CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`206406Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
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`

`

`Clinical Review of Envarsus XR Labeling
`Ergun Velidedeoglu, M.D.
`
`1
`
`DIVISION OF TRANSPLANT AND OPHTHALMOLOGY
`PRODUCTS
`Clinical Review of Envarsus XR®
`(tacrolimus extended-release tablets) Labeling
`NDA 206-406/S-046 SDN 49
`Class 1 Resubmission
`
`Name of Drug:
`
`Applicant:
`Initial FDA Approval:
`Submission Date:
`
`Goal Date:
`Date of Review Completion:
`Clinical Reviewer:
`Project Manager:
`Deputy Director for Safety:
`Division Director:
`
`Envarsus XR® (tacrolimus extended-
`release tablets) 0.75 mg, 1 mg, 4 mg
`Veloxis
`October 30, 2014 (Tentative Approval)
`June 12, 2015 (Class 1 resubmission)
`July 2, 2015, SDN 55 (MedGuide)
`July 7, 2015, SDN 57 (Package Insert)
`August 12, 2015
`July 8, 2015
`Ergun Velidedeoglu, M.D.
`Lois Almoza
`Ozlem Belen, MD, MPH
`Renata Albrecht, M.D.
`
`1. Summary of the Regulatory History:
`Envarsus XR is an extended release tablet formulation of tacrolimus which is a
`calcineurin (CNI) type of immunosuppressant forming one of the main
`components of most immunosuppressive treatment regimens utilized in the
`clinical practice of transplantation.
`
`Currently there is an immediate release formulation of tacrolimus (Prograf
`capsules and generics) and another extended release formulation (Astagraf XL)
`lawfully marketed in US.
`
`NDA 206406 was originally submitted on December 30, 2013 with a PDUFA goal
`date of October 30, 2014. NDA 206406 for Envarsus XR is a 505(b)(2)
`
`Reference ID: 3790215
`
`

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`Clinical Review of Envarsus XR Labeling
`Ergun Velidedeoglu, M.D.
`
`2
`
`application and the listed drug product on which the applicant is relying for
`nonclinical information is Prograf. The Applicant originally sought approval of the
`Envarsus XR extended release tablets for the prophylaxis of rejection in both the
`de novo and stable kidney transplant recipients (as conversion from Prograf or
`generics) and submitted the results of two Phase 3 randomized controlled
`studies in addition to Phase 2 and Phase 1 studies in support of this indication.
`
`The Phase 3 studies, LCP-Tacro 3002 (de novo) and LCP-Tacro 3001
`(conversion), along with the Phase 2 study, LCP-Tacro 2017 (de novo), reviewed
`in support of the proposed indication demonstrate that the Envarsus XR has
`comparable safety and efficacy to the active comparator Prograf.
`
`On October 30, 2014, FDA issued a tentative approval (TA) for NDA 206406
`because FDA determined that approval of the drug product was blocked by the
`three-year exclusivity of Astagraf XL (NDA 204096).
`
`As communicated in the October 30, 2014 TA Letter, final approval of NDA
`206406, is contingent on submission of an amendment titled “Request for Final
`Approval” by the Sponsor (Veloxis) two to six months prior to the:1) expiration of
`the exclusivity protection or 2) date the Sponsor believes that NDA 206406 will
`be eligible for final approval.
`
`During the course of subsequent communications between the FDA and the
`Applicant (Veloxis), in the January 12, 2015 letter, FDA stated that:
`
`“… FDA concludes that the Envarsus XR NDA is a once-daily, ER dosage
`form of tacrolimus for prophylaxis of organ rejection that is blocked from
`approval for de novo kidney transplant patients by Astagraf XL’s exclusivity
`until that exclusivity expires on July 19, 2016. FDA also concludes, however,
`that the Envarsus XR NDA can be approved now for conversion of stable
`kidney transplant patients from tacrolimus immediate-release (IR) products to
`Envarsus XR (the conversion use), pending Veloxis’ submission and FDA
`approval of an appropriate labeling amendment deleting reference to the de
`novo population and seeking approval for the conversion use only. ”
`
`The applicant chose to seek resolution of the issue through litigation. This review
`does not include the details of the litigation. Relevant FDA documents related to
`the review of Envarsus XR and Astagraf XL have been checked into DARRTS.
`
`On June 12, 2015, U.S. District Court ruled in favor of the FDA in the lawsuit filed
`by Veloxis against FDA. The Court's ruling leaves intact FDA's October 30, 2014
`tentative approval of Envarsus XR (tacrolimus extended-release tablets), which
`delays full approval for use in de novo kidney transplanted recipients ("de novo"
`patients). On the same date (June 12, 2015) Veloxis submitted revised labeling
`to FDA as a Class 1 resubmission for the “conversion use indication” only,
`
`Reference ID: 3790215
`
`

`

`Clinical Review of Envarsus XR Labeling
`
`3
`
`Ergun Velidedeoglu, MD.
`
`requesting approval of Envarsus XR in stable kidney transplant patients who
`wish to convert from twice-daily immediate release tacrolimus products to once-
`daily Envarsus XR.
`
`In the revised labeling submitted on June 12, 2015, Veloxis removed sections
`and statements dealing with the “de novo indication” (since this indication is still
`protected by the exclusivity granted to Astagraf XL).. The Division made a few
`additional edits, removing remaining statements of results in de novo kidney
`transplant patients.
`
`The revised labeling for the PI and MG was sent to Veloxis, and the final agreed
`upon Pl was submitted July 7, 2015 and the MG was submitted on July 2, 2015.
`
`In addition, the CMC reviewer noted that the container, overwrap and carton
`labels submitted to the NDA on September 26, October 9, and October 16, 2014,
`respectively, were considered acceptable. Clinical agrees with the CMC
`recommendations. The package insert and the Medication Guide attached at the
`end of this review are the final agreed upon versions by the FDA and the
`applicant.
`
`The major changes pertaining to the clinical discipline in the currently agreed
`upon labeling compared to the labeling communicated to the applicant in the
`October 30, 2014 TA Letter are below. For changes pertaining to other
`disciplines including Clinical Pharmacology, refer to respective reviews in
`DARRTS.
`
`o
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`1 INDICATIONS AND USAGE
`
`The indication has been changed
`
`from:
`
`to:
`
`“ENVARSUS XR is indicated for the prophylaxis of"”organ rejection
`in kidney transplant patients in
`
`“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.”
`
`o
`
`2 DOSAGE AND ADMINISTRATION
`
`- Subsection
`
`m"
`
`has been deleted.
`
`Reference ID: 379021 5
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`

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`Clinical Review of Envarsus XR Labeling
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`4
`
`Ergun Velidedeoglu, M.D.
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`- Subsection 2.1 Administration Instructions have been revised
`
`based on the applicant’s modeling of missed doses of Envarsus XR
`using data from LCP-Tacro Study 2011.
`
`Changed from:
`
`
`
`to:
`
`If a dose is missedl 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.
`
`For more information about the changes under DOSAGE AND
`ADMINISTRATION see Clinical Pharmacology review dated July 9, 2015
`in DARRTS.
`
`o
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`6 ADVERSE REACTIONS
`
`
`
`
`e conversion Study LCP-Tacro 3001.
`
`pe aInIng o
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`o
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`14 CLINICAL STUDIES
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`subsection"
`_ as een remove .
`
`Clinical Reviewer’s Comment:
`B removin
`
`Pharmacokinetics as a footnote under Table 5:
`
`section.
`
`has also been removed from this
`
`However, to prevent any loss of important safety information from the labeling,
`the current final agreed upon labeling contains this warning in section 12.2
`
`Reference ID: 379021 5
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`

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`Clinical Review of Envarsus XR Labeling
`Ergun Velidedeoglu, M.D.
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`5
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`“g) Starting ENVARSUS XR dose = 0.17 mg/kg/day. In de novo kidney transplant
`patients who received ENVARSUS XR starting dose of 0.17 mg/kg/day achieved
`higher than recommended target tacrolimus trough concentrations, as high as 57
`ng/mL during the first 1 to 2 weeks posttransplant.”
`
`Information on this pharmacokinetic measurement following specific doses is
`considered important safety information.
`
`2. Clinical Reviewer’s Recommendation:
`I recommend approval of the final agreed upon Package Insert (PI), Medication
`Guide (MG) and Carton and Container Labeling. The text of the PI and MG are
`included in the following section of this review.
`
`3. Final Agreed upon Labeling and MG
`Envarsus XR (tacrolimus extended-release tablets)
`
`FULL PRESCRIBING INFORMATION
`
`WARNING: MALIGNANCIES AND SERIOUS INFECTIONS
`
`Increased risk for developing serious infections and malignancies with ENVARSUS
`XR or other immunosuppressants that may lead to hospitalization or death [see
`Warnings and Precautions (5.1, 5.2)]
`
`1 INDICATIONS AND USAGE
`ENVARSUS XR is indicated for the prophylaxis of organ rejection in kidney transplant patients
`converted from tacrolimus immediate-release formulations, in combination with other
`immunosuppressants.
`Limitation of Use
`ENVARSUS XR extended-release tablets are not interchangeable or substitutable with other
`tacrolimus extended-release or immediate-release products [see Warnings and Precautions
`(5.3)].
`
`Reference ID: 3790215
`
`

`

`Clinical Review of Envarsus XR Labeling
`Ergun Velidedeoglu, M.D.
`
`6
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`2 DOSAGE AND ADMINISTRATION
`
`2.1 Administration Instructions
`
`
`
`
`
` Take ENVARSUS XR on an empty stomach at the same time of the day, preferably in
`the morning (to ensure consistent and maximum possible drug exposure) [see Clinical
`Pharmacology (12.2)].
`Swallow ENVARSUS XR whole with fluid (preferably water); do not chew, divide, or
`crush the tablets.
`If a dose is missed, take it as soon as possible within 15 hours after missing the dose;
`beyond the 15-hour time frame, wait until the usual scheduled time to take the next
`regular daily dose. Do not double the next dose..
` Avoid eating grapefruit or drinking grapefruit juice or alcoholic beverage while taking
`ENVARSUS XR [see Drug Interactions (7.2)].
` African-American patients, compared to Caucasian patients, may need to be titrated to
`higher ENVARSUS XR dosages to attain comparable trough concentrations [see Use in
`Specific Populations (8.8) and Clinical Pharmacology (12.2)].
`
`2.2 Conversion from Tacrolimus Immediate-Release Formulations
`To convert from a tacrolimus immediate-release product to ENVARSUS XR, administer an
`ENVARSUS XR once daily dose that is 80% of the total daily dose of the tacrolimus immediate-
`release product. Monitor tacrolimus whole blood trough concentrations and titrate ENVARSUS
`XR dosage to achieve target whole blood trough concentration ranges of 4 to 11 ng/mL.
`
`2.3 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.
`
`3 DOSAGE FORMS AND STRENGTHS
`Oval, white to off-white uncoated extended-release tablets debossed with “TCS” on one side:
` 0.75 mg extended-release tablet: debossed with “0.75” on the other side.
`
`Reference ID: 3790215
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`

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`Clinical Review of Envarsus XR Labeling
`Ergun Velidedeoglu, M.D.
`
`7
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` 1 mg extended-release tablet: debossed with “1” on the other side.
` 4 mg extended-release tablet: debossed with “4” on the other side.
`
`4 CONTRAINDICATIONS
`ENVARSUS XR is contraindicated in patients with known hypersensitivity to tacrolimus.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 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.
`
`5.2 Serious Infections
`Immunosuppressants, including ENVARSUS XR, increase the risk of developing bacterial, viral,
`fungal, and protozoal infections, including opportunistic infections. These infections may lead to
`serious, including fatal, outcomes. Serious viral infections reported include:
`Polyomavirus-associated nephropathy (especially due to BK virus infection),
`
`JC virus-associated progressive multifocal leukoencephalopathy (PML), and
`
` Cytomegalovirus (CMV) infections: CMV seronegative transplant patients who receive
`an organ from a CMV seropositive donor are at highest risk of CMV viremia and CMV
`disease.
`Monitor for the development of infection and adjust the immunosuppressive regimen to balance
`the risk of rejection with the risk of infection [see Adverse Reactions (6.1)].
`
`5.3 Graft Rejection and Other Serious Adverse Reactions due to Medication Errors
`Medication errors, including substitution and dispensing errors, between tacrolimus immediate-
`release products and tacrolimus extended-release products were reported outside the U.S. This led
`to serious adverse reactions, including graft rejection, or other adverse reactions due to under- or
`over-exposure to tacrolimus. ENVARSUS XR is not interchangeable or substitutable with
`tacrolimus immediate-release products or other tacrolimus extended-release products. Instruct
`patients and caregivers to recognize the appearance of ENVARSUS XR tablet [see Dosage
`Forms and Strengths (3)].
`
`5.4 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
`
`Reference ID: 3790215
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`

`

`Clinical Review of Envarsus XR Labeling
`Ergun Velidedeoglu, M.D.
`
`8
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`transplant patients are at an increased risk. Monitor blood glucose concentrations and treat
`appropriately [see Adverse Reactions (6.1) and Use in Specific Populations (8.8)].
`
`5.5 Nephrotoxicity due to ENVARSUS XR and Drug Interactions
`ENVARSUS XR, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity.
`Consider dosage reduction in patients with elevated serum creatinine and tacrolimus whole blood
`trough concentrations greater than the recommended range. The risk for nephrotoxicity may
`increase when ENVARSUS XR is concomitantly administered with CYP3A inhibitors (by
`increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g.,
`aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase
`inhibitors, protease inhibitors) [see Drug Interactions (7.2)]. Monitor renal function and
`consider dosage reduction if nephrotoxicity occurs.
`
`5.6 Neurotoxicity
`ENVARSUS XR may cause a spectrum of neurotoxicities. The most severe neurotoxicities
`include posterior reversible encephalopathy syndrome (PRES), delirium, seizure, and coma;
`others include tremors, paresthesias, headache, mental status changes, and changes in motor and
`sensory functions [see Adverse Reactions (6.1, 6.2)]. As symptoms may be associated with
`tacrolimus whole blood trough concentrations at or above the recommended range, monitor for
`neurologic symptoms and consider dosage reduction or discontinuation of ENVARSUS XR if
`neurotoxicity occurs.
`
`5.7 Hyperkalemia
`Mild to severe hyperkalemia, which may require treatment, has been reported with tacrolimus
`including ENVARSUS XR. Concomitant use of agents associated with hyperkalemia (e.g.,
`potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) may increase the risk
`for hyperkalemia [see Adverse Reactions (6.1)]. Monitor serum potassium levels periodically
`during treatment.
`
`5.8 Hypertension
`Hypertension is a common adverse reaction of ENVARSUS XR therapy and may require
`antihypertensive therapy [see Adverse Reactions (6.1)]. Some antihypertensive drugs can
`increase the risk for hyperkalemia [see Warnings and Precautions (5.7)]. Calcium-channel
`blocking agents may increase tacrolimus blood concentrations and require dosage reduction of
`ENVARSUS XR [see Drug Interactions (7.2)].
`
`5.9 Risk of Rejection with Strong CYP3A Inducers and Risk of Serious Adverse Reactions
`with Strong CYP3A Inhibitors
`The concomitant use of strong CYP3A inducers may increase the metabolism of tacrolimus,
`leading to lower whole blood trough concentrations and greater risk of rejection. In contrast, the
`concomitant use of strong CYP3A inhibitors may decrease the metabolism of tacrolimus, leading
`to higher whole blood trough concentrations and greater risk of serious adverse reactions (e.g.,
`neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.10)] Therefore, adjust
`ENVARSUS XR dose and monitor tacrolimus whole blood trough concentrations when
`coadministering ENVARSUS XR with strong CYP3A inhibitors (e.g., telaprevir, boceprevir,
`
`Reference ID: 3790215
`
`

`

`Clinical Review of Envarsus XR Labeling
`Ergun Velidedeoglu, M.D.
`
`9
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`ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) or strong CYP3A inducers
`(e.g., rifampin, rifabutin) [see Dosage and Administration (2.3) and Drug Interactions (7.2)].
`
`5.10 QT Prolongation
`
`ENVARSUS XR may prolong the QT/QTc interval and cause Torsade de Pointes. Avoid
`ENVARSUS XR in patients with congenital long QT syndrome. Consider obtaining
`electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically
`during treatment in patients with congestive heart failure, bradyarrhythmias, those taking certain
`antiarrhythmic medications or other products that lead to QT prolongation, and those with
`electrolyte disturbances (e.g., hypokalemia, hypocalcemia, or hypomagnesemia).
`
`When coadministering ENVARSUS XR with other substrates and/or inhibitors of CYP3A, a
`reduction in ENVARSUS XR dosage, monitoring of tacrolimus whole blood concentrations, and
`monitoring for QT prolongation is recommended [see Drug Interactions (7.2)].
`
`5.11 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.
`
`5.12 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.
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Studies Experience
`Because clinical studies are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
`studies of another drug and may not reflect the rates observed in practice. In addition, the clinical
`studies were not designed to establish comparative differences across study arms with regards to
`the adverse reactions discussed below.
`
`In an open label, randomized, multinational conversion study, stable kidney transplant patients on
`a tacrolimus immediate-release product and concomitant immunosuppressants were randomized
`to treatment with ENVARSUS XR (N=162) or to continued treatment on the tacrolimus
`immediate-release product (N=162) and treated for a duration of 12 months [see Clinical Studies
`(14)].
`
`Reference ID: 3790215
`
`

`

`Clinical Review of Envarsus XR Labeling
`Ergun Velidedeoglu, M.D.
`
`10
`
`The proportion of patients who discontinued treatment due to adverse reactions was 7.4% and
`1.2% in the ENVARSUS XR and tacrolimus immediate-release treatment groups, respectively,
`through 12 months of treatment. The most common adverse reactions leading to discontinuation
`of study drug in the ENVARSUS XR treatment group was cardiac arrest (2 events).
`Infections
`The overall incidence of infections, serious infections, and infections with identified etiology
`reported in stable kidney transplant recipients treated with ENVARSUS XR or tacrolimus
`immediate-release product are shown in Table 1.
`
`Table 1. Percentage of Stable Patients with Infections Through One Year Post- Treatment
`in the Conversion Study a
`
`ENVARSUS XR ±
`steroids, MMF/MPS or
`AZA
`
`Tacrolimus immediate-
`release product ± steroids,
`MMF/MPS or AZA
`
`N=162
`N=162
`48%
`46%
`All infections
`28%
`26%
`Respiratory Infections
`14%
`10%
`Urinary Tract Infections
`5%
`7%
`Bacterial Infections
`4%
`4%
`Fungal Infections
`5%
`4%
`Gastrointestinal Infections
`2%
`2%
`BK virus b
`1%
`2%
`Cytomegalovirus Infections
`9%
`8%
`Serious Infections
`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 [see Warnings and Precautions (5.4)].
`
`Reference ID: 3790215
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`

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`Clinical Review of Envarsus XR Labeling
`Ergun Velidedeoglu, M.D.
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`11
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`Table 2. Percentage of Stable Patients with NODAT Through 1 Year Post- Treatment in the
`Conversion Study a
`
`ENVARSUS XR ±
`steroids , MMF/MPS or
`AZA
`(N=90)
`10%
`3%
`
`Tacrolimus immediate-
`release product ± steroids,
`MMF/MPS or AZA
`(N=95)
`11%
`7%
`
`Composite NODAT b
` HbA1c ≥6.5%
`Fasting Plasma Glucose Values ≥126 mg/dL
`on 2 consecutive occurrences
`Oral hypoglycemic use
`Insulin Use ≥31 days
`a The stable kidney transplant study was not designed to support comparative claims of ENVARSUS XR
`compared to tacrolimus immediate-release product for the adverse reactions reported in this table.
`b Analyses restricted to patients at risk for NODAT
`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.
`
`8%
`
`1%
`
`1%
`
`6%
`
`1%
`
`0%
`
`ENVARSUS XR
`N=162
`
`Table 3. Adverse Reactions ( ≥ 5%) in Stable Kidney Transplant Patients Through 1 Year
`Post- Treatment in the Conversion Studya
`Adverse Reaction
`
`Tacrolimus immediate-
`release product
`N=162
`9%
`14%
`Diarrhea
`9%
`12%
`Blood Creatinine Increased
`14%
`9%
`Urinary Tract Infection
`11%
`9%
`Nasopharyngitis
`7%
`9%
`Headache
`9%
`7%
`Upper Respiratory Tract Infection
`6%
`7%
`Peripheral Edema
`6%
`4%
`Hypertension
`aThe stable kidney transplant study was not designed to support comparative claims of ENVARSUS XR
`compared to tacrolimus immediate-release for the adverse reactions reported in this table.
`
`Reference ID: 3790215
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`

`

`Clinical Review of Envarsus XR Labeling
`Ergun Velidedeoglu, M.D.
`
`12
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`6.2 Postmarketing Experience
`The following adverse reactions have been reported from marketing experience with tacrolimus
`in the U.S. and outside the U.S. Because these reactions are reported voluntarily from a
`population of uncertain size, it is not always possible to reliably estimate their frequency or
`establish a causal relationship to drug exposure.
`Blood and Lymphatic System Disorders: Agranulocytosis, decreased blood fibrinogen,
`disseminated intravascular coagulation, hemolytic anemia, hemolytic uremic syndrome,
`pancytopenia, prolonged activated partial thromboplastin time, pure red cell aplasia [see
`Warnings and Precaution (5.12)], thrombocytopenic purpura, thrombotic thrombocytopenic
`purpura
`Cardiac Disorders: Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest,
`electrocardiogram T wave abnormal, flushing, myocardial hypertrophy, myocardial infarction,
`myocardial ischaemia, pericardial effusion, QT prolongation, supraventricular extrasystoles,
`supraventricular tachycardia, Torsade de Pointes, deep limb venous thrombosis, ventricular
`fibrillation
`Ear Disorders: Hearing loss including deafness
`Eye Disorders: Blindness, photophobia, optic atrophy
`Gastrointestinal Disorders: Colitis, dysphagia, gastrointestinal perforation, impaired gastric
`emptying, intestinal obstruction, mouth ulceration, peritonitis, stomach ulcer
`Hepatobiliary Disorders: Bile duct stenosis, cholangitis, cirrhosis, fatty liver, hepatic cytolysis,
`hepatic failure, hepatic necrosis, hepatic steatosis, jaundice, hemorrhagic pancreatitis, necrotizing
`pancreatitis, venoocclusive liver disease
`Hypersensitivity Reactions: Hypersensitivity, Stevens-Johnson syndrome, toxic epidermal
`necrolysis, urticaria
`Immune System Disorders: Graft versus host disease (acute and chronic)
`Metabolism and Nutrition Disorders: Glycosuria, increased amylase, pancreatitis
`Musculoskeletal and Connective Tissue Disorders: Myalgia, polyarthritis, rhabdomyolysis
`Neoplasms: Lymphoma including EBV-associated lymphoproliferative disorder, PTLD [see
`Warnings and Precautions (5.1)]; leukemia
`Nervous System Disorders: Carpal tunnel syndrome, cerebral infarction, coma, dysarthria, flaccid
`paralysis, hemiparesis, mental disorder, mutism, nerve compression, posterior reversible
`encephalopathy syndrome (PRES) [see Warnings and Precautions (5.6)], progressive multifocal
`leukoencephalopathy (PML) sometimes fatal [see Warnings and Precautions (5.2)],
`quadriplegia, speech disorder, status epilepticus, syncope
`Renal and Urinary Disorder: Acute renal failure, hemorrhagic cystitis, hemolytic uremic
`syndrome, micturition disorder
`Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome,
`interstitial lung disease, lung infiltration, pulmonary hypertension, respiratory distress, respiratory
`failure
`Skin and Subcutaneous Tissue Disorders: Hyperpigmentation, photosensitivity
`
`Reference ID: 3790215
`
`

`

`Clinical Review of Envarsus XR Labeling
`Ergun Velidedeoglu, M.D.
`
`13
`
`7 DRUG INTERACTIONS
`
`7.1 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.
`
`7.2 Effects of Other Drugs/Substances on ENVARSUS XR
`
`Table 4. Effects of Other Drugs/Substances on ENVARSUS XRa
`Drug/Substance Class or Name
`Drug Interaction Effect
`Recommendations
`Grapefruit or grapefruit juiceb
`May increase tacrolimus
`Avoid grapefruit or grapefruit
`whole blood trough
`juice
`concentrations and increase
`the risk of serious adverse
`reactions (e.g.,
`neurotoxicity, QT
`prolongation) [see
`Warnings and Precautions
`(5.6, 5.10)]
`May modify the rate of
`tacrolimus release
`May decrease tacrolimus
`whole blood trough
`concentrations and increase
`the risk of rejection [see
`Warnings and Precautions
`(5.9)]
`
`Avoid alcoholic beverages
`
`Increase ENVARSUS XR
`dose and monitor tacrolimus
`whole blood trough
`concentrations [see Dosage
`and Administration (2.3) and
`Clinical Pharmacology
`(12.2)]
`Reduce ENVARSUS XR
`dose (for voriconazole and
`posaconazole, give one-third
`of the original dose) and
`adjust dose based on
`tacrolimus whole blood
`trough concentrations [see
`Dosage and Administration
`(2.3) and Clinical
`Pharmacology (12.2)]
`
`Alcohol
`
`Strong CYP3A Inducersc such as:
`Antimycobacterials (e.g.,
`rifampin, rifabutin),
`anticonvulsants (e.g.,
`phenytoin, carbamazepine and
`phenobarbital), St John’s Wort
`
`Strong CYP3A Inhibitorsc, such
`as:
`
`Protease inhibitors (e.g.,
`nelfinavir, telaprevir,
`boceprevir, ritonavir), azole
`antifungals (e.g., voriconazole,
`posaconazole, itraconazole,
`ketoconazole), antibiotics
`(e.g., clarithromycin,
`troleandomycin,
`chloramphenicol), nefazodone
`
`May increase tacrolimus
`whole blood trough
`concentrations and increase
`the risk of serious adverse
`reactions (e.g.,
`neurotoxicity, QT
`prolongation) [see
`Warnings and Precautions
`(5.6, 5.9, 5.10)]
`
`Reference ID: 3790215
`
`

`

`Clinical Review of Envarsus XR Labeling
`Ergun Velidedeoglu, M.D.
`
`14
`
`Mild or Moderate CYP3A
`Inhibitors, such as:
`antibiotics (e.g.,
`erythromycin), calcium
`channel blockers (e.g.,
`verapamil, diltiazem,
`nifedipine, nicardipine),
`amiodarone, danazol, ethinyl
`estradiol, cimetidine,
`lansoprazole and omeprazole,
`azole antifungals (e.g.,
`clotrimazole, fluconazole)
`Other drugs, such as:
`Magnesium and aluminum
`hydroxide antacids
`
`Metoclopramide
`
`May increase tacrolimus
`whole blood trough
`concentrations and increase
`the risk of serious adverse
`reactions (e.g.,
`neurotoxicity, QT
`prolongation) [see
`Warnings and Precautions
`(5.6, 5.10)]
`
`Monitor tacrolimus whole
`blood trough concentrations
`and reduce ENVARSUS XR
`dose if needed [see Dosage
`and Administration (2.3),
`Clinical Pharmacology
`(12.2)]
`
`Monitor tacrolimus whole
`blood trough concentrations
`and reduce ENVARSUS XR
`dose if needed [see Dosage
`and Administration (2.3),
`Clinical Pharmacology
`(12.2)]
`
`May increase tacrolimus
`whole blood trough
`concentrations and increase
`the risk of serious adverse
`reactions (e.g.,
`neurotoxicity, QT
`prolongation) [see
`Warnings and Precautions
`(5.6, 5.10)]
`May decrease tacrolimus
`concentrations
`
`Mild or Moderate CYP3A
`Inducers, such as:
`Methylprednisolone,
`prednisone
`
`Monitor tacrolimus whole
`blood trough concentrations
`and adjust ENVARSUS XR
`dose if needed [see Dosage
`and Administration (2.3)]
`a ENVARSUS XR dosage adjustment recommendation based on observed effect of coadministered drug on tacrolimus
`exposures [see Clinical Pharmacology (12.2)], literature reports of altered tacrolimus exposures, or the other drug’s
`known CYP3A inhibitor/inducer status
`b High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice
`is a moderate CYP3A inhibitor
`c Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting in vitro
`CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe
`substrate)
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`Pregnancy Category C
`There are no adequate and well-controlled studies in pregnant women. Tacrolimus is transferred
`across the placenta. The use of tacrolimus during pregnancy in humans has been associated with
`neonatal hyperkalemia and renal dysfunction.
`
`Tacrolimus given orally to pregnant rabbits at 0.7 times the maximum clinical dose and pregnant
`rats at 1.1 times the maximum clinical dose was associated with an increased incidence of fetal
`death in utero, fetal malformations (cardiovascular, skeletal, omphalocele, and gallbladder
`agenesis) and maternal toxicity. ENVARSUS XR should be use