Envarsus XR (Page 7 of 9)

14.2 Conversion Study from Tacrolimus Capsules in Stable Kidney Transplant Recipients

Study 3

The conversion study, Study 3 (NCT00817206), was a Phase 3 randomized, open-label, multinational study evaluating once daily ENVARSUS XR when used to replace tacrolimus [immediate-release] capsules 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] capsules 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 capsules to once daily ENVARSUS XR (N=163) or 2) continue tacrolimus capsules 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.

The mean age of study population was 50 years; 67% were male; 73% were Caucasian, 22% were African-American, 2% were Asian and 3% were categorized as other races. Living donors provided 35% of the organs and 65% of patients received a kidney transplant from a deceased donor. Premature discontinuation from treatment at the end of one year occurred in 13% of ENVARSUS XR patients and 6% of tacrolimus capsule patients.

Tacrolimus Therapy

In Study 3, stable kidney transplant patients converted to ENVARSUS XR at an average daily dose that was 80% of their tacrolimus [immediate-release] capsules 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 capsules 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 capsules continuation group; the baseline values were 7.8 ± 2.3, and 8.0 ± 2.3, respectively.

MMF Therapy

In Study 3, the average daily mycophenolate equivalent doses were comparable between the ENVARSUS XR and tacrolimus capsules treatment groups.

Efficacy Results

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, are shown by treatment group in Table 11 for the modified intent-to-treat population.

Table 11. Incidence of BPAR, Graft Loss, Death or Lost to Follow-up at 12 Months in Stable Kidney Transplant Patients in Study 3
a 95% CI was calculated using an exact method that is based on the standardized statistic and inverting a 2-sided test
ENVARSUS XR ± Steroids ± MMF, MPS, or AZA N=162 Tacrolimus [Immediate-Release] Capsules ± Steroids ± MMF, MPS, or AZA N=162
Treatment Failure 4 (2.5%) 4 (2.5%)
Overall Treatment Difference of efficacy failure compared to tacrolimus immediate-release (95% CI)a 0% (-4.2%, 4.2%)
Biopsy Proven Acute Rejection 2 (1.2%) 2 (1.2%)
Graft Failure 0% 0%
Death 2 (1.2%) 1 (0.6%)
Lost to Follow-up 0% 1 (0.6%)

Glomerular Filtration Rates

The mean estimated glomerular filtration rates (eGFR), using the Modification of Diet in Renal Disease 7 (MDRD7) formula, were 61.5 ml/min/1.73 m2 and 60.0 ml/min/1.73 m2 at baseline (Day 0) and 62.0 ml/min/1.73 m2 and 61.4 ml/min/1.73 m2 at 12 months in the ENVARSUS XR and tacrolimus capsules treatment groups, respectively.

16 HOW SUPPLIED/STORAGE AND HANDLING

ENVARSUS XR is supplied in round HDPE bottles with twist-off caps (see Table 12); the statement ‘ONCE-DAILY’ appears on its labels.

Table 12. Strengths of ENVARSUS XR
Strength Description NDC
0.75 mg Oval, white to off-white uncoated extended-release tablet, debossed with “0.75” on one side and “TCS” on the other side. 30-count (NDC 68992-3075-3) 100-count (NDC 68992-3075-1)
1 mg Oval, white to off-white uncoated extended-release tablet, debossed with “1” on one side and “TCS” on the other side. 30-count (NDC 68992-3010-3)100-count (NDC 68992-3010-1)
4 mg Oval, white to off-white uncoated extended-release tablet, debossed with “4” on one side and “TCS” on the other side. 30-count (NDC 68992-3040-3)100-count (NDC 68992-3040-1)

Store and Dispense
Store at 25 °C (77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 86 °F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

17.1 Administration

Advise patients to:

  • Inspect their ENVARSUS XR medicine when they receive a new prescription and before taking it. If the appearance of the tablet is not the same as usual, or if dosage instructions have changed, advise patients to contact their healthcare provider as soon as possible to make sure that you have the right medicine. Other tacrolimus products cannot be substituted for ENVARSUS XR [see Warnings and Precautions (5.3)].
  • Take once-daily ENVARSUS XR at the same time every day (preferably in the morning) on an empty stomach. at least 1 hour before or at least 2 hours after a meal to ensure consistent and maximum possible drug concentrations in the blood.
  • Swallow tablet whole with liquid, preferably water. Do not chew, divide or crush tablet.
  • Avoid alcoholic beverages, grapefruit, and grapefruit juice while on ENVARSUS XR [see Dosage and Administration (2.1) and Drug Interactions (7.2)].
  • Take a missed dose as soon as possible but not more than 15 hours after the scheduled time (i.e., for a missed 8 AM dose, take it no later than 10 PM). Beyond the 15-hour timeframe, instruct the patient to wait until the usual scheduled time the following morning to take the next regularly scheduled dose. Do not take two doses at the same time [see Dosage and Administration (2.1)].

17.2 Development of Lymphoma and Other Malignancies

Inform patients that they are at an increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and use a sunscreen with a high protection factor [see Boxed Warning and Warnings and Precautions (5.1)].

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