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Patient Considerations


ENVARSUS XR works in all patient types, including difficult-to-treat rapid metabolizers, who are sometimes referred to as fast metabolizers.1,2

Identifying and treating rapid metabolizers

As many as 1 in 3 patients may be rapid or fast metabolizers of tacrolimus.3 Although this characteristic is most frequently associated with African Americans, race alone should not be used to predict the pharmacokinetic challenges that these patients are facing.2,3

Rapid metabolizers are found across ethnicities2,4-6

African-American patients represent a significant proportion of rapid metabolizers of tacrolimus

45%-80% 

African-American2,4

Asian patients also represent a proportion of rapid metabolizers of tacrolimus

15%-35%

Asian4

Caucasian patients have been shown to rapidly metabolize tacrolimus

5%-30%

Caucasian4,5

Hispanic patients are also rapid metabolizers of tacrolimus

13%-26% 

Hispanic6

ENVARSUS XR works across all patient types.

Hear from real patients their experience with ENVARSUS XR.

Why are rapid metabolizers at risk?

Rapid metabolizers require 1.5-2x higher doses of immediate-release tacrolimus (IR-Tac) to achieve target trough levels, putting them at risk of higher peaks.7,8 A study showed that the higher tacrolimus dose resulted in a 34% increase in peak blood concentration to achieve the same target trough.2

Rapid metabolizers experience a 34% increase in Cmax in order to achieve the same target trough2

High IR tacrolimus doses needed for efficacy in rapid metabolizers caused a 34% increase in Cmax

aSubjects not expressing the CYP3A5*1 genotype.

ENVARSUS XR delivers — even in rapid metabolizers2

Patients who rapidly metabolize tacrolimus achieved target trough levels with a 20% lower dose of ENVARSUS XR, avoiding the high peaks seen with the immediate-release formulation.2

Rapid metabolizers achieve smooth tacrolimus pharmacokinetics with a once-daily dose2

ENVARSUS XR resulted in a 30% decrease in Cmax in rapid metabolizers compared with IR tacrolimus

aSubjects not expressing the CYP3A5*1 genotype.

Study Design: 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). Patients were randomized to receive either IR-Tac for 7 days and then switched to ENVARSUS XR for 14 days or ENVARSUS XR for 7 days and switched to IR-Tac for 14 days. Patients continued concomitant immunosuppression per standard of care. Patients were genotyped and PK assessments were completed on study Days 7, 14, and 21.2

Evaluating your patients’ status

Consider making changes in the immunosuppressive regimens of patients who:

  • Are unable to maintain adequate immunosuppression
  • Require high doses of immediate-release tacrolimus
  • Experience undesirable side effects
Review white papers and publications on ENVARSUS XR Learn how to prescribe ENVARSUS XR

INDICATIONS AND USAGE

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

Limitation of Use: ENVARSUS XR extended-release tablets are not interchangeable or substitutable with other tacrolimus products.

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.

Graft Rejection and Other Serious Adverse Reactions due to Medication Errors: Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products 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 immediate-release products or other tacrolimus extended-release products.

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.

ADVERSE REACTIONS

Most common adverse reactions (incidence 10%) reported with ENVARSUS XR include: diarrhea and blood creatinine increased.

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on animal data may cause fetal harm. Use only if the potential benefit justifies the risk.

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

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.

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.

 

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

INDICATIONS AND USAGE

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

Limitation of Use: ENVARSUS XR extended-release tablets are not interchangeable or substitutable with other tacrolimus products.

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.

Graft Rejection and Other Serious Adverse Reactions due to Medication Errors: Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products 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 immediate-release products or other tacrolimus extended-release products.

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.

ADVERSE REACTIONS

Most common adverse reactions (incidence 10%) reported with ENVARSUS XR include: diarrhea and blood creatinine increased.

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on animal data may cause fetal harm. Use only if the potential benefit justifies the risk.

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

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.

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. ENVARSUS XR [package insert]. Cary, NC: Veloxis Pharmaceuticals, Inc.: 2017. 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 DisPublished Online: November 20, 2017 (doi:10.1053/j.ajkd.2017.07.018). 3. Data on file. Veloxis Pharmaceuticals, Inc.: 2016. 4. Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: part I. Clin Pharmacokinet. 2010;49(3):141-175. 5. 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. 6. 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. 7. 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. 8. Thölking G, Gerth HU, Schuette-Nuetgen K, Reuter S. Influence of tacrolimus metabolism rate on renal function after solid organ transplantation. World J Transplant. 2017;7(1):26-33.