUS XR tablets whole with fluid (preferably water); patients must not chew, divide, crush, or dissolve the tablets
  • If a dose is missed, instruct the patient to take it as soon as possible within 15 hours after missing the dose. Beyond the 15-hour time frame, instruct the patient to wait until the usual scheduled time to take the next regular daily dose. Instruct the patient not to double the next dose
  • Patients should avoid eating grapefruit or drinking grapefruit juice or alcoholic beverage while taking ENVARSUS XR
    • If a dose is missed, take it as soon as possible up to 15 hours after missing the dose. If more than 15 hours have passed, wait until the next dose.

    Take ENVARSUS XR on an empty stomach at the same time of day, preferably in the morning, to ensure consistent and maximum possible drug exposure.

    Take at least 1 hour before a meal or at least 2 hours after a meal.

    If a dose is missed, take it as soon as possible within 15 hours after missing the dose.

    Beyond the 15-hour time frame, wait until the usual scheduled time to take the next regular daily dose.

    Do not double the next dose.

    Contact your healthcare provider if a dose is missed.

ENVARSUS XR starting doses in de novo kidney transplant patients

Recommended starting dosing1:

  • De novo patients (with antibody induction)—0.14 mg/kg/day
  • Dosing adjustments to consider when administered concomitantly with CYP3A inducers or inhibitors
    • Patients with severe hepatic impairment may require a lower starting dose
    • African American patients may require titration to higher ENVARSUS XR dosages to attain comparable trough concentrations
  • Should be taken once daily on an empty stomach, preferably in the morning, at least 1 hour before or 2 hours after a meal
  • Recommended target whole blood trough concentration range
    • Month 1: 6 to 11 ng/mL
    • After Month 1: 4 to 11 ng/mL

Switching from immediate-release tacrolimus is a straightforward process

20% reduction icon

80% of the preconversion dose of immediate-release tacrolimus1

  • Start ENVARSUS XR at 80% of the total daily dose of immediate-release tacrolimus
  • Due to reduced clearance and prolonged half-life, patients with severe hepatic impairment (Child-Pugh ≥10) may require a lower starting dosage of ENVARSUS XR
  • African American patients, compared with Caucasian patients, may need to be titrated to higher ENVARSUS XR dosages to attain comparable trough concentrations
  • Dose adjustments may be necessary when administered concomitantly with CYP3A inducers or inhibitors
Once-a-day icon

Dose once a day1

  • Administer the first dose in the morning
  • There is no need to administer any other form of tacrolimus to achieve target trough levels after conversion
  • Monitor tacrolimus trough concentrations and titrate ENVARSUS XR dose to achieve the target trough level desired for each patient†
Educate patients icon

Educate your patients

  • Be sure they understand exactly how to take ENVARSUS XR and how it is different from the tacrolimus they had been taking
†Recommended target whole blood trough concentration range is 4 to 11 ng/mL after the first month.

Immunosuppression prescribing considerations

Ask your patients if they prefer a once-daily regimen

It is important patients understand that missing a dose may lead to underimmunosuppression. Adverse events have been correlated with nonadherence to transplant medications.5

Young adult patients—65% of patients aged 20 to 30 years demonstrated nonadherence6

Adult patients—Nonadherence rose from 17% at baseline to 31% at 18 months post-transplant7

Elderly patients—Reduced cognitive abilities and polypharmacy should be considered during tacrolimus therapy8

See ENVARSUS XR Dose Converter >
AUC=area under the curve; CYP3A=cytochrome family P450, subfamily 3A.

INDICATIONS AND USAGE

ENVARSUS XR is indicated for the prophylaxis of organ rejection in de novo kidney transplant patients in combination with other immunosuppressants.

ENVARSUS XR is also indicated for the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations in combination with other immunosuppressants.

IMPORTANT SAFETY INFORMATION

WARNING: MALIGNANCIES AND SERIOUS INFECTIONS

Increased risk for developing serious infections and malignancies with ENVARSUS XR or other immunosuppressants that may lead to hospitalization or death

CONTRAINDICATIONS

ENVARSUS XR is contraindicated in patients with known hypersensitivity to tacrolimus.

WARNINGS AND PRECAUTIONS

INDICATIONS AND USAGE

ENVARSUS XR is indicated for the prophylaxis of organ rejection in de novo kidney transplant patients in combination with other immunosuppressants.

ENVARSUS XR is also indicated for the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations in combination with other immunosuppressants.

IMPORTANT SAFETY INFORMATION

WARNING: MALIGNANCIES AND SERIOUS INFECTIONS

Increased risk for developing serious infections and malignancies with ENVARSUS XR or other immunosuppressants that may lead to hospitalization or death

CONTRAINDICATIONS

ENVARSUS XR is contraindicated in patients with known hypersensitivity to tacrolimus or to any of the ingredients in ENVARSUS XR.

WARNINGS AND PRECAUTIONS

Lymphoma and Other Malignancies: Immunosuppressants, including ENVARSUS XR, increase the risk of developing lymphomas and other malignancies, particularly of the skin. Post-transplant lymphoproliferative disorder (PTLD), associated with Epstein-Barr Virus (EBV), has been reported in immunosuppressed organ transplant patients.

Serious Infections: Immunosuppressants, including ENVARSUS XR, increase the risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes.

Not Interchangeable with Other Tacrolimus Products - Medication Errors: Medication errors, including substitution and dispensing errors, between tacrolimus capsules and tacrolimus extended-release capsules were reported outside the U.S. in some cases leading to adverse reactions. ENVARSUS XR is not interchangeable or substitutable with tacrolimus extended-release capsules, tacrolimus capsules or tacrolimus for oral suspension.

New Onset Diabetes after Transplant: ENVARSUS XR caused new onset diabetes after transplant (NODAT) in kidney transplant patients, which may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk.

Nephrotoxicity due to ENVARSUS XR and Drug Interactions: ENVARSUS XR, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity. In patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range, consider dosage reduction or temporary interruption of tacrolimus administration. The risk for nephrotoxicity may increase when ENVARSUS XR is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity. When tacrolimus is used concurrently with CYP3A inhibitors or other known nephrotoxic drugs, monitor renal function and tacrolimus blood concentrations, and adjust dose of both tacrolimus and/or concomitant medications during concurrent use.

Neurotoxicity: ENVARSUS XR may cause a spectrum of neurotoxicities. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure, and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions.

Hyperkalemia: Mild to severe hyperkalemia, which may require treatment, has been reported with tacrolimus including ENVARSUS XR. Concomitant use of agents associated with hyperkalemia may increase the risk for hyperkalemia.

Hypertension: Hypertension is a common adverse reaction of ENVARSUS XR therapy and may require antihypertensive therapy.

Risk of Rejection with Strong CYP3A Inducers and Risk of Serious Adverse Reactions with Strong CYP3A Inhibitors: The concomitant use of strong CYP3A inducers may increase the metabolism of tacrolimus, leading to lower whole blood trough concentrations and greater risk of rejection. In contrast, the concomitant use of strong CYP3A inhibitors may decrease the metabolism of tacrolimus, leading to higher whole blood trough concentrations and greater risk of serious adverse reactions. Therefore, adjust ENVARSUS XR dose and monitor tacrolimus whole blood trough concentrations when co-administering ENVARSUS XR with strong CYP3A inhibitors or strong CYP3A inducers. A rapid, sharp rise in tacrolimus levels has been reported after co-administration with strong CYP3A4 inhibitors despite an initial reduction of tacrolimus dose. Early and frequent monitoring of tacrolimus whole blood trough levels is recommended.

QT Prolongation: ENVARSUS XR may prolong the QT/QTc interval and cause Torsade de pointes. Avoid ENVARSUS XR in patients with congenital long QT syndrome. Consider obtaining electrocardiograms and monitoring electrolytes periodically during treatment in patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other products that lead to QT prolongation, and those with electrolyte disturbances. When co-administering ENVARSUS XR with other substrates and/or inhibitors of CYP3A, especially those that also have the potential to prolong the QT interval, a reduction in ENVARSUS XR dosage, monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended.

Immunizations: Whenever possible, administer the complete complement of vaccines before transplantation and treatment with ENVARSUS XR. Avoid the use of live attenuated vaccines during treatment with ENVARSUS XR. Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with ENVARSUS XR.

Pure Red Cell Aplasia: Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. If PRCA is diagnosed, consider discontinuation of ENVARSUS XR.

Cannabidiol Drug Interactions: When cannabidiol and ENVARSUS XR are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of ENVARSUS XR should be considered as needed when ENVARSUS XR is co-administered with cannabidiol.

Thrombotic Microangiopathy (TMA) Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: Cases of thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported in patients treated with ENVARSUS XR. Transplant patients may have other risk factors which contribute to the risk of TMA. In patients with signs and symptoms of TMA, consider ENVARSUS XR as a risk factor. Concurrent use of ENVARSUS XR and mammalian target of rapamycin (mTOR) inhibitors may contribute to the risk of TMA.

ADVERSE REACTIONS

De Novo kidney transplant patients: Most common adverse reactions (incidence ≥15%) reported with ENVARSUS XR are diarrhea, anemia, urinary tract infection, hypertension, tremor, constipation, diabetes mellitus, peripheral edema, hyperkalemia and headache.

Conversion of kidney transplant patients from immediate-release tacrolimus: Most common adverse reactions (incidence ≥10%) reported with ENVARSUS XR include: diarrhea and blood creatinine increased.

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on postmarketing surveillance, registry and animal data may cause fetal harm. Advise pregnant women of the potential risk to the fetus.

Nursing Mothers: Tacrolimus is present in human milk. Discontinue drug or nursing, taking into account the importance of drug to the mother.

Females and Males of Reproductive Potential: Advise female and male patients of reproductive potential to speak with their healthcare provider on family planning options including appropriate contraception prior to starting treatment with ENVARSUS XR. Based on animal studies, ENVARSUS XR may affect fertility in males and females.

Pediatric Use: The safety and efficacy of ENVARSUS XR in pediatric patients have not been established.

Geriatric Use: Clinical studies of ENVARSUS XR did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Renal Impairment: Frequent monitoring of renal function is recommended. Lower doses may be required.

Hepatic Impairment: Frequent monitoring of tacrolimus trough concentrations is recommended. With greater tacrolimus whole blood trough concentrations in patients with severe hepatic impairment, there is a greater risk of adverse reactions and dosage reduction is recommended.

Race: African-American patients may require higher doses to attain comparable trough concentrations compared to Caucasian patients. African-American and Hispanic kidney transplant patients are at an increased risk for new onset diabetes after transplant. Monitor blood glucose concentrations and treat appropriately.

To report SUSPECTED ADVERSE REACTIONS, contact Veloxis Pharmaceuticals, Inc. at 1-844-VELOXIS (835-6947) or FDA at 1-800-FDA-1088 or visit www.fda.gov/medwatch.

Please see full Prescribing Information, including Boxed Warning, and updated Warnings and Precautions.

References: 1. ENVARSUS XR [package insert]. Cary, NC: Veloxis Pharmaceuticals, Inc.; 4/2024. 2. Tremblay S, Nigro V, Weinberg J, Woodle ES, Alloway RR. A steady-state head-to-head pharmacokinetic comparison of all FK-506 (tacrolimus) formulations (ASTCOFF): an open-label, prospective, randomized, two-arm, three-period crossover study. Am J Transplant. 2017;17(2):432-442. 3. Trofe-Clark J, Brennan DC, West-Thielke P, et al. Results of ASERTAA, a randomized prospective crossover pharmacogenetic study of immediate-release versus extended-release tacrolimus in African American kidney transplant recipients. Am J Kidney Dis. 2018;71(3):315-326. 4. Food and Drug Administration. Orange Book: approved drug products with therapeutic equivalence evaluations [tacrolimus]. Accessed January 3, 2022. https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm 5. Sellarés J, de Freitas DG, Mengel M, et al. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant. 2012;12(2):388-399. 6. Massey EK, Meys K, Kerner R, et al. Young adult kidney transplant recipients: nonadherent and happy. Transplantation. 2015;99(8):e89-e96. 7. Massey EK, Tielen M, Laging M, et al. Discrepancies between beliefs and behavior: a prospective study into immunosuppressive medication adherence after kidney transplantation. Transplantation. 2015;99(2):375-380. 8. Staatz CE, Tett SE. Pharmacokinetic considerations relating to tacrolimus dosing in the elderly. Drugs Aging. 2005;22(7):541-557.