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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
WARNING: MALIGNANCIES AND SERIOUS INFECTIONS
See full prescribing information for complete boxed warning.
Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead to hospitalization or death.
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:
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:
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
WARNING: MALIGNANCIES AND SERIOUS INFECTIONS IN TRANSPLANT PATIENTS; and INCREASED MORTALITY IN FEMALE LIVER TRANSPLANT PATIENTS
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:
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.
What is PROGRAF?
IMPORTANT SAFETY INFORMATION
What is the most important information I should know about PROGRAF?
PROGRAF can cause serious side effects, including:
Do not take PROGRAF if you are allergic to tacrolimus or any of the ingredients in PROGRAF.
What should I tell my healthcare provider before taking PROGRAF?
Before you take PROGRAF, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, and when you start a new medicine or stop taking a medicine, including prescription and over-the-counter medicines; vitamins; natural, herbal or nutritional supplements. Especially tell your healthcare provider if you take:
Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above. PROGRAF may affect the way other medicines work, and other medicines may affect how PROGRAF works. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.
How Should I Take PROGRAF?
PROGRAF capsules:
PROGRAF Granules:
What should I avoid while taking PROGRAF?
PROGRAF may cause serious side effects, including:
problems from medicine errors. People who take PROGRAF have sometimes been given the wrong type of tacrolimus product. Tacrolimus extended-release medicines are not the same as PROGRAF capsules or granules and cannot be substituted for each other, unless specifically prescribed by your healthcare provider, who will send you to get blood tacrolimus levels at a lab. Check your PROGRAF when you get a new prescription and before you take it to make sure you have received PROGRAF capsules or PROGRAF Granules. Check with the pharmacist and call your healthcare provider if you think you were given the wrong medicine.
high blood sugar (diabetes). Your healthcare provider may do blood tests to check for diabetes. Call your healthcare provider right away if you have any symptoms of high blood sugar, including:
kidney problems. Kidney problems are a serious and common side effect of PROGRAF. Your healthcare provider may do blood tests to check your kidney function.
nervous system problems. Nervous system problems are a serious and common side effect of PROGRAF. Call your healthcare provider right away if you get any of these symptoms that could be signs of a serious nervous system problem:
high levels of potassium in your blood. Your healthcare provider may do blood tests to check your potassium level.
high blood pressure. High blood pressure is a serious and common side effect of PROGRAF. Your healthcare provider will monitor your blood pressure and may prescribe blood pressure medicine for you, if needed. Your healthcare provider may instruct you to check your blood pressure at home.
changes in the electrical activity of your heart (QT prolongation).
heart problems (myocardial hypertrophy). Tell your healthcare provider right away if you get any of these symptoms of heart problems:
severe low red blood cell count (anemia).
The most common side effects of PROGRAF in people who have received a kidney, liver or heart transplant are:
Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of PROGRAF. For more information, ask your healthcare provider or pharmacist. Call your healthcare provider for medical advice about side effects.
General information about the safe and effective use of PROGRAF.
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1‑800‑FDA‑1088.
Please see the Patient Information and full Prescribing Information, including Boxed Warning, for PROGRAF.
What is ASTAGRAF XL?
IMPORTANT SAFETY INFORMATION
What is the most important information I should know about ASTAGRAF XL?
ASTAGRAF XL can cause serious side effects, including:
Increased risk of cancer. People who take ASTAGRAF XL have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma).
Increased risk of infection. ASTAGRAF XL is a medicine that affects your immune system. ASTAGRAF XL can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving ASTAGRAF XL that can cause death. Call your healthcare provider right away if you have symptoms of an infection such as:
Increased risk of death in females who have had a liver transplant. You should not take ASTAGRAF XL if you have had a liver transplant without talking to your healthcare provider.
Who should not take ASTAGRAF XL?
Do not take ASTAGRAF XL if you are allergic to tacrolimus or any of the ingredients in ASTAGRAF XL.
What should I tell my healthcare provider before taking ASTAGRAF XL?
Before you take ASTAGRAF XL tell your healthcare provider if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, natural, herbal or nutritional supplements. ASTAGRAF XL may affect the way other medicines work, and other medicines may affect how ASTAGRAF XL works.
How should I take ASTAGRAF XL?
What should I avoid while taking ASTAGRAF XL?
What are the possible side effects of ASTAGRAF XL?
ASTAGRAF XL may cause serious side effects, including:
See "What is the most important information I should know about ASTAGRAF XL?"
Problems from medication errors such as graft rejection and other serious reactions. People who take ASTAGRAF XL have sometimes been given the wrong medicine, because some medicines have the same ingredient (tacrolimus) as ASTAGRAF XL. Serious reactions have happened including graft rejection. Check your ASTAGRAF XL when you get a new prescription to make sure you have received the right medicine.
high blood sugar (diabetes). Your healthcare provider may do certain tests to check for diabetes. Call your healthcare provider right away if you have:
kidney problems. Kidney problems are serious and common side effects of ASTAGRAF XL. Your healthcare provider may do certain tests to check your kidney function while you take ASTAGRAF XL.
nervous system problems. Nervous system problems are a serious and common side effect of ASTAGRAF XL. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms while taking ASTAGRAF XL. These could be signs of serious nervous system problems:
high levels of potassium in your blood. Your healthcare provider may do certain tests to check your potassium level while you take ASTAGRAF XL.
high blood pressure. High blood pressure is a serious and common side effect of ASTAGRAF XL. Your healthcare provider will monitor your blood pressure and may ask you to check your blood pressure at home.
changes in the electrical activity of your heart (QT prolongation).
severe low blood cell count (anemia).
The most common side effects of ASTAGRAF XL are diarrhea, constipation, nausea, swelling of the hands, ankles or legs, and tremors (shaking of the body).
These are not all the possible side effects of ASTAGRAF XL. For more information, ask your healthcare provider or pharmacist. Call your healthcare provider for medical advice about side effects.
General information about the safe and effective use of ASTAGRAF XL.
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1‑800‑FDA‑1088.
Please see the accompanying Medication Guide and full Prescribing Information, including Boxed Warning, for ASTAGRAF XL.
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.
Dosage1
Administration Instructions1
Take ASTAGRAF XL consistently every morning at the same time to ensure consistent and maximum possible drug exposure, on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal
Swallow ASTAGRAF XL capsules whole with liquid; do not chew, divide, or crush the capsules
If a dose is missed, take the dose up to 14 hours after the scheduled time (ie, for a missed 8:00 am dose, take by 10:00 pm). Beyond the 14-hour time frame, wait until the usual scheduled time the following morning 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 ASTAGRAF XL
REFERENCE:
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
WARNING: MALIGNANCIES AND SERIOUS INFECTIONS
See full prescribing information for complete boxed warning.
Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead to hospitalization or death.
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:
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:
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
WARNING: MALIGNANCIES AND SERIOUS INFECTIONS IN TRANSPLANT PATIENTS; and INCREASED MORTALITY IN FEMALE LIVER TRANSPLANT PATIENTS
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:
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.
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
WARNING: MALIGNANCIES AND SERIOUS INFECTIONS
See full prescribing information for complete boxed warning.
Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead to hospitalization or death.
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:
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:
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
WARNING: MALIGNANCIES AND SERIOUS INFECTIONS IN TRANSPLANT PATIENTS; and INCREASED MORTALITY IN FEMALE LIVER TRANSPLANT PATIENTS
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:
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.
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
WARNING: MALIGNANCIES AND SERIOUS INFECTIONS
See full prescribing information for complete boxed warning.
Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead to hospitalization or death.
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:
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:
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
WARNING: MALIGNANCIES AND SERIOUS INFECTIONS IN TRANSPLANT PATIENTS; and INCREASED MORTALITY IN FEMALE LIVER TRANSPLANT PATIENTS
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:
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.
