ENVARSUS XR Clinical Data

ENVARSUS XR has been studied across multiple kidney transplant recipient types, including de novo patients, stable patients converting from other tacrolimus formulations, and rapid metabolizers of tacrolimus.1,2

Trial results icon

Trial results in de novo kidney transplant patients

DE NOVO STUDY DESIGN3,4

Phase 3, double-blind, randomized, multicenter trial to compare the efficacy and safety of ENVARSUS XR vs Prograf® in adult de novo transplant recipients of a living or deceased donor kidney transplant (except for donation after cardiac death) (N=543). The primary efficacy endpoint was the incidence of treatment failures within 12 months after the randomization date; 507 patients completed the 24-month study period.

ENVARSUS XR offers lasting efficacy1,4,5

Patient and graft protection at 1 and 2 years1,4

Patient and graft protection at 1 and 2 years.
*Treatment failure was a composite endpoint of biopsy-proven acute rejection, graft failure, death, and loss to follow-up.
P value not significant for all measures.
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Year 1 (ENVARSUS XR %, Prograf® %)

  • Biopsy-proven acute rejection: 13.4% vs 13.5%
  • Graft failure: 3.4% vs 4.0%
  • Death: 3.0% vs 2.9%
  • Loss to follow-up: 1.5% vs 1.8%
  • Treatment failure composite*: 18.7% vs 19.6%

Year 2 (ENVARSUS XR %, Prograf® %)

  • Biopsy-proven acute rejection: 17.2% vs 18.2%
  • Graft failure: 4.1% vs 5.5%
  • Death: 4.1% vs 4.7%
  • Loss to follow-up: 1.5% vs 2.9%
  • Treatment failure composite*: 23.1% vs 27.3%
*Treatment failure was a composite endpoint of biopsy-proven acute rejection, graft failure, death, and loss to follow-up.
P value not significant for all measures.

DGF rates after transplant3*

7.1% of ENVARSUS XR patients vs 10.9% of Prograf® patients
*DGF was assessed via a post hoc analysis of adverse events of interest from a 12-month, Phase 3 clinical trial.

Treatment failure rates at 3 months3*

10.4% of ENVARSUS XR patients vs 14.2% of Prograf® patients
*Treatment failure was a composite endpoint of biopsy-proven acute rejection, graft failure, death, and loss to follow-up.

Freedom from treatment failure at 2 years4,6

Over 24 months of follow-up, ENVARSUS XR demonstrated consistent protection from treatment failure vs Prograf®6*

  • At 1 year, recipients on ENVARSUS XR had a 9% lower risk of treatment failure vs those on Prograf®
  • At 2 years, recipients on ENVARSUS XR had a 17% lower risk of treatment failure vs those on Prograf®
*Treatment failure was a composite endpoint of biopsy-proven acute rejection, graft failure, death, and loss to follow-up.
Graph comparing the percentage of patients' HR between Prograf and Envarsus XR over a 2 year period
eGFR was comparable over 2 years.
Clinical findings were not statistically significant.
Expand for Image Description

Kaplan-Meier analysis of the proportion of patients free of treatment failure over 24 months. No significant difference was seen between the ENVARSUS XR and Prograf® groups in treatment failure by time-to-event distribution (log-rank test). Both groups had more treatment failures in the first year compared with the second; the ENVARSUS XR group had fewer treatment failures in both years.

In clinical trials of de novo kidney transplant recipients, the most common adverse reactions (incidence ≥15%) included: diarrhea, anemia, urinary tract infection, hypertension, tremor, constipation, diabetes mellitus, peripheral edema, hyperkalemia, and headache.1

Trial results in patients converting from immediate-release tacrolimus

MELT TRIAL STUDY DESIGN7

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 months1

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 tacrolimus7

Chart comparing results of ENVARSUS XR and immediate-release tacrolimus capsules
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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.

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.1

Expected safety outcomes demonstrated across clinical trials

Across all safety measures, there were no significant differences between the 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.1,4†

ENVARSUS XR has been studied in 27 trials with 1657 participants6

Phase 1

19

Trials

516

Healthy Participants

Phase 2

3

Trials

147

Patients

Phase 3

2

Trials

869

Patients

Phase 3b

3

Trials

125

Patients

Analysis restricted to patients at risk of NODAT.
AZA=azathioprine; CI=confidence interval; DGF=delayed graft function; eGFR=estimated glomerular filtration rate; HR=hazard ratio; MDRD7=Modification of Diet in Renal Disease 7; MELT=Multicenter Evaluation of LCP-Tacro Trial.; MMF=mycophenolate mofetil; MPS=mycophenolate sodium; NODAT=new-onset diabetes after transplantation.

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. 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. 3. Budde K, Bunnapradist S, Grinyo JM, et al. 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. 4. Rostaing L, Bunnapradist S, Grinyó JM, et al. 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. 5. Bunnapradist S, Rostaing L, Alloway RR, et al. LCPT once-daily extended-release tacrolimus tablets versus twice-daily capsules: a pooled analysis of two phase 3 trials in important de novo and stable kidney transplant recipient subgroups. Transpl Int. 2016;29(5):603-611. 6. Data on file. Veloxis Pharmaceuticals, Inc.; 2018. 7. Bunnapradist S, Ciechanowski K, West-Thielke P, et al. Conversion from twice-daily tacrolimus to once-daily extended-release tacrolimus (LCPT): the phase III randomization MELT trial. Am J Transplant. 2013;13(3):760-769.