General Information

Envarsus XR is an extended release formulation of tacrolimus, a calcineurin-inhibitor immunosuppressant.

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

Envarsus XR is supplied as a tablet for oral administration. It should be taken on an empty stomach at the same time of the day, preferably in the morning (to ensure consistent and maximum possible drug exposure). The Envarsus XR tablets should be swallowed whole with fluid (preferably water). Do not chew, divide, or crush the tablets. If a dose is missed, take it as soon as possible within 15 hours after missing the dose; beyond the 15-hour time frame, wait until the usual scheduled time to take the next regular daily dose. Do not double the next dose. Avoid eating grapefruit or drinking grapefruit juice or alcoholic beverage while taking Envarsus XR. African-American patients, compared to Caucasian patients, may need to be titrated to higher Envarsus XR dosages to attain comparable trough concentrations.

To convert from a tacrolimus immediate-release product to Envarsus XR, administer an Envarsus XR once daily dose that is 80% of the total daily dose of the tacrolimus immediate-release product. Monitor tacrolimus whole blood trough concentrations and titrate Envarsus XR dosage to achieve target whole blood trough concentration ranges of 4 to 11 ng/mL.

Clinical Results

FDA Approval

The FDA approval of Envarsus XR was based on a conversion study. The conversion study was a randomized, open-label, multinational study evaluating once daily Envarsus XR when used to replace tacrolimus immediate-release administered twice daily for maintenance immunosuppression to prevent acute allograft rejection in stable adult kidney transplant patients. Patients who received a kidney transplant 3 months to 5 years before study entry and on a stable dose of tacrolimus immediate-release of at least 2 mg per day and tacrolimus whole blood trough concentrations between 4 and 15 ng/mL were randomized to 1) switch from twice daily tacrolimus immediate-release to once daily Envarsus XR (N=163) or 2) continue tacrolimus immediate-release twice daily (N=163). MMF or mycophenolate sodium (MPS), or azathioprine (AZA) and/or corticosteroids were allowed as concomitant immunosuppressants during the study period according to the standard of care at the participating site. In the conversion study, stable kidney transplant patients converted to Envarsus XR at an average daily dose that was 80% of their tacrolimus immediate-release daily dose prior to conversion. Mean tacrolimus whole blood trough concentrations were maintained within a relatively narrow range throughout the duration of the study for both the Envarsus XR conversion group and the tacrolimus immediate-release continuation group. At Week 1 (after 7 days of stable dosing), the mean ± SD tacrolimus trough concentrations were 7.2 ± 3.1 ng/mL for the Envarsus XR conversion group and 7.7 ± 2.5 for the tacrolimus immediate-release continuation group; the baseline values were 7.8 ± 2.3, and 8.0 ± 2.3, respectively. Study Drug: MMF In the conversion study, the average daily mycophenolate equivalent doses were comparable between the Envarsus XR and tacrolimus immediate-release treatment groups. The efficacy failure rates including patients who developed BPAR, graft failure, death, and/or lost to follow-up at 12 months, as well as the rates of the individual events were essentially the same between the tacrolimus immediate-release and tacrolimus extended-release groups.

Mechanism of Action

Envarsus XR is an extended release formulation of tacrolimus, a calcineurin-inhibitor immunosuppressant. Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (an ubiquitous mammalian intracellular enzyme) is then formed and the phosphatase activity of calcineurin inhibited. Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT) and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB). Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony stimulating factor. Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor-beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).