Tacrolimus (extended release)
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
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WARNING
See full prescribing information for complete Boxed Warning.
MALIGNANCIES AND SERIOUS INFECTIONS
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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)
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
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WARNING
See full prescribing information for complete Boxed Warning.
MALIGNANCIES AND SERIOUS INFECTIONS
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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.
- 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).
- 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 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.
Postmarketing Experience
There is limited information regarding Tacrolimus (extended release) Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Tacrolimus (extended release) Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Tacrolimus (extended release) in women who are pregnant.
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
There is no FDA guidance on the use of Tacrolimus (extended release) in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Tacrolimus (extended release) in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Tacrolimus (extended release) in geriatric settings.
Gender
There is no FDA guidance on the use of Tacrolimus (extended release) with respect to specific gender populations.
Race
There is no FDA guidance on the use of Tacrolimus (extended release) with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Tacrolimus (extended release) in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Tacrolimus (extended release) in patients with hepatic impairment.
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
There is limited information regarding Tacrolimus (extended release) Administration in the drug label.
Monitoring
There is limited information regarding Tacrolimus (extended release) Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Tacrolimus (extended release) and IV administrations.
Overdosage
There is limited information regarding Tacrolimus (extended release) overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Tacrolimus (extended release) Pharmacology in the drug label.
Mechanism of Action
There is limited information regarding Tacrolimus (extended release) Mechanism of Action in the drug label.
Structure
There is limited information regarding Tacrolimus (extended release) Structure in the drug label.
Pharmacodynamics
There is limited information regarding Tacrolimus (extended release) Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Tacrolimus (extended release) Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Tacrolimus (extended release) Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Tacrolimus (extended release) Clinical Studies in the drug label.
How Supplied
There is limited information regarding Tacrolimus (extended release) How Supplied in the drug label.
Storage
There is limited information regarding Tacrolimus (extended release) Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
There is limited information regarding Tacrolimus (extended release) Patient Counseling Information in the drug label.
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
There is limited information regarding Tacrolimus (extended release) Brand Names in the drug label.
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.