Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

ENVARSUS XR (NDA-206406)

(TACROLIMUS)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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04/08/2024 (SUPPL-9)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

ENVARSUS XR is contraindicated in patients with known hypersensitivity to tacrolimus or to any of the ingredients in ENVARSUS XR.

5 Warnings and Precautions

5.5 Nephrotoxicity due to ENVARSUS XR and Drug Interactions

Additions and/or revisions underlined:

ENVARSUS XR, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity in transplant patients due to its vasoconstrictive effect on renal vasculature, toxic tubulopathy and tubular-interstitial effects. Acute renal impairment associated with tacrolimus toxicity can result in high serum creatinine, hyperkalemia, decreased secretion of urea and hyperuricemia, and is usually reversible. In patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range, consider dosage reduction or temporary interruption of tacrolimus administration.

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). When tacrolimus is used concurrently with CYP3A inhibitors or other known nephrotoxic drugs, monitor renal function and tacrolimus blood concentrations, and adjust dose of both tacrolimus and/or concomitant medications during concurrent use [see Adverse Reactions (6.1, 6.2) and Drug Interactions (7.2)].

5.9 Risk of Rejection with Strong CYP3A Inducers and Risk of Serious Adverse Reactions with Strong CYP3A Inhibitors

Additions and/or revisions underlined:

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 co-administering ENVARSUS XR with strong CYP3A inhibitors (e.g., including but not limited to telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) or strong CYP3A inducers (e.g., including but not limited to rifampin, rifabutin) [see Dosage and Administration (2.4, 2.5), Drug Interactions (7.2)]. A rapid, sharp rise in tacrolimus levels has been reported after co-administration with strong CYP3A4 inhibitors despite an initial reduction of tacrolimus dose. Early and frequent monitoring of tacrolimus whole blood trough levels is recommended [see Drug Interactions (7.2)].

5.10 QT Prolongation

Additions and/or revisions underlined:

ENVARSUS XR may prolong the QT/QTc interval and cause Torsades 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 co-administering ENVARSUS XR with other substrates and/or inhibitors of CYP3A, especially those that also have the potential to prolong the QT interval, a reduction in ENVARSUS XR dosage, monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended [see Dosage and Administration (2.5), Drug Interactions (7.2)].

5.14 Thrombotic Microangiopathy (TMA) Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura

Newly added subsection:

Cases of thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported in patients treated with ENVARSUS XR. TMA may have a multifactorial etiology. Risk factors for TMA that can occur in transplant patients include, for example, severe infections, graft-versus-host disease (GVHD), Human Leukocyte Antigen (HLA) mismatch, the use of calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors. These risk factors may, either alone or combined, contribute to the risk of TMA.

In patients with signs and symptoms of TMA, consider ENVARSUS XR as a risk factor. Concurrent use of ENVARSUS XR and mTOR inhibitors may contribute to the risk of TMA.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura [see Warnings and Precautions (5.13)]

7 Drug Interactions

7.2 Effects of Other Drugs/Substances on ENVARSUS XR

Changes to Table 7; please refer to label for complete information

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Extensive changes; please refer to label for complete information

PATIENT COUNSELING INFORMATION

17.9 Thrombotic Microangiopathy

Newly added subsection:

Inform patients that ENVARSUS XR can cause blood clotting problems. The risk of this occurring increases when patients take ENVARSUS XR and sirolimus or everolimus concomitantly, or when patients develop certain infections. Advise them to seek medical attention promptly if they develop fever, petequiae or bruises, fatigue, confusion, jaundice, oliguria [see Warnings and Precautions (5.13)].

09/14/2023 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.13 Cannabidiol Drug Interactions

Newly added subsection:

When cannabidiol and ENVARSUS XR are co-administered, closely monitor for an increase in tacrolimus blood levels

and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of ENVARSUS XR should be considered as

needed when ENVARSUS XR is co-administered with cannabidiol [see Dosage and Administration (2.4, 2.5), Drug

Interactions (7.3)].

7 Drug Interactions

7.3 Cannabidiol

Newly added subsection:

The blood levels of tacrolimus may increase upon concomitant use with cannabidiol. When cannabidiol and ENVARSUS XR are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of ENVARSUS XR should be considered as needed when ENVARSUS XR is coadministered with cannabidiol [see Dosage and Administration (2.5) and Warnings and Precautions (5.13)].

09/16/2020 (SUPPL-8)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions underlined)

…

Blood and Lymphatic System Disorders: Agranulocytosis, decreased blood fibrinogen, disseminated intravascular coagulation, hemolytic anemia, hemolytic uremic syndrome, leukopenia, febrile neutropenia, pancytopenia, prolonged activated partial thromboplastin time, pure red cell aplasia [see Warnings and Precautions (5.12)], thrombocytopenic purpura, thrombotic thrombocytopenic purpura, thrombotic microangiopathy
…
Eye Disorders: Blindness, optic neuropathy, photophobia, optic atrophy
…
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, hepatitis (acute and chronic)
…

7 Drug Interactions

7.2 Effects of Other Drugs/Substances on ENVARSUS XR

(Additions underlined; also updates made to Table 7, please refer to label to view Table 7)

Table 7. Effects of Other Drugs/Substances on ENVARSUS XR

…

Direct Acting Antiviral (DAA) Therapy

The pharmacokinetics of tacrolimus may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. Close monitoring and potential dose adjustment of tacrolimus is warranted to ensure continued efficacy.

12/19/2018 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Lymphoma and Other Malignancies

(Additions and/or revisions are underlined)

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 by wearing protective clothing and using a sunscreen with a high protection factor.

5.3 Not Interchangeable with Other Tacrolimus Products-Medication Errors

(Additions and/or revisions are underlined)

Medication errors, including substitution and dispensing errors, between tacrolimus capsules and tacrolimus extended- release capsules 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 extended-release capsules, tacrolimus capsules or tacrolimus for oral suspension. Instruct patients and caregivers to recognize the appearance of ENVARSUS XR tablet and to confirm with their healthcare provider if a different product is dispensed or if dosing instructions have changed.

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following clinically significant adverse drug reactions are discussed in greater detail in other sections of the labeling:

Lymphoma and Other Malignancies

Serious Infections

New Onset Diabetes after Transplant

Nephrotoxicity due to ENVARSUS XR and Drug Interactions

Neurotoxicity

Hyperkalemia

Hypertension

QT Prolongation

Pure Red Cell Aplasia

6.1 Clinical Trial Experience

(Extensive changes; please refer to labeling)

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

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. The following reactions have been included due to either their seriousness, frequency of reporting or strength of causal connection to ENVARSUS XR:

Blood and Lymphatic System Disorders : Agranulocytosis, decreased blood fibrinogen, disseminated intravascular coagulation, hemolytic anemia, hemolytic uremic syndrome, leukopenia,..

Gastrointestinal Disorders: Abdominal pain,..

Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, pulmonary embolism, pulmonary hypertension, respiratory distress, respiratory failure

Skin and Subcutaneous Tissue Disorders: Hyperpigmentation, photosensitivity, pruritus, rash

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Extensive changes – please refer to labeling)

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

Controlled lactation studies have not been conducted in humans; however tacrolimus has been reported to be present in human milk. The effects of tacrolimus on the breastfed infant, or on milk production have not been assessed. Tacrolimus is excreted in rat milk and in peri-/postnatal rat studies, exposure to tacrolimus during the postnatal period was associated with developmental toxicity in the offspring at clinically relevant doses.

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for ENVARSUS XR and any potential adverse effects on the breastfed child from ENVARSUS XR or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions are underlined)

Contraception

ENVARSUS XR can cause fetal harm when administered to pregnant women. Advise female and male patients of reproductive potential to speak with their healthcare provider on family planning options including appropriate contraception prior to starting treatment with ENVARSUS XR.

Infertility

Based on findings in animals, male and female fertility may be compromised by treatment with ENVARSUS XR.

8.8 Race

(Additions and/or revisions are underlined)

African-American and Hispanic kidney transplant patients are at an increased risk for new onset diabetes after transplant. Monitor blood glucose concentrations and treat appropriately.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Extensive changes; please refer to labeling)

06/22/2016 (SUPPL-3)

Approved Drug Label (PDF)

8 Use in Specific Populations

Race

(Addition of sentence) The pharmacokinetics of ENVARSUS XR were evaluated in a study of 46 stable African-American kidney transplant recipients converted from tacrolimus immediate-release to ENVARSUS XR and indicated that an 80% conversion factor is appropriate for African-American patients.