Envarsus XR

ENVARSUS XR®
(En var' sus XR)
(tacrolimus) Extended-release Tablets

Read this Medication Guide before you start taking ENVARSUS XR and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about ENVARSUS XR, ask your doctor or pharmacist.

What is the most important information I should know about ENVARSUS XR?

ENVARSUS XR can cause serious side effects, including:

1. Increased risk of cancer. People who take ENVARSUS XR have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma).
2. Increased risk of infection. ENVARSUS XR is a medicine that affects your immune system. ENVARSUS XR can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving ENVARSUS XR that can cause death.

Call your doctor right away if you have symptoms of an infection such as:

• fever
• muscle aches
• cough or flu-like symptoms
• sweats or chills
• warm, red, or painful areas on your skin

What is ENVARSUS XR?

• ENVARSUS XR is a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney transplant.
• ENVARSUS XR is an extended-release tablet and is not the same as tacrolimus extended-release capsules or tacrolimus immediate-release capsules. Your doctor should decide what medicine is right for you.

Who should not take ENVARSUS XR?

Do not take ENVARSUS XR if you are allergic to tacrolimus or any of the ingredients in ENVARSUS XR. See the end of this leaflet for a complete list of ingredients in ENVARSUS XR.

What should I tell my doctor before taking ENVARSUS XR?

Before you take ENVARSUS XR, tell your doctor if you:

• plan to receive any live vaccines. Ask your doctor if you are not sure if your vaccine is a live vaccine.
• have or have had liver, kidney or heart problems.
• have any other medical conditions.
• are pregnant or plan to become pregnant. ENVARSUS XR may harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
• are breastfeeding or plan to breastfeed. ENVARSUS XR can pass into your breast milk. You and your doctor should decide if you will take ENVARSUS XR or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and over-the­counter medicines, vitamins, and herbal supplements.

ENVARSUS XR may affect the way other medicines work, and other medicines may affect how ENVARSUS XR works.

How should I take ENVARSUS XR?

• Take ENVARSUS XR exactly as your doctor tells you to take it.
• Your doctor may change your dose of ENVARSUS XR if needed. Do not stop taking or change your dose of ENVARSUS XR without talking to your doctor.
• Take ENVARSUS XR once daily with fluid (preferably water) on an empty stomach at the same time each day (preferably in the morning).
• Take ENVARSUS XR tablets whole. Do not chew, divide or crush ENVARSUS XR tablets before swallowing. If you cannot swallow ENVARSUS XR tablets whole, tell your doctor.
• If you miss your dose of ENVARSUS XR, it should be taken as soon as possible, but no longer than 14 hours, the missed dose should be skipped and the next dose should be taken the following morning at your regularly scheduled time. Do not take 2 doses at the same time.
• If you take too much ENVARSUS XR, call your doctor or go to the nearest hospital emergency room right away.

What should I avoid while taking ENVARSUS XR?

• Live vaccines such as flu vaccine through your nose, measles, mumps, rubella, polio by mouth, BCG (TB vaccine), yellow fever, chicken pox (varicella), or typhoid.
• Exposure to sunlight and UV light such as tanning machines. Wear protective clothing and use a sunscreen.
• You should not eat grapefruit or drink grapefruit juice while taking ENVARSUS XR.
• You should not drink alcohol while taking ENVARSUS XR.

What are the possible side effects of ENVARSUS XR?

ENVARSUS XR may cause serious side effects, including:

• See “What the most important information I should know about ENVARSUS XR?”
• graft rejection and other serious reactions. People who take ENVARSUS XR have sometimes been given the wrong medicine because some medicines have the same ingredient (tacrolimus) as ENVARSUS XR. Check your ENVARSUS XR when you get a new prescription to make sure you have received the right medicine.
  • Call your doctor right away if you think you were given the wrong medicine.
  • Ask your doctor or pharmacist if you are not sure what ENVARSUS XR should look like.
• high blood sugar (diabetes). Your doctor may do certain tests to check for diabetes while you take ENVARSUS XR. Call your doctor right away if you have:
  • frequent urination
  • confusion
  • fruity smell on your breath
  • increased thirst or hunger
  • drowsiness
  • nausea, vomiting, or stomach pain
  • blurred vision
  • loss of appetite
• kidney problems. Your doctor may do certain tests to check for kidney function while you take ENVARSUS XR.
• nervous system problems. Call your doctor right away if you get any of these symptoms while taking ENVARSUS XR. These could be signs of a serious nervous system problem:
  • confusion
  • numbness and tingling
  • vision changes
  • coma
  • headache
  •  muscle tremors
  • seizures
• high levels of potassium in your blood. Your doctor may do certain tests to check your potassium level while you take ENVARSUS XR.
• high blood pressure. Your doctor will monitor your blood pressure while you take ENVARSUS XR.
• changes in the electrical activity of your heart (QT prolongation).

The most common side effects of ENVARSUS XR include, diarrhea, urinary tract infection, low red blood cell count (anemia), high blood pressure, and constipation.

These are not all the possible side effects of ENVARSUS XR. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store ENVARSUS XR?

• Store ENVARSUS XR at room temperature between 68 °F to 77 °F (20 °C to 25 °C).
• Safely throw away medicine that is out of date or no longer needed.

Keep ENVARSUS XR and all medicines out of reach of children.

General information about the safe and effective use of ENVARSUS XR.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ENVARSUS XR for a condition for which it was not prescribed. Do not give ENVARSUS XR to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about ENVARSUS XR. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about ENVARSUS XR that is written for health professionals. For more information, go to www.ENVARSUSXR.com or call 1-844-Veloxis (1-844-835-6947).

What are the ingredients in ENVARSUS XR?

Active ingredient: tacrolimus USP

Inactive ingredients: hypromellose USP, lactose monohydrate NF, polyethylene glycol NF, poloxamer NF, magnesium stearate NF, tartaric acid NF, butylated hydroxytoluene NF, and dimethicone NF

Serious side effects have been reported with Envarsus XR. See the "Envarsus XR Precautions" section. 

Common side effects of Envarsus XR include the following:

• diarrhea
• an increase of a substance in the blood called creatinine
• urinary tract infection
• low red blood cell count (anemia)
• high blood pressure
• constipation

This is not a complete list of Envarsus XR side effects. Ask your doctor or pharmacist for more information. 

Tell your doctor if you have any side effect that bothers you or that does not go away. 

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you are taking:

• mycophenolic acid (Myfortic)
• medications that increase the activity of the enzyme CYP3A4 such as carbamazepine (Tegretol, Equetro, Carbatrol), phenobarbital, John's wort, and nimodipine (Nimotop)
• medications that block a protein in the body (CYPA4) such as some macrolide antibiotics (clarithromycin, telithromycin), some HIV protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir), some HCV protease inhibitors (boceprevir, telaprevir), some azole antifungals (ketoconazole, itraconazole, posaconazole, voriconazole), conivaptan (Vaprisol), delavirdine (Rescriptor), and nefazodone
• antacids (magnesium and aluminum hydroxide antacids)
• metoclopramide (Reglan)

Do not drink alcohol while taking Envarsus XR.

This is not a complete list of Envarsus XR drug interactions. Ask your doctor or pharmacist for more information. 

Take Envarsus XR exactly as prescribed.

• Take Envarsus XR on an empty stomach at the same time of the day, preferably in the morning.
• Swallow Envarsus XR whole with fluid (preferably water). Do not chew, divide, or crush the tablets. If you cannot swallow Envarsus XR tablets whole, tell your doctor.
• Your doctor may change your dose of Envarsus XR if needed. Do not stop taking or change your dose of Envarsus XR without talking to your doctor.
• If you miss your dose of Envarsus XR, it should be taken as soon as possible, but no longer than 14 hours, the missed dose should be skipped and the next dose should be taken the following morning at your regularly scheduled time. Do not take 2 doses at the same time. 
• Avoid eating grapefruit or drinking grapefruit juice or alcoholic beverage while taking Envarsus XR. 

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.

In an open label, randomized, multinational conversion study, stable kidney transplant patients on a tacrolimus immediate-release product and concomitant immunosuppressants were randomized to treatment with ENVARSUS XR (N=162) or to continued treatment on the tacrolimus immediate-release product (N=162) and treated for a duration of 12 months [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 immediate-release 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).

The overall incidence of infections, serious infections, and infections with identified etiology reported in stable kidney transplant recipients treated with ENVARSUS XR or tacrolimus immediate-release product are shown in Table 1.

Table 1: Percentage of Stable Patients with Infections Through One Year Post-Treatment in the Conversion Studya

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 2 below [see WARNINGS AND PRECAUTIONS].

Table 2: Percentage of Stable Patients with NODAT Through 1 Year Post-Treatment in the Conversion Studya

The incidence of adverse reactions that occurred in ≥ 5% of ENVARSUS XR-treated patients compared to tacrolimus immediate-release product through one year of treatment in the conversion study is shown by treatment group in Table 3.

Table 3: Adverse Reactions ( ≥ 5%) in Stable Kidney Transplant Patients Through 1 Year Post-Treatment in the Conversion Studya

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.

Blood and Lymphatic System Disorders: Agranulocytosis, decreased blood fibrinogen, disseminated intravascular coagulation, hemolytic anemia, hemolytic uremic syndrome, 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: 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 hypertension, respiratory distress, respiratory failure

Skin and Subcutaneous Tissue Disorders: Hyperpigmentation, photosensitivity

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

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly. Blood and urine tests may be needed to check for unwanted effects.

This medicine may increase your risk of getting skin cancer or cancer of the lymph system (lymphoma). Talk to your doctor if you have concerns about this risk.

Use sunscreen or sunblock lotions with a sun protection factor (SPF) of at least 15 on a regular basis when you are outdoors. Wear protective clothing and hats, and stay out of direct sunlight between the hours of 10 am and 3 pm. Avoid sunlamps and tanning beds.

This medicine may increase your risk of developing infections. Avoid being near people who are sick while you are using this medicine. Wash your hands often. Tell your doctor if you have any kind of infection before you start using this medicine. Tell your doctor if you have ever had an infection that would not go away or an infection that kept coming back.

While you are being treated with tacrolimus, and after you stop treatment with it, do not have any immunizations (vaccines) without your doctor's approval. Tacrolimus may lower your body's resistance and the vaccine may not work as well or you might get the infection the vaccine is meant to prevent. In addition, you should not be around other persons living in your household who receive live virus vaccines because there is a chance they could pass the virus on to you. Some examples of live vaccines include measles, mumps, influenza (nasal flu vaccine), poliovirus (oral form), rotavirus, and rubella. Do not get close to them and do not stay in the same room with them for very long. If you have questions about this, talk to your doctor.

This medicine may increase your risk for developing a rare and serious virus infection with the BK polyoma virus. This virus may affect how your kidneys work and cause a transplanted kidney to fail. Check with your doctor right away if you are having more than one of these symptoms: bloody urine, a decreased frequency or amount of urine, increased thirst, loss of appetite, lower back or side pain, nausea, swelling of the face, fingers, or lower legs, trouble breathing, unusual tiredness or weakness, vomiting, or weight gain.

This medicine may increase your risk of developing a serious and rare brain infection called progressive multifocal leukoencephalopathy (PML). Check with your doctor right away if you are having more than one of these symptoms: vision changes, loss of coordination, clumsiness, confusion, memory loss, difficulty speaking or understanding what others say, or weakness in the legs.

This medicine may increase your risk of a stomach problem called gastrointestinal perforation. Talk to your doctor if you have concerns about this risk.

This medicine may cause serious nervous system problems. Tell your doctor right away if you have the following symptoms while using this medicine: blurred vision, dizziness, headache, mental changes, seizures, high blood pressure, or a fast heartbeat.

Hyperkalemia (high potassium in the blood) may occur while you are using this medicine. Check with your doctor right away if you have abdominal or stomach pain, confusion, difficulty with breathing, an irregular heartbeat, nausea or vomiting, nervousness, numbness or tingling in the hands, feet, or lips, or weakness or heaviness of the legs.

Tacrolimus may cause a condition called pure red cell aplasia (PRCA). This is a very rare condition where the body no longer makes red blood cells and the patient has severe anemia. Check with your doctor right away if you have a fever and sore throat, pale skin, unusual bleeding or bruising, or unusual tiredness or weakness.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (eg, St. John's wort) or vitamin supplements.

• If you have an allergy to tacrolimus or any other part of Envarsus XR (tacrolimus extended-release tablets).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have a long QT on ECG.
• If you are taking any of these drugs: Cyclosporine or sirolimus.
• If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Envarsus XR with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

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.

In an open label, randomized, multinational conversion study, stable kidney transplant patients on a tacrolimus immediate-release product and concomitant immunosuppressants were randomized to treatment with Envarsus XR (N=162) or to continued treatment on the tacrolimus immediate-release product (N=162) and treated for a duration of 12 months [see Clinical Studies (14)] .

The proportion of patients who discontinued treatment due to adverse reactions was 7.4% and 1.2% in the Envarsus XR and tacrolimus immediate-release 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 immediate-release product are shown in Table 1.

New Onset Diabetes After Transplantation (NODAT)

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 2 below [see Warnings and Precautions (5.4)].

Common Adverse Reactions

The incidence of adverse reactions that occurred in ≥5% of Envarsus XR-treated patients compared to tacrolimus immediate-release product through one year of treatment in the conversion study is shown by treatment group in Table 3.

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.

Blood and Lymphatic System Disorders: Agranulocytosis, decreased blood fibrinogen, disseminated intravascular coagulation, hemolytic anemia, hemolytic uremic syndrome, pancytopenia, prolonged activated partial thromboplastin time, pure red cell aplasia [see Warnings and Precautions (5.12)], 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: 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 (5.1)]; 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 (5.6)], progressive multifocal leukoencephalopathy (PML) sometimes fatal [see Warnings and Precautions (5.2)], 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 hypertension, respiratory distress, respiratory failure

Skin and Subcutaneous Tissue Disorders: Hyperpigmentation, photosensitivity

Mechanism of Action

Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (an ubiquitous mammalian intracellular enzyme) is then formed and the phosphatase activity of calcineurin inhibited. Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT) and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB).

Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony stimulating factor. Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor-beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).

Pharmacokinetics

Table 5 summarizes the pharmacokinetic (PK) parameters of tacrolimus following oral administration of once-daily Envarsus XR in healthy subjects and in kidney transplant patients, under fasted conditions. Whole blood tacrolimus concentrations in the pharmacokinetic studies were measured using validated HPLC/MS/MS assays.

In adult kidney transplant patients ≥ 6 months post-transplant switched to Envarsus XR at 67% to 80% of the daily dose of tacrolimus immediate-release capsules, the steady state tacrolimus exposures (AUC24) and tacrolimus trough concentrations (C24) were comparable to the AUC24 and C24 measured prior to the switch. However, the mean Cmax estimate was 30% lower and the median Tmax was more prolonged (6 hours versus 2 hours) following administration of Envarsus XR as compared to that of tacrolimus immediate-release capsules.

Absorption

Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. In healthy subjects, the oral bioavailability of Envarsus XR was approximately 50% higher as compared with both tacrolimus immediate-release and extended-release formulations at steady state. In healthy subjects who received single Envarsus XR doses ranging from 5 mg to 10 mg, the mean AUC and C24 of tacrolimus increased linearly and the elimination half-life did not change with increasing doses.

Food Effects

The presence of a meal affects the absorption of tacrolimus; the rate and extent of absorption is greatest under fasted conditions. In 26 healthy subjects, administration of Envarsus XR following a high-fat breakfast reduced the systemic exposure (AUC) to tacrolimus by approximately 55% and the peak plasma concentration of tacrolimus (Cmax) by 22%, with no effect on the time to reach maximum plasma concentration (Tmax), compared to when Envarsus XR was administered under fasted conditions.

Chronopharmacokinetic Effect

In 26 healthy subjects, administration of Envarsus XR tablets in the evening resulted in a 15% lower AUC0-inf, and a 20% lower C24, as compared to morning dosing.

Distribution

The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a U.S. trial in which tacrolimus was administered as immediate-release formulation, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).

Metabolism

The desired pharmacological activity of tacrolimus is primarily due to the parent drug. Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system 3A (CYP3A). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.

Excretion

In a mass balance study of orally administered radiolabeled tacrolimus to 6 healthy subjects, the mean recovery of the radiolabel was 94.9 ± 30.7%. Fecal elimination accounted for 92.6 ± 30.7% and urinary elimination accounted for 2.3 ± 1.1% of the total radiolabel administered. The elimination half-life based on radioactivity was 31.9 ± 10.5 hours, whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and the mean clearance of tacrolimus was 0.172 ± 0.088 L/hr/kg.

The elimination half-life of tacrolimus after oral administration of 2 mg Envarsus XR once-daily for 10 days was 31.0 ± 8.1 hours (mean ± SD) in 25 healthy subjects.

Specific Populations

Renal Impairment

Tacrolimus pharmacokinetics following a single administration of tacrolimus (administered as a continuous IV infusion) were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9±1.6 and 12.0±2.4 mg/dL, respectively) prior to their kidney transplant. The mean clearance of tacrolimus in patients with renal dysfunction given IV tacrolimus was similar to that in healthy subjects given tacrolimus IV and in healthy subjects given oral tacrolimus immediate-release [see Use in Specific Populations (8.6)].

Hepatic Impairment

Tacrolimus pharmacokinetics have been determined in 6 patients with mild hepatic impairment (mean Pugh score: 6.2) following single oral administration of tacrolimus immediate-release. The mean clearance of tacrolimus in patients with mild hepatic impairment was not substantially different from that in healthy subjects. Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic impairment (mean Pugh score: >10). The mean clearance was substantially lower in patients with severe hepatic impairment [see Dosage and Administration (2.2) and Use in Specific Populations (8.7)].

Race

The pharmacokinetics of Envarsus XR were evaluated in a study of 46 stable African American kidney transplant recipients converted from tacrolimus immediate-release to Envarsus XR. Approximately 80% of the African American patients were carriers of the active, wild type CYP3A5*1 allele. Regardless of genotype status, the PK results demonstrated similar exposure, lower Cmax, prolonged Tmax, and increased bioavailability compared to tacrolimus immediate-release [see Dosage and Administration (2.2) and Use in Specific Populations (8.8)].

Gender

A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted. In a sub-group analysis from two combined Phase 3 studies in kidney transplant recipients performed with Envarsus XR over one year of treatment, no gender-dependent differences in tacrolimus systemic exposures were observed.

Drug Interaction Studies

No drug-drug interaction studies were conducted specifically with Envarsus XR.

Because tacrolimus is metabolized mainly by CYP3A enzymes, drugs or substances known to inhibit these enzymes and/or are known CYP3A substrates may increase tacrolimus whole blood concentrations. Drugs known to induce CYP3A enzymes may decrease tacrolimus whole blood concentrations [see Warnings and Precautions (5.9) and Drug Interactions (7.2)].