Envarsus XR: Package Insert and Label Information

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)].

5.3 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. Instruct patients and caregivers to recognize the appearance of ENVARSUS XR tablet [see Dosage Forms and Strengths (3)] and to confirm with their healthcare provider if a different product is dispensed or if dosing instructions have changed.

5.4 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. Monitor blood glucose concentrations and treat appropriately [see Adverse Reactions (6.1) and Use in Specific Populations (8.8)].

5.5 Nephrotoxicity due to ENVARSUS XR and Drug Interactions

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 (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors) [see Adverse Reactions (6.1, 6.2), Drug Interactions (7.2)]. Monitor renal function and consider dosage reduction if nephrotoxicity occurs.

5.6 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 [see Adverse Reactions (6.1, 6.2)]. As symptoms may be associated with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of ENVARSUS XR if neurotoxicity occurs.

5.7 Hyperkalemia

Mild to severe hyperkalemia, which may require treatment, has been reported with tacrolimus including ENVARSUS XR. Concomitant use of agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) may increase the risk for hyperkalemia [see Adverse Reactions (6.1)]. Monitor serum potassium levels periodically during treatment.

5.8 Hypertension

Hypertension is a common adverse reaction of ENVARSUS XR therapy and may require antihypertensive therapy [see Adverse Reactions (6.1)]. Some antihypertensive drugs can increase the risk for hyperkalemia [see Warnings and Precautions (5.7)]. Calcium-channel blocking agents may increase tacrolimus blood concentrations and require dosage reduction of ENVARSUS XR [see Drug Interactions (7.2)].

5.9 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 (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.10)]. Therefore, adjust ENVARSUS XR dose and monitor tacrolimus whole blood trough concentrations when coadministering ENVARSUS XR with strong CYP3A inhibitors (e.g., including but not limited to telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) or strong CYP3A inducers (e.g., including but not limited to rifampin, rifabutin) [see Dosage and Administration (2.3, 2.5), Drug Interactions (7.2)].

5.10 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 (magnesium, potassium, calcium) 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 (e.g., hypokalemia, hypocalcemia, or hypomagnesemia).

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 [see Dosage and Administration (2.5), Drug Interactions (7.2)].

5.11 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 (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines).

Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with ENVARSUS XR.

5.12 Pure Red Cell Aplasia

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. All of these patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. A mechanism for tacrolimus-induced PRCA has not been elucidated. If PRCA is diagnosed, consider discontinuation of ENVARSUS XR.

6 ADVERSE REACTIONS

The following clinically significant adverse drug reactions are discussed in greater detail in other sections of the labeling:

6.1 Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In addition, the clinical studies were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.

Study 1- Phase 3 Clinical Study in De Novo Kidney Transplant Recipients

Study 1 (NCT 01187953), was a Phase 3 randomized study in de novo kidney transplant patients that were treated with ENVARSUS XR (N=268) or tacrolimus [immediate-release] capsules (N=275) and concomitant immunosuppressants in a double-blind, randomized, multinational study [see Clinical Studies (14.1)]. The proportion of patients who discontinued treatment due to adverse reactions was 8.6% and 9.8% in the ENVARSUS XR and tacrolimus capsules treatment groups, respectively, through 12 months of treatment. The most common adverse reactions leading to discontinuation of study drug in the ENVARSUS XR treatment group were esophagitis, polyomavirus-associated nephropathy, graft dysfunction, complications of transplanted kidney, and diabetes mellitus, each resulting in 0.7% discontinuations among ENVARSUS XR treatment patients. In Study 1, de novo kidney transplant patients who received a starting dose of 0.17 mg/kg/day, which is higher than the recommended ENVARSUS XR starting dose of 0.14 mg/kg/day, exceeded the recommended target tacrolimus trough concentrations as high as 57 ng/mL during the first 1 to 2 weeks post-transplant [see Dosage and Administration (2.2)].

Infections

The overall incidence of infections, serious infections, and infections with identified etiology reported in de novo kidney transplant recipients treated with ENVARSUS XR or tacrolimus [immediate-release] capsules in Study 1 are shown in Table 2.

Table 2 Percentage of Patients with Infections Through 1 Year Post-Kidney Transplant in Study 1 a
MMF/MPS- Mycophenolate mofetil/mycophenolate sodium; AZA-azathioprinea Study 1 was not designed to support comparative claims of ENVARSUS XR compared to tacrolimus [immediate-release] capsules for the adverse reactions reported in this table.
b BK virus-associated nephropathy (BKVAN) occurred in 1.5% (4/268) and 0.7% (2/275) in the ENVARSUS XR and tacrolimus capsules treatment groups, respectively.
ENVARSUS XR ± steroids, IL-2 receptor antagonist induction therapy, MMF/MPS or AZA N=268 Tacrolimus [immediate-release] capsules ± steroids, IL-2 receptor antagonist induction therapy, MMF/MPS or AZA N=275
All infections 70% 65%
Urinary Tract Infections 29% 27%
Respiratory Infections 28% 24%
Bacterial Infections 13% 18%
Cytomegalovirus Infections 11% 9%
Fungal Infections 9% 8%
Gastrointestinal Infections 6% 4%
BK virus b 6% 9%
Serious Infections 26% 24%

New Onset Diabetes After Transplantation

New onset diabetes after transplantation (NODAT) was defined by the composite occurrence of fasting plasma glucose values ≥126 mg/dL, 2-hour post-prandial plasma glucose of at least 200 mg/dL (in oral glucose tolerance test) on two or more consecutive occasions post-baseline, insulin requirement for ≥31 days, an oral hypoglycemic agent use ≥31 days, or HbA1c ≥6.5% (at least 3 months after randomization) among kidney transplant patients with no medical history of diabetes. The incidence of NODAT for Study 1 through one year post-transplant is summarized in Table 3 below [see Warnings and Precautions (5.4)].

Table 3. Percentage of Patients with NODAT Through 1 Year Post-Kidney Transplant in Study 1 a
MMF/MPS- Mycophenolate mofetil/mycophenolate sodium; AZA-azathioprinea Study 1 was not designed to support comparative claims of ENVARSUS XR compared to tacrolimus [immediate-release] capsules for the adverse reactions reported in this table.
b Analyses restricted to patients at risk for NODAT.
ENVARSUS XR ± steroids, IL-2 receptor antagonist induction therapy, MMF/MPS or AZA (N=88) Tacrolimus [immediate-release] capsules ± steroids, IL-2 receptor antagonist induction therapy, MMF/MPS or AZA(N=74)
Composite NODAT b 21% 15%
HbA1c ≥6.5% 13% 8%
Fasting Plasma Glucose Values ≥126 mg/dL on 2 consecutive occurrences 8% 11%
Oral hypoglycemic use 7% 5%
Insulin use ≥31 days 1% 4%

Common Adverse Reactions

The incidence of adverse reactions that occurred in ≥10% of ENVARSUS XR-treated patients compared to tacrolimus [immediate-release] capsules through one year of treatment in Study 1 is shown by treatment group in Table 4 .

Table 4. Adverse Reactions ( ≥ 10%) in Kidney Transplant Patients Through 1 Year Post-Transplant in Study 1a
a Study 1 was not designed to support comparative claims of ENVARSUS XR compared to tacrolimus [immediate-release] capsules for the adverse reactions reported in this table.
Adverse Reaction ENVARSUS XR N=268 Tacrolimus [immediate-release] capsules N=275
Diarrhea 31% 34%
Anemia 26% 29%
Urinary Tract Infection 25% 25%
Hypertension 23% 23%
Tremor 19% 17%
Constipation 18% 25%
Diabetes Mellitus 16% 14%
Peripheral Edema 16% 21%
Hyperkalemia 15% 11%
Headache 15% 10%
Hypophosphatemia 13% 15%
Leukopenia 13% 14%
Nausea 13% 15%
Insomnia 13% 11%
Increased Blood Creatinine 12% 14%
Hypomagnesemia 12% 12%
Hypokalemia 12% 12%
Hyperglycemia 11% 12%

Study 2- Phase 2 Clinical Study in De Novo Kidney Transplant Recipients

Study 2 (NCT00765661) was an open-label Phase 2 study conducted in de novo kidney transplant patients randomized to once daily ENVARSUS XR (N=32) or twice daily tacrolimus [immediate-release] capsules (N=31). The study was conducted in the US and patients received an organ from a deceased or living donor. Pharmacokinetics were evaluated during the first 2 weeks with an additional 50-week treatment and follow-up to evaluate safety and efficacy [see Clinical Studies (14.1)].

The starting dosage was 0.14 mg/kg/day (given once daily) for ENVARSUS XR and 0.2 mg/kg/day (given twice daily) for tacrolimus [immediate-release] capsules. On Day 2 predose, the proportion of patients in the ENVARSUS XR group with tacrolimus trough concentration that were within, above, and below 6 to 11 ng/mL was 53%, 11%, and 37%, respectively. The starting dose of 0.14 mg/kg/day in Study 2 formed the basis of dosing recommendations in de novo kidney transplant patients.

There were no deaths or graft failures in Study 2. Two patients in each arm discontinued due to adverse events. The most common adverse reactions included infections and cardiovascular events, and were generally similar to those reported in Study 1.

Study 3- Phase 3 Clinical Studies in Stable Kidney Transplant Recipients Converted from Tacrolimus Capsules

In Study 3 (NCT00817206) stable kidney transplant patients were treated with ENVARSUS XR (N=162) or tacrolimus [immediate-release] capsules (N=162) and concomitant immunosuppressants in an open-label, randomized, multinational study [see Clinical Studies (14.2)]. The proportion of patients who discontinued treatment due to adverse reactions was 7.4% and 1.2% in the ENVARSUS XR and tacrolimus capsules treatment groups, respectively, through 12 months of treatment. The most common adverse reactions leading to discontinuation of study drug in the ENVARSUS XR treatment group was cardiac arrest (2 events).

Infections

The overall incidence of infections, serious infections, and infections with identified etiology reported in stable kidney transplant recipients treated with ENVARSUS XR or tacrolimus capsules are shown in Table 5.

Table 5. Percentage of Stable Patients with Infections Through 1 Year Post-Treatment in Study 3 a
MMF/MPS- Mycophenolate mofetil/mycophenolate sodium; AZA-azathioprine a The stable kidney transplant study was not designed to support comparative claims of ENVARSUS XR compared to tacrolimus capsules for the adverse reactions reported in this table.
b BK virus associated nephropathy (BKVAN) occurred in 1.2% (2/162) and 0.6% (1/162) in the ENVARSUS XR and tacrolimus capsules treatment groups, respectively.
ENVARSUS XR ± steroids, MMF/MPS or AZA N=162 Tacrolimus [immediate-release] capsules± steroids, MMF/MPS or AZAN=162
All infections 46% 48%
Respiratory Infections 26% 28%
Urinary Tract Infections 10% 14%
Bacterial Infections 7% 5%
Fungal Infections 4% 4%
Gastrointestinal Infections 4% 5%
BK virus b 2% 2%
Cytomegalovirus Infections 2% 1%
Serious Infections 8% 9%

New Onset Diabetes After Transplantation

New onset diabetes after transplantation (NODAT) was defined by the composite occurrence of fasting plasma glucose values ≥126 mg/dL, 2-hour postprandial plasma glucose of at least 200 mg/dL (in oral glucose tolerance test) on 2 or more consecutive occasions post-baseline, insulin requirement for ≥31 days, an oral hypoglycemic agent use ≥31 days, or HbA1c ≥6.5% (at least 3 months after randomization) among kidney transplant patients with no medical history of diabetes. The incidence of NODAT for the stable kidney transplant study through one year post-transplant is summarized in Table 6 below [see Warnings and Precautions (5.4)].

Table 6. Percentage of Stable Patients with NODAT Through 1 Year Post- Treatment in Study 3 a
MMF/MPS- Mycophenolate mofetil/mycophenolate sodium; AZA-azathioprinea The stable kidney transplant study was not designed to support comparative claims of ENVARSUS XR compared to tacrolimus capsules for the adverse reactions reported in this table.
b Analyses restricted to patients at risk for NODAT.
ENVARSUS XR ± steroids, MMF/MPS or AZA (N=90) Tacrolimus [immediate-release] capsules ± steroids, MMF/MPS or AZA(N=95)
Composite NODAT b 10% 11%
HbA1c ≥6.5% 3% 7%
Fasting Plasma Glucose Values ≥126 mg/dL on 2 consecutive occurrences 8% 6%
Oral hypoglycemic use 1% 1%
Insulin use ≥31 days 1% 0%

Common Adverse Reactions

In Study 3, the most common (≥10%) adverse reactions observed with Envarsus XR were diarrhea (14%), and blood creatinine increased (12%).

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