Envarsus XR

ENVARSUS XR- tacrolimus tablet, extended release
Veloxis Pharmaceuticals, Inc

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 [see Warnings and Precautions (5.1, 5.2)].

1 INDICATIONS AND USAGE

1.1 Prophylaxis of Organ Rejection in De Novo Kidney Transplant Patients

ENVARSUS XR is indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants [see Clinical Studies (14.1)].

1.2 Prophylaxis of Organ Rejection in Stable Kidney Transplant Patients Converting from Immediate-Release Formulations

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 [see Clinical Studies (14.2)].

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

  • ENVARSUS XR (tacrolimus extended-release tablets) is not interchangeable or substitutable with tacrolimus extended-release capsules, tacrolimus capsules, and tacrolimus for oral suspension. Under or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions [see Warnings and Precautions (5.3)]. ENVARSUS XR should not be used without the supervision of a physician with experience in immunosuppressive therapy.
  • ENVARSUS XR should be taken on an empty stomach consistently at the same time of the day, preferably in the morning to ensure consistent and maximum possible drug exposure, at least 1 hour before a meal or at least 2 hours after a meal [see Clinical Pharmacology (12.3)].
  • Advise patients to swallow ENVARSUS XR tablets whole with fluid (preferably water); patients must not chew, divide, or crush the tablets.
  • If a dose is missed, instruct the patient to take it as soon as possible within 15 hours after missing the dose. Beyond the 15-hour time frame, instruct the patient to wait until the usual scheduled time to take the next regular daily dose. Instruct the patient not to double the next dose.
  • Patients should avoid eating grapefruit or drinking grapefruit juice or alcoholic beverage while taking ENVARSUS XR [see Drug Interactions (7.2)].

2.2 Dosing in De Novo Kidney Transplant Patients

The recommended starting dose of ENVARSUS XR in de novo kidney transplant patients is 0.14 mg/kg/day. Titrate ENVARSUS XR dosage based on clinical assessments of rejection and tolerability and to achieve whole blood trough concentration ranges (see Table 1).

Table 1. Recommended Tacrolimus Whole Blood Trough Concentration Ranges in Kidney Transplant Patients with Antibody Induction
Time Period Post Transplant Target Tacrolimus Whole Blood Trough Concentration Ranges
During Month 1 6 to 11 ng/mL
> Month 1 4 to 11 ng/mL

2.3 Dosing for Conversion from Tacrolimus Immediate-Release Formulations

To convert from a tacrolimus immediate-release product to ENVARSUS XR, administer ENVARSUS XR once daily at a 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 whole blood trough concentration ranges of 4 to 11 ng/mL.

2.4 Dosing Adjustments in African-American Patients, Patients with Hepatic Impairment, Drug Interactions

African-American patients, compared to Caucasian patients, may need to be titrated to higher ENVARSUS XR dosages to attain comparable trough concentrations [see Use in Specific Populations (8.8), Clinical Pharmacology (12.3)].

Due to reduced clearance and prolonged half-life seen in patients with severe hepatic impairment (Child-Pugh ≥10) these patients may require a lower starting dosage of ENVARSUS XR [see Clinical Pharmacology (12.3)].

Dose adjustments of ENVARSUS XR may be necessary when administered concomitantly with CYP3A inducers or CYP3A inhibitors [see Warnings and Precautions (5.9), Drug Interactions (7.2)].

2.5 Therapeutic Drug Monitoring

Measure tacrolimus whole blood trough concentrations at least two times on separate days during the first week after initiation of dosing and after any change in dosage, after a change in co-administration of CYP3A inducers and/or inhibitors [see Drug Interactions (7)], or after a change in renal or hepatic function. When interpreting measured concentrations, consider that the time to achieve tacrolimus steady state is approximately 7 days after initiating or changing the ENVARSUS XR dose.

Monitor tacrolimus whole blood trough concentrations using a validated assay [e.g., immunoassays or high-performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS)]. The immunosuppressive activity of tacrolimus is mainly due to the parent drug rather than to its metabolites. Immunoassays may react with metabolites as well as the parent drug. Therefore, whole blood tacrolimus trough concentrations obtained with immunoassays may be numerically higher than concentrations obtained with an assay using HPLC/MS/MS. Comparison of the whole blood tacrolimus trough concentrations of patients to those described in the prescribing information and other published literature must be made with knowledge of the assay method(s) employed.

3 DOSAGE FORMS AND STRENGTHS

Oval, white to off-white uncoated extended-release tablets debossed with “TCS” on one side:

  • 0.75 mg extended-release tablet: debossed with “0.75” on the other side.
  • 1 mg extended-release tablet: debossed with “1” on the other side.
  • 4 mg extended-release tablet: debossed with “4” on the other side.

4 CONTRAINDICATIONS

ENVARSUS XR is contraindicated in patients with known hypersensitivity to tacrolimus.

5 WARNINGS AND PRECAUTIONS

5.1 Lymphoma and Other Malignancies

Immunosuppressants, including ENVARSUS XR, increase the risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. Examine patients for skin changes and advise to avoid or limit exposure to sunlight and UV light by wearing protective clothing and using a sunscreen with a high protection factor.

Post-transplant lymphoproliferative disorder (PTLD), associated with Epstein-Barr Virus (EBV), has been reported in immunosuppressed organ transplant patients. The risk of PTLD appears greatest in those individuals who are EBV seronegative. Monitor EBV serology during treatment.

5.2 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. Serious viral infections reported include:

  • Polyomavirus-associated nephropathy (especially due to BK virus infection),
  • JC virus-associated progressive multifocal leukoencephalopathy (PML), and
  • Cytomegalovirus (CMV) infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at highest risk of CMV viremia and CMV disease.

Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection [see Adverse Reactions (6.1)].

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