Tacrolimus (extended release)

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Tacrolimus (extended release)
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shivani Chaparala M.B.B.S [2]

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Black Box Warning

WARNING
See full prescribing information for complete Boxed 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.

Overview

Tacrolimus (extended release) is a calcineurin-inhibitor immunosuppressant 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 (incidence ≥10%): diarrhea and blood creatinine increased.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

  • 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.

Extended-release tablets: 0.75 mg, 1 mg, 4 mg.

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 [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.

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.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-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.

Non–Guideline-Supported Use

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

Contraindications

  • TACROLIMUS (EXTENDED RELEASE) is contraindicated in patients with known hypersensitivity to tacrolimus.

Warnings

WARNING
See full prescribing information for complete Boxed 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.

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

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

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

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

Immunizations

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)
This image is provided by the U.S. National Library of Medicine.

(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.

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 ENVARSUS XR-treated patients compared to tacrolimus immediate-release product through one year of treatment in the conversion study is shown by treatment group in TABLE 3.

Postmarketing Experience

  • The following adverse reactions have been reported from marketing experience with tacrolimus in the U.S. and outside the U.S.
  • Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
  • Ear Disorders: Hearing loss including deafness.

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

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.
  • 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.


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 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.

Geriatic 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.
  • 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 ENVARSUS XR 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 [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.

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:
  • 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

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

Mechanism of Action

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Structure

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Pharmacodynamics

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Pharmacokinetics

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Nonclinical Toxicology

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Clinical Studies

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How Supplied

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Storage

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Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

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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

123

Look-Alike Drug Names

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

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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