Tacrolimus (extended release)

# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider.  WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery.  The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements.  WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.

# Black Box Warning

# Overview
Tacrolimus (extended release) is a calcineurin inhibitor that is FDA approved for the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations in combination with other immunosuppressants. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include diarrhea and increased blood creatinine.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Tacrolimus (extended release) is indicated for the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations, in combination with other immunosuppressants.

### Administration Instructions
- Take TACROLIMUS (EXTENDED RELEASE) on an empty stomach at the same time of the day, preferably in the morning (to ensure consistent and maximum possible drug exposure).
- Swallow TACROLIMUS (EXTENDED RELEASE) 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 TACROLIMUS (EXTENDED RELEASE).
- African-American patients, compared to Caucasian patients, may need to be titrated to higher TACROLIMUS (EXTENDED RELEASE) dosages to attain comparable trough concentrations.

### Conversion from Tacrolimus Immediate-Release Formulations
- To convert from a tacrolimus immediate-release product to TACROLIMUS (EXTENDED RELEASE), administer an TACROLIMUS (EXTENDED RELEASE) 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 TACROLIMUS (EXTENDED RELEASE) 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 TACROLIMUS (EXTENDED RELEASE) dose.
- Monitor tacrolimus whole blood trough concentrations using a validated assay .
- 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.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tacrolimus (extended release) in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Tacrolimus (extended release) in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of TACROLIMUS (EXTENDED RELEASE) in pediatric patients have not been established.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tacrolimus (extended release) in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Tacrolimus (extended release) in pediatric patients.

# Contraindications
- TACROLIMUS (EXTENDED RELEASE) is contraindicated in patients with known hypersensitivity to tacrolimus.

# Warnings

### Lymphoma and Other Malignancies
- Immunosuppressants, including TACROLIMUS (EXTENDED RELEASE), 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 TACROLIMUS (EXTENDED RELEASE), 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.
- 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.

### 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.
- TACROLIMUS (EXTENDED RELEASE) 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 TACROLIMUS (EXTENDED RELEASE) tablet.

### New Onset Diabetes After Transplant
- TACROLIMUS (EXTENDED RELEASE) 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.

### Nephrotoxicity due to TACROLIMUS (EXTENDED RELEASE) and Drug Interactions
- TACROLIMUS (EXTENDED RELEASE), 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 TACROLIMUS (EXTENDED RELEASE) 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.

### Neurotoxicity
- TACROLIMUS (EXTENDED RELEASE) 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 TACROLIMUS (EXTENDED RELEASE) if neurotoxicity occurs.

### Hyperkalemia
- Mild to severe hyperkalemia, which may require treatment, has been reported with tacrolimus including TACROLIMUS (EXTENDED RELEASE).
- 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
- Hypertension is a common adverse reaction of TACROLIMUS (EXTENDED RELEASE) 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 TACROLIMUS (EXTENDED RELEASE).

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

### QT Prolongation
- TACROLIMUS (EXTENDED RELEASE) may prolong the QT/QTc interval and cause Torsade de Pointes.
- Avoid TACROLIMUS (EXTENDED RELEASE) 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 TACROLIMUS (EXTENDED RELEASE) 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.

### Immunizations
- Whenever possible, administer the complete complement of vaccines before transplantation and treatment with TACROLIMUS (EXTENDED RELEASE).
- Avoid the use of live attenuated vaccines during treatment with TACROLIMUS (EXTENDED RELEASE) (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 TACROLIMUS (EXTENDED RELEASE).

### 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 TACROLIMUS (EXTENDED RELEASE).

# Adverse Reactions

## Clinical Trials 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 TACROLIMUS (EXTENDED RELEASE) (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 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 TACROLIMUS (EXTENDED RELEASE) 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 TACROLIMUS (EXTENDED RELEASE) or tacrolimus immediate-release product are shown in 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 TACROLIMUS (EXTENDED RELEASE) 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 TACROLIMUS (EXTENDED RELEASE) and tacrolimus immediate-release treatment groups, respectively.

### 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.

### Common Adverse Reactions
- The incidence of adverse reactions that occurred in 5% of TACROLIMUS (EXTENDED RELEASE)-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,  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.

# Drug Interactions

### Mycophenolic Acid
- When TACROLIMUS (EXTENDED RELEASE) is prescribed with a given dose of mycophenolic acid (MPA) product, exposure to MPA is higher with TACROLIMUS (EXTENDED RELEASE) 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 TACROLIMUS (EXTENDED RELEASE)

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 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.
- TACROLIMUS (EXTENDED RELEASE) 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.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tacrolimus (extended release) in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Tacrolimus (extended release) during labor and delivery.

### Nursing Mothers
- Tacrolimus is present in breast milk. Because of the potential for serious adverse drug reactions in nursing infants from TACROLIMUS (EXTENDED RELEASE), a decision should be made whether to discontinue nursing or to discontinue TACROLIMUS (EXTENDED RELEASE), taking into account the importance of drug to the mother.

### Pediatric Use
- The safety and effectiveness of TACROLIMUS (EXTENDED RELEASE) in pediatric patients have not been established.

### Geriatic Use
- Clinical studies of TACROLIMUS (EXTENDED RELEASE) 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.

### Gender
There is no FDA guidance on the use of Tacrolimus (extended release) with respect to specific gender populations.

### Race
- African-American patients may need to be titrated to higher TACROLIMUS (EXTENDED RELEASE) dosages to attain comparable trough concentrations compared to Caucasian patients.

### 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.

### 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.
- 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.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tacrolimus (extended release) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Tacrolimus (extended release) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Take TACROLIMUS (EXTENDED RELEASE) on an empty stomach at the same time of the day, preferably in the morning (to ensure consistent and maximum possible drug exposure).
- Swallow TACROLIMUS (EXTENDED RELEASE) 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 TACROLIMUS (EXTENDED RELEASE).
- African-American patients, compared to Caucasian patients, may need to be titrated to higher TACROLIMUS (EXTENDED RELEASE) dosages to attain comparable trough concentrations.

### 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 TACROLIMUS (EXTENDED RELEASE) dose.
- Monitor tacrolimus whole blood trough concentrations using a validated assay .
- 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.

# IV Compatibility
There is limited information regarding the compatibility of Tacrolimus (extended release) and IV administrations.

# 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 .
- 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 .
- 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.

# 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-B).
- 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).

## Structure
- TACROLIMUS (EXTENDED RELEASE), 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 TACROLIMUS (EXTENDED RELEASE).
- Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis.
- The chemical structure of tacrolimus is:
- Tacrolimus has an empirical formula of C44H69NO12H2O 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.

## Pharmacodynamics
There is limited information regarding Tacrolimus (extended release) Pharmacodynamics in the drug label.

## Pharmacokinetics
- Table below summarizes the pharmacokinetic (PK) parameters of tacrolimus following oral administration of once-daily TACROLIMUS (EXTENDED RELEASE) 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 TACROLIMUS (EXTENDED RELEASE) 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 TACROLIMUS (EXTENDED RELEASE) 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 TACROLIMUS (EXTENDED RELEASE) was approximately 50% higher as compared with both tacrolimus immediate-release and extended-release formulations at steady state.
- In healthy subjects who received single TACROLIMUS (EXTENDED RELEASE) 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 TACROLIMUS (EXTENDED RELEASE) 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 TACROLIMUS (EXTENDED RELEASE) was administered under fasted conditions.

### Chronopharmacokinetic Effect
- In 26 healthy subjects, administration of TACROLIMUS (EXTENDED RELEASE) 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.

### Specific Populations
- No dedicated pharmacokinetic studies in specific populations were conducted with TACROLIMUS (EXTENDED RELEASE).

### 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 3.91.6 and 12.02.4 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.

### 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.

### Race
- The pharmacokinetics of tacrolimus was studied following single oral administration of tacrolimus immediate-release (5 mg) in 10 African-American, 12 Latino-American, and 12 Caucasian healthy subjects:
The mean (SD) tacrolimus Cmax in African-Americans (23.612.1 ng/mL) was lower than in Caucasians (40.212.6 ng/mL) and Latino-Americans (36.215.8 ng/mL).
Mean AUC0-inf tended to be lower in African-Americans (203115 nghr/mL) than Caucasians (344186 nghr/mL) and Latino-Americans (274150 nghr/mL).
The mean (SD) absolute oral bioavailability (F) in African-Americans (124.5%) and Latino-Americans (147.4%) was lower than in Caucasians (195.8%).
There was no significant difference in mean terminal half-life among the three ethnic groups (range from approximately 25 to 30 hours).
- The mean (SD) tacrolimus Cmax in African-Americans (23.612.1 ng/mL) was lower than in Caucasians (40.212.6 ng/mL) and Latino-Americans (36.215.8 ng/mL).
- Mean AUC0-inf tended to be lower in African-Americans (203115 nghr/mL) than Caucasians (344186 nghr/mL) and Latino-Americans (274150 nghr/mL).
- The mean (SD) absolute oral bioavailability (F) in African-Americans (124.5%) and Latino-Americans (147.4%) was lower than in Caucasians (195.8%).
- There was no significant difference in mean terminal half-life among the three ethnic groups (range from approximately 25 to 30 hours).

### 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 TACROLIMUS (EXTENDED RELEASE) 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 TACROLIMUS (EXTENDED RELEASE).
- 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.

## Nonclinical Toxicology

### Carcinogenesis, Mutagenesis, Impairment of Fertility
- 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 TACROLIMUS (EXTENDED RELEASE).
- 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 systems 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.

# Clinical Studies

### Conversion Study from Tacrolimus Immediate-Release in Stable Kidney Transplant Recipients
- The conversion study was a randomized, open-label, multinational study evaluating once daily TACROLIMUS (EXTENDED RELEASE) when used to replace tacrolimus immediate-release administered twice daily for maintenance immunosuppression to prevent acute allograft rejection in stable adult kidney transplant patients.
- Patients who received a kidney transplant 3 months to 5 years before study entry and on a stable dose of tacrolimus immediate-release of at least 2 mg per day and tacrolimus whole blood trough concentrations between 4 and 15 ng/mL were randomized to 1) switch from twice daily tacrolimus immediate-release to once daily TACROLIMUS (EXTENDED RELEASE) (N=163) or 2) continue tacrolimus immediate-release twice daily (N=163).
- MMF or mycophenolate sodium (MPS), or azathioprine (AZA) and/or corticosteroids were allowed as concomitant immunosuppressants during the study period according to the standard of care at the participating site.
- The mean age of study population was 50 years; 67% were male; 73% were Caucasian, 22% were African-American, 2% were Asian and 3% were categorized as other races.
- Living donors provided 35% of the organs and 65% of patients received a kidney transplant from a deceased donor.
- Premature discontinuation from treatment at the end of one year occurred in 13% of TACROLIMUS (EXTENDED RELEASE) patients and 6% of tacrolimus immediate-release patients.
- In the conversion study, stable kidney transplant patients converted to TACROLIMUS (EXTENDED RELEASE) at an average daily dose that was 80% of their tacrolimus immediate-release daily dose prior to conversion.
- Mean tacrolimus whole blood trough concentrations were maintained within a relatively narrow range throughout the duration of the study for both the TACROLIMUS (EXTENDED RELEASE) conversion group and the tacrolimus immediate-release continuation group.
- At Week 1 (after 7 days of stable dosing), the mean  SD tacrolimus trough concentrations were 7.2  3.1 ng/mL for the TACROLIMUS (EXTENDED RELEASE) conversion group and 7.7  2.5 for the tacrolimus immediate-release continuation group; the baseline values were 7.8  2.3, and 8.0  2.3, respectively.
- In the conversion study, the average daily mycophenolate equivalent doses were comparable between the TACROLIMUS (EXTENDED RELEASE) and tacrolimus immediate-release treatment groups.
- The efficacy failure rates including patients who developed BPAR, graft failure, death, and/or lost to follow-up at 12 months, as well as the rates of the individual events, are shown by treatment group in the table for the modified intent-to-treat population.

### Glomerular Filtration Rates
- The mean estimated glomerular filtration rates (eGFR), using the Modification of Diet in Renal Disease 7 (MDRD7) formula, were 61.5 ml/min/1.73 m2 and 60.0 ml/min/1.73 m2 at baseline (Day 0) and 62.0 ml/min/1.73 m2 and 61.4 ml/min/1.73 m2 at 12 months in the ENVARSUS XR and tacrolimus immediate-release treatment groups, respectively.

# How Supplied
TACROLIMUS (EXTENDED RELEASE) is supplied in round bottles: the statement ONCE-DAILY appears on its label.

## Storage

### Storage and Dispense
- Store at 25 C (77 F); excursions permitted to 15 C-30 C (59 F-86 F) .

# Images

## Drug Images

## Package and Label Display Panel

### PRINCIPAL DISPLAY PANEL - Envarsus 0.75mg 30 Tablets Carton Label

### PRINCIPAL DISPLAY PANEL - Envarsus 1mg 30 Tablets Carton Label

### PRINCIPAL DISPLAY PANEL - Envarsus 4mg 30 Tablets Carton Label

### PRINCIPAL DISPLAY PANEL - Envarsus 0.75mg 100 Tablets Carton Label

### PRINCIPAL DISPLAY PANEL - Envarsus 1mg 100 Tablets Carton Label

### PRINCIPAL DISPLAY PANEL - Envarsus 4mg 100 Tablets Carton Label

# Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).

### Administration
Advise patients to:
- Inspect their TACROLIMUS (EXTENDED RELEASE) 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 TACROLIMUS (EXTENDED RELEASE).
- Take once-daily TACROLIMUS (EXTENDED RELEASE) 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 TACROLIMUS (EXTENDED RELEASE).
- Take a missed dose as soon as possible but not more than 15 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.

### Development of Lymphoma and Other Malignancies
- 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.

### Increased Risk of Infection
- 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.

### New Onset Diabetes After Transplant
- Inform patients that TACROLIMUS (EXTENDED RELEASE) can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst or hunger.

### Nephrotoxicity
- Inform patients that TACROLIMUS (EXTENDED RELEASE) 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.

### Neurotoxicity
- 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.

### Hyperkalemia
- Inform patients that TACROLIMUS (EXTENDED RELEASE) can cause hyperkalemia.
- Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia.

### Hypertension
- Inform patients that TACROLIMUS (EXTENDED RELEASE) can cause high blood pressure which may require treatment with anti-hypertensive therapy.

### Drug Interactions
- 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 adjustment of the dosage of TACROLIMUS (EXTENDED RELEASE). Avoid alcohol, grapefruit.

### Immunizations
- Inform patients that TACROLIMUS (EXTENDED RELEASE) can interfere with the usual response to immunizations and that they should avoid live vaccines.

# Precautions with Alcohol
Alcohol-Tacrolimus (extended release) interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
Envarsus XR

# Look-Alike Drug Names
There is limited information regarding Tacrolimus (extended release) Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price