How ENVARSUS XR Works

[VOICEOVER]

(On-screen text reads, “IR-TACROLIMUS. FDA approval in 1994. ONE OF THE MOST WIDELY USED IMMUNOSUPPRESSION DRUGS IN KIDNEY TRANSPLANTATION”)

Initially approved by the FDA in 1994, tacrolimus is one of the most widely used immunosuppression drugs in kidney transplantation.

(On-screen text reads, “HIGHLY EFFECTIVE IN PREVENTING GRAFT REJECTION”)

Although immediate-release tacrolimus has been proven highly effective in preventing graft rejection, it is not without limitations.

(On-screen text reads, “LIMITATION”)

Immediate-release tacrolimus has low bioavailability,

(On-screen text reads, “Low Bioavailability. Less than 20% of an orally administered dose. Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. Prograf® [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc.; 2018”)

often reported to be less than 20% of an orally administered dose.

The low bioavailability of tacrolimus is largely due to the high rate of presystemic metabolism. Presystemic metabolism is primarily the result of 2 systems, which are active in the transport and metabolism of drugs from the GI tract.

(On-screen text reads, “P-glycoprotein and cytochrome P450 systems. ENVARSUS XR® [prescribing information]. Cary, NC: Veloxis Pharmaceuticals, Inc.; 2020”)

This first system is the P-glycoprotein system, which is responsible for transporting the drug out of cells and back into the lumen of the intestine.

(On-screen text reads: “LUMEN, PGP, ENTEROCYTE”)

The other active system is the cytochrome P450 isoenzyme system, which is a group of enzymes that converts tacrolimus into predominately inactive metabolites. P450 enzymes are present both on the intestinal luminal cells as well as in the liver, affecting both presystemic tacrolimus and tacrolimus absorbed into the bloodstream.

(On-screen text reads: “CYP450” “Effecting both presystemic tacrolimus and tacrolimus absorbed into the blood stream” “UNCHANGED DRUG” “INACTIVE METABOLITE” “BLOOD STREAM”)

Importantly, only tacrolimus in the bloodstream, in its unchanged form, is able to suppress T cells and prevent rejection.

(On-screen text reads, “Only tacrolimus in the bloodstream in its unchanged form is able to suppress T cells and prevent rejection”)

In reality, these 2 systems function simultaneously to transport and metabolize tacrolimus so effectively that only about 20% of the drug is absorbed into the bloodstream.

(On-screen text reads, “Only about 20% of the unchanged drug is absorbed into the bloodstream”)

This limited oral bioavailability of tacrolimus creates clinical challenges for the transplant clinician.

Introducing ENVARSUS XR controlled release with MeltDose® technology for stable delivery.

(On-screen text reads, “Introducing ENVARSUS XR® and MeltDose® technology”)

Please see Boxed Warning regarding malignancies and serious infections, as well as additional full Important Safety Information, at the end of this video.

(On-screen text reads:
“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.

See full Important Safety Information, including Boxed Warning, at the end of this video.”)

(On-screen text reads, “MeltDose® technology” “A specially designed carrier matrix”)

ENVARSUS XR uses MeltDose® technology to apply single-molecule tacrolimus to a specially designed carrier matrix. This allows it to be held in a solid suspension and released in a delayed fashion over the length of the GI tract.

(On-screen text reads, “The differences in the THREE TACROLIMUS FORMULATIONS Time to peak” “PROGRAF®” “ASTAGRAF XL®” “ENVARSUS XR®” “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. Normalized to mean whole blood concentration of tacrolimus based on conversion factors of 1 (Prograf®): 1.08 (Astagraf XL): 0.7 (ENVARSUS XR).”)

To understand the impact of formulation on 24-hour pharmacokinetics, a study was done to assess the 3 tacrolimus formulations. It entailed frequent assessment of tacrolimus levels over a 24-hour period.

As demonstrated in this study, immediate-release tacrolimus achieves maximum concentrations at 1.5 hours and declines rapidly until the evening dose is administered, 12 hours later. There is long-standing evidence with immediate-release tacrolimus that diurnal variation and bioavailability exists. Thus the nighttime dose is typically less bioavailable and contributes less to the overall, 24-hour exposure.

(On-screen text reads, [HEADER]“PROGRAF®”
[LINE GRAPH: Y-AXIS]“Mean Whole Blood Concentration (ng/mL) 5, 10, 15, 20, 25” [CHART LEGEND]“PROGRAF®” [LINE GRAPH: X-AXIS]“Time (hr) 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24” [FOOTER] “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. Normalized to mean whole blood concentration of tacrolimus based on conversion factors of 1 (Prograf®): 1.08 (Astagraf XL): 0.7 (ENVARSUS XR).”)

In an attempt to delay and lower the peak, while providing similar overall exposure, sustained release dosage forms were created. ASTAGRAF results in slightly lower and slightly delayed peaks, though these were not found to be significantly different than immediate-release tacrolimus.

(On-screen text reads, [HEADER]“ASTAGRAF XL®”
[LINE GRAPH: Y-AXIS]“Mean Whole Blood Concentration (ng/mL) 5, 10, 15, 20, 25” [CHART LEGEND]“ASTAGRAF XL®” [LINE GRAPH: X-AXIS]“Time (hr) 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24” [FOOTER] “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. Normalized to mean whole blood concentration of tacrolimus based on conversion factors of 1 (Prograf®): 1.08 (Astagraf XL): 0.7 (ENVARSUS XR).”)

ENVARSUS XR was designed to deliver the drug throughout the GI tract, creating a truly delayed drug delivery to the patient. Given the controlled release of tacrolimus from ENVARSUS XR tablets, ENVARSUS XR results in significantly lower maximum concentrations, a longer time to peak, and less fluctuation in level, while still delivering a similar overall exposure over 24 hours.

(On-screen text reads, [HEADER]“ENVARSUS XR^® Impact of MeltDose^®: Target exposure with a significantly lower peak” [LINE GRAPH: Y-AXIS]“Mean Whole Blood Concentration (ng/mL) 5, 10, 15, 20, 25” [CHART LEGEND] ]“PROGRAF®” “ASTAGRAF XL®” “ENVARSUS XR®” [LINE GRAPH: X-AXIS]“Time (hr) 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24” [FOOTER] “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. Normalized to mean whole blood concentration of tacrolimus based on conversion factors of 1 (Prograf®): 1.08 (Astagraf XL): 0.7 (ENVARSUS XR). Clinical benefit of the differences in ENVARSUS XR PK has not been established”)

In subsequent Phase 3 clinical studies, results demonstrated that once-daily ENVARSUS XR was noninferior to twice-daily immediate-release Prograf® in treatment failure in de novo renal transplant patients. The clinical benefit of the differences in ENVARSUS XR PK has not been established.

(On-screen text reads, [HEADER]“Patients remaining free from treatment failure TIME FREE FROM TREATMENT FAILURE VS PROGRAF®” [LINE GRAPH: Y-AXIS]“% Patients 50, 60, 70, 80, 90, 100” [CHART LEGEND] “ENVARSUS XR® (n=268)” “PROGRAF® (n=275)” [PLOT POINT 1]“HR 0.91 (95% CI, 0.62-1.34)” [PLOT POINT 2]“HR 0.83 (95% CI, 0.59-1.16)” [LINE GRAPH: X-AXIS]“Days after randomization 0, 30, 60, 90, 120, 180, 240, 300, 360, 420, 480, 540, 600, 660, 720” [FOOTER] “The clinical benefit of the differences in ENVARSUS XR PK has not been established” “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.”)

ENVARSUS XR. Consider the impact of this technology for your transplant patients.

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

BOXED 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.

[TEXT ON-SCREEN]
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

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.