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.

PROGRAF (NDA-210115)

(TACROLIMUS)

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

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09/14/2023 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.17 Cannabidiol Drug Interactions

Newly added subsection:

When cannabidiol and PROGRAF are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of PROGRAF should be considered as needed when PROGRAF is co-administered with cannabidiol [see Dosage and Administration (2.2, 2.6) and 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 PROGRAF are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of PROGRAF should be considered as needed when PROGRAF is co-administered with cannabidiol [see Dosage and Administration (2.2, 2.6)and Warnings and Precautions (5.17)].

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

Medication Guide

Additions and revisions underlined:

Especially tell your healthcare provider if you take:

. . .

cannabidiol (EPIDIOLEX)
. . .

11/22/2022 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Nephrotoxicity due to PROGRAF and Drug Interactions

Subsection title revised; Additions and/or revisions underlined:

PROGRAF, 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. Nephrotoxicity was reported in clinical trials [see Adverse Reactions (6.1)].

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 PROGRAF 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 other known nephrotoxic drugs, monitor renal function and tacrolimus blood concentrations, and adjust doses of both tacrolimus and/or concomitant medications during concurrent use [see Drug Interactions (7.2)].

5.10 Not Recommended for Use with Sirolimus

Addition of the following to the bulleted line listing:

The use of sirolimus with PROGRAF may increase the risk of thrombotic microangiopathy [see Warnings and Precautions (5.16)].

5.16 Thrombotic Microangiopathy (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 PROGRAF. 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 tacrolimus as a risk factor. Concurrent use of tacrolimus 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 (5.16)]

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Other reactions include:

Cardiovascular: Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischemia, pericardial effusion, QT prolongation, Torsades de pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation, myocardial hypertrophy
Gastrointestinal: Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastroesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis hemorrhagic, pancreatitis necrotizing, stomach ulcer, veno-occlusive liver disease

Hemic/Lymphatic: Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, febrile neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pure red cell aplasia, thrombotic microangiopathy

…

7 Drug Interactions

7.2 Effects of Other Drugs/Substances on PROGRAF

Addition of Caspofungin drug interaction to Table 15

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

PATIENT COUNSELING INFORMATION

17.9 Thrombotic Microangiopathy

Newly added subsection:

Inform patients that PROGRAF can cause blood clotting problems. The risk of this occurring increases when patients take PROGRAF 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 (5.16)]

PATIENT INFORMATION

Additions and/or revisions underlined:

…

blood clotting problems: Tell your healthcare provider right away if you have fever and bruising under the skin that may appear as red dots, with or without unexplained tiredness, confusion, yellowing of the skin or eyes, decreased urination. When taken with sirolimus or everolimus, the risk of developing these symptoms may increase.

…

07/16/2021 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 New Onset Diabetes After Transplant

(Additions and/or revisions underlined)

PROGRAF was shown to cause new onset diabetes mellitus in clinical trials of kidney, liver, heart, or lung transplantation. New onset diabetes after transplantation may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk. Blood glucose concentrations should be monitored closely in patients using PROGRAF [see Adverse Reactions (6.1)].

6 Adverse Reactions

6.1 Clinical Studies Experience

(Additions and/or revisions underlined)

…

Lung Transplantation

Adverse reactions in lung transplant patients were similar to those in kidney, liver, or heart transplant patients treated with PROGRAF [see Adverse Reactions (6.2)].

6.2 Postmarketing Experience

(Subsection title revised; Additions and/or revisions underlined)

…

Postmarketing Adverse Reactions in Lung Transplantation

Based on U.S. Scientific Registry of Transplant Recipients (SRTR) data, published clinical trials, and postmarketing reports, the safety profile for lung transplant patients treated with PROGRAF is consistent with the safety profile

in kidney, liver, and heart transplant patients treated with PROGRAF. The primary adverse reactions described include renal dysfunction, infection, diabetes, gastrointestinal disturbances (e.g., diarrhea), hypertension, and neurological events (e.g., tremor). As expected, lung transplant patients have a higher incidence of pulmonary complications (e.g., pneumonia, bronchiolitis obliterans syndrome) than other solid organ transplant patients, which is in part due to the underlying disease and to the nature of the transplanted organ.

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

Safety and effectiveness have been established in pediatric liver, kidney, heart, and lung transplant patients.

Liver Transplantation

Safety and efficacy using PROGRAF Granules in pediatric de novo liver transplant patients less than 16 years of age are based on evidence from active controlled studies that included 56 pediatric patients, 31 of which received PROGRAF, and supported by two pharmacokinetic and safety studies in 151 children who received PROGRAF. Additionally, 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Dose adjustments were made in the PK studies based on clinical status and whole blood concentrations. Pediatric patients generally required higher doses of PROGRAF to maintain blood trough concentrations of tacrolimus similar to adult patients [see Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.2)].

Kidney and Heart Transplantation

Use of PROGRAF capsules and PROGRAF Granules in pediatric kidney and heart transplant patients is supported by adequate and well-controlled studies and pharmacokinetic data in adult kidney and heart transplant patients with additional pharmacokinetic data in pediatric kidney and heart transplant patients and safety data in pediatric liver transplant patients [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Lung Transplantation

The use of PROGRAF capsules and PROGRAF Granules in pediatric lung transplantation is supported by the experience in the U.S. Scientific Registry of Transplant Recipients (SRTR) including 450 pediatric patients receiving tacrolimus immediate-release products in combination with mycophenolate mofetil and 72 pediatric patients receiving tacrolimus immediate-release products in combination with azathioprine between 1999-2017.

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

PATIENT INFORMATION

(Extensive changes; please refer to label)

12/30/2020 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.11 Interactions with CYP3A4 Inhibitors and Inducers

Additions underlined

… A rapid, sharp rise in tacrolimus levels has been reported after co-administration with a strong CYP3A4 inhibitor, clarithromycin, despite an initial reduction of tacrolimus dose. Early and frequent monitoring of tacrolimus whole blood trough levels is recommended [see Drug Interactions (7.2)].

7 Drug Interactions

7.2 Effects of Other Drugs on PROGRAF

Additions and revisions to Table 15, please refer to label for complete information. Other additions are underlined.

…

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 PROGRAF is warranted to ensure continued efficacy and safety [see Dosage and Administration (2.2, 2.6)].

06/11/2019 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Lymphoma and Other Malignancies

As usual for patients with increased risk for skin cancer, examine patients for skin changes; exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor.

… Monitor EBV serology during treatment.

5.3 Not Interchangeable with Extended Release Tacrolimus Products – Medication Errors

… PROGRAF is not interchangeable or substitutable for tacrolimus extended-release products. Changes between tacrolimus immediate-release and extended- release dosage forms must occur under physician supervision. Instruct patients and caregivers to recognize the appearance of PROGRAF dosage forms and to confirm with the healthcare provider if a different product is dispensed.

5.7 Hyperkalemia

… Monitor serum potassium levels periodically during treatment.

5.14 Immunizations

Whenever possible, administer the complete complement of vaccines before transplantation and treatment with PROGRAF.

The use of live vaccines should be avoided … 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 PROGRAF.

6 Adverse Reactions

6.2 Postmarketing Adverse Reactions

Addition of ‘febrile neutropenia’ to the Hemic/Lymphatic category and of “optic neuropathy’ to the Special Senses category.

7 Drug Interactions

7.2 Effects of Other Drugs on PROGRAF

Table 15 displays the effects of other drugs on PROGRAF.

Table 15: Effects of Other Drugs/Substances on PROGRAF*

Addition of ‘letermovir’ to the list of Strong CYP3A Inhibitor agents which may increase tacrolimus whole blood trough concentrations.

8 Use in Specific Populations

Newly added subsection:

8.8 Race or Ethnicity

African-American patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to Caucasian patients.

African-American and Hispanic patients are at 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)

PATIENT COUNSELING INFORMATION

17.2 Development of Lymphoma and Other Malignancies

Addition of ‘broad spectrum’ to sunscreen.

Newly added subsections below:

17.5 Nephrotoxicity

Inform patients that PROGRAF can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team.

17.7 Hyperkalemia

Inform patients that PROGRAF can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia.

12/02/2018 (SUPPL-1)

6 Adverse Reactions

6.2 Postmarketing Adverse Reactions

(addition underlined)

…

Musculoskeletal and Connective Tissue Disorders: Pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS)

…