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Fostering control, from 
transplant to long-term 
protection

See how ENVARSUS XR can provide ongoing protection from treatment failure

In both de novo and conversion patients, ENVARSUS XR delivers proven control from the beginning and control over time.1,2

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Laying the groundwork to achieve target trough early

With ENVARSUS XR, target exposure is achieved quickly—even after a single dose—helping to support your post-transplant monitoring plan.3,4

In an open-label, Phase 2 study of de novo kidney transplant patients, more than half of all patients (53%) achieved target tacrolimus levels (6–11 ng/mL) on Day 2 (pre-dose) after a single starting dose of ENVARSUS XR (0.14 mg/kg/day).3 Therapeutic drug monitoring is recommended to optimize tacrolimus dosing for individual patient needs.3

PATIENTS WITHIN 6 TO 11 ng/mL AFTER THE FIRST DOSE WITH 0.14 mg/kg/DAY

 

The starting dose of 0.14 mg/kg/day in this study formed the basis of dosing recommendations in de novo kidney transplant patients.3

Demonstrated efficacy with durable outcomes

De novo patients

ENVARSUS XR offers demonstrated efficacy from 3 months to 2 years in de novo kidney transplant patients, providing confidence in results both early post transplant and over time.1,3,5

In head-to-head, noninferiority studies in de novo kidney transplant patients, ENVARSUS XR demonstrated comparable long-term outcomes to PROGRAF®, including BPAR, graft loss, death, and lost to follow-up at 1 and 2 years.1,3

Patient and graft protection at 1 and 2 years1,3

control-table-mob
 YEAR 13YEAR 21
ENVARSUS XR (n=268)PROGRAF (n=275)ENVARSUS XR (n=268)PROGRAF (n=275)
Biopsy-proven acute rejection13.4%13.5%17.2%18.2%
Graft failure3.4%4.0%4.1%5.5%
Death3.0%2.9%4.1%4.7%
Loss to follow-up1.5%1.8%1.5%2.9%
Treatment failure composite*18.7%19.6%23.1%27.3%

BPAR=biopsy-proven acute rejection.

*Treatment failure was a composite endpoint of BPAR, graft failure, death, and lost to follow-up.1,5

P value not significant for all measures.5

In clinical trials of de novo kidney transplant recipients, the most common adverse events (incidence ≥15%) included: diarrhea, anemia, urinary tract infection, hypertension, tremor, constipation, diabetes mellitus, peripheral edema, hyperkalemia, and headache.

 
 

Trial results in patients converting from immediate-release tacrolimus

MELT trial study design2

In a controlled, open-label Phase 3 study, 324 adult (aged ≥18 years) renal transplant patients on a stable tacrolimus dose (with trough levels 4-15 ng/mL) were randomized to convert to ENVARSUS XR or remain on maintenance therapy with tacrolimus twice daily (n=162 in each treatment group; modified intent-to-treat population). The primary endpoint was the proportion of patients with efficacy failures (death, graft failure, locally read biopsy-proven acute rejection, or loss to follow-up) within 12 months.

Efficacy failure rates at 12 months3

With its increased bioavailability, a lower dosage of ENVARSUS XR is needed to achieve equivalent therapeutic drug levels and deliver comparable efficacy and safety to immediate-release tacrolimus2

 ENVARSUS XR
± Steroids, ± MMF, MPS, or AZA
(n=162)		Immediate-Release Tacrolimus
Capsules ± Steroids ± MMF, MPS,
or AZA (n=162)
Treatment failure4 (2.5%)4 (2.5%)
Overall treatment difference of efficacy failure compared to immediate-release tacrolimus (95% CI)*0%
(-4.2%, 4.2%)		 
Biopsy-proven acute rejection2 (1.2%)2 (1.2%)
Graft failure0%0%
Death2 (1.2%)1 (0.6%)
Lost to follow-up0%1 (0.6%)
table-Efficacy-Failure-mob

AZA=azathioprine; CI=confidence interval; DGF=delayed graft function; eGFR=estimated glomerular filtration rate; MDRD7=Modification of Diet in Renal Disease 7; MELT=Multicenter Evaluation of LCP-Tacro Trial.; MMF=mycophenolate mofetil; MPS=mycophenolate sodium.

The mean eGFR, using the MDRD7 formula, was 61.5 mL/min/1.73 m2 and 60.0 mL/min/1.73 m2 at baseline (Day 0) and 62.0 mL/min/1.73 m2 and 61.4 mL/min/1.73 m2 at 12 months in the ENVARSUS XR and tacrolimus capsules treatment groups, respectively.

*95% CI was calculated using an exact method that is based on the standardized statistic and inverting a 2-sided test.

In a clinical trial of stable kidney transplant recipients who converted from immediate-release tacrolimus to ENVARSUS XR, the most common adverse reactions (incidence ≥10%) were diarrhea and blood creatinine increased.3

Control from the beginning, control over time

In a Phase 3, randomized, double-blind trial of de novo kidney transplant patients, ENVARSUS XR demonstrated comparable efficacy to PROGRAF.1,5

Freedom From Treatment Failure vs PROGRAF1,6*

 

HR=hazard ratio.

*Treatment failure was a composite endpoint of BPAR, graft failure, death, and lost to follow-up.1,5

Patients on ENVARSUS XR vs patients on PROGRAF

year-1

Experienced a

9% REDUCTION

in treatment failure6†

year-2

Experienced a

17% REDUCTION

in treatment failure6†

†Treatment failure was a composite endpoint of BPAR, graft failure, death, and lost to follow-up.1,5

doc-patient-mob

Proven efficacy across patient subgroups

In a 24-month, randomized, double-blind Phase 3 trial in de novo kidney transplant recipients, once-daily LCPT (ENVARSUS XR) demonstrated comparable efficacy and safety to twice-daily tacrolimus (IR-Tac) overall and across all evaluated subgroups, including elderly ( ≥65 years), black, and female recipients.1

In a 12-month post hoc analysis of a Phase 3 trial in stable kidney transplant recipients who self-identified as Hispanic or Latino and were converted from twice-daily IR-Tac to once-daily LCPT (ENVARSUS XR), efficacy and safety outcomes were comparable to patients who remained on IR-Tac, with similar rates of composite treatment failure and stable renal function in both groups.7*

BPAR=biopsy-proven acute rejection; LCPT=LCP-tacrolimus.

*Treatment failure was a composite endpoint of BPAR, graft failure, death, and lost to follow-up.7

See the Control Case Study See the Control Case Study

See the Control Case Study

This case study highlights the first days of a rapid metabolizer’s post-transplant journey to target tacrolimus levels as quickly as possible.

Download Case Study

A growing foundation of clinical evidence

ENVARSUS XR is built on a robust foundation of evidence—more than 27 trials involving over 1,657 participants.6

Phase 1

19

Trials

516

Healthy Participants

Phase 2

3

Trials

147

Healthy Participants

Phase 3

2

Trials

869

Healthy Participants

Phase 3b

3

Trials

125

Healthy Participants

patient-old-mob

ENVARSUS XR delivers efficacy with an 
established safety profile

Across all safety measures, there were no significant differences between ENVARSUS XR and PROGRAF groups in predefined, potentially clinically significant laboratory measures, opportunistic infections, malignancies, or composite NODAT in both de novo and conversion patients.1,3,5

 
 

IR-Tac=immediate-release tacrolimus; NODAT=new-onset diabetes after transplant.

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References: 1. Rostaing L, Bunnapradist S, Grinyó JM, et al; Envarsus Study Group. Novel once-daily extended-release tacrolimus versus twice-daily tacrolimus in de novo kidney transplant recipients: two-year results of phase 3, double-blind, randomized trial. Am J Kidney Dis. 2016;67(4):648-659. 2. Bunnapradist S, Ciechanowski K, West-Thielke P, et al; MELT Investigators. Conversion from twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized MELT trial. Am J Transplant. 2013;13(3):760-769. 3. ENVARSUS XR [package insert]. Cary, NC: Veloxis Pharmaceuticals, Inc.; 4/2024. 4. 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. 5. Budde K, Bunnapradist S, Grinyo JM, et al; Envarsus Study Group. Novel once-daily extended-release tacrolimus (LCPT) versus twice-daily tacrolimus in de novo kidney transplants: one-year results of phase III, double-blind, randomized trial. Am J Transplant. 2014;14(12):2796-2806. 6. Data on file. Veloxis Pharmaceuticals, Inc.;2020. 7. Faravardeh A, Akkina S, Villicana R, et al. Efficacy and safety of once-daily LCP-tacrolimus versus twice-daily immediate-release tacrolimus in adult Hispanic stable kidney transplant recipients: sub-group analysis from a phase 3 trial. Ann Transplant. 2021;16:26:e929535.

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 to 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.