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Envarsus

Last reviewed on RxList: 9/8/2020
Envarsus Side Effects Center

What Is Envarsus XR?

Envarsus XR (tacrolimus extended-release tablets) is a calcineurin-inhibitor immunosuppressant indicated to prevent organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations in combination with other immunosuppressants.

What Are Side Effects of Envarsus XR?

Common side effects of Envarsus XR include diarrhea, urinary tract infection, sore throat and nose (nasopharyngitis), headache, upper respiratory tract infection, swelling of the extremities, high blood pressure (hypertension), and increased blood creatinine.

Dosage for Envarsus XR

Envarsus XR comes in doses of 0.75 mg, 1 mg, and 4 mg. Take the prescribed dose once daily on empty stomach, preferably in the morning.

What Drugs, Substances, or Supplements Interact with Envarsus XR?

Envarsus XR may interact with grapefruit or grapefruit juice, alcohol, antimycobacterials, anticonvulsants, St John's Wort, protease inhibitors, azole antifungals, antibiotics, nefazodone, calcium channel blockers, amiodarone, danazol, ethinyl estradiol, cimetidine, magnesium and aluminum hydroxide antacids, metoclopramide, and corticosteroids. Tell your doctor all medications and supplements you use.

Envarsus XR During Pregnancy and Breastfeeding

Envarsus XR should be used during pregnancy only if prescribed. It may harm a fetus. Envarsus XR passes into breast milk. Consult your doctor before breastfeeding.

Additional Information

Our Envarsus XR (tacrolimus extended-release tablets) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

SLIDESHOW

Digestive Disorders: Common Misconceptions See Slideshow
Envarsus Professional Information

SIDE EFFECTS

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

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]. 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 recommend:ed 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].

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 1a

  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%
MMF/MPS- Mycophenolate mofetil/mycophenolate sodium; AZA-azathioprin
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.
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.

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].

Table 3: Percentage of Patients with NODAT Through 1 Year Post-Kidney Transplant in Study 1a

  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 NODATb 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%
MMF/MPS- Mycophenolate mofetil/mycophenolate sodium; AZA-azathioprin
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.
b Analyses restricted to patients at risk for NODAT.

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

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%
Hypomagnesmia 12% 12%
Hypokalemia 12% 12%
Hyperglycemia 11% 12%
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.

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].

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]. 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 3a

  ENVARSUS XR ± steroids, MMF/MPS or AZA
N=162
Tacrolimus [immediate-release] capsules± steroids, MMF/MPS or AZA
N=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%
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.

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].

Table 6: Percentage of Stable Patients with NODAT Through 1 Year Post- Treatment in Study 3a

  ENVARSUS XR ± steroids, MMF/MPS or AZA
(N=90)
Tacrolimus [immediate-release] capsules ± steroids, MMF/MPS or AZA
(N=95)
Composite NODATb 10% 11%
HbAic ≥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%
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 Analyses restricted to patients at risk for NODAT.

Common Adverse Reactions

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

Postmarketing Experience

The following adverse reactions have been reported from marketing experience with tacrolimus in the U.S. and outside the U.S. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following reactions have been included due to either their seriousness, frequency of reporting or strength of causal connection to ENVARSUS XR:

  • Blood and Lymphatic System Disorders : Agranulocytosis, decreased blood fibrinogen, disseminated intravascular coagulation, hemolytic anemia, hemolytic uremic syndrome, leukopenia, pancytopenia, prolonged activated partial thromboplastin time, pure red cell aplasia [see WARNINGS AND PRECAUTIONS], thrombocytopenic purpura, thrombotic thrombocytopenic purpura
  • Cardiac Disorders: Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial hypertrophy, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation, supraventricular extrasystoles, supraventricular tachycardia, Torsade de Pointes, deep limb venous thrombosis, ventricular fibrillation
  • Ear Disorders: Hearing loss including deafness
  • Eye Disorders: Blindness, photophobia, optic atrophy
  • Gastrointestinal Disorders: Abdominal pain, colitis, dysphagia, gastrointestinal perforation, impaired gastric emptying, intestinal obstruction, mouth ulceration, peritonitis, stomach ulcer
  • Hepatobiliary Disorders: Bile duct stenosis, cholangitis, cirrhosis, fatty liver, hepatic cytolysis, hepatic failure, hepatic necrosis, hepatic steatosis, jaundice, hemorrhagic pancreatitis, necrotizing pancreatitis, venoocclusive liver disease
  • Hypersensitivity Reactions: Hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
  • Immune System Disorders: Graft versus host disease (acute and chronic)
  • Metabolism and Nutrition Disorders: Glycosuria, increased amylase, pancreatitis
  • Musculoskeletal and Connective Tissue Disorders: Myalgia, polyarthritis, rhabdomyolysis
  • Neoplasms: Lymphoma including EBV-associated lymphoproliferative disorder, PTLD [see WARNINGS AND PRECAUTIONS]; leukemia
  • Nervous System Disorders: Carpal tunnel syndrome, cerebral infarction, coma, dysarthria, flaccid paralysis, hemiparesis, mental disorder, mutism, nerve compression, posterior reversible encephalopathy syndrome (PRES) [see WARNINGS AND PRECAUTIONS], progressive multifocal leukoencephalopathy (PML) sometimes fatal [see WARNINGS AND PRECAUTIONS], quadriplegia, speech disorder, status epilepticus, syncope
  • Renal and Urinary Disorder: Acute renal failure, hemorrhagic cystitis, hemolytic uremic syndrome, micturition disorder
  • Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, pulmonary embolism, pulmonary hypertension, respiratory distress, respiratory failure
  • Skin and Subcutaneous Tissue Disorders: Hyperpigmentation, photosensitivity, pruritus, rash

Read the entire FDA prescribing information for Envarsus (Tacrolimus Extended-release Tablets)

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© Envarsus Patient Information is supplied by Cerner Multum, Inc. and Envarsus Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

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