Envarsusxr

Overdose

Postmarketing cases of overdose with tacrolimus have been reported. Overdosage adverse reactions included:

• nervous system disorders (tremor, headache, confusional state, balance disorders, encephalopathy, lethargy and somnolence)
• gastrointestinal disturbances (nausea, vomiting, and diarrhea)
• abnormal renal function (increased blood urea nitrogen and elevated serum creatinine)
• urticaria
• hypertension
• peripheral edema, and
• infections [one fatal postmarketing case of bilateral pneumopathy and CMV infection was attributed to tacrolimus (extended-release capsules) overdose].

Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

Envarsusxr price

Contraindications

Envarsusxr is contraindicated in patients with known hypersensitivity to tacrolimus.

Pharmaceutical form

Undesirable effects

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.

The proportion of patients who discontinued treatment due to adverse reactions was 7.4% and 1.2% in the Envarsusxr 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 Envarsusxr 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 Envarsusxr 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.

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 Envarsusxr-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

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 , 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 ; leukemia

Nervous System Disorders: Carpal tunnel syndrome, cerebral infarction, coma, dysarthria, flaccid paralysis, hemiparesis, mental disorder, mutism, nerve compression, posterior reversible encephalopathy syndrome (PRES) , progressive multifocal leukoencephalopathy (PML) sometimes fatal , 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

Therapeutic indications

Envarsusxr is indicated for the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations, in combination with other immunosuppressants.

Envarsusxr extended-release tablets are not interchangeable or substitutable with other tacrolimus extended-release or immediate-release products.

Pharmacokinetic properties

Table 5 summarizes the pharmacokinetic (PK) parameters of tacrolimus following oral administration of once-daily Envarsusxr 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.

Table 5: Pharmacokinetic Parameters of Envarsusxr by Study Day in Healthy Subjects and Kidney Transplant Patients Under Fasted Conditions

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 Envarsusxr as compared to that of tacrolimus immediate-release capsules.

Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. In healthy subjects, the oral bioavailability of Envarsusxr was approximately 50% higher as compared with both tacrolimus immediate-release and extended-release formulations at steady state. In healthy subjects who received single Envarsusxr 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 Envarsusxr 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 Envarsusxr was administered under fasted conditions.

Chronopharmacokinetic Effect

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

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).

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.

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 Envarsusxr once-daily for 10 days was 31.0 ± 8.1 hours (mean ± SD) in 25 healthy subjects.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Immunosuppressants, including Envarsusxr, 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.

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.

Immunosuppressants, including Envarsusxr, 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.

Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products 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. Envarsusxr is not interchangeable or substitutable with tacrolimus immediate-release products or other tacrolimus extended-release products. Instruct patients and caregivers to recognize the appearance of Envarsusxr tablet.

Envarsusxr 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.

Envarsusxr, 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 Envarsusxr 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). Monitor renal function and consider dosage reduction if nephrotoxicity occurs.

Envarsusxr 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. 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 Envarsusxr if neurotoxicity occurs.

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

Hypertension is a common adverse reaction of Envarsusxr therapy and may require antihypertensive therapy. Some antihypertensive drugs can increase the risk for hyperkalemia. Calcium-channel blocking agents may increase tacrolimus blood concentrations and require dosage reduction of Envarsusxr.

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) Therefore, adjust Envarsusxr dose and monitor tacrolimus whole blood trough concentrations when coadministering Envarsusxr with strong CYP3A inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) or strong CYP3A inducers (e.g., rifampin, rifabutin).

Envarsusxr may prolong the QT/QTc interval and cause Torsade de Pointes. Avoid Envarsusxr 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 Envarsusxr with other substrates and/or inhibitors of CYP3A, a reduction in Envarsusxr dosage, monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended.

Whenever possible, administer the complete complement of vaccines before transplantation and treatment with Envarsusxr.

Avoid the use of live attenuated vaccines during treatment with Envarsusxr (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 Envarsusxr.

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 Envarsusxr.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Advise patients to:

• Inspect their Envarsusxr medicine when they receive a new prescription and before taking it. If the appearance of the tablet is not the same as usual, or if dosage instructions have changed, advise patients to contact their healthcare provider as soon as possible to make sure that you have the right medicine. Other tacrolimus products cannot be substituted for Envarsusxr.
• Take once-daily Envarsusxr at the same time every day (preferably in the morning) on an empty stomach to ensure consistent and maximum possible drug concentrations in the blood.
• Swallow tablet whole with liquid, preferably water. Do not chew, divide or crush tablet.
• Avoid alcohol, grapefruit, and grapefruit juice while on Envarsusxr.
• Take a missed dose as soon as possible but not more than 14 hours after the scheduled time. Beyond the 14-hour timeframe, instruct the patient to wait until the usual scheduled time the following morning to take the next regularly scheduled dose. Do not take two doses at the same time..

Inform patients that they are at an increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and use a sunscreen with a high protection factor.

Inform patients that they are at an increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection.

Inform patients that Envarsusxr can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst or hunger.

Inform patients that Envarsusxr can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team.

Inform patients that they are at risk of developing adverse neurologic effects including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, delirium, or tremors.

Inform patients that Envarsusxr can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia.

Inform patients that Envarsusxr can cause high blood pressure which may require treatment with anti-hypertensive therapy.

Instruct patients to tell their health care providers when they start or stop taking any concomitant medications, including prescription and non-prescription medicines, herbal and dietary supplements. Some medications could alter tacrolimus concentrations in the blood and thus may require the adjustment of the dosage of Envarsusxr.

Inform patients that Envarsusxr can interfere with the usual response to immunizations and that they should avoid live vaccines.

Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3.0 mg/kg/day (0.84 times the AUC at the maximum clinical dose of 0.14 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.24 times the AUC at the maximum clinical dose of 0.14 mg/kg/day).

A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03%-3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/ m²/day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high-dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment; 2.5-fold the human exposure in stable adult renal transplant patients converted from tacrolimus immediate-release product to Envarsusxr). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown.

The implications of these carcinogenicity studies are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune system's ability to inhibit unrelated carcinogenesis.

No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.

Tacrolimus given orally at 1.0 mg/kg (1.2 times the maximum clinical dose based on body surface area) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre-implantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (3.7 times the maximum clinical dose based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.

There are no adequate and well-controlled studies in pregnant women. Tacrolimus is transferred across the placenta. The use of tacrolimus during pregnancy in humans has been associated with neonatal hyperkalemia and renal dysfunction.

Tacrolimus given orally to pregnant rabbits at 0.7 times the maximum clinical dose and pregnant rats at 1.1 times the maximum clinical dose was associated with an increased incidence of fetal death in utero, fetal malformations (cardiovascular, skeletal, omphalocele, and gallbladder agenesis) and maternal toxicity. Envarsusxr should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

In pregnant rabbits, tacrolimus at oral doses of 0.32 and 1.0 mg/kg (0.7 and 2.3 times the maximum clinical dose based on body surface area, respectively) was associated with maternal toxicity as well as an increased incidence of abortions. At the 1 mg/kg dose, fetal rabbits showed an increased incidence of malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosis, interrupted ossification of vertebral arch, vertebral and rib malformations, omphalocele, and gallbladder agenesis) and developmental variations. In pregnant rats, tacrolimus at oral doses of 3.2 mg/kg (3.7 times the maximum clinical dose) was associated with maternal toxicity, an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally to pregnant rats after organogenesis and during lactation at 1.0 and 3.2 mg/kg (1.2 and 3.7 times the maximum recommended clinical dose, respectively) was associated with reduced pup weights and pup viability (3.2 mg/kg only); among the high dose pups that died early, an increased incidence of kidney hydronephrosis was observed.

Tacrolimus is present in breast milk. Because of the potential for serious adverse drug reactions in nursing infants from ENVARSUS XR, a decision should be made whether to discontinue nursing or to discontinue Envarsusxr, taking into account the importance of drug to the mother.

The safety and effectiveness of Envarsusxr in pediatric patients have not been established.

Clinical studies of Envarsusxr did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In the stable kidney transplant study, there were 17 patients 65 years of age and older, and no patients were over 75 years. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The pharmacokinetics of tacrolimus in patients with renal impairment was similar to that in healthy subjects with normal renal function. However, due to its potential for nephrotoxicity, monitoring of renal function in patients with renal impairment is recommended; tacrolimus dosage should be reduced if indicated.

The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: > 10) compared to healthy subjects with normal hepatic function. With greater tacrolimus whole blood trough concentrations in patients with severe hepatic impairment, there is a greater risk of adverse reactions and dosage reduction is recommended. For patients with moderate hepatic impairment, monitor tacrolimus whole blood trough concentrations. For patients with mild hepatic impairment, no dosage adjustments are needed.

African-American patients may need to be titrated to higher Envarsusxr dosages to attain comparable trough concentrations compared to Caucasian patients

Dosage (Posology) and method of administration

• Take Envarsusxr on an empty stomach at the same time of the day, preferably in the morning (to ensure consistent and maximum possible drug exposure).
• Swallow Envarsusxr whole with fluid (preferably water); do not chew, divide, or crush the tablets.
• If a dose is missed, take it as soon as possible within 15 hours after missing the dose; beyond the 15-hour time frame, wait until the usual scheduled time to take the next regular daily dose. Do not double the next dose.
• Avoid eating grapefruit or drinking grapefruit juice or alcoholic beverage while taking Envarsusxr.
• African-American patients, compared to Caucasian patients, may need to be titrated to higher Envarsusxr dosages to attain comparable trough concentrations.

To convert from a tacrolimus immediate-release product to Envarsusxr, administer an Envarsusxr once daily dose that is 80% of the total daily dose of the tacrolimus immediate-release product. Monitor tacrolimus whole blood trough concentrations and titrate Envarsusxr dosage to achieve target whole blood trough concentration ranges of 4 to 11 ng/mL.

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, 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 Envarsusxr 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.