they are trying Envarsus XR Generic Name: tacrolimus Dosage Form: tablet, extended release Overview Side Effects Dosage Professional Interactions More Pregnancy Warnings Breastfeeding Warnings User Reviews Drug Images Support Group Q & A Pricing & Coupons WARNING: MALIGNANCIES AND SERIOUS INFECTIONS Increased risk for developing serious infections and malignancies with Envarsus XR or other immunosuppressants that may lead to hospitalization or death [see Warnings and Precautions ( 5.1 , 5.2 )]. Indications and Usage for Envarsus XR Envarsus XR is indicated for the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations, in combination with other immunosuppressants. Limitation of Use Envarsus XR extended-release tablets are not interchangeable or substitutable with other tacrolimus extended-release or immediate-release products [see Warnings and Precautions (5.3) ] . Slideshow Donate Life: What You Need To Know About Organ Donorship Envarsus XR Dosage and Administration Administration Instructions Take Envarsus XR on an empty stomach at the same time of the day, preferably in the morning (to ensure consistent and maximum possible drug exposure) [see Clinical Pharmacology (12.2) ]. Swallow Envarsus XR 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 Envarsus XR [see Drug Interactions (7.2) ] . African-American patients, compared to Caucasian patients, may need to be titrated to higher Envarsus XR dosages to attain comparable trough concentrations [see Use in Specific Populations (8.8) and Clinical Pharmacology (12.2) ]. Conversion from Tacrolimus Immediate-Release Formulations To convert from a tacrolimus immediate-release product to Envarsus XR, administer an Envarsus XR 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 Envarsus XR dosage to achieve target whole blood trough concentration ranges of 4 to 11 ng/mL. Therapeutic Drug Monitoring Measure tacrolimus whole blood trough concentrations at least two times on separate days during the first week after initiation of dosing and after any change in dosage, after a change in co-administration of CYP3A inducers and/or inhibitors, or after a change in renal or hepatic function. When interpreting measured concentrations, consider that the time to achieve tacrolimus steady state is approximately 7 days after initiating or changing the Envarsus XR dose. Monitor tacrolimus whole blood trough concentrations using a validated assay [e.g., immunoassays or high-performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS)]. The immunosuppressive activity of tacrolimus is mainly due to the parent drug rather than to its metabolites. Immunoassays may react with metabolites as well as the parent drug. Therefore, whole blood tacrolimus trough concentrations obtained with immunoassays may be numerically higher than concentrations obtained with an assay using HPLC/MS/MS. Comparison of the whole blood tacrolimus trough concentrations of patients to those described in the prescribing information and other published literature must be made with knowledge of the assay method(s) employed. Dosage Forms and Strengths Oval, white to off-white uncoated extended-release tablets debossed with TCS on one side: 0.75 mg extended-release tablet: debossed with 0.75 on the other side. 1 mg extended-release tablet: debossed with 1 on the other side. 4 mg extended-release tablet: debossed with 4 on the other side. Contraindications Envarsus XR is contraindicated in patients with known hypersensitivity to tacrolimus. Warnings and Precautions Lymphoma and Other Malignancies Immunosuppressants, including Envarsus XR, increase the risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. Examine patients for skin changes and advise to avoid or limit exposure to sunlight and UV light. 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. Serious Infections Immunosuppressants, including Envarsus XR, increase the risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. Serious viral infections reported include: Polyomavirus-associated nephropathy (especially due to BK virus infection), JC virus-associated progressive multifocal leukoencephalopathy (PML), and Cytomegalovirus (CMV) infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at highest risk of CMV viremia and CMV disease. Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection [see Adverse Reactions (6.1) ] . Graft Rejection and Other Serious Adverse Reactions due to Medication Errors 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. Envarsus XR 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 Envarsus XR tablet [see Dosage Forms and Strengths (3) ] . 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) ] . 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 Drug Interactions (7.2) ] . Monitor renal function and consider dosage reduction if nephrotoxicity occurs. 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. 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. 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) ] . 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., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) or strong CYP3A inducers (e.g., rifampin, rifabutin) [see Dosage and Administration (2.3) and Drug Interactions (7.2) ] . 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 Drug Interactions (7.2) ] . 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. 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. Adverse Reactions 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 . Table 1. Percentage of Stable Patients with Infections Through One Year Post- Treatment in the Conversion Study a a The stable kidney transplant study was not designed to support comparative claims of Envarsus XR compared to tacrolimus immediate-release product 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 immediate-release treatment groups, respectively. Envarsus XR steroids, MMF/MPS or AZA N=162 Tacrolimus immediate-release product 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% 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 HbA 1c ≥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) ] . Table 2. Percentage of Stable Patients with NODAT Through 1 Year Post- Treatment in the Conversion Study a a The stable kidney transplant study was not designed to support comparative claims of Envarsus XR compared to tacrolimus immediate-release product 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 product steroids, MMF/MPS or AZA (N=95) Composite NODAT b 10% 11% HbA 1c ≥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 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 Study a a The stable kidney transplant study was not designed to support comparative claims of Envarsus XR compared to tacrolimus immediate-release for the adverse reactions reported in this table. Adverse Reaction Envarsus XR N=162 Tacrolimus immediate-release product N=162 Diarrhea 14% 9% Blood Creatinine Increased 12% 9% Urinary Tract Infection 9% 14% Nasopharyngitis 9% 11% Headache 9% 7% Upper Respiratory Tract Infection 7% 9% Peripheral Edema 7% 6% Hypertension 4% 6% 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 Drug Interactions Mycophenolic Acid When Envarsus XR is prescribed with a given dose of mycophenolic acid (MPA) product, exposure to MPA is higher with Envarsus XR coadministration than with cyclosporine coadministration because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Monitor for MPA associated adverse reactions and reduce the dose of concomitantly administered mycophenolic acid products as needed. Effects of Other Drugs/Substances on Envarsus XR Table 4. Effects of Other Drugs/Substances on Envarsus XR a a Envarsus XR dosage adjustment recommendation based on observed effect of coadministered drug on tacrolimus exposures [see Clinical Pharmacology (12.2) ] , literature reports of altered tacrolimus exposures, or the other drug s known CYP3A inhibitor/inducer status b High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor c Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate) Drug/Substance Class or Name Drug Interaction Effect Recommendations Grapefruit or grapefruit juice b May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.10) ] Avoid grapefruit or grapefruit juice Alcohol May modify the rate of tacrolimus release Avoid alcoholic beverages Strong CYP3A Inducers c such as: Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John s Wort May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see Warnings and Precautions (5.9) ] Increase Envarsus XR dose and monitor tacrolimus whole blood trough concentrations [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2) ] Strong CYP3A Inhibitors c , such as: Protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.9, 5.10) ] Reduce Envarsus XR dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2) ] Mild or Moderate CYP3A Inhibitors, such as: antibiotics (e.g., erythromycin), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole, azole antifungals (e.g., clotrimazole, fluconazole) May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.10) ] Monitor tacrolimus whole blood trough concentrations and reduce Envarsus XR dose if needed [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2) ] Other drugs, such as: Magnesium and aluminum hydroxide antacids Metoclopramide May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.10) ] Monitor tacrolimus whole blood trough concentrations and reduce Envarsus XR dose if needed [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2) ] Mild or Moderate CYP3A Inducers, such as: Methylprednisolone, prednisone May decrease tacrolimus concentrations Monitor tacrolimus whole blood trough concentrations and adjust Envarsus XR dose if needed [see Dosage and Administration (2.3) ] USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C 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. Envarsus XR 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. Nursing Mothers 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 Envarsus XR, taking into account the importance of drug to the mother. Pediatric Use The safety and effectiveness of Envarsus XR in pediatric patients have not been established. Geriatric Use Clinical studies of Envarsus XR 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 [see Clinical Studies (14) ] . 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. Renal Impairment 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 [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.2) ] . Hepatic Impairment 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 [see Clinical Pharmacology (12.2) ] . 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 [see Dosage and Administration (2.2) ] . For patients with moderate hepatic impairment, monitor tacrolimus whole blood trough concentrations. For patients with mild hepatic impairment, no dosage adjustments are needed. Race African-American patients may need to be titrated to higher Envarsus XR dosages to attain comparable trough concentrations compared to Caucasian patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.2) ] . 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 and indicated that an 80% conversion factor is appropriate for African-American patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.2) ] . Overdosage 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. Envarsus XR Description Envarsus XR, a calcineurin-inhibitor immunosuppressant, is available for oral administration as extended-release tablets containing the equivalent of 0.75 mg, 1 mg, or 4 mg of anhydrous tacrolimus USP. Inactive ingredients include hypromellose USP, lactose monohydrate NF, polyethylene glycol NF, poloxamer NF, magnesium stearate NF, tartaric acid NF, butylated hydroxytoluene NF, and dimethicone NF. Tacrolimus is the active ingredient in Envarsus XR. Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis . Chemically, tacrolimus is designated as [3 S -[3 R * [ E (1 S * ,3 S * ,4 S * )], 4 S * ,5 R * ,8 S * ,9 E ,12 R * ,14 R * ,15 S * ,16 R * ,18 S * ,19 S * ,26a R * ]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclo-hexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1- c ][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate. The chemical structure of tacrolimus is: Tacrolimus has an empirical formula of C 44 H 69 NO 12 •H 2 O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform. Envarsus XR - Clinical Pharmacology 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. Table 5. Pharmacokinetic Parameters of Envarsus XR by Study Day in Healthy Subjects and Kidney Transplant Patients Under Fasted Conditions a) Healthy adult subjects (administered mg/day dose); Adult de novo kidney transplant patients (group average of administered mg/day dose); Adult kidney ≥ 6 months post-transplant (group average of administered mg/day dose of Envarsus XR, following conversion to 67% to 80% of the daily tacrolimus immediate-release capsules dose) b) Day of Envarsus XR dosing and PK profiling c) Arithmetic means S.D. d) Median [range] e) De novo refers to immunosuppression starting at the time of transplantation f) Starting Envarsus XR dose = 0.14 mg/kg/day g) Starting Envarsus XR dose = 0.17 mg/kg/day. In de novo kidney transplant patients who received Envarsus XR starting dose of 0.17 mg/kg/day achieved higher than recommended target tacrolimus trough concentrations, as high as 57 ng/mL during the first 1 to 2 weeks post-transplant h) Tacrolimus trough concentration before the next dose i) After 7 days of stable dosing with Envarsus XR j) AUC 0-24 to- C 24 correlation coefficient (r) at steady state was 0.80 or higher k) Conversion to Envarsus XR at a mean dose of 80% of the total daily dose of tacrolimus immediate-release resulted in equivalent exposure with a 30% reduction in C max . Population ENVARSUS XR Dose a Day b Pharmacokine a fairly big
of questions of safety Envarsus XR currently
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