Drug Safety-related Labeling Changes (SrLC)

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PROGRAF (NDA-050709)

(TACROLIMUS)

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

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11/22/2022 (SUPPL-47)

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-45)

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-44)

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-42)

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-41)

Approved Drug Label (PDF)

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)

…

05/24/2018 (SUPPL-40)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions are underlined)

• Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead to hospitalization or death.

5 Warnings and Precautions

5.10 Not Recommended for Use with Sirolimus

(Additions and/or revisions are underlined)

PROGRAF is not recommended for use with sirolimus:..

5.2 Serious Infections

(Additions and/or revisions are underlined)

Patients receiving immunosuppressants, including  PROGRAF, are at increased 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:

• Cytomegalovirus Infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at higher risk of developing 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.

5.3 Not Interchangeable With Extended-Release Tacrolimus Products - Medication Errors

(Newly Added Subsection)

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. PROGRAF is not interchangeable or substitutable with tacrolimus extended-release products. Instruct patients and caregivers to recognize the appearance of PROGRAF dosage forms.

5.5 Nephrotoxicity

(Additions and/or revisions are underlined)

PROGRAF, like other calcineurin inhibitors, can cause acute or chronic nephrotoxicity. Nephrotoxicity was reported in clinical trials. 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 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. Monitor renal function and consider dosage reduction if nephrotoxicity occurs.

5.6 Neurotoxicity

(Additions and/or revisions are underlined)

PROGRAF 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 PROGRAF if neurotoxicity occurs.

5.9 Anaphylactic Reactions with PROGRAF Injection

(Additions and/or revisions are underlined)

Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including PROGRAF, in a small percentage of patients (0.6%). The exact cause of these reactions is not known. PROGRAF injection should be reserved for patients who are unable to take PROGRAF orally. Monitor patients for anaphylaxis when using the intravenous route of administration.

6 Adverse Reactions

6.1 Clinical Studies Experience

(Additions and/or revisions are underlined)

Kidney Transplantation

The most common adverse reactions (greater than or equal to 30%) observed in PROGRAF-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, and anemia. Based on reported adverse reactions terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients.

Less frequently observed adverse reactions in kidney transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.”

Liver Transplantation

The most common adverse reactions (? 40%) observed in PROGRAF-treated liver transplant patients are: tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia. These all occur with oral and IV administration of PROGRAF and some may respond to a reduction in dosing (e.g., tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting. Based on reported adverse reactions terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving PROGRAF in the U.S. and European randomized trials.

Less frequently observed adverse reactions in liver transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.”

Heart Transplantation

The most common adverse reactions (greater than or equal to15%) observed in PROGRAF-treated heart transplant patients are: abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, and hyperlipemia. Based on reported adverse reactions terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial.

Other targeted treatment-emergent adverse reactions in PROGRAF-treated patients occurred at a rate of less than 15%, and include the following: Cushingoid features, impaired wound healing, hyperkalemia, Candida infection, and CMV infection/syndrome. Other less frequently observed adverse reactions in heart transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney and Heart Transplant Studies.”

7 Drug Interactions

7.1 Mycophenolic Acid

(Additions and/or revisions are underlined)

When PROGRAF is prescribed with a given dose of a mycophenolic acid (MPA) product, exposure to MPA is higher with PROGRAF co-administration than with cyclosporine co-administration 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 on PROGRAF

(Newly added table; please refer to labeling)

Table 15 displays the effects of other drugs on PROGRAF.

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

8.3 Females and Males of Reproductive Potential

(Newly Added Subsection)

Contraception

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

Infertility

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

8.4 Pediatric Use

(Additions and/or revisions are underlined)

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

Liver transplant:

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.

Kidney and heart transplant:

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.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

17.1 Administration

Advise the patient or caregiver to:

• Inspect their PROGRAF medicine when they receive a new prescription and before taking it. If the appearance of the capsule is not the same as usual, or if dosage instructions have changed, advise patients to contact their healthcare provider as soon as possible to make sure that they have the right medicine. Other tacrolimus products cannot be substituted for PROGRAF.

• If the patient is receiving PROGRAF Granules advise that the dose should be given immediately after preparation and not to save the dose for later. Advise the caregiver to read carefully the Instructions for Use.

17.3 Increased Risk of Infection

Inform patients they are at increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection such as fever, sweats or chills, cough or flu-like symptoms, muscle aches, or warm, red, painful areas on the skin.

17.6 Hypertension

Inform patients that PROGRAF can cause high blood pressure which may require treatment with anti-hypertensive therapy. Advise patients to monitor their blood pressure.

17.7 Drug Interactions

Instruct patients to tell their healthcare providers when they start or stop taking all the medicines, including prescription medicines and non-prescription medicines, natural or herbal remedies, nutritional supplements, and vitamins. Advise patients to avoid grapefruit and grapefruit juice.

 17.8 Pregnancy, Lactation and Infertility

Inform women of childbearing potential that PROGRAF can harm the fetus. Instruct male and female patients to discuss with their healthcare provider family planning options including appropriate contraception. Also, discuss with pregnant patients the risks and benefits of breastfeeding their infant.

Encourage female transplant patients who become pregnant and male patients who have fathered a pregnancy, exposed to immunosuppressants including tacrolimus, to enroll in the voluntary Transplantation Pregnancy Registry International. To enroll or register, patients can call the toll free number 1-877-955-6877 or https://www.transplantpregnancyregistry.org.

Based on animal studies, PROGRAF may affect fertility in males and females.

17.9 Myocardial Hypertrophy

Inform patients to report symptoms of tiredness, swelling, and/or shortness of breath (heart failure).