Tacrolimus (extended release)

{{DrugProjectFormSinglePage |authorTag=Shivani Chaparala M.B.B.S [1] |genericName=Tacrolimus (extended release) |aOrAn=a |drugClass=calcineurin-inhibitor immunosuppressant |indicationType=prophylaxis |indication=organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations in combination with other immunosuppressants |hasBlackBoxWarning=Yes |adverseReactions=(incidence ≥10%): diarrhea and blood creatinine increased |blackBoxWarningTitle=WARNING |blackBoxWarningBody=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

|fdaLIADAdult===== 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).
• 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.
• African-American patients, compared to Caucasian patients, may need to be titrated to higher ENVARSUS XR dosages to attain comparable trough concentrations.

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.

|offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Tacrolimus (extended release) in adult patients. |offLabelAdultNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Tacrolimus (extended release) in adult patients. |fdaLIADPed=The safety and effectiveness of ENVARSUS XR in pediatric patients have not been established. |offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Tacrolimus (extended release) in pediatric patients. |offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Tacrolimus (extended release) in pediatric patients. |contraindications=* ENVARSUS XR is contraindicated in patients with known hypersensitivity to tacrolimus. |warnings===== 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.

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.

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.

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).
• 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.
• 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.
• Monitor serum potassium levels periodically during treatment.

Hypertension

• Hypertension is a common adverse reaction of ENVARSUS XR 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 ENVARSUS XR.

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 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).

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).
• 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.

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.

|clinicalTrials=* Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

• In addition, the clinical studies were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.
• In an open label, randomized, multinational conversion study, stable kidney transplant patients on a tacrolimus immediate-release product and concomitant immunosuppressants were randomized to treatment with ENVARSUS XR (N=162) or to continued treatment on the tacrolimus immediate-release product (N=162) and treated for a duration of 12 months.
• The proportion of patients who discontinued treatment due to adverse reactions was 7.4% and 1.2% in the 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.