Envarsus XR (Page 2 of 9)

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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