Rapid Metabolizer Data

For all kidney transplant patient types, even rapid metabolizers of tacrolimus, once-daily ENVARSUS XR delivers consistent control.1-4

After transplant, rapid metabolizers of tacrolimus face unique risks

Complications

Bear trap

Rapid metabolizers are at risk for5

  • Significantly more for-cause biopsies
  • Greater CNI nephrotoxicity
  • More BK nephropathy

Higher Peaks

Bear trap

Compared with nonexpressors of CYP3A5*1, rapid metabolizers experience a 34% increase in Cmax of tacrolimus4

Rejection

Bear trap

Patients with high tacrolimus clearance were 2.4 times as likely to have biopsy-proven rejection in the first 90 days post-transplantation compared to those with low clearance (P<0.006)6

Trial results in rapid metabolizers of tacrolimus

ASERTAA STUDY DESIGN4

Phase 3b prospective, randomized, open-label, 2-sequence, crossover pharmacogenetic study to compare the steady-state PK of IR-Tac twice daily to ENVARSUS XR once daily in adult stable African American kidney transplant patients (N=46).

Identifying and treating rapid metabolizers

ENVARSUS XR works in all patient types, including difficult-to-treat rapid metabolizers, who are sometimes referred to as fast metabolizers.2,4,7

To achieve therapeutic trough levels of tacrolimus with IR-Tac formulations, rapid metabolizer patients require 1.5 to 2 times higher doses of IR-Tac, putting them at risk of significantly higher peak concentrations, potentially magnifying the risk of toxicity and adverse outcomes.4,5,8 Rapid metabolizers are found across ethnicities, predominately but not exclusively in those of Black African descent.8

African American Patient

45%-80%
African American4,10

Asian Patient

15%-35%
Asian10

Caucasian Patient

5%-30%
Caucasian10,11

Hispanic Patient

13%-26%
Hispanic10,12

Rapid metabolizers achieved target trough levels with a 20% lower dose of ENVARSUS XR4

Pharmacokinetic chart of immediate-release tacrolimus rapid metabolizers vs rapid metabolizers of ENVARSUS XR
*Subjects not expressing the CYP3A5*1 genotype.
Clinical benefit of the differences in ENVARSUS XR PK has not been established.
Expand for Image Description

Whole blood concentration of tacrolimus (ng/mL) over time after morning dose, represented in 2-hour increments:

  • 30% decrease in Cmax in ENVARSUS XR rapid metabolizers (n=35) compared with IR-Tac rapid metabolizers (n=35) and ENVARSUS XR in nonexpressors* (n=11)
*Subjects not expressing the CYP3A5*1 genotype.
Clinical benefit of the differences in ENVARSUS XR PK has not been established.

Rapid metabolizers achieve a smooth tacrolimus PK profile with a once-daily dose of ENVARSUS XR, avoiding the high peaks seen with the immediate-release formulations4

ASERTAA=A Study of Extended Release Tacrolimus in African Americans; BK=BK virus; Cmax=maximum concentration; CNI=calcineurin inhibitor; CYP3A5*1=cytochrome family P450, subfamily 3A, member 5, variant 1; IR-Tac=immediate-release tacrolimus; PK=pharmacokinetics.

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.

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. This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under- or over-exposure to tacrolimus. 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: ENVARSUS XR, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity. Consider dosage reduction in patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range. 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.

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 coadministering ENVARSUS XR with strong CYP3A inhibitors or strong CYP3A inducers.

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 coadministering ENVARSUS XR with other substrates and/or inhibitors of CYP3A, 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.

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.

References: 1. Data on file. Veloxis Pharmaceuticals, Inc.; 2023. 2. ENVARSUS XR [package insert]. Cary, NC: Veloxis Pharmaceuticals, Inc.; 2023. 3. 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. 4. 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. 5. Thölking G, Fortmann C, Koch R, et al. The tacrolimus metabolism rate influences renal function after kidney transplantation. PLoS One. 2014;9(10):e111128. 6. Egeland EJ, Robertsen I, Hermann M, et al. High tacrolimus clearance is a risk factor for acute rejection in the early phase after renal transplantation. Transplantation. 2017;101(8):e273-e279. 7. Nigro V, Glicklich A, Weinberg J. Improved bioavailability of MELTDOSE once-daily formulation of tacrolimus (LCP-Tacro) with controlled agglomeration allows for consistent absorption over 24 hrs: a scintigraphic and pharmacokinetic evaluation [abstract]. Am J Transplant. 2013;13(suppl 5):335. 8. Birdwell KA, Decker B, Barbarino JM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP3A5 genotype and tacrolimus dosing. Clin Pharmacol Ther. 2015;98(1):19-24. 9. Lamba J, Hebert JM, Schuetz EG, Klein TE, Altman RB. PharmGKB summary: very important pharmacogene information for CYP3A5. Pharmacogenet Genomics. 2012;22(7):555-558. 10. Staatz CE, Goodman LK, Tett SE. Effect of CYP3A5 and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: part I. Clin Pharmacokinet. 2010;49(3):141-175. 11. Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 2001;27(4):383-391. 12. Claudio-Campos K, Duconge J, Cadilla CL, Ruaño G. Pharmacogenetics of drug-metabolizing enzymes in US Hispanics. Drug Metab Pers Ther. 2015;30(2):87-105.