Prograf
Tacrolimus · Capsule, Gelatin Coated · Oral, Intravenous
Uses
1 INDICATIONS AND USAGE PROGRAF is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic liver, kidney, heart, or lung transplants, in combination with other immunosuppressants. ( 1.1 ) 1.1 Prophylaxis of Organ Rejection in Kidney, Liver, Heart, or Lung Transplant PROGRAF ® is indicated for the prophylaxis of organ rejection, in adult and pediatric patients receiving allogeneic kidney transplant [see Clinical Studies ( 14.1 )], liver transplant [see Clinical Studies ( 14.2 )], heart transplant [see Clinical Studies ( 14.3 )], or lung transplant [see Clinical Studies ( 14.4 )] in combination with other immunosuppressants.
Dosage and administration
• Intravenous (IV) use recommended for patients who cannot tolerate oral formulations (capsules or suspension). ( 2.1 , 2.2 )
• Administer capsules or suspension consistently with or without food. ( 2.1 )
• Therapeutic drug monitoring is recommended. ( 2.1 , 2.6 )
• Avoid eating grapefruit or drinking grapefruit juice. ( 2.1 )
• See dosage adjustments for African-American patients ( 2.2 ), hepatic and renal impaired. ( 2.4 , 2.5 )
• For complete dosing information, see Full Prescribing Information. ADULT Patient Population Initial Oral Dosage (formulation) Whole Blood Trough Concentration Range Kidney Transplant With azathioprine 0.2 mg/kg/day capsules, divided in two doses, every 12 hours Month 1-3: 7-20 ng/mL Month 4-12: 5-15 ng/mL With MMF/IL-2 receptor antagonist 0.1 mg/kg/day capsules, divided in two doses, every 12 hours Month 1-12: 4-11 ng/mL Liver Transplant With corticosteroids only 0.1-0.15 mg/kg/day capsules, divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL Heart Transplant With azathioprine or MMF 0.075 mg/kg/day capsules, divided in two doses, every 12 hours Month 1-3: 10-20 ng/mL Month ≥ 4: 5-15 ng/mL Lung Transplant With azathioprine or MMF 0.075 mg/kg/day Patients with cystic fibrosis may require higher doses due to lower bioavailability. capsules, divided in two doses, every 12 hours Month 1-3: 10-15 ng/mL Month 4-12: 8-12 ng/mL PEDIATRIC Patient Population Initial Oral Dosage (formulation) Whole Blood Trough Concentration Range Kidney Transplant 0.3 mg/kg/day capsules or oral suspension, divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL Liver Transplant 0.15-0.2 mg/kg/day capsules or 0.2 mg/kg/day oral suspension, divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL Heart Transplant 0.3 mg/kg/day Dose at 0.1 mg/kg/day if antibody induction treatment is administered. capsules or oral suspension, divided in two doses, every 12 hours Month 1-12: 5-20 ng/mL Lung Transplant 0.3 mg/kg/day , capsules or oral suspension, divided in two doses, every 12 hours Weeks 1-2: 10-20 ng/mL Week 2 to Month 12: 10-15 ng/mL MMF= Mycophenolate mofetil 2.1 Important Administration Instructions PROGRAF should not be used without supervision by a physician with experience in immunosuppressive therapy. PROGRAF capsules and PROGRAF Granules are not interchangeable or substitutable for other tacrolimus extended-release products. This is because rate of absorption following the administration of an extended-release tacrolimus product is not equivalent to that of an immediate-release tacrolimus drug product. 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 ( 5.3 )]. Intravenous Formulation - Administration Precautions due to Risk of Anaphylaxis Intravenous use is recommended for patients who cannot tolerate oral formulations, and conversion from intravenous to oral PROGRAF is recommended as soon as oral therapy can be tolerated to minimize the risk of anaphylactic reactions that occurred with injectables containing castor oil derivatives [see Warnings and Precautions ( 5.9 )] . Patients receiving PROGRAF injection should be under continuous observation for at least the first 30 minutes following the start of the infusion and at frequent intervals thereafter. If signs or symptoms of anaphylaxis occur, the infusion should be stopped. An aqueous solution of epinephrine should be available at the bedside as well as a source of oxygen. Oral Formulations (Capsules and Oral Suspension) If patients are able to initiate oral therapy, the recommended starting doses should be initiated. PROGRAF Granules for oral suspension or PROGRAF capsules may be taken with or without food. However, since the presence of food affects the bioavailability of PROGRAF, if taken with food, it should be taken consistently the same way each time [see Clinical Pharmacology ( 12.3 )]. General Administration Instructions Patients should not eat grapefruit or drink grapefruit juice in combination with PROGRAF [see Drug Interactions ( 7.2 )]. PROGRAF should not be used simultaneously with cyclosporine. PROGRAF or cyclosporine should be discontinued at least 24 hours before initiating the other. In the presence of elevated PROGRAF or cyclosporine concentrations, dosing with the other drug usually should be further delayed. Therapeutic drug monitoring (TDM) is recommended for all patients receiving PROGRAF [see Dosage and Administration ( 2.6 )]. 2.2 Dosage Recommendations for Adult Kidney, Liver, Heart, or Lung Transplant Patients - Capsules and Injection Capsules If patients are able to tolerate oral therapy, the recommended oral starting doses should be initiated. The initial dose of PROGRAF capsules should be administered no sooner than 6 hours after transplantation in the liver, heart, or lung transplant patients. In kidney transplant patients, the initial dose of PROGRAF capsules may be administered within 24 hours of transplantation, but should be delayed until renal function has recovered. The initial oral PROGRAF capsule dosage recommendations for adult patients with kidney, liver, heart, or lung transplants and whole blood trough concentration range are shown in Table 1 . Perform therapeutic drug monitoring (TDM) to ensure that patients are within the ranges listed in Table 1 . Table 1. Summary of Initial Oral PROGRAF Capsules Dosage Recommendations and Whole Blood Trough Concentration Range in Adults Patient Population PROGRAF Capsules African-American patients may require higher doses compared to Caucasians (see Table 2 ).
Dosage forms and strengths
3 DOSAGE FORMS AND STRENGTHS PROGRAF is available in the following dosage forms and strengths: Capsules Oblong, hard capsule for oral administration contains anhydrous tacrolimus USP as follows:
• 0.5 mg, light-yellow color, imprinted in red “0.5 mg” on the capsule cap and “ 607” on capsule body
• 1 mg, white color, imprinted in red “1 mg” on the capsule cap and “ 617” on capsule body
• 5 mg, grayish-red color, imprinted with white “5 mg” on the capsule cap and “ 657” on capsule body Injection 1 mL ampule for intravenous infusion contains anhydrous tacrolimus USP, 5 mg/mL For Oral Suspension Unit-dose packets with white granules for oral suspension contains anhydrous tacrolimus USP:
• 0.2 mg
• 1 mg
• Capsules: 0.5 mg, 1 mg and 5 mg ( 3 )
• Injection: 5 mg/mL ( 3 )
• For oral suspension: 0.2 mg, 1 mg unit-dose packets containing granules ( 3 ) Letter f logo Letter f logo Letter f logo
Contraindications
4 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). Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome [see Adverse Reactions ( 6 )] .
• Hypersensitivity to tacrolimus or HCO-60 (polyoxyl 60 hydrogenated castor oil). ( 4 )
Warnings and precautions
• Not Interchangeable with Extended-Release Tacrolimus Products - Medication Errors: Instruct patients or caregivers to recognize the appearance of PROGRAF capsules. ( 5.3 )
• New Onset Diabetes After Transplant: Monitor blood glucose. ( 5.4 )
• Nephrotoxicity (acute and/or chronic): Reduce the dose; use caution with other nephrotoxic drugs. ( 5.5 )
• Neurotoxicity: Including risk of Posterior Reversible Encephalopathy Syndrome (PRES); monitor for neurologic abnormalities; reduce or discontinue PROGRAF. ( 5.6 )
• Hyperkalemia: Monitor serum potassium levels. Consider carefully before using with other agents also associated with hyperkalemia. ( 5.7 )
• Hypertension: May require antihypertensive therapy. Monitor relevant drug-drug interactions. ( 5.8 )
• Anaphylactic Reactions with IV formulation: Observe patients receiving PROGRAF injection for signs and symptoms of anaphylaxis. ( 5.9 )
• Not recommended for use with sirolimus: Not recommended in liver and heart transplant due to increased risk of serious adverse reactions. ( 5.10 )
• Myocardial Hypertrophy: Consider dose reduction/discontinuation. ( 5.13 )
• Immunizations: Avoid live vaccines. ( 5.14 )
• Pure Red Cell Aplasia: Consider discontinuation of PROGRAF. ( 5.15 )
• Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura: May occur, especially in patients with infections and certain concomitant medications. ( 5.16 ) 5.1 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 majority of PTLD events appear related to Epstein-Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children. Monitor EBV serology during treatment. 5.2 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:
• Polyomavirus-associated nephropathy (PVAN), mostly due to BK virus infection
• JC virus-associated progressive multifocal leukoencephalopathy (PML)
• Cytomegalovirus infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor disease are at higher risk of developing CMV viremia and CMV disease. Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection [see Adverse Reactions ( 6.1 , 6.2 )]. 5.3 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 overexposure 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 [see Dosage Forms and Strengths ( 3 )] and to confirm with the healthcare provider if a different product is dispensed . 5.4 New Onset Diabetes After Transplant PROGRAF was shown to cause new onset diabetes mellitus in clinical trials of kidney, liver, heart, or lung transplantation. New onset diabetes after transplantation may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk. Blood glucose concentrations should be monitored closely in patients using PROGRAF [see Adverse Reactions ( 6.1 )] . 5 .5 Nephrotoxicity due to PROGRAF and Drug Interactions PROGRAF, like other calcineurin inhibitors, can cause acute or chronic nephrotoxicity in transplant patients due to its vasoconstrictive effect on renal vasculature, toxic tubulopathy and tubular-interstitial effects. Nephrotoxicity was reported in clinical trials [see Adverse Reactions ( 6.1 )] . Acute renal impairment associated with tacrolimus toxicity can result in high serum creatinine, hyperkalemia, decreased secretion of urea and hyperuricemia, and is usually reversible. In patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range, consider dosage reduction or temporary interruption of tacrolimus administration. The risk for nephrotoxicity may increase when PROGRAF is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors). When tacrolimus is used concurrently with other known nephrotoxic drugs, monitor renal function and tacrolimus blood concentrations, and adjust doses of both tacrolimus and/or concomitant medications during concurrent use [see Drug Interactions ( 7.2 )] . 5.6 Neurotoxicity PROGRAF may cause a spectrum of neurotoxicities.
Side effects
The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:
• Lymphoma and Other Malignancies [see Warnings and Precautions ( 5.1 )]
• Serious Infections [see Warnings and Precautions ( 5.2 )]
• New Onset Diabetes After Transplant [see Warnings and Precautions ( 5.4 )]
• Nephrotoxicity [see Warnings and Precautions ( 5.5 )]
• Neurotoxicity [see Warnings and Precautions ( 5.6 )]
• Hyperkalemia [see Warnings and Precautions ( 5.7 )]
• Hypertension [see Warnings and Precautions ( 5.8 )]
• Anaphylactic Reactions with PROGRAF Injection [see Warnings and Precautions ( 5.9 )]
• Myocardial Hypertrophy [see Warnings and Precautions ( 5.13 )]
• Pure Red Cell Aplasia [see Warnings and Precautions ( 5.15 )]
• Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura [see Warnings and Precautions ( 5.16 )] The most common adverse reactions (≥ 15%) were abnormal renal function, hypertension, diabetes mellitus, fever, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, constipation, diarrhea, headache, abdominal pain, insomnia, paresthesia, peripheral edema, nausea, hyperkalemia, hypomagnesemia, and hyperlipemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below. Kidney Transplantation The incidence of adverse reactions was determined in three randomized kidney transplant trials. One of the trials used azathioprine (AZA) and corticosteroids and two of the trials used mycophenolate mofetil (MMF) and corticosteroids concomitantly for maintenance immunosuppression. PROGRAF-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a trial where 205 patients received PROGRAF-based immunosuppression and 207 patients received cyclosporine-based immunosuppression. The trial population had a mean age of 43 years (mean ± SD was 43 ± 13 years on PROGRAF and 44 ± 12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), African-American (25%), Hispanic (12%), and Other (5%). The 12-month post-transplant information from this trial is presented below. The most common adverse reactions (≥ 30%) observed in PROGRAF-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, and anemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients. Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with PROGRAF in conjunction with azathioprine are presented below: Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with PROGRAF in Conjunction with Azathioprine (AZA) PROGRAF/AZA (N = 205) Cyclosporine/AZA (N = 207) Nervous System Tremor 54% 34% Headache 44% 38% Insomnia 32% 30% Paresthesia 23% 16% Dizziness 19% 16% Gastrointestinal Diarrhea 44% 41% Nausea 38% 36% Constipation 35% 43% Vomiting 29% 23% Dyspepsia 28% 20% Cardiovascular Hypertension 50% 52% Chest Pain 19% 13% Urogenital Creatinine Increased 45% 42% Urinary Tract Infection 34% 35% Metabolic and Nutritional Hypophosphatemia 49% 53% Hypomagnesemia 34% 17% Hyperlipemia 31% 38% Hyperkalemia 31% 32% Diabetes Mellitus 24% 9% Hypokalemia 22% 25% Hyperglycemia 22% 16% Edema 18% 19% Hemic and Lymphatic Anemia 30% 24% Leukopenia 15% 17% Miscellaneous Infection 45% 49% Peripheral Edema 36% 48% Asthenia 34% 30% Abdominal Pain 33% 31% Pain 32% 30% Fever 29% 29% Back Pain 24% 20% Respiratory System Dyspnea 22% 18% Cough Increased 18% 15% Musculoskeletal Arthralgia 25% 24% Skin Rash 17% 12% Pruritus 15% 7% Two trials were conducted for PROGRAF-based immunosuppression in conjunction with MMF and corticosteroids. In the non-US trial (Study 1), the incidence of adverse reactions was based on 1195 kidney transplant patients that received PROGRAF (Group C, n = 403), or one of two cyclosporine (CsA) regimens (Group A, n = 384 and Group B, n = 408) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial population had a mean age of 46 years (range 17 to 76); the distribution was 65% male, and the composition was 93% Caucasian. The 12-month post-transplant information from this trial is presented below. Adverse reactions that occurred in ≥ 10% of kidney transplant patients treated with PROGRAF in conjunction with MMF in Study 1 [Note: This trial was conducted entirely outside of the United States. Such trials often report a lower incidence of adverse reactions in comparison to U.S. trials] are presented below: Table 5.
Drug interactions
• Mycophenolic Acid Products: Can increase MPA exposure after crossover from cyclosporine to PROGRAF; monitor for MPA-related adverse reactions and adjust MMF or MPA dose as needed. ( 7.1 )
• Nelfinavir and Grapefruit Juice: Increased tacrolimus concentrations via CYP3A inhibition; avoid concomitant use. ( 7.2 )
• CYP3A Inhibitors: Increased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed. ( 5.11 , 7.2 )
• CYP3A4 Inducers: Decreased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed. ( 5.11 , 7.2 )
• Therapeutic drug monitoring and dose reduction for PROGRAF should be considered when PROGRAF is co-administered with cannabidiol ( 5.17 , 7.3 ). 7.1 Mycophenolic Acid When PROGRAF is prescribed with a given dose of a mycophenolic acid (MPA) product, exposure to MPA is higher with PROGRAF co-administration than with cyclosporine co-administration with MPA, because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Monitor for MPA-associated adverse reactions and reduce the dose of concomitantly administered mycophenolic acid products as needed. 7.2 Effects of Other Drugs on PROGRAF Table 15 displays the effects of other drugs on PROGRAF. Table 15. Effects of Other Drugs/Substances on PROGRAF PROGRAF dosage adjustment recommendation based on observed effect of co-administered drug on tacrolimus exposures [see Clinical Pharmacology ( 12.3 )] , literature reports of altered tacrolimus exposures, or the other drug’s known CYP3A inhibitor/inducer status. Drug/Substance Class or Name Drug Interaction Effect Recommendations Grapefruit or grapefruit juice High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor. May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions ( 5.6 , 5.11 , 5.12 )] . Avoid grapefruit or grapefruit juice. Strong CYP3A Inducers Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate). : Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John’s wort May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see Warnings and Precautions ( 5.11 )] . Increase PROGRAF dose and monitor tacrolimus whole blood trough concentrations [see Dosage and Administration ( 2.2 , 2.6 ) and Clinical Pharmacology ( 12.3 )] . Strong CYP3A Inhibitors : Protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, Schisandra sphenanthera extracts May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation). A rapid, sharp rise in tacrolimus levels may occur early, despite an immediate reduction of tacrolimus dose [see Warnings and Precautions ( 5.6 , 5.11 , 5.12 )] . Reduce PROGRAF dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations [see Dosage and Administration ( 2.2 , 2.6 ) and Clinical Pharmacology ( 12.3 )] . Early and frequent monitoring of tacrolimus whole blood trough levels should start within 1-3 days and continue monitoring as necessary [see Warnings and Precautions ( 5.11 )]. Mild or Moderate CYP3A Inhibitors: Clotrimazole, antibiotics (e.g., erythromycin, fluconazole), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions ( 5.6 , 5.11 , 5.12 )] . Monitor tacrolimus whole blood trough concentrations and reduce PROGRAF dose if needed [see Dosage and Administration ( 2.2 , 2.6 ) and Clinical Pharmacology ( 12.3 )] . Other drugs, such as: Magnesium and aluminum hydroxide antacids Metoclopramide May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions ( 5.6 , 5.11 , 5.12 )] . Monitor tacrolimus whole blood trough concentrations and reduce PROGRAF dose if needed [see Dosage and Administration ( 2.2 , 2.6 ) and Clinical Pharmacology ( 12.3 )] . Mild or Moderate CYP3A Inducers Methylprednisolone, prednisone May decrease tacrolimus whole blood trough concentrations. Monitor tacrolimus whole blood trough concentrations and adjust PROGRAF dose if needed [see Dosage and Administration ( 2.2 , 2.6 )] . Caspofungin May decrease tacrolimus whole blood trough concentrations. Monitor tacrolimus whole blood trough concentrations and adjust PROGRAF dose if needed [see Dosage and Administration ( 2.2 , 2.6 )] . Direct Acting Antiviral (DAA) Therapy The pharmacokinetics of tacrolimus may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. Close monitoring and potential dose adjustment of PROGRAF is warranted to ensure continued efficacy and safety [see Dosage and Administration ( 2.2 , 2.6 )] . 7.3 Cannabidiol The blood levels of tacrolimus may increase upon concomitant use with cannabidiol. When cannabidiol and PROGRAF are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity.
Use in specific populations
Pregnancy: Can cause fetal harm. Advise pregnant women of the potential risk to the fetus. ( 8.1 , 8.3 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to PROGRAF 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/ . Risk Summary Tacrolimus can cause fetal harm when administered to a pregnant woman. Data from postmarketing surveillance and 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 [see Human Data]. Advise pregnant women of the potential risk to the fetus. 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 to 6.9 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). 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 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). 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 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data]. 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. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk 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. Maternal Adverse Reactions PROGRAF may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions ( 5.4 )]. PROGRAF may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure [see Warnings and Precautions ( 5.7 , 5.8 )]. Fetal/Neonatal Adverse Reactions Renal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at the time of delivery in infants of mothers taking PROGRAF. Labor or Delivery There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to PROGRAF. Data Human Data 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 in utero have an increased risk for miscarriage, pre-term delivery (< 37 weeks), low birth weight (< 2500 g), birth defects/congenital anomalies and fetal distress. 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 16 . 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 renal 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. Table 16. TPRI Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus 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.
Pregnancy
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to PROGRAF 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/ . Risk Summary Tacrolimus can cause fetal harm when administered to a pregnant woman. Data from postmarketing surveillance and 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 [see Human Data]. Advise pregnant women of the potential risk to the fetus. 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 to 6.9 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis). 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 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). 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 to 6.9 times the recommended clinical dose range, on a mg/m 2 basis). Interventricular septal defects, hydronephrosis, craniofacial malformations and skeletal effects were observed in offspring that died [see Animal Data]. 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. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk 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. Maternal Adverse Reactions PROGRAF may increase hyperglycemia in pregnant women with diabetes (including gestational diabetes). Monitor maternal blood glucose levels regularly [see Warnings and Precautions ( 5.4 )]. PROGRAF may exacerbate hypertension in pregnant women and increase pre-eclampsia. Monitor and control blood pressure [see Warnings and Precautions ( 5.7 , 5.8 )]. Fetal/Neonatal Adverse Reactions Renal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at the time of delivery in infants of mothers taking PROGRAF. Labor or Delivery There is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to PROGRAF. Data Human Data 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 in utero have an increased risk for miscarriage, pre-term delivery (< 37 weeks), low birth weight (< 2500 g), birth defects/congenital anomalies and fetal distress. 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 16 . 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 renal 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. Table 16. TPRI Reported Pregnancy Outcomes in Transplant Recipients with Exposure to Tacrolimus 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. Animal Data Administration of oral tacrolimus to pregnant rabbits throughout organogenesis produced maternal toxicity and abortion at 0.32 mg/kg (0.5 to 1.4 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day], on a mg/m 2 basis).
Pediatric use
8.4 Pediatric Use Safety and effectiveness have been established in pediatric liver, kidney, heart, and lung transplant patients. Liver Transplantation Safety and efficacy using PROGRAF Granules in pediatric de novo liver transplant patients less than 16 years of age are based on evidence from active controlled studies that included 56 pediatric patients, 31 of which received PROGRAF, and supported by two pharmacokinetic and safety studies in 151 children who received PROGRAF. Additionally, 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Dose adjustments were made in the PK studies based on clinical status and whole blood concentrations. Pediatric patients generally required higher doses of PROGRAF to maintain blood trough concentrations of tacrolimus similar to adult patients [see Dosage and Administration ( 2.3 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.2 )]. Kidney and Heart Transplantation Use of PROGRAF capsules and PROGRAF Granules in pediatric kidney and heart transplant patients is supported by adequate and well-controlled studies and pharmacokinetic data in adult kidney and heart transplant patients with additional pharmacokinetic data in pediatric kidney and heart transplant patients and safety data in pediatric liver transplant patients [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 )]. Lung Transplantation The use of PROGRAF capsules and PROGRAF Granules in pediatric lung transplantation is supported by the experience in the U.S. Scientific Registry of Transplant Recipients (SRTR) including 450 pediatric patients receiving tacrolimus immediate-release products in combination with mycophenolate mofetil and 72 pediatric patients receiving tacrolimus immediate-release products in combination with azathioprine between 1999-2017 .
Geriatric use
8.5 Geriatric Use Clinical trials of PROGRAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Overdosage
Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions consistent with those reported with the use of PROGRAF [see Adverse Reactions ( 6.1 , 6.2 )] , including tremors, abnormal renal function, hypertension, and peripheral edema; in one case of acute overdosage, transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.
Description
Tacrolimus, previously known as FK506, is the active ingredient in PROGRAF. Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis . Chemically, tacrolimus is designated as [3 S -[3 R *[ E (1 S *,3 S *,4 S *)], 4 S *,5 R *,8 S *,9 E ,12 R *,14 R *,15 S *,16 R *,18 S *,19 S *,26a R *]] -5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1- c ][1,4] oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate. The chemical structure of tacrolimus is: Tacrolimus has an empirical formula of C 44 H 69 NO 12
• H 2 O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform. PROGRAF is available for oral administration as capsules (tacrolimus capsules USP) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive ingredients include croscarmellose sodium NF, hypromellose USP, lactose monohydrate NF, and magnesium stearate NF. The 0.5 mg capsule shell contains ferric oxide NF, gelatin NF and titanium dioxide USP, the 1 mg capsule shell contains gelatin NF and titanium dioxide USP, and the 5 mg capsule shell contains ferric oxide NF, gelatin NF, and titanium dioxide USP. PROGRAF is also available as a sterile solution (tacrolimus injection) containing the equivalent of 5 mg anhydrous tacrolimus USP in 1 mL for administration by intravenous infusion only. Each mL contains the following inactive ingredients: dehydrated alcohol USP, 80.0% v/v and polyoxyl 60 hydrogenated castor oil (HCO-60), 200 mg. PROGRAF injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection before use. PROGRAF Granules is available for oral administration as a suspension containing the equivalent of 0.2 mg or 1 mg of anhydrous tacrolimus USP. Inactive ingredients include croscarmellose sodium NF, hypromellose USP, and lactose monohydrate NF. Tacrolimus structural formula
Mechanism of action
12.1 Mechanism of Action Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (a ubiquitous mammalian intracellular enzyme) is then formed, after which the phosphatase activity of calcineurin is inhibited. Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT), and nuclear factor kappa-light-chain enhancer of activated B-cells (NF-κB). Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony-stimulating factor. Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation, as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).
How supplied
16.1 PROGRAF (tacrolimus) Capsules, USP Strength 0.5 mg (containing the equivalent of 0.5 mg anhydrous tacrolimus USP) 1 mg (containing the equivalent of 1 mg anhydrous tacrolimus USP) 5 mg (containing the equivalent of 5 mg anhydrous tacrolimus USP) Shape/color oblong/light yellow oblong/white oblong/grayish red Branding on capsule cap/body 607 617 657 100 count bottle NDC 0469-0607-73 NDC 0469-0617-73 NDC 0469-0657-73 Note: PROGRAF capsules USP are not filled to maximum capsule capacity. Capsule contains labeled amount. Store and Dispense Store at 20°C to 25°C (68°F to 77°F); excursions permitted 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. f f f 16.2 PROGRAF (tacrolimus) Injection (for Intravenous infusion only) NDC 0469-3016-01 Product Code 301601 5 mg/mL (equivalent of 5 mg of anhydrous tacrolimus USP per mL) supplied as a sterile solution in a 1 mL ampule, in boxes of 10 ampules Store and Dispense Store between 5°C and 25°C (41°F and 77°F). 16.3 PROGRAF Granules (tacrolimus for oral suspension) Strength 0.2 mg (containing the equivalent of 0.2 mg anhydrous tacrolimus USP) 1 mg (containing the equivalent of 1 mg anhydrous tacrolimus USP) Shape/color White granules White granules 1 carton containing 50 packets NDC 0469-1230-50 NDC 0469-1330-50 Store and Dispense Store at 20°C to 25°C (68°F to 77°F); excursions permitted 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. 16.4 Handling and Disposal Tacrolimus can cause fetal harm. PROGRAF capsules should not be opened or crushed. Wearing disposable gloves is recommended during dilution of the injection or when preparing the oral suspension in the hospital and when wiping any spills. Avoid inhalation or direct contact with skin or mucous membranes of the powder or granules contained in PROGRAF capsules and PROGRAF Granules, respectively. If such contact occurs, wash the skin thoroughly with soap and water; if ocular contact occurs, rinse eyes with water. In case a spill occurs, wipe the surface with a wet paper towel. Follow applicable special handling and disposal procedures 1 .
Patient information
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). 17.1 Administration Advise the patient or caregiver to:
• Inspect their PROGRAF medicine when they receive a new prescription and before taking it. If the appearance of the capsule is not the same as usual, or if dosage instructions have changed, advise patients to contact their healthcare provider as soon as possible to make sure that they have the right medicine. Other tacrolimus products cannot be substituted for PROGRAF.
• Take PROGRAF at the same 12-hour intervals every day to achieve consistent blood concentrations.
• Take PROGRAF consistently either with or without food because the presence and composition of food decreases the bioavailability of PROGRAF.
• Not to eat grapefruit or drink grapefruit juice in combination with PROGRAF [see Drug Interactions ( 7.2 )].
• If the patient is receiving PROGRAF Granules, advise that the dose should be given immediately after preparation and not to save the dose for later. Advise the caregiver to carefully read the Instructions for Use. 17.2 Development of Lymphoma and Other Malignancies Inform patients they are at increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor [see Warnings and Precautions ( 5.1 )] . 17.3 Increased Risk of Infection Inform patients they are at increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection such as fever, sweats or chills, cough or flu-like symptoms, muscle aches, or warm, red, painful areas on the skin [see Warnings and Precautions ( 5.2 )] . 17.4 New Onset Diabetes After Transplant Inform patients that PROGRAF can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst, or hunger [see Warnings and Precautions ( 5.4 )] . 17.5 Nephrotoxicity Inform patients that PROGRAF can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team [see Warnings and Precautions ( 5.5 )] . 17.6 Neurotoxicity Inform patients that they are at risk of developing adverse neurologic reactions including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, delirium, or tremors [see Warnings and Precautions ( 5.6 )] . 17.7 Hyperkalemia Inform patients that PROGRAF can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia [see Warnings and Precautions ( 5.7 )] . 17.8 Hypertension Inform patients that PROGRAF can cause high blood pressure which may require treatment with antihypertensive therapy. Advise patients to monitor their blood pressure [see Warnings and Precautions ( 5.8 )] . 17.9 Thrombotic Microangiopathy Inform patients that PROGRAF can cause blood clotting problems. The risk of this occurring increases when patients take PROGRAF and sirolimus or everolimus concomitantly, or when patients develop certain infections. Advise them to seek medical attention promptly if they develop fever, petequiae or bruises, fatigue, confusion, jaundice, oliguria. [see Warnings and Precautions ( 5.16 )] 17.10 Drug Interactions Instruct patients to tell their healthcare providers when they start or stop taking any medicines, including prescription medicines and nonprescription medicines, natural or herbal remedies, nutritional supplements, and vitamins. Advise patients to avoid grapefruit and grapefruit juice [see Drug Interactions ( 7 )]. 17.11 Pregnancy, Lactation and Infertility Inform women of childbearing potential that PROGRAF can harm the fetus. Instruct male and female patients to discuss with their healthcare provider family planning options including appropriate contraception. Also, discuss with pregnant patients the risks and benefits of breastfeeding their infant [see Use in Specific Populations ( 8.1 , 8.2 , 8.3 )]. Encourage female transplant patients who become pregnant and male patients who have fathered a pregnancy, exposed to immunosuppressants including tacrolimus, to enroll in the voluntary Transplantation Pregnancy Registry International. To enroll or register, patients can call the toll free number 1-877-955-6877 or https://www.transplantpregnancyregistry.org/ [see Use in Specific Populations ( 8.1 )] . Based on animal studies, PROGRAF may affect fertility in males and females [see Nonclinical Toxicology ( 13.1 )]. 17.12 Myocardial Hypertrophy Inform patients to report symptoms of tiredness, swelling, and/or shortness of breath (heart failure). 17.13 Immunizations Inform patients that PROGRAF can interfere with the usual response to immunizations and that they should avoid live vaccines . [see Warnings and Precautions ( 5.14 )] . Distributed by: Astellas Pharma US, Inc. Northbrook, IL 60062 PROGRAF ® is a registered trademark of Astellas Pharma Inc. All other trademarks and registered trademarks are the property of their respective owners. 398977-PRG
Label text from the FDA structured product label by Astellas Pharma US, Inc. (revised Aug 25, 2023). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Tacrolimus in 6 products
Prograf NDC products (6)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 0469-0607 | Tacrolimus .5 mg/1 Capsule, Gelatin Coated | Astellas Pharma US, Inc. | NDA |
| 0469-0617 | Tacrolimus 1 mg/1 Capsule, Gelatin Coated | Astellas Pharma US, Inc. | NDA |
| 0469-0657 | Tacrolimus 5 mg/1 Capsule, Gelatin Coated | Astellas Pharma US, Inc. | NDA |
| 0469-1230 | Tacrolimus .2 mg/1 Granule, For Suspension | Astellas Pharma US, Inc. | NDA |
| 0469-1330 | Tacrolimus 1 mg/1 Granule, For Suspension | Astellas Pharma US, Inc. | NDA |
| 0469-3016 | Tacrolimus 5 mg/mL Injection, Solution | Astellas Pharma US, Inc. | NDA |
Prograf recalls
- D-0211-2025 Feb 5, 2025 · Class I · Ongoing
Failed Tablet/Capsule Specifications: Bottles shipped to the USA may contain empty capsules
Frequently asked questions
What is Prograf used for?
1 INDICATIONS AND USAGE PROGRAF is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic liver, kidney, heart, or lung transplants, in combination with other immunosuppressants. ( 1.1 ) 1.1 Prophylaxis of Organ Rejection in Kidney, Liver, Heart, or Lung Transplant PROGRAF ® is indicated for the prophylaxis…
What are the side effects of Prograf?
The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: • Lymphoma and Other Malignancies [see Warnings and Precautions ( 5.1 )] • Serious Infections [see Warnings and Precautions ( 5.2 )] • New Onset Diabetes After Transplant [see Warnings and Precautions ( 5.4 )] • Nephrotoxicity [see Warnings and Precautions ( 5.5 )] •… See the full label for the complete list.
Who makes Prograf?
Prograf is listed by 1 labeler in the FDA NDC directory, including Astellas Pharma US, Inc..
Has Prograf been recalled?
The FDA enforcement database lists 1 recall for Prograf, most recently D-0211-2025 (class i): Failed Tablet/Capsule Specifications: Bottles shipped to the USA may contain empty capsules