Dosage & Administration
| MMF = Mycophenolate mofetil | ||
Recommended ASTAGRAF XL Initial Dosage | ||
Patient Population | Initial Oral Dosage | Whole Blood Trough Concentration Range |
ADULT | ||
With basiliximab, MMF and steroids | 0.15 to 0.2 mg/kg once daily prior to reperfusion or within 48 hours of completion of transplant | |
With MMF and steroids, without basiliximab induction | ||
PEDIATRIC | ||
With basiliximab, MMF and steroids | 0.3 mg/kg once daily, administered within 24 hours following reperfusion | |
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Astagraf XL Prescribing Information
• Increased risk for developing serious infections and malignancies with ASTAGRAF XL® or other immunosuppressants that may lead to hospitalization or death. [see(5 WARNINGS AND PRECAUTIONS• Not Interchangeable with Other Tacrolimus Products-Medication Errors: Instruct patients or caregivers to recognize the appearance of ASTAGRAF XL capsules.• New onset diabetes after transplant: Monitor blood glucose.• Nephrotoxicity (acute and/or chronic): May occur due to ASTAGRAF XL, drug interactions, concomitant nephrotoxic drugs. Monitor renal function; consider dosage reduction.• Neurotoxicity: Including risk of posterior reversible encephalopathy syndrome (PRES), monitor for neurologic abnormalities; reduce dosage or discontinue ASTAGRAF XL.• Hyperkalemia: Risk may be increased with other agents associated with hyperkalemia; monitor serum potassium levels.• Hypertension: May require antihypertensive therapy; monitor relevant drug interactions.• QT prolongation: Consider obtaining electrocardiograms and monitoring electrolytes in patients at high risk.• Immunizations: Avoid live vaccines.• Pure red cell aplasia: Consider discontinuation of ASTAGRAF XL.• Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: May occur, especially in patients with infections and certain concomitant medications.
5.1 Lymphoma and Other MalignanciesImmunosuppressants, 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.
5.2 Serious InfectionsImmunosuppressants, including ASTAGRAF XL, increase the risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. Serious viral infections reported include:
• Polyomavirus-associated nephropathy (especially due to BK virus infection)• JC virus-associated progressive multifocal leukoencephalopathy (PML)• Cytomegalovirus (CMV) infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at highest risk of CMV viremia and CMV disease.
Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection
[see Adverse Reactions].5.3 Increased Mortality in Female Liver Transplant PatientsIn a clinical trial of 471 liver transplant patients randomized to ASTAGRAF XL or tacrolimus immediate-release product, mortality at 12 months was 10% higher among the 76 female patients (18%) treated with ASTAGRAF XL compared to the 64 female patients (8%) treated with tacrolimus immediate-release product. ASTAGRAF XL is not approved for the prophylaxis of organ rejection in patients who received a liver transplant.
5.4 Not Interchangeable with Other Tacrolimus Products - Medication ErrorsMedication 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
[see Dosage Forms and Strengths]and to confirm with the healthcare provider if a different product is dispensed or if dosing instructions have changed.5.5 New Onset Diabetes After TransplantASTAGRAF 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
[see Adverse Reactions and Use in Specific Populations].5.6 Nephrotoxicity due to ASTAGRAF XL and Drug InteractionsASTAGRAFXL, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity in transplant patients due to its vasoconstrictive effect on renal vasculature, toxic tubulopathy and tubular-interstitial effects. Acute renal impairment associated with tacrolimus toxicity can result in high serum creatinine, hyperkalemia, decreased secretion of urea and hyperuricemia, and is usually reversible. In patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range, consider dosage reduction or temporary interruption of tacrolimus administration.The risk for nephrotoxicity may increase when 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). When tacrolimus is used concurrently with other known nephrotoxic drugs, monitor renal function and tacrolimus blood concentrations, and adjust dose of both tacrolimus and/or concomitant medications during concurrent use[see Adverse Reactions and Drug Interactions].5.7 NeurotoxicityASTAGRAF 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
[see Adverse Reactions]. 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.5.8 HyperkalemiaMild 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
[see Adverse Reactions]. Monitor serum potassium levels periodically during treatment.5.9 HypertensionHypertension is a common adverse reaction of ASTAGRAF XL therapy and may require antihypertensive therapy
[see Adverse Reactions]. Some antihypertensive drugs can increase the risk for hyperkalemia[see Warnings and Precautions]. Calcium-channel blocking agents may increase tacrolimus blood concentrations and require dosage reduction of ASTAGRAF XL[see Drug Interactions].5.10 Risk of Rejection with Strong CYP3A Inducers and Risk of Serious Adverse Reactions with Strong CYP3A InhibitorsThe concomitant use of strong CYP3A inducers may increase the metabolism of tacrolimus, leading to lower whole blood trough concentrations and greater risk of rejection. In contrast, the concomitant use of strong CYP3A inhibitors may decrease the metabolism of tacrolimus, leading to higher whole blood trough concentrations and greater risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation)
[see Warnings and Precautions]. Therefore, adjust ASTAGRAF XL dose and monitor tacrolimus whole blood trough concentrations when co-administering ASTAGRAF XL with strong CYP3A inhibitors (e.g., including, but not limited to, telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) or strong CYP3A inducers (e.g., including, but not limited to, rifampin, rifabutin)[see Dosage and Administration and Drug Interactions]. A rapid, sharp rise in tacrolimus levels has been reported after co-administration with a strong CYP3A4 inhibitor, clarithromycin, despite an initial reduction of tacrolimus dose. Early and frequent monitoring of tacrolimus whole blood trough levels is recommended [seeDrug Interactions(7.2)].5.11 QT ProlongationASTAGRAF XL may prolong the QT/QTc interval and cause
Torsades 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 (e.g., hypokalemia, hypocalcemia, or hypomagnesemia).When co-administering 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
[see Dosage and Administration and Drug Interactions].5.12 ImmunizationsWhenever 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.
5.13 Pure Red Cell AplasiaCases 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.
5.000000000000000e+0014Thrombotic Microangiopathy (TMA) Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic PurpuraCases of thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported in patients treated with ASTAGRAF XL TMA may have a multifactorial etiology. Risk factors for TMA that can occur in transplant patients include, for example, severe infections, graft-versus-host disease (GVHD), Human Leukocyte Antigen (HLA) mismatch, the use of calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors. These risk factors may, either alone or combined, contribute to the risk of TMA.In patients with signs and symptoms of TMA, consider tacrolimus as a risk factor. Concurrent use of tacrolimus and mTOR inhibitors may contribute to the risk of TMA.5.000000000000000e+0015Cannabidiol Drug InteractionsWhen cannabidiol and ASTAGRAF XL are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of ASTAGRAF XL should be considered as needed when ASTAGRAF XL is co-administered with cannabidiol [see Dosage and Administration and Drug Interactions].)],5.1 Lymphoma and Other MalignanciesImmunosuppressants, 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.
5.2 Serious InfectionsImmunosuppressants, including ASTAGRAF XL, increase the risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. Serious viral infections reported include:
• Polyomavirus-associated nephropathy (especially due to BK virus infection)• JC virus-associated progressive multifocal leukoencephalopathy (PML)• Cytomegalovirus (CMV) infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at highest risk of CMV viremia and CMV disease.
Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection
[see Adverse Reactions].• Increased mortality in female liver transplant patients with ASTAGRAF XL. ASTAGRAF XL is not approved for use in liver transplantation. [see(5 WARNINGS AND PRECAUTIONS• Not Interchangeable with Other Tacrolimus Products-Medication Errors: Instruct patients or caregivers to recognize the appearance of ASTAGRAF XL capsules.• New onset diabetes after transplant: Monitor blood glucose.• Nephrotoxicity (acute and/or chronic): May occur due to ASTAGRAF XL, drug interactions, concomitant nephrotoxic drugs. Monitor renal function; consider dosage reduction.• Neurotoxicity: Including risk of posterior reversible encephalopathy syndrome (PRES), monitor for neurologic abnormalities; reduce dosage or discontinue ASTAGRAF XL.• Hyperkalemia: Risk may be increased with other agents associated with hyperkalemia; monitor serum potassium levels.• Hypertension: May require antihypertensive therapy; monitor relevant drug interactions.• QT prolongation: Consider obtaining electrocardiograms and monitoring electrolytes in patients at high risk.• Immunizations: Avoid live vaccines.• Pure red cell aplasia: Consider discontinuation of ASTAGRAF XL.• Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: May occur, especially in patients with infections and certain concomitant medications.
5.1 Lymphoma and Other MalignanciesImmunosuppressants, 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.
5.2 Serious InfectionsImmunosuppressants, including ASTAGRAF XL, increase the risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. Serious viral infections reported include:
• Polyomavirus-associated nephropathy (especially due to BK virus infection)• JC virus-associated progressive multifocal leukoencephalopathy (PML)• Cytomegalovirus (CMV) infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at highest risk of CMV viremia and CMV disease.
Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection
[see Adverse Reactions].5.3 Increased Mortality in Female Liver Transplant PatientsIn a clinical trial of 471 liver transplant patients randomized to ASTAGRAF XL or tacrolimus immediate-release product, mortality at 12 months was 10% higher among the 76 female patients (18%) treated with ASTAGRAF XL compared to the 64 female patients (8%) treated with tacrolimus immediate-release product. ASTAGRAF XL is not approved for the prophylaxis of organ rejection in patients who received a liver transplant.
5.4 Not Interchangeable with Other Tacrolimus Products - Medication ErrorsMedication 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
[see Dosage Forms and Strengths]and to confirm with the healthcare provider if a different product is dispensed or if dosing instructions have changed.5.5 New Onset Diabetes After TransplantASTAGRAF 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
[see Adverse Reactions and Use in Specific Populations].5.6 Nephrotoxicity due to ASTAGRAF XL and Drug InteractionsASTAGRAFXL, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity in transplant patients due to its vasoconstrictive effect on renal vasculature, toxic tubulopathy and tubular-interstitial effects. Acute renal impairment associated with tacrolimus toxicity can result in high serum creatinine, hyperkalemia, decreased secretion of urea and hyperuricemia, and is usually reversible. In patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range, consider dosage reduction or temporary interruption of tacrolimus administration.The risk for nephrotoxicity may increase when 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). When tacrolimus is used concurrently with other known nephrotoxic drugs, monitor renal function and tacrolimus blood concentrations, and adjust dose of both tacrolimus and/or concomitant medications during concurrent use[see Adverse Reactions and Drug Interactions].5.7 NeurotoxicityASTAGRAF 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
[see Adverse Reactions]. 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.5.8 HyperkalemiaMild 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
[see Adverse Reactions]. Monitor serum potassium levels periodically during treatment.5.9 HypertensionHypertension is a common adverse reaction of ASTAGRAF XL therapy and may require antihypertensive therapy
[see Adverse Reactions]. Some antihypertensive drugs can increase the risk for hyperkalemia[see Warnings and Precautions]. Calcium-channel blocking agents may increase tacrolimus blood concentrations and require dosage reduction of ASTAGRAF XL[see Drug Interactions].5.10 Risk of Rejection with Strong CYP3A Inducers and Risk of Serious Adverse Reactions with Strong CYP3A InhibitorsThe concomitant use of strong CYP3A inducers may increase the metabolism of tacrolimus, leading to lower whole blood trough concentrations and greater risk of rejection. In contrast, the concomitant use of strong CYP3A inhibitors may decrease the metabolism of tacrolimus, leading to higher whole blood trough concentrations and greater risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation)
[see Warnings and Precautions]. Therefore, adjust ASTAGRAF XL dose and monitor tacrolimus whole blood trough concentrations when co-administering ASTAGRAF XL with strong CYP3A inhibitors (e.g., including, but not limited to, telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) or strong CYP3A inducers (e.g., including, but not limited to, rifampin, rifabutin)[see Dosage and Administration and Drug Interactions]. A rapid, sharp rise in tacrolimus levels has been reported after co-administration with a strong CYP3A4 inhibitor, clarithromycin, despite an initial reduction of tacrolimus dose. Early and frequent monitoring of tacrolimus whole blood trough levels is recommended [seeDrug Interactions(7.2)].5.11 QT ProlongationASTAGRAF XL may prolong the QT/QTc interval and cause
Torsades 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 (e.g., hypokalemia, hypocalcemia, or hypomagnesemia).When co-administering 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
[see Dosage and Administration and Drug Interactions].5.12 ImmunizationsWhenever 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.
5.13 Pure Red Cell AplasiaCases 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.
5.000000000000000e+0014Thrombotic Microangiopathy (TMA) Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic PurpuraCases of thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported in patients treated with ASTAGRAF XL TMA may have a multifactorial etiology. Risk factors for TMA that can occur in transplant patients include, for example, severe infections, graft-versus-host disease (GVHD), Human Leukocyte Antigen (HLA) mismatch, the use of calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors. These risk factors may, either alone or combined, contribute to the risk of TMA.In patients with signs and symptoms of TMA, consider tacrolimus as a risk factor. Concurrent use of tacrolimus and mTOR inhibitors may contribute to the risk of TMA.5.000000000000000e+0015Cannabidiol Drug InteractionsWhen cannabidiol and ASTAGRAF XL are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of ASTAGRAF XL should be considered as needed when ASTAGRAF XL is co-administered with cannabidiol [see Dosage and Administration and Drug Interactions].)]5.3 Increased Mortality in Female Liver Transplant PatientsIn a clinical trial of 471 liver transplant patients randomized to ASTAGRAF XL or tacrolimus immediate-release product, mortality at 12 months was 10% higher among the 76 female patients (18%) treated with ASTAGRAF XL compared to the 64 female patients (8%) treated with tacrolimus immediate-release product. ASTAGRAF XL is not approved for the prophylaxis of organ rejection in patients who received a liver transplant.
Warnings and Precautions (
Warnings and Precautions, Cannabidiol Drug Interactions (
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
Pregnancy: Can cause fetal harm. Advise pregnant women of the potential risk to the fetus.
There is a pregnancy registry that monitors pregnancy outcomes in women exposed to ASTAGRAF XL during pregnancy. The Transplantation Pregnancy Registry International (TPRI) is a voluntary pregnancy exposure registry that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants including tacrolimus. Healthcare providers are encouraged to advise their patients to register by contacting the Transplantation Pregnancy Registry International at 1-877-955-6877 or https://www.transplantpregnancyregistry.org/.
Tacrolimus can cause fetal harm when administered to a pregnant woman. Data from postmarketing surveillance and TPRI suggest that infants exposed to tacrolimus
Administration of oral tacrolimus to pregnant rabbits and rats throughout the period of organogenesis was associated with maternal toxicity/lethality, and an increased incidence of abortion, malformation and embryofetal death at clinically relevant doses [0.5 the maximum recommended clinical dose (0.2 mg/kg/day), on a mg/m2basis]. Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 the maximum recommended clinical dose, on a mg/m2basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 times the maximum recommended clinical dose, on a mg/m2basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died
The background risk of major birth defects and miscarriage in the indicated population is unknown.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Risks during pregnancy are increased in organ transplant recipients. The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death.
Cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population. However, COP symptoms resolved postpartum and no long-term effects on the offspring were reported.
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.
There are no adequate and well-controlled studies on the effects of tacrolimus in human pregnancy.
Safety data from the TPRI and postmarketing surveillance suggest infants exposed to tacrolimus
TPRI reported 450 and 241 total pregnancies in kidney and liver transplant recipients exposed to tacrolimus, respectively. The TPRI pregnancy outcomes are summarized in Table 6. In the table below, the number of recipients exposed to tacrolimus concomitantly with mycophenolic acid (MPA) products during the preconception and first trimester periods is high (27% and 29% for kidney and liver transplant recipients, respectively). Because MPA products may also cause birth defects, the birth defect rate may be confounded and this should be taken into consideration when reviewing the data, particularly for birth defects. Birth defects observed include cardiac malformations, craniofacial malformations, renal/urogenital disorders, skeletal abnormalities, neurological abnormalities and multiple malformations.
Kidney | Liver | |
Pregnancy Outcomes Includes multiple births and terminations. | 462 | 253 |
Miscarriage | 24.5% | 25% |
Live births | 331 | 180 |
| Pre-term delivery (< 37 weeks) | 49% | 42% |
Low birth weight (< 2500 g) | 42% | 30% |
Birth defects | 8%Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects. | 5% |
Additional information reported by TPRI in pregnant transplant patients receiving tacrolimus included diabetes during pregnancy in 9% of kidney recipients and 13% of liver recipients and hypertension during pregnancy in 53% of kidney recipients and 16.2% of liver recipients.
Administration of oral tacrolimus to pregnant rabbits throughout organogenesis produced maternal toxicity and abortion at 0.32 mg/kg (0.5 times the maximum recommended clinical dose [0.2 mg/kg/day], on a mg/m2basis). At 1 mg/kg (1.6 times the maximum recommended clinical dose), embryofetal lethality and fetal malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, omphalocele, gallbladder agenesis, skeletal anomalies) were observed. Administration of 3.2 mg/kg oral tacrolimus (2.6 times the maximum recommended clinical dose) to pregnant rats throughout organogenesis produced maternal toxicity/lethality, embryofetal lethality and decreased fetal body weight in the offspring of C-sectioned dams; and decreased pup viability and interventricular septal defect in offspring of dams that delivered.
In a peri-/postnatal development study, oral administration of tacrolimus to pregnant rats during late gestation (after organogenesis) and throughout lactation produced maternal toxicity, effects on parturition, and reduced pup viability at 3.2 mg/kg (2.6 times the maximum recommended clinical dose); among these pups that died early, an increased incidence of kidney hydronephrosis was observed. Reduced pup weight was observed at 1.0 mg/kg (0.8 times the maximum recommended clinical dose).
Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, embryofetal loss and reduced pup viability at 3.2 mg/kg (2.6 times the maximum recommended clinical dose range). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died. Effects on parturition (incomplete delivery of nonviable pups) were observed at 1 mg/kg (0.8 times the maximum recommended clinical dose)
Controlled lactation studies have not been conducted in humans; however, tacrolimus has been reported to be present in human milk. The effects of tacrolimus on the breastfed infant, or on milk production, have not been assessed. Tacrolimus is excreted in rat milk and in peri-/postnatal rat studies; exposure to tacrolimus during the postnatal period was associated with developmental toxicity in the offspring at clinically relevant doses
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ASTAGRAF XL and any potential adverse effects on the breastfed child from ASTAGRAF XL or from the underlying maternal condition.
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
Based on findings in animals, male and female fertility may be compromised by treatment with ASTAGRAF XL
The safety and effectiveness of ASTAGRAF XL in
A pharmacokinetic and safety study included 25
Another pharmacokinetic and safety study included 48 stable pediatric kidney transplant patients, 5 to 16 years of age, who were converted from a Prograf-based regimen to ASTAGRAF XL. Tacrolimus systemic exposures for the two drug products were comparable
Clinical studies of ASTAGRAF XL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In Studies 1 and 2, 29 patients were 65 years of age and older, and 3 patients were 75 years of age and over
The pharmacokinetics of tacrolimus in patients with renal impairment was similar to that in healthy subjects with normal renal function. However, due to its potential for nephrotoxicity, monitoring of renal function in patients with renal impairment is recommended; tacrolimus dosage should be reduced if indicated
The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: > 10) compared to healthy subjects with normal hepatic function
African-American patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to Caucasian patients
African-American and Hispanic patients are at increased risk for new onset diabetes after transplant. Monitor blood glucose concentrations and treat appropriately
The safety and effectiveness of ASTAGRAF XL in
A pharmacokinetic and safety study included 25
Another pharmacokinetic and safety study included 48 stable pediatric kidney transplant patients, 5 to 16 years of age, who were converted from a Prograf-based regimen to ASTAGRAF XL. Tacrolimus systemic exposures for the two drug products were comparable
Study 1 was a 12-month, randomized, open-label trial of ASTAGRAF XL (N=214) compared to active-control of tacrolimus (Prograf) immediate-release (N=212), conducted primarily in the U.S. in patients who were a recipient of a primary or retransplanted non-HLA-identical living or deceased donor kidney transplant. All patients received basiliximab induction and concomitant mycophenolate mofetil (MMF) and corticosteroids. The study population was 17 to 77 years of age, the mean age was 48 years; 64% were male and 36% were female; 73% were Caucasian, 22% were African-American, 2% were Asian, and 3% were categorized as other races. Living donors provided 49% of the organs and 51% of patients received a kidney transplant from a deceased donor with a mean cold ischemia time of 19 hours. The most frequent diseases leading to transplantation were balanced between the groups and included nephrosclerosis/hypertensive nephropathy, diabetic nephropathy, glomerulonephritis, and polycystic kidney disease. In the study, 97% of patients had no previous transplant and 3% had a previous transplant.
The initial dose of ASTAGRAF XL was administered prior to reperfusion or within 48 hours after completion of the transplant procedure. The protocol-defined initial post-operative daily doses were 0.15 to 0.20 mg per kg given as a single dose in the morning for ASTAGRAF XL and 0.075 to 0.10 mg per kg twice daily for control. The ASTAGRAF XL and control dosage was then adjusted on the basis of safety and efficacy and a target whole blood tacrolimus trough concentration range of 7 to 16 ng/mL for the first 90 days post-transplant and 5 to 15 ng/mL thereafter.
The average recorded starting tacrolimus daily dose, given any time up to day 2 post-transplant, was higher for ASTAGRAF XL than for control (0.14 mg per kg per day versus 0.10 mg per kg per day). Thereafter, to achieve comparable mean tacrolimus trough concentrations, on average 15% higher total mean daily doses of tacrolimus were required for ASTAGRAF XL than for control.
Tacrolimus whole blood trough concentrations were monitored on Days 3, 7, 10, 14, and 21, then Months 1, 2, 4, 6, 8, 10, and 12. Table 10 shows the tacrolimus whole blood trough concentrations measured at protocol-specified time points for ASTAGRAF XL. Approximately 80% of ASTAGRAF XL-treated patients maintained tacrolimus whole trough blood concentrations between 5 to 17 ng/mL during months 1 through 2 and between 4 to 12 ng/mL from months 3 through 12.
Scheduled Visit | Tacrolimus Whole Blood Trough Concentrations (ng/mL) Immunoassay was used in most laboratories.[Median (10thto 90thPercentile)] |
Day 3 | 9.6 (4.9 to 20.2) |
Day 7 | 9.1 (4.4 to 16.8) |
Day 14 | 10.0 (5.7 to 16.9) |
Month 1 | 10.5 (5.6 to 17.1) |
Month 2 | 9.4 (6.1 to 14.2) |
Month 6 | 7.7 (4.4 to 11.5) |
Month 12 | 7.2 (3.8 to 10.4) |
African-American patients required higher ASTAGRAF XL dosages to attain similar trough concentrations as Caucasian patients (see Table 11).
Time After Transplant | Caucasian Patients N=160 | African-American Patients N=41 | ||
Dose (mg/kg) | Mean Trough Concentration (ng/mL) | Dose (mg/kg) | Mean Trough Concentration (ng/mL) | |
Day 7 | 0.14 | 10.65 | 0.14 | 7.78 |
Month 1 | 0.14 | 11.11 | 0.17 | 10.92 |
Month 6 | 0.10 | 7.95 | 0.13 | 8.42 |
Month 12 | 0.09 | 7.53 | 0.12 | 7.33 |
The initial dose of MMF was 1 gram administered orally or intravenously prior to or within 48 hours of completion of the transplant procedure. Subsequent MMF was administered orally 1 gram twice daily or up to 1.5 grams twice daily in African-American patients. Dose-equivalent three times daily or four times daily dosing was permitted if MMF tolerability was a concern.
The MMF dosages administered by time period in ASTAGRAF XL-treated patients are shown in Table 12. The MMF dosage was reduced to less than 2 grams per day by month 12 in 56% of ASTAGRAF XL-treated patients. Approximately 57% of the MMF dose reductions were because of adverse reactions in the ASTAGRAF XL group
| aTime-averaged MMF dosage is the total MMF dosage per day divided by the duration of treatment. A time-averaged MMF dosage of 2 grams per day means that the MMF dosage was not reduced in those patients during the time period. | ||||
Time period (Days) | Patients on MMF | Time-averaged MMF dosagea | ||
N | Less than 2 grams per day | 2 grams per day | Greater than 2 grams per day | |
1-30 | 211 | 30% | 64% | 6% |
31-90 | 208 | 38% | 57% | 5% |
91-180 | 205 | 49% | 48% | 3% |
181-365 | 201 | 51% | 47% | 3% |
All patients were administered 2 doses of basiliximab induction therapy (20 mg intravenously) with the first dose on day 0 before skin closure and the second dose between days 3 and 5.
All patients were administered an intravenous bolus of 500 to 1000 mg of methylprednisolone (or an equivalent steroid dose) on day 0 followed by oral administration of 200 mg methylprednisolone (or an equivalent dose of steroid) on day 1 and subsequent tapering to achieve a targeted mean prednisone dose of 5 to 10 mg/day after the first 3 months.
The efficacy failure rate, defined as the percentage of patients with biopsy-proven acute rejection (BPAR), graft failure, death, and/or lost to follow at 12 months, is shown in Table 13for the intent-to-treat population, as well as the rates of the individual events.
| a95% confidence interval calculated using normal approximation. | ||
ASTAGRAF XL + MMF, steroids, basiliximab induction (N=214) | Prograf + MMF, steroids, basiliximab induction (N=212) | |
Efficacy Failure | 30 (14.0%) | 32 (15.1%) |
Treatment Difference (95% CIa) | -1.1% (-7.8%, +5.6%) | |
Efficacy Failure Endpoints | ||
Biopsy-Proven Acute Rejection | 22 (10.3%) | 16 (7.5%) |
Graft Loss | 5 (2.3%) | 9 (4.2%) |
Death | 3 (1.4%) | 9 (4.2%) |
Lost to follow-up | 3 (1.4%) | 4 (1.9%) |
The estimated mean glomerular filtration rates, using the Modification of Diet in Renal Disease (MDRD) formula, by treatment group at Month 12 in the intent-to-treat population is shown in Table 14.
| aLast observation carried forward (LOCF); patients who died, lost the graft, or were lost to follow-up are imputed as zeroes. bResults from analysis of covariance model with Month 1 baseline as a covariate. | ||
ASTAGRAF XL + MMF, steroids, basiliximab induction (N=201) | Prograf + MMF, steroids, basiliximab induction (N=202) | |
Month 1 Baseline Mean (SD) Month 12 LOCFa Mean (Standard deviation) Mean Difference XL minus Prograf (tacrolimus immediate-release)b | 56 (20) 58 (21) +2.3 (-1.2, +5.8) | 56 (21) 56 (23) |
Study 2 was a 12-month, randomized, double-blind trial of ASTAGRAF XL (N=331) compared to active control of tacrolimus (Prograf) immediate-release (N=336), in non-U.S. patients who received a primary or retransplanted non-HLA-identical living or deceased donor kidney transplant. This trial was designed to remain double-blind until the last patient enrolled had completed 24 weeks on study treatment. Patients with a high immunologic risk defined as a panel reactive antibody (PRA) grade > 50% in the previous 6 months and/or with a previous graft survival of less than 12 months due to immunologic reasons were excluded, as were patients of donor kidneys with cold ischemia time > 30 hours, or donor kidneys from a non heart-beating donor. The patient treatment assignments remained blinded for 12 months for 96% of the patients participating in the trial.
All patients received concomitant MMF and corticosteroids without induction. The population was 18 to 65 years of age; the mean age was 48 years; 63% of the study population was male; 82% were Caucasian, 5% were African-American, 2% were Asian, and 11% were categorized as other races. Living donors provided 27% of the organs and 73% of patients received a kidney transplant from a deceased donor with a mean cold ischemia time of 17 hours. The most frequent diseases leading to transplantation were balanced between the groups and included nephrosclerosis/hypertensive nephropathy, diabetic nephropathy, glomerulonephritis, and polycystic kidney disease.
The protocol-specified initial preoperative dose for both ASTAGRAF XL and control was 0.1 mg per kg given orally in one dose within 12 hours prior to reperfusion, given at any time of the day. The initial post-operative tacrolimus daily dose (0.2 mg per kg per day) was given orally in one dose, preferably in the morning for ASTAGRAF XL, and was given as 0.1 mg/kg twice daily for control. Subsequent doses of ASTAGRAF XL and control were adjusted on the basis of clinical evidence of efficacy, occurrence of adverse events and according to whole blood tacrolimus trough concentration target ranges of 10 to 15 ng/mL for the first 28 days post-transplant, 5 to 15 ng/mL from Day 29 to Day 168, 5 to 10 ng/mL thereafter.
The actual tacrolimus doses on day 0 (0.1 mg per kg per day preoperative) and day 1 (0.2 mg per kg per day post-operative) were comparable between ASTAGRAF XL and control. Thereafter, to achieve comparable mean tacrolimus trough concentrations, on average, 25% higher total mean daily doses of tacrolimus were required for ASTAGRAF XL than for control.
Tacrolimus whole blood trough concentrations were monitored on Days 1, 3, 7, 14, then Months 1, 2, 3, 6, 11, 12, and then every 3 months.
Table 15shows the tacrolimus whole blood trough concentrations measured at protocol-specified time points for ASTAGRAF XL. Approximately 80% of ASTAGRAF XL-treated patients maintained tacrolimus whole trough blood concentrations between 6 to 20 ng/mL during months 1 through 2, and between 6 to 14 ng/mL from months 3 through 12.
Scheduled Visit | Tacrolimus Whole Blood Trough Concentrations (ng/mL) Immunoassay was used in most laboratories.[Median (10thto 90thPercentile)] |
Day 3 | 13.8 (6.5 to 25.5) |
Day 7 | 10.1 (5.5 to 17.3) |
Day 14 | 10.8 (6.7 to 17.9) |
Month 1 | 12.0 (7.5 to 17.6) |
Month 2 | 11.1 (6.6 to 17.3) |
Month 6 | 9.2 (5.7 to 13.5) |
Month 12 | 8.0 (5.1 to 13.8) |
The initial dose of MMF was 1 gram orally twice daily starting preoperatively and given for the first 14 days of the study. Thereafter the MMF dose was reduced to 0.5 grams twice daily to be maintained throughout the study.
The MMF dosages administered by time period in ASTAGRAF XL-treated patients are shown in Table 16. The MMF dosage was reduced to 0.5 grams twice daily starting after day 14 in the majority of patients.
| aTime-averaged MMF dosage is the total MMF dosage per day divided by the duration of treatment. A time-averaged MMF dosage of 2 grams per day means that the MMF dosage was not reduced in those patients during the time period. bOne patient had a time-averaged dose during the first and last period of > 2 gm/day. | ||||
Time period (Days) | Patients on MMF | Time-averaged MMF dosagea, b | ||
N | Less than 1 gram per day | 1 gram to less than 2 grams per day | 2 grams per day | |
1-30 | 331 | 1% | 78% | 21% |
31-90 | 303 | 8% | 87% | 6% |
91-180 | 281 | 12% | 85% | 3% |
181-365 | 258 | 15% | 83% | 2% |
An intravenous (IV) bolus of up to 1000 mg methylprednisolone (or equivalent) was administered perioperatively (Day 0) with a second IV bolus of 125 mg being administered 1 day after reperfusion (Day 1). On Day 2, oral prednisone was started at 20 mg per day. Thereafter, the dose of oral prednisone (or equivalent) was tapered to a dose of 0 to 5 mg/day.
Antibody induction therapy was not allowed.
The efficacy failure rate, defined as the percentage of patients with biopsy-proven acute rejection (BPAR), graft failure, death, and/or lost to follow at 12 months, is shown in Table 17for the intent-to-treat population, as well as the rates of the individual events. About 1% of randomized patients were not transplanted and were not included in the ITT analysis.
| a95% confidence interval calculated using normal approximation. | ||
ASTAGRAF XL + MMF and steroids (N=331) | Prograf + MMF and steroids (N=336) | |
Efficacy Failure | 93 (28.1%) | 78 (23.2%) |
Treatment Difference (95% CIa) | +4.9% (-1.7%, +11.5%) | |
Efficacy Failure Endpoints | ||
Biopsy-Proven Acute Rejection | 68 (20.5%) | 54 (16.1%) |
Graft loss | 28 (8.5%) | 24 (7.1%) |
Death | 10 (3%) | 8 (2.4%) |
Lost to follow-up | 4 (1.2%) | 7 (2.1%) |
The estimated mean glomerular filtration rates, using the Modification of Diet in Renal Disease (MDRD) formula, by treatment group at Month 12 in the intent-to-treat population in Study 2 is shown in Table 18.
| aLast observation carried forward (LOCF); patients who died, lost the graft or were lost to follow-up are imputed as zeroes. bResults from analysis of covariance model with Month 1 baseline as a covariate. | ||
ASTAGRAF XL + MMF and steroids (N=287) | Prograf + MMF and steroids (N=300) | |
Month 1 Baseline Mean (SD) Month 12 LOCFa Mean (Standard deviation) Mean Difference ASTAGRAF XL minus Prograf (tacrolimus immediate-release)b | 51 (19) 52 (20) -1.8 (-4.6, +0.8) | 52 (20) 55 (19) |
Study 1 was a 12-month, randomized, open-label trial of ASTAGRAF XL (N=214) compared to active-control of tacrolimus (Prograf) immediate-release (N=212), conducted primarily in the U.S. in patients who were a recipient of a primary or retransplanted non-HLA-identical living or deceased donor kidney transplant. All patients received basiliximab induction and concomitant mycophenolate mofetil (MMF) and corticosteroids. The study population was 17 to 77 years of age, the mean age was 48 years; 64% were male and 36% were female; 73% were Caucasian, 22% were African-American, 2% were Asian, and 3% were categorized as other races. Living donors provided 49% of the organs and 51% of patients received a kidney transplant from a deceased donor with a mean cold ischemia time of 19 hours. The most frequent diseases leading to transplantation were balanced between the groups and included nephrosclerosis/hypertensive nephropathy, diabetic nephropathy, glomerulonephritis, and polycystic kidney disease. In the study, 97% of patients had no previous transplant and 3% had a previous transplant.
The initial dose of ASTAGRAF XL was administered prior to reperfusion or within 48 hours after completion of the transplant procedure. The protocol-defined initial post-operative daily doses were 0.15 to 0.20 mg per kg given as a single dose in the morning for ASTAGRAF XL and 0.075 to 0.10 mg per kg twice daily for control. The ASTAGRAF XL and control dosage was then adjusted on the basis of safety and efficacy and a target whole blood tacrolimus trough concentration range of 7 to 16 ng/mL for the first 90 days post-transplant and 5 to 15 ng/mL thereafter.
The average recorded starting tacrolimus daily dose, given any time up to day 2 post-transplant, was higher for ASTAGRAF XL than for control (0.14 mg per kg per day versus 0.10 mg per kg per day). Thereafter, to achieve comparable mean tacrolimus trough concentrations, on average 15% higher total mean daily doses of tacrolimus were required for ASTAGRAF XL than for control.
Tacrolimus whole blood trough concentrations were monitored on Days 3, 7, 10, 14, and 21, then Months 1, 2, 4, 6, 8, 10, and 12. Table 10 shows the tacrolimus whole blood trough concentrations measured at protocol-specified time points for ASTAGRAF XL. Approximately 80% of ASTAGRAF XL-treated patients maintained tacrolimus whole trough blood concentrations between 5 to 17 ng/mL during months 1 through 2 and between 4 to 12 ng/mL from months 3 through 12.
Scheduled Visit | Tacrolimus Whole Blood Trough Concentrations (ng/mL) Immunoassay was used in most laboratories.[Median (10thto 90thPercentile)] |
Day 3 | 9.6 (4.9 to 20.2) |
Day 7 | 9.1 (4.4 to 16.8) |
Day 14 | 10.0 (5.7 to 16.9) |
Month 1 | 10.5 (5.6 to 17.1) |
Month 2 | 9.4 (6.1 to 14.2) |
Month 6 | 7.7 (4.4 to 11.5) |
Month 12 | 7.2 (3.8 to 10.4) |
African-American patients required higher ASTAGRAF XL dosages to attain similar trough concentrations as Caucasian patients (see Table 11).
Time After Transplant | Caucasian Patients N=160 | African-American Patients N=41 | ||
Dose (mg/kg) | Mean Trough Concentration (ng/mL) | Dose (mg/kg) | Mean Trough Concentration (ng/mL) | |
Day 7 | 0.14 | 10.65 | 0.14 | 7.78 |
Month 1 | 0.14 | 11.11 | 0.17 | 10.92 |
Month 6 | 0.10 | 7.95 | 0.13 | 8.42 |
Month 12 | 0.09 | 7.53 | 0.12 | 7.33 |
The initial dose of MMF was 1 gram administered orally or intravenously prior to or within 48 hours of completion of the transplant procedure. Subsequent MMF was administered orally 1 gram twice daily or up to 1.5 grams twice daily in African-American patients. Dose-equivalent three times daily or four times daily dosing was permitted if MMF tolerability was a concern.
The MMF dosages administered by time period in ASTAGRAF XL-treated patients are shown in Table 12. The MMF dosage was reduced to less than 2 grams per day by month 12 in 56% of ASTAGRAF XL-treated patients. Approximately 57% of the MMF dose reductions were because of adverse reactions in the ASTAGRAF XL group
| aTime-averaged MMF dosage is the total MMF dosage per day divided by the duration of treatment. A time-averaged MMF dosage of 2 grams per day means that the MMF dosage was not reduced in those patients during the time period. | ||||
Time period (Days) | Patients on MMF | Time-averaged MMF dosagea | ||
N | Less than 2 grams per day | 2 grams per day | Greater than 2 grams per day | |
1-30 | 211 | 30% | 64% | 6% |
31-90 | 208 | 38% | 57% | 5% |
91-180 | 205 | 49% | 48% | 3% |
181-365 | 201 | 51% | 47% | 3% |
All patients were administered 2 doses of basiliximab induction therapy (20 mg intravenously) with the first dose on day 0 before skin closure and the second dose between days 3 and 5.
All patients were administered an intravenous bolus of 500 to 1000 mg of methylprednisolone (or an equivalent steroid dose) on day 0 followed by oral administration of 200 mg methylprednisolone (or an equivalent dose of steroid) on day 1 and subsequent tapering to achieve a targeted mean prednisone dose of 5 to 10 mg/day after the first 3 months.
The efficacy failure rate, defined as the percentage of patients with biopsy-proven acute rejection (BPAR), graft failure, death, and/or lost to follow at 12 months, is shown in Table 13for the intent-to-treat population, as well as the rates of the individual events.
| a95% confidence interval calculated using normal approximation. | ||
ASTAGRAF XL + MMF, steroids, basiliximab induction (N=214) | Prograf + MMF, steroids, basiliximab induction (N=212) | |
Efficacy Failure | 30 (14.0%) | 32 (15.1%) |
Treatment Difference (95% CIa) | -1.1% (-7.8%, +5.6%) | |
Efficacy Failure Endpoints | ||
Biopsy-Proven Acute Rejection | 22 (10.3%) | 16 (7.5%) |
Graft Loss | 5 (2.3%) | 9 (4.2%) |
Death | 3 (1.4%) | 9 (4.2%) |
Lost to follow-up | 3 (1.4%) | 4 (1.9%) |
The estimated mean glomerular filtration rates, using the Modification of Diet in Renal Disease (MDRD) formula, by treatment group at Month 12 in the intent-to-treat population is shown in Table 14.
| aLast observation carried forward (LOCF); patients who died, lost the graft, or were lost to follow-up are imputed as zeroes. bResults from analysis of covariance model with Month 1 baseline as a covariate. | ||
ASTAGRAF XL + MMF, steroids, basiliximab induction (N=201) | Prograf + MMF, steroids, basiliximab induction (N=202) | |
Month 1 Baseline Mean (SD) Month 12 LOCFa Mean (Standard deviation) Mean Difference XL minus Prograf (tacrolimus immediate-release)b | 56 (20) 58 (21) +2.3 (-1.2, +5.8) | 56 (21) 56 (23) |
Study 2 was a 12-month, randomized, double-blind trial of ASTAGRAF XL (N=331) compared to active control of tacrolimus (Prograf) immediate-release (N=336), in non-U.S. patients who received a primary or retransplanted non-HLA-identical living or deceased donor kidney transplant. This trial was designed to remain double-blind until the last patient enrolled had completed 24 weeks on study treatment. Patients with a high immunologic risk defined as a panel reactive antibody (PRA) grade > 50% in the previous 6 months and/or with a previous graft survival of less than 12 months due to immunologic reasons were excluded, as were patients of donor kidneys with cold ischemia time > 30 hours, or donor kidneys from a non heart-beating donor. The patient treatment assignments remained blinded for 12 months for 96% of the patients participating in the trial.
All patients received concomitant MMF and corticosteroids without induction. The population was 18 to 65 years of age; the mean age was 48 years; 63% of the study population was male; 82% were Caucasian, 5% were African-American, 2% were Asian, and 11% were categorized as other races. Living donors provided 27% of the organs and 73% of patients received a kidney transplant from a deceased donor with a mean cold ischemia time of 17 hours. The most frequent diseases leading to transplantation were balanced between the groups and included nephrosclerosis/hypertensive nephropathy, diabetic nephropathy, glomerulonephritis, and polycystic kidney disease.
The protocol-specified initial preoperative dose for both ASTAGRAF XL and control was 0.1 mg per kg given orally in one dose within 12 hours prior to reperfusion, given at any time of the day. The initial post-operative tacrolimus daily dose (0.2 mg per kg per day) was given orally in one dose, preferably in the morning for ASTAGRAF XL, and was given as 0.1 mg/kg twice daily for control. Subsequent doses of ASTAGRAF XL and control were adjusted on the basis of clinical evidence of efficacy, occurrence of adverse events and according to whole blood tacrolimus trough concentration target ranges of 10 to 15 ng/mL for the first 28 days post-transplant, 5 to 15 ng/mL from Day 29 to Day 168, 5 to 10 ng/mL thereafter.
The actual tacrolimus doses on day 0 (0.1 mg per kg per day preoperative) and day 1 (0.2 mg per kg per day post-operative) were comparable between ASTAGRAF XL and control. Thereafter, to achieve comparable mean tacrolimus trough concentrations, on average, 25% higher total mean daily doses of tacrolimus were required for ASTAGRAF XL than for control.
Tacrolimus whole blood trough concentrations were monitored on Days 1, 3, 7, 14, then Months 1, 2, 3, 6, 11, 12, and then every 3 months.
Table 15shows the tacrolimus whole blood trough concentrations measured at protocol-specified time points for ASTAGRAF XL. Approximately 80% of ASTAGRAF XL-treated patients maintained tacrolimus whole trough blood concentrations between 6 to 20 ng/mL during months 1 through 2, and between 6 to 14 ng/mL from months 3 through 12.
Scheduled Visit | Tacrolimus Whole Blood Trough Concentrations (ng/mL) Immunoassay was used in most laboratories.[Median (10thto 90thPercentile)] |
Day 3 | 13.8 (6.5 to 25.5) |
Day 7 | 10.1 (5.5 to 17.3) |
Day 14 | 10.8 (6.7 to 17.9) |
Month 1 | 12.0 (7.5 to 17.6) |
Month 2 | 11.1 (6.6 to 17.3) |
Month 6 | 9.2 (5.7 to 13.5) |
Month 12 | 8.0 (5.1 to 13.8) |
The initial dose of MMF was 1 gram orally twice daily starting preoperatively and given for the first 14 days of the study. Thereafter the MMF dose was reduced to 0.5 grams twice daily to be maintained throughout the study.
The MMF dosages administered by time period in ASTAGRAF XL-treated patients are shown in Table 16. The MMF dosage was reduced to 0.5 grams twice daily starting after day 14 in the majority of patients.
| aTime-averaged MMF dosage is the total MMF dosage per day divided by the duration of treatment. A time-averaged MMF dosage of 2 grams per day means that the MMF dosage was not reduced in those patients during the time period. bOne patient had a time-averaged dose during the first and last period of > 2 gm/day. | ||||
Time period (Days) | Patients on MMF | Time-averaged MMF dosagea, b | ||
N | Less than 1 gram per day | 1 gram to less than 2 grams per day | 2 grams per day | |
1-30 | 331 | 1% | 78% | 21% |
31-90 | 303 | 8% | 87% | 6% |
91-180 | 281 | 12% | 85% | 3% |
181-365 | 258 | 15% | 83% | 2% |
An intravenous (IV) bolus of up to 1000 mg methylprednisolone (or equivalent) was administered perioperatively (Day 0) with a second IV bolus of 125 mg being administered 1 day after reperfusion (Day 1). On Day 2, oral prednisone was started at 20 mg per day. Thereafter, the dose of oral prednisone (or equivalent) was tapered to a dose of 0 to 5 mg/day.
Antibody induction therapy was not allowed.
The efficacy failure rate, defined as the percentage of patients with biopsy-proven acute rejection (BPAR), graft failure, death, and/or lost to follow at 12 months, is shown in Table 17for the intent-to-treat population, as well as the rates of the individual events. About 1% of randomized patients were not transplanted and were not included in the ITT analysis.
| a95% confidence interval calculated using normal approximation. | ||
ASTAGRAF XL + MMF and steroids (N=331) | Prograf + MMF and steroids (N=336) | |
Efficacy Failure | 93 (28.1%) | 78 (23.2%) |
Treatment Difference (95% CIa) | +4.9% (-1.7%, +11.5%) | |
Efficacy Failure Endpoints | ||
Biopsy-Proven Acute Rejection | 68 (20.5%) | 54 (16.1%) |
Graft loss | 28 (8.5%) | 24 (7.1%) |
Death | 10 (3%) | 8 (2.4%) |
Lost to follow-up | 4 (1.2%) | 7 (2.1%) |
The estimated mean glomerular filtration rates, using the Modification of Diet in Renal Disease (MDRD) formula, by treatment group at Month 12 in the intent-to-treat population in Study 2 is shown in Table 18.
| aLast observation carried forward (LOCF); patients who died, lost the graft or were lost to follow-up are imputed as zeroes. bResults from analysis of covariance model with Month 1 baseline as a covariate. | ||
ASTAGRAF XL + MMF and steroids (N=287) | Prograf + MMF and steroids (N=300) | |
Month 1 Baseline Mean (SD) Month 12 LOCFa Mean (Standard deviation) Mean Difference ASTAGRAF XL minus Prograf (tacrolimus immediate-release)b | 51 (19) 52 (20) -1.8 (-4.6, +0.8) | 52 (20) 55 (19) |
• Capsules must be taken whole. ()2.1 Important Administration Instructions• ASTAGRAF XL should not be used without the supervision by a physician with experience in immunosuppressive therapy.• ASTAGRAF XL (tacrolimus extended-release capsules) is not interchangeable or substitutable for tacrolimus extended-release tablets, tacrolimus immediate-release capsules or tacrolimus for oral suspension. Under or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision[see Warnings and Precautions].• Advise patients to swallow ASTAGRAF XL capsules whole with liquid; patients must not chew, divide, or crush the capsules.• ASTAGRAF XL should be taken 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[see Clinical Pharmacology].• If a dose is missed, the dose may be taken up to 14 hours after the scheduled time (i.e., for a missed 8:00 AM dose, a dose may be taken by 10:00 PM). Beyond the 14-hour time frame, the patient should wait until the usual scheduled time the following morning to take the next regular daily dose. Instruct the patient not to double the next dose.• Advise patients to avoid eating grapefruit or drinking grapefruit juice or alcoholic beverages while taking ASTAGRAF XL[see Drug Interactions].• Therapeutic drug monitoring is recommended for all patients receiving ASTAGRAF XL[see Dosage and Administration].
• Take consistently every morning at the same time on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal. ()2.1 Important Administration Instructions• ASTAGRAF XL should not be used without the supervision by a physician with experience in immunosuppressive therapy.• ASTAGRAF XL (tacrolimus extended-release capsules) is not interchangeable or substitutable for tacrolimus extended-release tablets, tacrolimus immediate-release capsules or tacrolimus for oral suspension. Under or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision[see Warnings and Precautions].• Advise patients to swallow ASTAGRAF XL capsules whole with liquid; patients must not chew, divide, or crush the capsules.• ASTAGRAF XL should be taken 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[see Clinical Pharmacology].• If a dose is missed, the dose may be taken up to 14 hours after the scheduled time (i.e., for a missed 8:00 AM dose, a dose may be taken by 10:00 PM). Beyond the 14-hour time frame, the patient should wait until the usual scheduled time the following morning to take the next regular daily dose. Instruct the patient not to double the next dose.• Advise patients to avoid eating grapefruit or drinking grapefruit juice or alcoholic beverages while taking ASTAGRAF XL[see Drug Interactions].• Therapeutic drug monitoring is recommended for all patients receiving ASTAGRAF XL[see Dosage and Administration].
• Avoid eating grapefruit or drinking grapefruit juice or alcohol. ()2.1 Important Administration Instructions• ASTAGRAF XL should not be used without the supervision by a physician with experience in immunosuppressive therapy.• ASTAGRAF XL (tacrolimus extended-release capsules) is not interchangeable or substitutable for tacrolimus extended-release tablets, tacrolimus immediate-release capsules or tacrolimus for oral suspension. Under or overexposure to tacrolimus may result in graft rejection or other serious adverse reactions. Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision[see Warnings and Precautions].• Advise patients to swallow ASTAGRAF XL capsules whole with liquid; patients must not chew, divide, or crush the capsules.• ASTAGRAF XL should be taken 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[see Clinical Pharmacology].• If a dose is missed, the dose may be taken up to 14 hours after the scheduled time (i.e., for a missed 8:00 AM dose, a dose may be taken by 10:00 PM). Beyond the 14-hour time frame, the patient should wait until the usual scheduled time the following morning to take the next regular daily dose. Instruct the patient not to double the next dose.• Advise patients to avoid eating grapefruit or drinking grapefruit juice or alcoholic beverages while taking ASTAGRAF XL[see Drug Interactions].• Therapeutic drug monitoring is recommended for all patients receiving ASTAGRAF XL[see Dosage and Administration].
• African-American patients and patients with severe hepatic impairment may require dosing adjustments. ()2.3 Dosage Modifications for African-American Patients, Patients with Hepatic Impairment, and Drug InteractionsAfrican-American patients, compared to Caucasian patients, may need to be titrated to higher ASTAGRAF XL dosages to attain comparable trough concentrations
[see Clinical Pharmacology and Clinical Studies].Patients with severe hepatic impairment (Child-Pugh ≥ 10) may require a lower starting dosage of ASTAGRAF XL, due to the reduced clearance and prolonged half-life
[see Clinical Pharmacology].Dose adjustments of ASTAGRAF XL may be necessary when administered concomitantly with CYP3A inducers or CYP3A inhibitors or cannabidiol
[see Warnings and Precautions and Drug Interactions].• Frequent monitoring of trough concentrations is recommended. ()2.4 Therapeutic Drug MonitoringMeasure tacrolimus whole blood trough concentrations at least two times on separate days during the first week after initiation of dosing and after a change in dosage, after a change in co-administration of CYP3A4 inducers and/or inhibitors or cannabidiol
[seeDrug Interactions( 7.2, 7.3)], or after a change in renal or hepatic function. When interpreting measured concentrations, consider that the time to achieve tacrolimus steady state is approximately 7 days after initiating or changing the ASTAGRAF XL dose.Monitor tacrolimus whole blood trough concentrations using a validated assay [e.g., immunoassays or high performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS)]. The immunosuppressive activity of tacrolimus is mainly due to the parent drug rather than to its metabolites. Immunoassays may react with metabolites as well as the parent drug. Therefore, whole blood tacrolimus trough concentrations obtained with immunoassays may be numerically higher than concentrations obtained with an assay using HPLC/MS/MS. Comparison of the whole blood tacrolimus trough concentrations of patients to those described in the prescribing information and other published literature must be made with knowledge of the assay method(s) employed.
• For complete dosing information, see Full Prescribing Information.
| MMF = Mycophenolate mofetil | ||
Recommended ASTAGRAF XL Initial Dosage | ||
Patient Population | Initial Oral Dosage | Whole Blood Trough Concentration Range |
ADULT | ||
With basiliximab, MMF and steroids | 0.15 to 0.2 mg/kg once daily prior to reperfusion or within 48 hours of completion of transplant |
|
With MMF and steroids, without basiliximab induction |
|
|
PEDIATRIC | ||
With basiliximab, MMF and steroids | 0.3 mg/kg once daily, administered within 24 hours following reperfusion |
|
ASTAGRAF XL CAPSULES:
• 0.5 mg: light yellow cap and orange body branded with red “
647” on the capsule body and “0.5 mg” on the capsule cap.
• 1 mg: white cap and orange body branded with red “
677” on the capsule body and “1 mg” on the capsule cap.
• 5 mg: grayish-red cap and orange body branded with red “
687” on the capsule body and “5 mg” on the capsule cap.
Pregnancy: Can cause fetal harm. Advise pregnant women of the potential risk to the fetus. (
There is a pregnancy registry that monitors pregnancy outcomes in women exposed to ASTAGRAF XL during pregnancy. The Transplantation Pregnancy Registry International (TPRI) is a voluntary pregnancy exposure registry that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants including tacrolimus. Healthcare providers are encouraged to advise their patients to register by contacting the Transplantation Pregnancy Registry International at 1-877-955-6877 or https://www.transplantpregnancyregistry.org/.
Tacrolimus can cause fetal harm when administered to a pregnant woman. Data from postmarketing surveillance and TPRI suggest that infants exposed to tacrolimus
Administration of oral tacrolimus to pregnant rabbits and rats throughout the period of organogenesis was associated with maternal toxicity/lethality, and an increased incidence of abortion, malformation and embryofetal death at clinically relevant doses [0.5 the maximum recommended clinical dose (0.2 mg/kg/day), on a mg/m2basis]. Administration of oral tacrolimus to pregnant rats after organogenesis and throughout lactation produced maternal toxicity, effects on parturition, reduced pup viability and reduced pup weight at clinically relevant doses (0.8 the maximum recommended clinical dose, on a mg/m2basis). Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, marked effects on parturition, embryofetal loss, malformations, and reduced pup viability at clinically relevant doses (0.8 times the maximum recommended clinical dose, on a mg/m2basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died
The background risk of major birth defects and miscarriage in the indicated population is unknown.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Risks during pregnancy are increased in organ transplant recipients. The risk of premature delivery following transplantation is increased. Pre-existing hypertension and diabetes confer additional risk to the pregnancy of an organ transplant recipient. Pre-gestational and gestational diabetes are associated with birth defects/congenital anomalies, hypertension, low birth weight and fetal death.
Cholestasis of pregnancy (COP) was reported in 7% of liver or liver-kidney (LK) transplant recipients, compared with approximately 1% of pregnancies in the general population. However, COP symptoms resolved postpartum and no long-term effects on the offspring were reported.
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.
There are no adequate and well-controlled studies on the effects of tacrolimus in human pregnancy.
Safety data from the TPRI and postmarketing surveillance suggest infants exposed to tacrolimus
TPRI reported 450 and 241 total pregnancies in kidney and liver transplant recipients exposed to tacrolimus, respectively. The TPRI pregnancy outcomes are summarized in Table 6. In the table below, the number of recipients exposed to tacrolimus concomitantly with mycophenolic acid (MPA) products during the preconception and first trimester periods is high (27% and 29% for kidney and liver transplant recipients, respectively). Because MPA products may also cause birth defects, the birth defect rate may be confounded and this should be taken into consideration when reviewing the data, particularly for birth defects. Birth defects observed include cardiac malformations, craniofacial malformations, renal/urogenital disorders, skeletal abnormalities, neurological abnormalities and multiple malformations.
Kidney | Liver | |
Pregnancy Outcomes Includes multiple births and terminations. | 462 | 253 |
Miscarriage | 24.5% | 25% |
Live births | 331 | 180 |
| Pre-term delivery (< 37 weeks) | 49% | 42% |
Low birth weight (< 2500 g) | 42% | 30% |
Birth defects | 8%Birth defect rate confounded by concomitant MPA products exposure in over half of offspring with birth defects. | 5% |
Additional information reported by TPRI in pregnant transplant patients receiving tacrolimus included diabetes during pregnancy in 9% of kidney recipients and 13% of liver recipients and hypertension during pregnancy in 53% of kidney recipients and 16.2% of liver recipients.
Administration of oral tacrolimus to pregnant rabbits throughout organogenesis produced maternal toxicity and abortion at 0.32 mg/kg (0.5 times the maximum recommended clinical dose [0.2 mg/kg/day], on a mg/m2basis). At 1 mg/kg (1.6 times the maximum recommended clinical dose), embryofetal lethality and fetal malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, omphalocele, gallbladder agenesis, skeletal anomalies) were observed. Administration of 3.2 mg/kg oral tacrolimus (2.6 times the maximum recommended clinical dose) to pregnant rats throughout organogenesis produced maternal toxicity/lethality, embryofetal lethality and decreased fetal body weight in the offspring of C-sectioned dams; and decreased pup viability and interventricular septal defect in offspring of dams that delivered.
In a peri-/postnatal development study, oral administration of tacrolimus to pregnant rats during late gestation (after organogenesis) and throughout lactation produced maternal toxicity, effects on parturition, and reduced pup viability at 3.2 mg/kg (2.6 times the maximum recommended clinical dose); among these pups that died early, an increased incidence of kidney hydronephrosis was observed. Reduced pup weight was observed at 1.0 mg/kg (0.8 times the maximum recommended clinical dose).
Administration of oral tacrolimus to rats prior to mating, and throughout gestation and lactation produced maternal toxicity/lethality, embryofetal loss and reduced pup viability at 3.2 mg/kg (2.6 times the maximum recommended clinical dose range). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died. Effects on parturition (incomplete delivery of nonviable pups) were observed at 1 mg/kg (0.8 times the maximum recommended clinical dose)
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
Based on findings in animals, male and female fertility may be compromised by treatment with ASTAGRAF XL