Considerations for ENVARSUS XR Protocol Development

If your facility is looking to establish an ENVARSUS XR protocol for adult renal transplant patients, we are here to help. Open lines of communication with your Veloxis Transplant Account Manager (TAM) can ensure we are doing everything we can to support you.

Align stakeholders within your facility

Depending on your facility, certain members of your team may fulfill multiple roles in a patient’s transplant success. No matter their role, everyone plays an important part in the successful adoption of a protocol for ENVARSUS XR. To ensure a successful rollout, make sure your team stays well informed on materials and resources.

Factors to consider with de novo ENVARSUS XR management

Determining optimal starting dosage, learning how to titrate, and monitoring labs for de novo patients are some of the important areas to understand at the beginning of your ENVARSUS XR protocol development.

  • In de novo patients (with antibody induction)—0.14 mg/kg/day is the recommended starting dose1
  • The elimination half-life of ENVARSUS XR is 31 hours1
  • Monitor tacrolimus trough levels and titrate dose to achieve the target trough level for individual patients1*
  • Dosing adjustment may be needed for African American patients, patients with hepatic impairment, or for drug interactions1
  • Measure tacrolimus whole blood trough concentrations at least 2 times on separate days during the first week after initiation of dosing and after any change in dosage, after a change in coadministration of CYP3A inducers and/or inhibitors, or after a change in renal or hepatic function1
    • When interpreting measured concentrations, consider that the time to achieve tacrolimus steady state is approximately 7 days after initiating or changing the ENVARSUS XR dose1
*Recommended target whole blood trough concentration range is 6 to 11 ng/mL for the first month and 4 to 11 ng/mL after the first month.1

Determine initial ENVARSUS XR dose selection

Backed by data from Phase 3 trials in conversion and de novo patients, the recommended starting doses for ENVARSUS XR are as follows1:

  • De novo patients: 0.14 mg/kg/day. Titrate dosage based on clinical assessments of rejection and tolerability and to achieve whole blood trough concentration ranges.
  • Patients converting from IR-Tac: Administer ENVARSUS XR once daily at a dose that is 80% of the total daily dose of the tacrolimus immediate-release product

Your team may need to determine a dosing strategy on a case-by-case basis. See the ENVARSUS XR dosing page for more details.

Developing a protocol to switch a patient from an IR-Tac formulation to ENVARSUS XR? Use this dose converter.

Consider a pilot group

Starting a small group of patients on ENVARSUS XR initially can allow your facility to gain experience with ENVARSUS XR.

Understand the educational needs of various stakeholders

When beginning the development of your ENVARSUS XR protocol, stakeholders in your facility may have questions. Veloxis representatives assigned to your facility will be available to answer every question your team may have on ENVARSUS XR, every step of the way.

Schedule a Veloxis Representative Meeting

Ensuring access is critical

ENVARSUS XR is not a generic tacrolimus, and there is no generic equivalent for ENVARSUS XR.2 Veloxis offers several financial support options that may be able to help your patients.

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30-day free trial*

Patients new to ENVARSUS XR may receive a one time per life time, voucher at no cost to them.

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$0 Co-pay Card*

The $0 Co-pay Card can offer savings to eligible patients with commercial insurance coverage.

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Veloxis Transplant Support*

Veloxis has a patient assistance program to provide free ENVARSUS XR to eligible patients in need who meet certain criteria.

*Subject to terms and conditions. See eligibility requirements.
CYP3A=cytochrome family P450, subfamily 3A; 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. ENVARSUS XR [package insert]. Cary, NC: Veloxis Pharmaceuticals, Inc.; 2023. 2. 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