INDICATION AND IMPORTANT SAFETY INFORMATION FOR PROGRAF

PROGRAF^® (tacrolimus) injection

PROGRAF^® (tacrolimus) capsules

PROGRAF^® Granules (tacrolimus for oral suspension)

INDICATION

PROGRAF is indicated for the prophylaxis of organ rejection, in adult and pediatric patients receiving allogeneic kidney transplant, liver transplants, and heart transplant, in combination with other immunosuppressants.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

PROGRAF is contraindicated in patients with a hypersensitivity to tacrolimus. PROGRAF injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil).

WARNINGS AND PRECAUTIONS
Lymphoma and Other Malignancies

Patients receiving immunosuppressants, including PROGRAF, are at increased 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. 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. Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The risk of PTLD appears greatest in those individuals who are Epstein-Barr Virus (EBV) seronegative, a population that includes many young children. Monitor EBV serology during treatment.

Serious Infections

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:

• Polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection
• JC virus-associated progressive multifocal leukoencephalopathy (PML)
• Cytomegalovirus infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor disease 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.

Not Interchangeable With Extended-Release Tacrolimus Products - 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. 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.

New Onset Diabetes After Transplant

PROGRAF was shown to cause new onset diabetes mellitus in clinical trials of kidney, liver, and heart 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.

Nephrotoxicity

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.

Neurotoxicity

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.

Hyperkalemia

Hyperkalemia has been reported with PROGRAF use. Serum potassium levels should be monitored. Careful consideration should be given prior to use of other agents also associated with hyperkalemia. Monitor serum potassium levels periodically during treatment.

Hypertension

Hypertension is a common adverse effect of PROGRAF therapy and may require antihypertensive therapy. Careful consideration should be given prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers). Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of PROGRAF.

Anaphylactic Reactions

Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including IV PROGRAF. 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.

Not Recommended for Use with Sirolimus

PROGRAF is not recommended for use with sirolimus:

• The use of sirolimus with PROGRAF in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis, and is not recommended.
• The use of sirolimus (2 mg per day) with PROGRAF in heart transplant patients in a U.S. study was associated with increased risk of renal function impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus, and is not recommended.

Interactions with CYP3A Inhibitors and Inducers

When coadministering PROGRAF with strong CYP3A4-inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin) adjustments in the dosing regimen of PROGRAF and subsequent frequent monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions are recommended.

QT Prolongation

PROGRAF may prolong the QT/QTc interval and may cause Torsade de Pointes. Avoid PROGRAF in patients with congenital long QT prolongation syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment. When coadministering PROGRAF with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, a reduction in PROGRAF dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. Use of PROGRAF with amiodarone has been reported to result in increased tacrolimus whole blood concentrations with or without concurrent QT prolongation.

Myocardial hypertrophy

Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving PROGRAF therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of PROGRAF should be considered.

Immunizations

Whenever possible, administer the complete complement of vaccines before transplantation and treatment with PROGRAF. The use of live vaccines should be avoided during treatment with tacrolimus; examples include (not limited to) the following: 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 PROGRAF.

Pure Red Cell Aplasia

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. If PRCA is diagnosed, discontinuation of PROGRAF should be considered.

ADVERSE REACTIONS

Kidney Transplant: The most common adverse reactions (≥ 30%) were 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.
Liver Transplant: The most common adverse reactions (≥ 40%) were tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia. 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.
Heart Transplant: The most common adverse reactions (≥ 15%) were 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 reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial.

SPECIFIC POPULATIONS

Pregnancy:

Risk Summary
Tacrolimus can cause fetal harm when administered to a pregnant woman. Data from postmarketing surveillance and Transplantation Pregnancy Registry International (TPRI) suggest that infants exposed to tacrolimus in utero are at a risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress. Advise pregnant women of the potential risk to the fetus. PROGRAF may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly. PROGRAF may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure. Renal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at the time of delivery in infants of mothers taking PROGRAF. There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to PROGRAF.

Lactation:

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.

Females and Males of Reproductive Potential: 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.

Pediatric Use: The safety and effectiveness of PROGRAF have been established in pediatric liver, kidney, and heart transplant patients.

Hepatic/Renal Impaired Patients: Patients should be administered the lowest recommended starting dose, with close monitoring of tacrolimus trough concentrations and renal function, and appropriate dosage adjustments.

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

PLEASE CLICK HERE FOR FULL PRESCRIBING INFORMATION, INCLUDING BOXED WARNING, FOR PROGRAF.

 

 

INDICATION AND IMPORTANT SAFETY INFORMATION FOR ASTAGRAF XL

ASTAGRAF XL^® (tacrolimus extended-release capsules)

Indication:

ASTAGRAF XL is indicated for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants in adult and pediatric patients who can swallow capsules intact.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

ASTAGRAF XL is contraindicated in patients with known hypersensitivity to tacrolimus.

WARNINGS AND PRECAUTIONS

Lymphoma and Other Malignancies

Immunosuppressants, including ASTAGRAF XL, 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 broad spectrum sunscreen with a high protection factor.

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 patients who are EBV seronegative, a population which includes many young children. Monitor EBV serology during treatment.

Serious Infections

Immunosuppressants, including ASTAGRAF XL, 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)
• 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.

Increased Mortality in Female Liver Transplant Patients

In a liver transplant study, mortality at 12 months was higher among female patients treated with ASTAGRAF XL compared to female patients treated with tacrolimus immediate-release product. ASTAGRAF XL is not approved for the prophylaxis of organ rejection in patients who received a liver transplant.

Not Interchangeable with Other Tacrolimus Products – Medication Errors

Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and ASTAGRAF XL (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. ASTAGRAF XL is not interchangeable or substitutable for tacrolimus extended-release tablets, tacrolimus immediate-release capsules or tacrolimus for oral suspension. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision. Instruct patients and caregivers to recognize the appearance of ASTAGRAF XL capsules and to confirm with the healthcare provider if a different product is dispensed or if dosing instructions have changed.

New Onset Diabetes After Transplant

ASTAGRAF XL caused new onset diabetes after transplant (NODAT) in kidney transplant patients, which may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk. Monitor blood glucose concentrations and treat appropriately.

Nephrotoxicity due to ASTAGRAF XL and Drug Interactions

ASTAGRAF XL, 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 ASTAGRAF XL is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors). Monitor renal function and consider dosage reduction if nephrotoxicity occurs.

Neurotoxicity

ASTAGRAF XL 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 ASTAGRAF XL if neurotoxicity occurs.

Hyperkalemia

Mild to severe hyperkalemia, which may require treatment, has been reported with tacrolimus including ASTAGRAF XL. Concomitant use of agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) may increase the risk for hyperkalemia. Monitor serum potassium levels periodically during treatment.

Hypertension

Hypertension is a common adverse effect of ASTAGRAF XL and may require antihypertensive therapy. Some antihypertensive drugs can increase the risk for hyperkalemia. Calcium-channel blocking agents may increase tacrolimus blood concentrations and require dosage reduction of ASTAGRAF XL.

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

The concomitant use of strong CYP3A inducers may increase the metabolism of tacrolimus, leading to lower whole blood trough concentrations and greater risk of rejection. In contrast, the concomitant use of strong CYP3A inhibitors may decrease the metabolism of tacrolimus, leading to higher whole blood trough concentrations and greater risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation). Therefore, adjust ASTAGRAF XL dose and monitor tacrolimus whole blood trough concentrations when coadministering ASTAGRAF XL with strong CYP3A4 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).

QT Prolongation

ASTAGRAF XL may prolong the QT/QTc interval and may cause Torsade de Pointes. Avoid ASTAGRAF XL 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 such as hypokalemia, hypocalcemia, or hypomagnesemia.

When coadministering ASTAGRAF XL with other substrates and/or inhibitors of CYP3A, especially those that also have the potential to prolong the QT interval, a reduction in ASTAGRAF XL dosage, monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended.

Immunizations

Whenever possible, administer the complete complement of vaccines before transplantation and treatment with ASTAGRAF XL. Avoid the use of live attenuated vaccines during treatment with ASTAGRAF XL (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 ASTAGRAF XL.

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 ASTAGRAF XL.

ADVERSE REACTIONS

Kidney transplant patients through one year post-transplant: The most common adverse reactions (≥ 30%) were diarrhea (45%), constipation (40%), nausea (36%), peripheral edema (36%), tremor (35%), and anemia (33%).

Pediatrics
De novo pediatric transplant patients started on 0.3 mg/kg daily of tacrolimus product, given once daily for ASTAGRAF XL and divided into two doses for PROGRAF. Thirteen (13) pediatric patients completed 52 weeks on ASTAGRAF XL. The most common adverse reactions were diarrhea [7/13 (54%)], increased blood creatinine [6/13 (46%)], hypertension [3/13 (23%)], cough [4/13 (31%)], and upper respiratory tract infection [4/13 (31%)].

Stable pediatric allograft recipients 5 to 16 years of age were converted 1:1 (mg:mg) from PROGRAF to ASTAGRAF XL. Seventy-six (76) pediatric patients completed at least one year of ASTAGRAF XL-based treatment. The most common adverse reactions were diarrhea (13.9%), headache (13.9%), and cough (11.4%).

SPECIFIC POPULATIONS

Pregnancy:

Risk Summary
Tacrolimus can cause fetal harm when administered to a pregnant woman. Data from postmarketing surveillance and Transplantation Pregnancy Registry International (TPRI) suggest that infants exposed to tacrolimus in utero are at a risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress. Advise pregnant women of the potential risk to the fetus. ASTAGRAF XL may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly. ASTAGRAF XL may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure. Renal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at the time of delivery in infants of mothers taking ASTAGRAF XL. There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to ASTAGRAF XL.

Lactation:

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.

Females and Males of Reproductive Potential: ASTAGRAF XL 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 ASTAGRAF XL.

Pediatric Use: The safety and effectiveness of ASTAGRAF XL in pediatric kidney transplant patients have been established. Use of ASTAGRAF XL in pediatric kidney transplant patients is based on adequate and well-controlled studies of ASTAGRAF XL in adult kidney transplant patients and supported by pharmacokinetic and safety data of ASTAGRAF XL in pediatric transplant patients 4 years of age and older who are able to swallow capsules intact.

Hepatic/Renal Impaired Patients: Patients should be administered the lowest recommended starting dose, with close monitoring of tacrolimus trough concentrations and renal function, and appropriate dosage adjustments.

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

PLEASE CLICK HERE FOR FULL PRESCRIBING INFORMATION, INCLUDING BOXED WARNING, FOR ASTAGRAF XL.