ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:oLymphoma and Other Malignancies [see Warnings and Precautions (5.1)]oSerious Infections [see Warnings and Precautions (5.2)]oNew Onset Diabetes After Transplant [see Warnings and Precautions (5.4)]oNephrotoxicity [see Warnings and Precautions (5.5)] oNeurotoxicity [see Warnings and Precautions (5.6)] oHyperkalemia [see Warnings and Precautions (5.7)]oHypertension [see Warnings and Precautions (5.8)]oAnaphylactic Reactions with PROGRAF Injection [see Warnings and Precautions (5.9)]oMyocardial Hypertrophy [see Warnings and Precautions (5.13)]oPure Red Cell Aplasia [see Warnings and Precautions (5.15)]. oLymphoma and Other Malignancies [see Warnings and Precautions (5.1)]. oSerious Infections [see Warnings and Precautions (5.2)]. oNew Onset Diabetes After Transplant [see Warnings and Precautions (5.4)]. oNephrotoxicity [see Warnings and Precautions (5.5)] oNeurotoxicity [see Warnings and Precautions (5.6)] oHyperkalemia [see Warnings and Precautions (5.7)]. oHypertension [see Warnings and Precautions (5.8)]. oAnaphylactic Reactions with PROGRAF Injection [see Warnings and Precautions (5.9)]. oMyocardial Hypertrophy [see Warnings and Precautions (5.13)]. oPure Red Cell Aplasia [see Warnings and Precautions (5.15)]. 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 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 TransplantationThe 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 trial where 205 patients received PROGRAF-based immunosuppression and 207 patients received cyclosporine-based immunosuppression. The trial population had 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% Headache44%38% Insomnia32%30% Paresthesia23%16% Dizziness19%16%Gastrointestinal Diarrhea44%41% Nausea38%36% Constipation35%43% Vomiting29%23% Dyspepsia28%20%Cardiovascular Hypertension 50%52% Chest Pain19%13%Urogenital Creatinine Increased 45%42% Urinary Tract Infection34%35%Metabolic and Nutritional Hypophosphatemia49%53% Hypomagnesemia34%17% Hyperlipemia31%38% Hyperkalemia31%32% Diabetes Mellitus24%9% Hypokalemia22%25% Hyperglycemia 22%16% Edema18%19%Hemic and Lymphatic Anemia30%24% Leukopenia15%17%Miscellaneous Infection45%49% Peripheral Edema36%48% Asthenia34%30% Abdominal Pain33%31% Pain32%30% Fever29%29% Back Pain24%20%Respiratory System Dyspnea22%18% Cough Increased18%15%Musculoskeletal Arthralgia25%24%Skin Rash17%12% Pruritus15%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, = 403), or one of two cyclosporine (CsA) regimens (Group A, = 384 and Group B, = 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 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 [Note: This trial was conducted entirely outside of the United States. Such trials often report lower incidence of adverse reactions in comparison to U.S. trials] are presented below:Table 5. Kidney Transplantation: Adverse Reactions Occurring in >= 10% of Patients Treated with PROGRAF in Conjunction with MMF (Study 1) PROGRAF(Group C)(N 403)Cyclosporine(Group A)(N 384)Cyclosporine(Group B)(N 408) Diarrhea25%16%13% Urinary Tract Infection24%28%24% Anemia17%19%17% Hypertension 13%14%12% Leukopenia13%10%10% Edema Peripheral11%12%13% Hyperlipidemia10%15%13% Key: Group = CsA/MMF/CS, = CsA/MMF/CS/Daclizumab, = Tac/MMF/CS/Daclizumab CsA Cyclosporine, CS Corticosteroids, Tac Tacrolimus, MMF mycophenolate mofetilIn the U.S. trial (Study 2) with PROGRAF-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received PROGRAF (n 212) or cyclosporine (n 212) in combination with MMF gram twice daily, basiliximab induction, and corticosteroids. The trial population had mean age of 48 years (range 17 to 77); the distribution was 63% male, and the composition was White (74%), African-American (20%), Asian (3%), and Other (3%). The 12-month post-transplant information from this trial is presented below. Adverse reactions that occurred in >= 15% of kidney transplant patients treated with PROGRAF in conjunction with MMF in Study are presented below:Table 6. Kidney Transplantation: Adverse Reactions Occurring in >= 15% of Patients Treated with PROGRAF in Conjunction with MMF (Study 2) PROGRAF/MMF(N 212)Cyclosporine/MMF(N 212) Gastrointestinal Disorders Diarrhea44%26% Nausea39%47% Constipation36%41% Vomiting26%25% Dyspepsia18%15%Injury, Poisoning, and Procedural Complications Post-Procedural Pain29%27% Incision Site Complication28%23% Graft Dysfunction24%18%Metabolism and Nutrition Disorders Hypomagnesemia28%22% Hypophosphatemia28%21% Hyperkalemia 26%19% Hyperglycemia 21%15% Hyperlipidemia18%25% Hypokalemia16%18%Nervous System Disorders Tremor 34%20% Headache24%25%Blood and Lymphatic System Disorders Anemia30%28% Leukopenia16%12%Miscellaneous Edema Peripheral35%46% Hypertension 32%35% Insomnia30%21% Urinary Tract Infection26%22% Blood Creatinine Increased23%23%Less frequently observed adverse reactions in kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions (> 3% and 15%) in Liver, Kidney, and Heart Transplant Studies.Liver TransplantationThere were two randomized comparative liver transplant trials. In the U.S. trial, 263 adult and pediatric patients received tacrolimus and steroids and 266 patients received cyclosporine-based immunosuppressive regimen (CsA/AZA). The trial population had mean age of 44 years (range 0.4 to 70); the distribution was 52% male, and the composition was White (78%), African-American (5%), Asian (2%), Hispanic (13%), and Other (2%). In the European trial, 270 patients received tacrolimus and steroids and 275 patients received CsA/AZA. The trial population had mean age of 46 years (range 15 to 68); the distribution was 59% male, and the composition was White (95.4%), Black (1%), Asian (2%), and Other (2%). The proportion of patients reporting more than one adverse event was 99% in both the tacrolimus group and the CsA/AZA group. Precautions must be taken when comparing the incidence of adverse reactions in the U.S. trial to that in the European trial. The 12-month post-transplant information from the U.S. trial and from the European trial is presented below. The two trials also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse reactions reported in >= 15% in tacrolimus patients (combined trial results) are presented below for the two controlled trials in liver transplantation.The most common adverse reactions (>= 40%) observed in PROGRAF-treated liver transplant patients are: tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia. These all occur with oral and IV administration of PROGRAF and some may respond to reduction in dosing (e.g., tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving PROGRAF in the U.S. and European randomized trials.Table 7. Liver Transplantation: Adverse Reactions Occurring in >= 15% of Patients Treated with PROGRAF U.S. TRIALEUROPEAN TRIALPROGRAF(N 250)Cyclosporine/AZA(N 250)PROGRAF(N 264)Cyclosporine/AZA(N 265)Nervous System Headache 64%60%37%26% Insomnia64%68%32%23% Tremor56%46%48%32% Paresthesia40%30%17%17%Gastrointestinal Diarrhea72%47%37%27% Nausea46%37%32%27% LFT Abnormal36%30%6%5% Anorexia34%24%7%5% Vomiting27%15%14%11% Constipation24%27%23%21%Cardiovascular Hypertension47%56%38%43%Urogenital Kidney Function Abnormal40%27%36%23% Creatinine Increased39%25%24%19% BUN Increased30%22%12%9% Oliguria18%15%19%12% Urinary Tract Infection16%18%21%19%Metabolic and Nutritional Hypomagnesemia48%45%16%9% Hyperglycemia47%38%33%22% Hyperkalemia45%26%13%9% Hypokalemia29%34%13%16%Hemic and Lymphatic Anemia47%38%5%1% Leukocytosis32%26%8%8% Thrombocytopenia24%20%14%19%Miscellaneous Pain63%57%24%22% Abdominal Pain59%54%29%22% Asthenia52%48%11%7% Fever48%56%19%22% Back Pain30%29%17%17% Ascites27%22%7%8% Peripheral Edema26%26%12%14%Respiratory System Pleural Effusion30%32%36%35% Dyspnea29%23%5%4% Atelectasis28%30%5%4%Skin and Appendages Pruritus36%20%15%7% Rash24%19%10%4%Table 8. Pediatric Liver Transplantation: Adverse Reactions Occurring in 10% of Patients Treated with PROGRAF Granules (STUDY 01-13)PROGRAF Granules(N 91)Cyclosporine(N 90)Body as Whole Fever46%51% Infection25%29% Sepsis22%20% CMV Infection15%24% EBV Infection26%11% Ascites17%20% Peritonitis12%7%Cardiovascular System Hypertension39%47%Digestive System Liver Function Tests Abnormal37%28% Diarrhea 26%26% Vomiting15%13% Gastrointestinal Hemorrhage11%12% Bile Duct Disorder12%8% Gastroenteritis12%4%Hemic and Lymphatic System Anemia29%19%Metabolic and Nutritional Disorders Hypomagnesemia40%29% Acidosis26%17% Hyperkalemia12%10%Respiratory System Pleural Effusion22%19% Bronchitis11%8%Urogenital System Kidney Function Abnormal13%14%Less frequently observed adverse reactions in liver transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions (> 3% and 15%) in Liver, Kidney, and Heart Transplant Studies.Heart TransplantationThe incidence of adverse reactions was determined based on two trials in primary orthotopic heart transplantation. In trial conducted in Europe, 314 patients received regimen of antibody induction, corticosteroids, and azathioprine (AZA) in combination with PROGRAF (n 157) or cyclosporine (n 157) for 18 months. The trial population had mean age of 51 years (range 18 to 65); the distribution was 82% male, and the composition was White (96%), Black (3%), and Other (1%).The most common adverse reactions (>= 15%) observed in PROGRAF-treated heart transplant patients are: abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, and hyperlipemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 59% of heart transplantation patients in the European trial.Adverse reactions in heart transplant patients in the European trial are presented below:Table 9. Heart Transplantation: Adverse Reactions Occurring in >= 15% of Patients Treated with PROGRAF in Conjunction with Azathioprine (AZA)PROGRAF/AZA(N 157)Cyclosporine/AZA(N 157)Cardiovascular System Hypertension 62%69% Pericardial Effusion15%14%Body as Whole CMV Infection32%30% Infection24%21%Metabolic and Nutritional Disorders Diabetes Mellitus 26%16% Hyperglycemia 23%17% Hyperlipemia18%27%Hemic and Lymphatic System Anemia 50%36% Leukopenia48%39%Urogenital System Kidney Function Abnormal 56%57% Urinary Tract Infection16%12%Respiratory System Bronchitis17%18%Nervous System Tremor 15%6%In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm.In U.S. trial, the incidence of adverse reactions was based on 331 heart transplant patients that received corticosteroids and PROGRAF in combination with sirolimus (n=109), PROGRAF in combination with MMF (n=107) or cyclosporine modified in combination with MMF (n=115) for year. The trial population had mean age of 53 years (range 18 to 75); the distribution was 78% male, and the composition was White (83%), African-American (13%) and Other (4%).Only selected targeted treatment-emergent adverse reactions were collected in the U.S. heart transplantation trial. Those reactions that were reported at rate of 15% or greater in patients treated with PROGRAF and MMF include the following: any target adverse reactions (99%), hypertension (89%), hyperglycemia requiring antihyperglycemic therapy (70%), hypertriglyceridemia (65%), anemia (hemoglobin 10.0 g/dL) (65%), fasting blood glucose 140 mg/dL (on two separate occasions) (61%), hypercholesterolemia (57%), hyperlipidemia (34%), WBCs 3000 cells/mcL (34%), serious bacterial infections (30%), magnesium 1.2 mEq/L (24%), platelet count 75,000 cells/mcL (19%), and other opportunistic infections (15%).Other targeted treatment-emergent adverse reactions in PROGRAF-treated patients occurred at rate of less than 15%, and include the following: Cushingoid features, impaired wound healing, hyperkalemia, Candida infection, and CMV infection/syndrome. Other less frequently observed adverse reactions in heart transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions (> 3% and 15%) in Liver, Kidney and Heart Transplant Studies.New Onset Diabetes After TransplantKidney TransplantationNew Onset Diabetes After Transplant (NODAT) is defined as composite of fasting plasma glucose >= 126 mg/dL, HbA1C >= 6%, insulin use >= 30 days, or oral hypoglycemic use. In trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the PROGRAF-treated and 61% in the NEORAL-treated patients without pre-transplant history of diabetes mellitus (Table 10) [see Clinical Studies (14.1)]. Table 10. Incidence of New Onset Diabetes After Transplant at year in Kidney Transplant Recipients in Phase Trial (Study 2)ParameterTreatment GroupPROGRAF/MMF(N 212)NEORAL/MMF(N 212)NODAT112/150 (75%)93/152 (61%) Fasting Plasma Glucose >= 126 mg/dL96/150 (64%)80/152 (53%) HbA1C >= 6%59/150 (39%)28/152 (18%) Insulin Use >= 30 days9/150 (6%)4/152 (3%) Oral Hypoglycemic Use15/150 (10%)5/152 (3%)In early trials of PROGRAF, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with more limited criterion of use of insulin for 30 or more consecutive days with 5-day gap in patients without prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Data are presented in Tables 11 to 14. PTDM was reported in 20% of PROGRAF/Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in Phase trial (Table 11). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at years post-transplant. African-American and Hispanic kidney transplant patients were at an increased risk of development of PTDM (Table 12).Table 11. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at Years in Kidney Transplant Recipients in Phase Trial using Azathioprine (AZA)Status of PTDMUse of insulin for 30 or more consecutive days, with 5-day gap, without prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.PROGRAF/AZACsA/AZA Patients without pre-transplant history of diabetes mellitus151151 New onset PTDM, 1st Year30/151 (20%)6/151 (4%) Still insulin-dependent at one year in those without prior history of diabetes25/151 (17%)5/151 (3%) New onset PTDM post year10 Patients with PTDM at years16/151 (11%)5/151 (3%)Table 12. Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in Phase TrialPatient RacePatients Who Developed PTDMUse of insulin for 30 or more consecutive days, with 5-day gap, without prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.PROGRAFCyclosporine African-American15/41 (37%)3 (8%) Hispanic5/17 (29%)1 (6%) Caucasian10/82 (12%)1 (1%) Other0/11 (0%)1 (10%) Total30/151 (20%)6 (4%)Liver TransplantationInsulin-dependent PTDM was reported in 18% and 11% of PROGRAF-treated liver transplant patients and was reversible in 45% and 31% of these patients at year post-transplant, in the U.S. and European randomized trials, respectively (Table 13). Hyperglycemia was associated with the use of PROGRAF in 47% and 33% of liver transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions (6.1)]. Table 13. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at Year in Liver Transplant RecipientsStatus of PTDMUse of insulin for 30 or more consecutive days, with 5-day gap, without prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.US TrialEuropean TrialPROGRAFCyclosporinePROGRAFCyclosporinePatients at riskPatients without pre-transplant history of diabetes mellitus. 239236239249New Onset PTDM 42 (18%)30 (13%)26 (11%)12 (5%)Patients still on insulin at year23 (10%)19 (8%)18 (8%)6 (2%)Heart TransplantationInsulin-dependent PTDM was reported in 13% and 22% of PROGRAF-treated heart transplant patients receiving mycophenolate mofetil (MMF) or azathioprine (AZA) and was reversible in 30% and 17% of these patients at one year post-transplant, in the U.S. and European randomized trials, respectively (Table 14). Hyperglycemia, defined as two fasting plasma glucose levels >= 126 mg/dL, was reported with the use of PROGRAF plus MMF or AZA in 32% and 35% of heart transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions (6.1)]. Table 14. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at Year in Heart Transplant RecipientsStatus of PTDMUse of insulin for 30 or more consecutive days without prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.US TrialEuropean TrialPROGRAF/MMFCyclosporine/MMFPROGRAF/AZACyclosporine/AZAPatients at riskPatients without pre-transplant history of diabetes mellitus. 7583132138New Onset PTDM 10 (13%)6 (7%)29 (22%)5 (4%)Patients still on insulin at year7-12 months for the U.S. trial. (9%)1 (1%)24 (18%)4 (3%)Less Frequently Reported Adverse Reactions (> 3% and 15%) in Liver, Kidney, and Heart Transplant StudiesThe following adverse reactions were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials.oNervous System:Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, hemorrhagic stroke, hallucinations, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired oSpecial Senses: Abnormal vision, amblyopia, ear pain, otitis media, tinnitusoGastrointestinal: Cholangitis, cholestatic jaundice, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, esophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, stomatitis oCardiovascular: Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation oUrogenital: Acute kidney failure, albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis oMetabolic/Nutritional: Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, dehydration, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, lactic dehydrogenase increased, weight gainoEndocrine: Cushings syndrome oHemic/Lymphatic: Coagulation disorder, ecchymosis, hematocrit increased, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreasedoMiscellaneous: Abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer oMusculoskeletal: Arthralgia, cramps, generalized spasm, leg cramps, myalgia, myasthenia, osteoporosisoRespiratory: Asthma, emphysema, hiccups, lung function decreased, pharyngitis, pneumonia, pneumothorax, pulmonary edema, rhinitis, sinusitis, voice alterationoSkin: Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin ulcer, sweatingLung TransplantationAdverse reactions in lung transplant patients were similar to those in kidney, liver, or heart transplant patients treated with PROGRAF [see Adverse Reactions (6.2)]. oNervous System:Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, hemorrhagic stroke, hallucinations, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired oSpecial Senses: Abnormal vision, amblyopia, ear pain, otitis media, tinnitus. oGastrointestinal: Cholangitis, cholestatic jaundice, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, esophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, stomatitis oCardiovascular: Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation oUrogenital: Acute kidney failure, albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis oMetabolic/Nutritional: Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, dehydration, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, lactic dehydrogenase increased, weight gain. oEndocrine: Cushings syndrome oHemic/Lymphatic: Coagulation disorder, ecchymosis, hematocrit increased, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreased. oMiscellaneous: Abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer oMusculoskeletal: Arthralgia, cramps, generalized spasm, leg cramps, myalgia, myasthenia, osteoporosis. oRespiratory: Asthma, emphysema, hiccups, lung function decreased, pharyngitis, pneumonia, pneumothorax, pulmonary edema, rhinitis, sinusitis, voice alteration. oSkin: Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin ulcer, sweating. 6.2 Postmarketing Experience. The following adverse reactions have been reported from worldwide marketing experience with tacrolimus. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to the drug.Other reactions include: oCardiovascular: Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram wave abnormal, flushing, myocardial infarction, myocardial ischemia, pericardial effusion, QT prolongation, Torsade de Pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation, myocardial hypertrophy oGastrointestinal: Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastroesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis hemorrhagic, pancreatitis necrotizing, stomach ulcer, veno-occlusive liver disease oHemic/Lymphatic: Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, febrile neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pure red cell aplasia oInfections: Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal; polyoma virus-associated nephropathy (PVAN) including graft loss oMetabolic/Nutritional: Glycosuria, increased amylase including pancreatitis, weight decreasedoMiscellaneous: Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction oMusculoskeletal and Connective Tissue Disorders: Pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS)oNervous System: Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), quadriplegia, speech disorder, syncope oRespiratory: Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure oSkin: Stevens-Johnson syndrome, toxic epidermal necrolysis oSpecial Senses: Blindness, optic neuropathy, blindness cortical, hearing loss including deafness, photophobiaoUrogenital: Acute renal failure, cystitis hemorrhagic, hemolytic-uremic syndrome Postmarketing Adverse Reactions in Lung Transplantation. oCardiovascular: Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram wave abnormal, flushing, myocardial infarction, myocardial ischemia, pericardial effusion, QT prolongation, Torsade de Pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation, myocardial hypertrophy oGastrointestinal: Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastroesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis hemorrhagic, pancreatitis necrotizing, stomach ulcer, veno-occlusive liver disease oHemic/Lymphatic: Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, febrile neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pure red cell aplasia oInfections: Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal; polyoma virus-associated nephropathy (PVAN) including graft loss oMetabolic/Nutritional: Glycosuria, increased amylase including pancreatitis, weight decreased. oMiscellaneous: Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction oMusculoskeletal and Connective Tissue Disorders: Pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS). oNervous System: Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), quadriplegia, speech disorder, syncope oRespiratory: Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure oSkin: Stevens-Johnson syndrome, toxic epidermal necrolysis oSpecial Senses: Blindness, optic neuropathy, blindness cortical, hearing loss including deafness, photophobia. oUrogenital: Acute renal failure, cystitis hemorrhagic, hemolytic-uremic syndrome. Postmarketing Adverse Reactions in Lung Transplantation.

BOXED WARNING SECTION.

Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead tohospitalization or death. (5.1, 5.2). Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead tohospitalization or death. (5.1, 5.2). WARNING: MALIGNANCIES and SERIOUS INFECTIONS See full prescribing information for complete boxed warning. Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead to hospitalization or death. (5.1, 5.2). Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead to hospitalization or death. (5.1, 5.2).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCarcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3.0 mg/kg/day (0.9 to 2.2 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.265 to 0.65 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) [see Warnings and Precautions (5.1)]. 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% 3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m2/day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high-dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at daily dose of 3.5 mg/kg (0.1% tacrolimus ointment). No drug-related tumors were noted in the mouse dermal carcinogenicity study at daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown.The implications of these carcinogenicity studies to the human condition are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune systems ability to inhibit unrelated carcinogenesis.MutagenesisNo evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.Impairment of FertilityTacrolimus, subcutaneously administered to male rats at paternally toxic doses of mg/kg/day (1.6 to 4.3 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day] on mg/m2 basis) or mg/kg/day (2.4 to 6.4 times the recommended clinical dose range), resulted in dose-related decrease in sperm count. Tacrolimus, administered orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by higher rate of pre- and post-implantation loss and increased numbers of undelivered and nonviable pups. When administered at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Tacrolimus binds to an intracellular protein, FKBP-12. 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-B).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).. 12.3 Pharmacokinetics. Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean +- S.D.) of tacrolimus have been determined following intravenous (IV) and/or oral (PO) administration in healthy volunteers, and in kidney transplant, liver transplant, and heart transplant patients (Table 17). Table 17. Pharmacokinetics Parameters (mean +- S.D.) of Tacrolimus in Healthy Volunteers and PatientsPopulationNRoute(Dose)ParametersCmax (ng/mL)Tmax (hr)AUC(ngohr/mL)t1/2 (hr)CL(L/hr/kg)V(L/kg) Healthy Volunteers 8IV (0.025 mg/kg/4 hr)Not applicable652AUC0-inf +- 15634.2 +- 7.70.040 +- 0.0091.91 +- 0.3130PO (5 mg) (granules)35.6 +- 10.91.3 +- 0.5320 +- 16432.1 +- 5.9Not availablePO (5 mg) (capsules)28.8 +- 8.91.5 +- 0.7266 +- 9532.3 +- 8.8 Kidney Transplant Patients26IV (0.02 mg/kg/12 hr)294 +- 26218.8 +- 16.70.083 +- 0.0501.41 +- 0.66PO (0.2 mg/kg/day)19.2 +- 10.33.0203 +- 42PO (0.3 mg/kg/day)24.2 +- 15.81.5288 +- 93 Liver Transplant Patients17IV (0.05 mg/kg/12 hr)3300 +- 213011.7 +- 3.90.053 +- 0.0170.85 +- 0.30PO (0.3 mg/kg/day)68.5 +- 30.02.3 +- 1.5519 +- 179 Heart Transplant Patients11IV (0.01 mg/kg/day as continuous infusion)954AUC0-t +- 33423.6 +- 9.220.051 +- 0.01511PO (0.075 mg/kg/day)Determined after the first dose 14.7 +- 7.792.1 [0.5-6.0]Median [range] 82.7AUC0-12 +- 63.214PO (0.15 mg/kg/day) 24.5 +- 13.71.5 [0.4-4.0] 142 +- 116Due to intersubject variability in tacrolimus pharmacokinetics, individualization of the dosing regimen is necessary for optimal therapy [see Dosage and Administration 2.6 )]. Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics.AbsorptionAbsorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability of tacrolimus was 17 +- 10% in adult kidney transplant patients (N 26), 22 +- 6% in adult liver transplant patients (N 17), 23 +- 9% in adult heart transplant patients (N 11) and 18 +- 5% in healthy volunteers (N 16).A single dose trial conducted in 32 healthy volunteers established the bioequivalence of the mg and mg capsules. Another single dose trial in 32 healthy volunteers established the bioequivalence of the 0.5 mg and mg capsules. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in dose-proportional fashion in 18 fasted healthy volunteers receiving single oral dose of 3, 7, and 10 mg.In 18 kidney transplant patients, tacrolimus trough concentrations from to 30 ng/mL measured at 10-12 hours post-dose (Cmin) correlated well with the AUC (correlation coefficient 0.93). In 24 liver transplant patients over concentration range of 10 to 60 ng/mL, the correlation coefficient was 0.94. In 25 heart transplant patients over concentration range of to 24 ng/mL, the correlation coefficient was 0.89 after an oral dose of 0.075 or 0.15 mg/kg/day at steady-state.In healthy volunteer adult study, the systemic exposure to tacrolimus (AUC) for PROGRAF Granules was approximately 16% higher than that for PROGRAF capsules when administered as single doses. If pediatric patients are converted between formulations, therapeutic drug monitoring must be performed and dose adjustments made to ensure that systemic exposure to tacrolimus is maintained. Food EffectsThe rate and extent of tacrolimus absorption were greatest under fasted conditions. The presence and composition of food decreased both the rate and extent of tacrolimus absorption when administered to 15 healthy volunteers.The effect was most pronounced with high-fat meal (848 kcal, 46% fat): mean AUC and Cmax were decreased 37% and 77%, respectively; Tmax was lengthened 5-fold. high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean Cmax by 28% and 65%, respectively.In healthy volunteers (N 16), the time of the meal also affected tacrolimus bioavailability. When given immediately following the meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition.In 11 liver transplant patients, PROGRAF administered 15 minutes after high fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC (27 +- 18%) and Cmax (50 +- 19%), as compared to fasted state.PROGRAF capsules should be taken consistently every day either with or without food because the presence and composition of food decreases the bioavailability of PROGRAF [see Dosage and Administration (2.1)].DistributionThe plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In U.S. trial, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).EliminationMetabolismTacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). metabolic pathway leading to the formation of possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, 31-demethyl metabolite has been reported to have the same activity as tacrolimus.ExcretionThe mean clearance following IV administration of tacrolimus is 0.040, 0.083, 0.053, and 0.051 L/hr/kg in healthy volunteers, adult kidney transplant patients, adult liver transplant patients, and adult heart transplant patients, respectively. In man, less than 1% of the dose administered is excreted unchanged in urine.In mass balance study of IV-administered radiolabeled tacrolimus to healthy volunteers, the mean recovery of radiolabel was 77.8 +- 12.7%. Fecal elimination accounted for 92.4 +- 1.0% and the elimination half-life based on radioactivity was 48.1 +- 15.9 hours whereas it was 43.5 +- 11.6 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.029 +- 0.015 L/hr/kg and clearance of tacrolimus was 0.029 +- 0.009 L/hr/kg. When administered PO, the mean recovery of the radiolabel was 94.9 +- 30.7%. Fecal elimination accounted for 92.6 +- 30.7%, urinary elimination accounted for 2.3 +- 1.1% and the elimination half-life based on radioactivity was 31.9 +- 10.5 hours whereas it was 48.4 +- 12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226 +- 0.116 L/hr/kg and clearance of tacrolimus was 0.172 +- 0.088 L/hr/kg.Specific PopulationsPediatric PatientsPROGRAF capsules Pharmacokinetics in Pediatric PatientsPharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following IV administration of 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 11.5 +- 3.8 hours, 2.6 +- 2.1 L/kg and 0.138 +- 0.071 L/hr/kg, respectively. Following oral administration to patients, mean AUC and Cmax were 337 +- 167 ng.hr/mL and 48.4 +- 27.9 ng/mL, respectively. The absolute bioavailability was 31 +- 24%.Pharmacokinetics of tacrolimus have also been studied in kidney transplantation patients, 8.2 +- 2.4 years of age. Following IV infusion of 0.06 mg/kg/day to 12 pediatric patients (8 male and female), mean terminal half-life and clearance were 10.2 +- 5.0 hours and 0.12 +- 0.04 L/hr/kg, respectively. Following oral administration to the same patients, mean AUC and Cmax were 181 +- 65 ng.hr/mL and 30 +- 11 ng/mL, respectively. The absolute bioavailability was 19 +- 14%.Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations [see Dosage and Administration 2.3 )]. PROGRAF Granules Pharmacokinetics in Pediatric PatientsA multicenter, open-label, single arm, pharmacokinetic study (OPTION, NCT01371331) was conducted using tacrolimus granules for oral suspension in pediatric patients undergoing de novo liver, kidney, or heart transplant. After an initial 24-hour continuous IV infusion of tacrolimus (0.025 mg/kg/hour) for 12 hours to days, oral PROGRAF Granules were dosed at 0.3 mg/kg/day in divided doses twice daily. Tacrolimus whole blood trough concentrations ranged from 5-15 ng/mL for the first month post-transplant, and 5-10 ng/mL thereafter. Two pharmacokinetic (PK) profiles, AUC, Cmax, Tmax and Ctrough, were taken after the first oral dose (Day 1) and at steady state (Day 7). Subsequent oral doses of PROGRAF Granules were adjusted based on clinical evidence of efficacy, the whole-blood trough levels, and/or occurrence of adverse events. Of 52 patients enrolled, thirty-eight (38) had an evaluable PK profile. The mean pediatric age was 6.1 years for heart transplant, 1.1 years for liver transplant and 3.6 years for kidney transplant. Summary results of PK parameters are presented in Table 18.Table 18. Summary of Whole Blood PK Parameters of Tacrolimus after Administration of PROGRAF Granules in Pediatric PatientsPopulationN(age range)ParametersAUCtau [hrng/mL]mean +- SDCmax [ng/mL]mean +- SDTmax [hr]mean +- SDCtrough [ng/mL]mean +- SDHeart Transplant Patients12 (0.58-13 years)Day 1Day 7224.13 +- 114.30165.17 +- 39.1245.61 +- 19.5532.69 +- 9.782.95 +- 4.330.84 +- 0.4412.60 +- 13.407.57 +- 1.80Liver Transplant Patients14 (0.33-12 years)Day 1Day 7210.56 +- 84.01195.08 +- 94.6325.11 +- 10.7830.52 +- 19.352.73 +- 1.841.71 +- 1.1213.41 +- 7.119.71 +- 4.03Kidney Transplant Patients12 (2.42-11 years)Day 1Day 797.40 +- 36.77208.32 +- 68.7518.04 +- 8.1036.63 +- 13.971.78 +- 0.881.09 +- 0.613.54 +- 1.458.92 +- 3.59Renal and Hepatic Impaired PatientsThe mean pharmacokinetic parameters for tacrolimus following single administrations to adult patients with renal and hepatic impairment are given in Table 19. Table 19. Pharmacokinetics in Renal and Hepatic Impaired Adult PatientsPopulation(No. of Patients)DoseAUC0-t (ng.hr/mL)t1/2 (hr)V(L/kg)CI(L/hr/kg) Renal Impairment (n 12)0.02mg/kg/4 hrIV393 +- 123(t 60 hr)26.3 +- 9.21.07 +- 0.200.038 +- 0.014 Mild Hepatic Impairment (n 6)0.02mg/kg/4 hrIV367 +- 107(t 72 hr)60.6 +- 43.8Range: 27.8 1413.1 +- 1.60.042 +- 0.027.7 mgPO488 +- 320(t 72 hr)66.1 +- 44.8Range: 29.5 1383.7 +- 4.7Corrected for bioavailability 0.034 +- 0.019 Severe Hepatic Impairment (n 6, IV)0.02 mg/kg/4 hrIV (n 2) 0.01 mg/kg/8 hrIV (n 4)762 +- 204(t 120 hr) 289 +- 117(t 144 hr)198 +- 158Range: 81 4363.9 +- 1.00.017 +- 0.013 (n 5, PO)1 patient did not receive the PO dose mg PO(n 1) mg PO(n 4)4 mg PO(n 1)658(t 120 hr) 533 +- 156(t 144 hr)119 +- 35Range: 85 178 0.016 +- 0.011 Patients with Renal ImpairmentTacrolimus pharmacokinetics, following single IV administration, were determined in 12 patients (7 not on dialysis and on dialysis, serum creatinine of 3.9 +- 1.6 and 12.0 +- 2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers (Table 19) [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].Patients with Hepatic ImpairmentTacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in patients with severe hepatic dysfunction (mean Pugh score: 10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [see Dosage and Administration (2.5) and Use in Specific Populations (8.7)].Patients with Cystic FibrosisLower bioavailability of tacrolimus has been reported in patients with cystic fibrosis [see Dosage and Administration (2.2, 2.3)].Racial or Ethnic GroupsThe pharmacokinetics of tacrolimus have been studied following single IV and oral administration of PROGRAF to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following 4-hour IV infusion of 0.015 mg/kg. However, after single oral administration of mg, mean (+- SD) tacrolimus Cmax in African-Americans (23.6 +- 12.1 ng/mL) was significantly lower than in Caucasians (40.2 +- 12.6 ng/mL) and the Latino-Americans (36.2 +- 15.8 ng/mL) (p 0.01). Mean AUC0-inf tended to be lower in African-Americans (203 +- 115 ng.hr/mL) than Caucasians (344 +- 186 ng.hr/mL) and Latino-Americans (274 +- 150 ng.hr/mL). The mean (+- SD) absolute oral bioavailability (F) in African-Americans (12 +- 4.5%) and Latino-Americans (14 +- 7.4%) was significantly lower than in Caucasians (19 +- 5.8%, = 0.011). There was no significant difference in mean terminal T1/2 among the three ethnic groups (range from approximately 25 to 30 hours). retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see Dosage and Administration (2.2)]. Male and Female PatientsA formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in dosing by gender in the kidney transplant trial. retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney, liver, and heart transplant patients indicated no gender-based differences.Drug Interaction StudiesFrequent monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when concomitant use of the following drugs with tacrolimus is initiated or discontinued [see Drug Interactions (7)].oTelaprevir: In single-dose study in healthy volunteers, co-administration of tacrolimus (0.5 mg single dose) with telaprevir (750 mg three times daily for 13 days) increased the tacrolimus dose-normalized Cmax by 9.3-fold and AUC by 70-fold compared to tacrolimus alone [see Drug Interactions (7.2)].oBoceprevir: In single-dose study in 12 subjects, co-administration of tacrolimus (0.5 mg single dose) with boceprevir (800 mg three times daily for 11 days) increased tacrolimus Cmax by 9.9-fold and AUC by 17-fold compared to tacrolimus alone [see Drug Interactions (7.2)].oNelfinavir: Based on clinical study of liver transplant recipients, co-administration of tacrolimus with nelfinavir increased blood concentrations of tacrolimus significantly and, as result, reduction in the tacrolimus dose by an average of 16-fold was needed to maintain mean trough tacrolimus blood concentrations of 9.7 ng/mL. It is recommended to avoid concomitant use of PROGRAF and nelfinavir unless the benefits outweigh the risks [see Drug Interactions (7.2)]. oRifampin: In study of normal volunteers, significant decrease in tacrolimus oral bioavailability (14 +- 6% vs. +- 3%) was observed with concomitant rifampin administration (600 mg). In addition, there was significant increase in tacrolimus clearance (0.036 +- 0.008 L/hr/kg vs. 0.053 +- 0.010 L/hr/kg) with concomitant rifampin administration [see Drug Interactions (7.2)]. oMagnesium and Aluminum-hydroxide: In single-dose crossover study in healthy volunteers, co-administration of tacrolimus and magnesium-aluminum-hydroxide resulted in 21% increase in the mean tacrolimus AUC and 10% decrease in the mean tacrolimus Cmax relative to tacrolimus administration alone [see Drug Interactions (7.2)]. oKetoconazole: In study of normal volunteers, significant increase in tacrolimus oral bioavailability (14 +- 5% vs. 30 +- 8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430 +- 0.129 L/hr/kg vs. 0.148 +- 0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients [see Drug Interactions (7.2)]. oVoriconazole (see complete prescribing information for VFEND): Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for days) increased tacrolimus (0.1 mg/kg single dose) Cmax and AUC in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see Drug Interactions (7.2)].oPosaconazole (see complete prescribing information for Noxafil): Repeat oral administration of posaconazole (400 mg twice daily for days) increased tacrolimus (0.05 mg/kg single dose) Cmax and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [see Drug Interactions (7.2)].oCaspofungin (see complete prescribing information for CANCIDAS): Caspofungin reduced the blood AUC0-12 of tacrolimus by approximately 20%, peak blood concentration (Cmax) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS 70 mg daily, as compared to results from control period in which tacrolimus was administered alone [see Drug Interactions (7.2)].. oTelaprevir: In single-dose study in healthy volunteers, co-administration of tacrolimus (0.5 mg single dose) with telaprevir (750 mg three times daily for 13 days) increased the tacrolimus dose-normalized Cmax by 9.3-fold and AUC by 70-fold compared to tacrolimus alone [see Drug Interactions (7.2)].. oBoceprevir: In single-dose study in 12 subjects, co-administration of tacrolimus (0.5 mg single dose) with boceprevir (800 mg three times daily for 11 days) increased tacrolimus Cmax by 9.9-fold and AUC by 17-fold compared to tacrolimus alone [see Drug Interactions (7.2)].. oNelfinavir: Based on clinical study of liver transplant recipients, co-administration of tacrolimus with nelfinavir increased blood concentrations of tacrolimus significantly and, as result, reduction in the tacrolimus dose by an average of 16-fold was needed to maintain mean trough tacrolimus blood concentrations of 9.7 ng/mL. It is recommended to avoid concomitant use of PROGRAF and nelfinavir unless the benefits outweigh the risks [see Drug Interactions (7.2)]. oRifampin: In study of normal volunteers, significant decrease in tacrolimus oral bioavailability (14 +- 6% vs. +- 3%) was observed with concomitant rifampin administration (600 mg). In addition, there was significant increase in tacrolimus clearance (0.036 +- 0.008 L/hr/kg vs. 0.053 +- 0.010 L/hr/kg) with concomitant rifampin administration [see Drug Interactions (7.2)]. oMagnesium and Aluminum-hydroxide: In single-dose crossover study in healthy volunteers, co-administration of tacrolimus and magnesium-aluminum-hydroxide resulted in 21% increase in the mean tacrolimus AUC and 10% decrease in the mean tacrolimus Cmax relative to tacrolimus administration alone [see Drug Interactions (7.2)]. oKetoconazole: In study of normal volunteers, significant increase in tacrolimus oral bioavailability (14 +- 5% vs. 30 +- 8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430 +- 0.129 L/hr/kg vs. 0.148 +- 0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients [see Drug Interactions (7.2)]. oVoriconazole (see complete prescribing information for VFEND): Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for days) increased tacrolimus (0.1 mg/kg single dose) Cmax and AUC in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see Drug Interactions (7.2)].. oPosaconazole (see complete prescribing information for Noxafil): Repeat oral administration of posaconazole (400 mg twice daily for days) increased tacrolimus (0.05 mg/kg single dose) Cmax and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [see Drug Interactions (7.2)].. oCaspofungin (see complete prescribing information for CANCIDAS): Caspofungin reduced the blood AUC0-12 of tacrolimus by approximately 20%, peak blood concentration (Cmax) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS 70 mg daily, as compared to results from control period in which tacrolimus was administered alone [see Drug Interactions (7.2)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Kidney Transplantation. PROGRAF/Azathioprine (AZA)PROGRAF-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in randomized, multicenter, non-blinded, prospective trial. There were 412 kidney transplant patients enrolled at 19 clinical sites in the United States. Study therapy was initiated when renal function was stable as indicated by serum creatinine <= mg/dL (median of days after transplantation, range to 14 days). Patients less than years of age were excluded.There were 205 patients randomized to PROGRAF-based immunosuppression and 207 patients were randomized to cyclosporine-based immunosuppression. All patients received prophylactic induction therapy consisting of an antilymphocyte antibody preparation, corticosteroids, and azathioprine. Overall, 1-year patient and graft survivals were 96.1% and 89.6%, respectively.Data from this trial of PROGRAF in conjunction with azathioprine indicate that during the first months of that trial, 80% of the patients maintained trough concentrations between 7-20 ng/mL, and then between 5-15 ng/mL, through year.PROGRAF/Mycophenolate Mofetil (MMF)PROGRAF-based immunosuppression in conjunction with MMF, corticosteroids, and induction has been studied. In randomized, open-label, multicenter trial (Study 1), 1589 kidney transplant patients received PROGRAF (Group C, = 401), sirolimus (Group D, = 399), or one of two cyclosporine (CsA) regimens (Group A, = 390 and Group B, = 399) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial was conducted outside the United States; the trial population was 93% Caucasian. In this trial, mortality at 12 months in patients receiving PROGRAF/MMF was similar (3%) compared to patients receiving cyclosporine/MMF (3% and 2%) or sirolimus/MMF (3%). Patients in the PROGRAF group exhibited higher estimated creatinine clearance rates (eCLcr) using the Cockcroft-Gault formula (Table 20) and experienced fewer efficacy failures, defined as biopsy-proven acute rejection (BPAR), graft loss, death, and/or loss to follow-up (Table 21) in comparison to each of the other three groups. Patients randomized to PROGRAF/MMF were more likely to develop diarrhea and diabetes after the transplantation and experienced similar rates of infections compared to patients randomized to either cyclosporine/MMF regimen [see Adverse Reactions (6.1)]. Table 20. Estimated Creatinine Clearance at 12 Months (Study 1)GroupeCLcr [mL/min] at Month 12All death/graft loss (n 41, 27, 23, and 42 in Groups A, B, C, and D) and patients whose last recorded creatinine values were prior to month visit (n 10, 9, 7, and in Groups A, B, C, and D, respectively) were imputed with Glomerular Filtration Rate (GFR) of 10 mL/min; subjects last observed creatinine value from month on was used for the remainder of subjects with missing creatinine at month 12 (n 11, 12, 15, and 19 for Groups A, B, C, and D, respectively). Weight was also imputed in the calculation of estimated GFR, if missing. NMEANSDMEDIANTreatment Difference with Group (99.2% CIAdjusted for multiple (6) pairwise comparisons using Bonferroni corrections.) (A) CsA/MMF/CS 39056.525.856.9-8.6 (-13.7, -3.7) (B) CsA/MMF/CS/Daclizumab39958.925.660.9-6.2 (-11.2, -1.2) (C) Tac/MMF/CS/Daclizumab 40165.127.466.2- (D) Siro/MMF/CS/Daclizumab 39956.227.457.3-8.9 (-14.1, -3.9) Total158959.226.860.5 Key: CsA Cyclosporine, CS Corticosteroids, Tac Tacrolimus, Siro SirolimusTable 21. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 1)Group AN 390Group BN 399Group CN 401Group DN 399 Overall Failure141 (36.2%)126 (31.6%)82 (20.4%)185 (46.4%) Components of efficacy failure BPAR113 (29.0%)106 (26.6%)60 (15.0%)152 (38.1%) Graft loss excluding death28 (7.2%)20 (5.0%)12 (3.0%)30 (7.5%) Mortality13 (3.3%)7 (1.8%)11 (2.7%)12 (3.0%) Lost to follow-up5 (1.3%)7 (1.8%)5 (1.3%)6 (1.5%) Treatment Difference of efficacy failure compared to Group (99.2% CIAdjusted for multiple (6) pairwise comparisons using Bonferroni corrections.)15.8%(7.1%, 24.3%)11.2%(2.7%, 19.5%)-26.0%(17.2%, 34.7%) Key: Group = CsA/MMF/CS, = CsA/MMF/CS/Daclizumab, = Tac/MMF/CS/Daclizumab, and = Siro/MMF/CS/DaclizumabThe protocol-specified target tacrolimus trough concentrations (Ctrough,Tac) were 3-7 ng/mL; however, the observed median Ctroughs,Tac approximated ng/mL throughout the 12-month trial (Table 22). Approximately 80% of patients maintained tacrolimus whole blood concentrations between 4-11 ng/mL through year post-transplant.Table 22. Tacrolimus Whole Blood Trough Concentration Range (Study 1)Time Median (P10-P9010 to 90th Percentile: range of Ctrough,Tac that excludes lowest 10% and highest 10% of Ctrough,Tac tacrolimus whole blood trough concentration range(ng/mL) Day 30 (N 366)6.9 (4.4 11.3) Day 90 (N 351)6.8 (4.1 10.7) Day 180 (N 355)6.5 (4.0 9.6) Day 365 (N 346)6.5 (3.8 10.0)The protocol-specified target cyclosporine trough concentrations (Ctrough,CsA) for Group were 50-100 ng/mL; however, the observed median Ctroughs,CsA approximated 100 ng/mL throughout the 12-month trial. The protocol-specified target Ctroughs,CsA for Group were 150-300 ng/mL for the first months and 100-200 ng/mL from month to month 12; the observed median Ctroughs,CsA approximated 225 ng/mL for the first months and 140 ng/mL from month to month 12. While patients in all groups started MMF at gram twice daily, the MMF dose was reduced to less than g per day in 63% of patients in the tacrolimus treatment arm by month 12 (Table 23); approximately 50% of these MMF dose reductions were due to adverse reactions. By comparison, the MMF dose was reduced to less than g per day in 49% and 45% of patients in the two cyclosporine arms (Group and Group B, respectively), by month 12 and approximately 40% of MMF dose reductions were due to adverse reactions.Table 23. MMF Dose Over Time in PROGRAF/MMF (Group C) (Study 1)Time period (Days)Time-averaged MMF dose (grams per day)Percentage of patients for each time-averaged MMF dose range during various treatment periods. Administration of g per day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods. Less than 2.02.0Greater than 2.0 0-30 (N 364)37%60%2% 0-90 (N 373)47%51%2% 0-180 (N 377)56%42%2% 0-365 (N 380)63%36%1% Key: Time-averaged MMF dose (total MMF dose)/(duration of treatment)In second randomized, open-label, multicenter trial (Study 2), 424 kidney transplant patients received PROGRAF (N 212) or cyclosporine (N 212) in combination with MMF gram twice daily, basiliximab induction, and corticosteroids. In this trial, the rate for the combined endpoint of BPAR, graft failure, death, and/or lost to follow-up at 12 months in the PROGRAF/MMF group was similar to the rate in the cyclosporine/MMF group. There was, however, an imbalance in mortality at 12 months in those patients receiving PROGRAF/MMF (4%) compared to those receiving cyclosporine/MMF (2%), including cases attributed to over-immunosuppression (Table 24).Table 24. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 2) PROGRAF/MMFCyclosporine/MMF (N 212)(N 212) Overall Failure32 (15.1%)36 (17.0%) Components of efficacy failure BPAR16 (7.5%)29 (13.7%) Graft loss excluding death6 (2.8%)4 (1.9%) Mortality9 (4.2%)5 (2.4%) Lost to follow-up4 (1.9%)1 (0.5%)Treatment Difference of efficacy failure compared to PROGRAF/MMF group (95% CI95% confidence interval calculated using Fishers Exact Test.) 1.9% (-5.2%, 9.0%)The protocol-specified target tacrolimus whole blood trough concentrations (Ctrough,Tac) in Study were 7-16 ng/mL for the first three months and 5-15 ng/mL thereafter. The observed median Ctroughs,Tac approximated 10 ng/mL during the first three months and ng/mL from month to month 12 (Table 25). Approximately 80% of patients maintained tacrolimus whole blood trough concentrations between to 16 ng/mL during months through and, then, between to 12 ng/mL from month through year.Table 25. Tacrolimus Whole Blood Trough Concentration Range (Study 2)Time Median (P10-P9010 to 90th Percentile: range of Ctrough,Tac that excludes lowest 10% and highest 10% of Ctrough,Tac. tacrolimus whole blood trough concentration range(ng/mL) Day 30 (N 174)10.5 (6.3 16.8) Day 60 (N 179)9.2 (5.9 15.3) Day 120 (N 176)8.3 (4.6 13.3) Day 180 (N 171)7.8 (5.5 13.2) Day 365 (N 178)7.1 (4.2 12.4)The protocol-specified target cyclosporine whole blood concentrations (Ctrough,CsA) were 125 to 400 ng/mL for the first three months, and 100 to 300 ng/mL thereafter. The observed median Ctroughs,CsA approximated 280 ng/mL during the first three months and 190 ng/mL from month to month 12. Patients in both groups started MMF at gram twice daily. The MMF dose was reduced to less than grams per day by month 12 in 62% of patients in the PROGRAF/MMF group (Table 26) and in 47% of patients in the cyclosporine/MMF group. Approximately 63% and 55% of these MMF dose reductions were because of adverse reactions in the PROGRAF/MMF group and the cyclosporine/MMF group, respectively [see Adverse Reactions (6.1)].Table 26. MMF Dose Over Time in the PROGRAF/MMF Group (Study 2)Time period (Days)Time-averaged MMF dose (g/day)Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time-averaged MMF dose means that the MMF dose was not reduced in those patients during the treatment periods. Less than 2.02.0Greater than 2.0 0-30 (N 212)25%69%6% 0-90 (N 212)41%53%6% 0-180 (N 212)52%41%7% 0-365 (N 212)62%34%4%Key: Time-averaged MMF dose (total MMF dose)/(duration of treatment). 14.2 Liver Transplantation. The safety and efficacy of PROGRAF-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter trials. The active control groups were treated with cyclosporine-based immunosuppressive regimen (CsA/AZA). Both trials used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These trials compared patient and graft survival rates at 12 months following transplantation.In one trial, 529 patients were enrolled at 12 clinical sites in the United States; prior to surgery, 263 were randomized to the PROGRAF-based immunosuppressive regimen and 266 to the CsA/AZA. In 10 of the 12 sites, the same CsA/AZA protocol was used, while sites used different control protocols. This trial excluded patients with renal dysfunction, fulminant hepatic failure with Stage IV encephalopathy, and cancers; pediatric patients (<= 12 years old) were allowed.In the second trial, 545 patients were enrolled at clinical sites in Europe; prior to surgery, 270 were randomized to the PROGRAF-based immunosuppressive regimen and 275 to CsA/AZA. In this trial, each center used its local standard CsA/AZA protocol in the active-control arm. This trial excluded pediatric patients, but did allow enrollment of subjects with renal dysfunction, fulminant hepatic failure in Stage IV encephalopathy, and cancers other than primary hepatic with metastases.One-year patient survival and graft survival in the PROGRAF-based treatment groups were similar to those in the CsA/AZA treatment groups in both trials. The overall 1-year patient survival (CsA/AZA and PROGRAF-based treatment groups combined) was 88% in the U.S. trial and 78% in the European trial. The overall 1-year graft survival (CsA/AZA and PROGRAF-based treatment groups combined) was 81% in the U.S. trial and 73% in the European trial. In both trials, the median time to convert from IV to oral PROGRAF dosing was days.Although there is lack of direct correlation between tacrolimus concentrations and drug efficacy, data from clinical trials of liver transplant patients have shown an increasing incidence of adverse reactions with increasing trough blood concentrations. Most patients are stable when trough whole blood concentrations are maintained between to 20 ng/mL. Long-term post-transplant patients are often maintained at the low end of this target range. Data from the U.S. clinical trial show that the median trough blood concentrations, measured at intervals from the second week to one year post-transplantation, ranged from 9.8 ng/mL to 19.4 ng/mL.Pediatric Liver Transplantation Using PROGRAF GranulesThe efficacy and safety of PROGRAF Granules plus corticosteroids were compared with triple regimen of cyclosporine/corticosteroids/azathioprine in randomized, open-label study, in de novo pediatric liver transplant patients. The study was conducted outside the United States and enrolled patients aged 16 years or younger. The distribution of pediatric patients by age was similar in both treatment groups, with majority 5 years. Patients were randomized to either tacrolimus for oral suspension 0.3 mg/kg/day (N 91) or cyclosporine 10 mg/kg/day orally (N 90) initiated hours after completion of transplant surgery. Doses throughout the 1-year study period were adjusted to maintain whole blood trough levels within 5-20 ng/mL [see Dosage and Administration (2.3)]. Based on trough levels, doses of tacrolimus were adjusted to 0.17 mg/kg/day and 0.14 mg/kg/day by days and 3, respectively. At 12 months, the incidence rate of BPAR, graft loss, death, or loss to follow-up was 52.7% in the tacrolimus group and 61.1% in the cyclosporine group (Table 27). Table 27. Key Efficacy Results at 12 Months in Pediatric Liver Transplant Recipients Receiving PROGRAF Granules or CyclosporinePROGRAF Granules(N 91)Cyclosporine(N 90)Overall Failure48 (52.7%)55 (61.1%) Components of efficacy failure BPAR40 (44.0%)49 (54.4%) Graft loss7 (7.7%)13 (14.4%) Graft loss excluding death1 (1.1%)6 (6.7%) Mortality6 (6.6%)7 (7.8%) Lost to follow-up2 (2.2%)0Treatment Difference of efficacy failure compared to cyclosporine (95% CI95% confidence interval calculated using normal approximation.)-8.4% (-22.7%, 6.0%). 14.3 Heart Transplantation. Two open-label, randomized, comparative trials evaluated the safety and efficacy of PROGRAF-based and cyclosporine-based immunosuppression in primary orthotopic heart transplantation. In trial conducted in Europe, 314 patients received regimen of antibody induction, corticosteroids, and azathioprine in combination with PROGRAF or cyclosporine modified for 18 months. In 3-arm trial conducted in the U.S., 331 patients received corticosteroids and PROGRAF plus sirolimus, PROGRAF plus mycophenolate mofetil (MMF) or cyclosporine modified plus MMF for year.In the European trial, patient/graft survival at 18 months post-transplant was similar between treatment arms, 92% in the tacrolimus group and 90% in the cyclosporine group. In the U.S. trial, patient and graft survival at 12 months was similar with 93% survival in the PROGRAF plus MMF group and 86% survival in the cyclosporine modified plus MMF group. In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm. Data from this European trial indicate that from week to months post-transplant, approximately 80% of patients maintained trough concentrations between to 20 ng/mL and, from months through 18 months post-transplant, approximately 80% of patients maintained trough concentrations between to 18 ng/mL.The U.S. trial contained third arm of combination regimen of sirolimus, mg per day, and full-dose PROGRAF; however, this regimen was associated with increased risk of wound-healing complications, renal function impairment, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Warnings and Precautions (5.10)]. 14.4 Lung Transplantation The efficacy and safety of PROGRAF-based immunosuppression in primary lung transplantation were assessed in non-interventional (observational) study using data from the U.S. Scientific Registry of Transplant Recipients (SRTR). The study analyzed outcomes based on discharge immunosuppression treatment regimen in recipients of primary lung transplant between 1999 and 2017 who were alive at the time of discharge. In adult patients receiving tacrolimus immediate-release products in combination with MMF (n=15,478) or tacrolimus immediate-release products in combination with AZA (n=4,263), the one-year graft survival estimates from time of discharge were 90.9% and 90.8%, respectively. In pediatric patients receiving tacrolimus immediate-release products in combination with MMF (n= 450) or tacrolimus immediate-release products in combination with AZA (n=72), the one-year graft survival estimates from time of discharge were 91.7% and 84.7%, respectively.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. PROGRAF is contraindicated in patients with hypersensitivity to tacrolimus. PROGRAF injection is contraindicated in patients with 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)].. oHypersensitivity to tacrolimus or HCO-60 (polyoxyl 60 hydrogenated castor oil). (4). oHypersensitivity to tacrolimus or HCO-60 (polyoxyl 60 hydrogenated castor oil). (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Tacrolimus, previously known as FK506, is the active ingredient in PROGRAF. Tacrolimus is calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as [3S-[3R[E(1S,3S,4S)], 4S,5R,8S,9E,12R,14R,15S,16R,18S,19S,26aR]] -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 C44H69NO12oH2O and 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, mg or 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 mg capsule shell contains gelatin NF and titanium dioxide USP, and the mg capsule shell contains ferric oxide NF, gelatin NF, and titanium dioxide USP.PROGRAF is also available as sterile solution (tacrolimus injection) containing the equivalent of mg anhydrous tacrolimus USP in 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 suspension containing the equivalent of 0.2 mg or mg of anhydrous tacrolimus USP. Inactive ingredients include croscarmellose sodium NF, hypromellose USP, and lactose monohydrate NF.. Tacrolimus structural formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. ADULTPatient PopulationInitial Oral Dosage (formulation)Whole Blood Trough Concentration RangeKidney TransplantWith azathioprine0.2 mg/kg/day capsules, divided in two doses, every 12 hoursMonth 1-3: 7-20 ng/mLMonth 4-12: 5-15 ng/mLWith MMF/IL-2 receptorantagonist0.1 mg/kg/day capsules, divided in two doses, every 12 hoursMonth 1-12: 4-11 ng/mLLiver TransplantWith corticosteroids only0.1-0.15 mg/kg/day capsules, divided in two doses, every 12 hoursMonth 1-12: 5-20 ng/mLHeart TransplantWith azathioprine or MMF0.075 mg/kg/day capsules, divided in two doses, every 12 hoursMonth 1-3: 10-20 ng/mLMonth >= 4: 5-15 ng/mLLung TransplantWith azathioprine or MMF 0.075 mg/kg/dayPatients with cystic fibrosis may require higher doses due to lower bioavailability.capsules, divided in two doses, every 12 hoursMonth 1-3: 10-15 ng/mL Month 4-12: 8-12 ng/mL PEDIATRICPatient PopulationInitial Oral Dosage (formulation)Whole Blood Trough Concentration RangeKidney Transplant0.3 mg/kg/day capsules or oral suspension, divided in two doses, every 12 hoursMonth 1-12: 5-20 ng/mLLiver Transplant0.15-0.2 mg/kg/day capsules or 0.2 mg/kg/day oral suspension, divided in two doses, every 12 hoursMonth 1-12: 5-20 ng/mLHeart Transplant0.3 mg/kg/dayDose at 0.1 mg/kg/day if antibody induction treatment is administered. capsules or oral suspension, divided in two doses, every 12 hoursMonth 1-12: 5-20 ng/mLLung Transplant0.3 mg/kg/day capsules or oral suspension, divided in two doses, every 12 hoursWeeks 1-2: 10-20 ng/mL Week to Month 12: 10-15 ng/mL MMF= Mycophenolate mofetiloIntravenous (IV) use recommended for patients who cannot tolerate oral formulations (capsules or suspension). (2.1, 2.2)oAdminister capsules or suspension consistently with or without food. (2.1)oTherapeutic drug monitoring is recommended. (2.1, 2.6)oAvoid eating grapefruit or drinking grapefruit juice. (2.1)oSee dosage adjustments for African-American patients (2.2), hepatic and renal impaired. (2.4, 2.5)oFor complete dosing information, see the full prescribing information.. oIntravenous (IV) use recommended for patients who cannot tolerate oral formulations (capsules or suspension). (2.1, 2.2). oAdminister capsules or suspension consistently with or without food. (2.1). oTherapeutic drug monitoring is recommended. (2.1, 2.6). oAvoid eating grapefruit or drinking grapefruit juice. (2.1). oSee dosage adjustments for African-American patients (2.2), hepatic and renal impaired. (2.4, 2.5). oFor complete dosing information, see the full prescribing information.. 2.1 Important Administration Instructions. PROGRAF should not be used without supervision by 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 AnaphylaxisIntravenous 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 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 InstructionsPatients 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. CapsulesIf 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 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 AdultsPatient PopulationPROGRAF CapsulesAfrican-American patients may require higher doses compared to Caucasians (see Table 2). Initial Oral DosageWhole Blood Trough Concentration RangeKidney Transplant With Azathioprine0.2 mg/kg/day, divided in two doses, administered every 12 hoursMonth 1-3: 7-20 ng/mLMonth 4-12: 5-15 ng/mL With MMF/IL-2 receptor antagonistIn second smaller trial, the initial dose of tacrolimus was 0.15-0.2 mg/kg/day and observed tacrolimus concentrations were 6-16 ng/mL. during month 1-3 and 5-12 ng/mL during month 4-12 [see Clinical Studies (14.1)]. 0.1 mg/kg/day, divided in two doses, administered every 12 hoursMonth 1-12: 4-11 ng/mLLiver Transplant With corticosteroids only0.10-0.15 mg/kg/day, divided in two doses, administered every 12 hoursMonth 1-12: 5-20 ng/mLHeart Transplant With azathioprine or MMF0.075 mg/kg/day, divided in two doses, administered every 12 hoursMonth 1-3: 10-20 ng/mLMonth >= 4: 5-15 ng/mLLung Transplant With azathioprine or MMF0.075 mg/kg/dayPatients with cystic fibrosis may require higher doses due to lower bioavailability[see Clinical Pharmacology (12.3)]., divided in two doses, administered every 12 hoursMonth 1-3: 10-15 ng/mLMonth 4-12: 8-12 ng/mLDosage should be titrated based on clinical assessments of rejection and tolerability. PROGRAF dosages lower than the recommended initial dosage may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended early post-transplant.The data in kidney transplant patients indicate that the African-American patients required higher dose to attain comparable trough concentrations compared to Caucasian patients (Table 2) [see Use in Specific Populations (8.8) and Clinical Pharmacology (12.3)].Table 2. Comparative Dose and Trough Concentrations Based on RaceTime After TransplantCaucasian = 114African-AmericanN 56Dose(mg/kg)Trough Concentrations(ng/mL)Dose(mg/kg)Trough Concentrations (ng/mL)Day 70.1812.00.2310.9Month 10.1712.80.2612.9Month 60.1411.80.2411.5Month 120.1310.10.1911.0In lung transplantation, cystic fibrosis patients may have reduced bioavailability of orally administered tacrolimus resulting in the need for higher doses to achieve target tacrolimus trough concentrations. Monitor tacrolimus trough concentrations and adjust the dose accordingly.Intravenous InjectionPROGRAF injection should be used only as continuous intravenous infusion and should be discontinued as soon as the patient can tolerate oral administration. The first dose of PROGRAF capsules should be given 8-12 hours after discontinuing the intravenous infusion. The recommended starting dose of PROGRAF injection is 0.03-0.05 mg/kg/day in kidney or liver transplant, 0.01 mg/kg/day in heart transplant, and 0.01-0.03 mg/kg/day in lung transplant, given as continuous intravenous infusion. Adult patients should receive doses at the lower end of the dosing range. Concomitant adrenal corticosteroid therapy is recommended early post-transplantation.The whole blood trough concentration range described in Table pertains to oral administration of PROGRAF only; while monitoring PROGRAF concentrations in patients receiving PROGRAF injection as continuous intravenous infusion may have some utility, the observed concentrations will not represent comparable exposures to those estimated by the trough concentrations observed in patients on oral therapy.Anaphylactic reactions have occurred with injectables containing castor oil derivatives, such as PROGRAF injection. Therefore, monitoring for signs and symptoms of anaphylaxis is recommended [see Warnings and Precautions (5.9)].. 2.3 Dosage Recommendations for Pediatric Kidney, Liver, Heart, or Lung Transplant Patients. Oral formulations (capsules or oral suspension)Pediatric patients, in general, need higher tacrolimus doses compared to adults: the higher dose requirements may decrease as the child grows older. Recommendations for the initial oral dosage for pediatric transplant patients and whole blood trough concentration range are shown in Table 3. Perform TDM to ensure that patients are within the ranges listed in Table 3.Table 3. Summary of Initial PROGRAF Capsule and PROGRAF Granules Dosage Recommendations and Whole Blood Trough Concentration Range in ChildrenPatient PopulationInitial PROGRAF Capsule and PROGRAF Granules DosingWhole Blood Trough Concentration RangePediatric kidney transplant patientsSee Clinical Pharmacology (12.3), PROGRAF Granules Pharmacokinetics in Pediatric Patients. 0.3 mg/kg/day capsules or oral suspension, divided in two doses, administered every 12 hoursMonth 1-12: 5-20 ng/mLPediatric liver transplant patientsSee Clinical Studies (14.2), Liver Transplantation. 0.15-0.2 mg/kg/day capsules or 0.2 mg/kg/day oral suspension, divided in two doses, administered every 12 hoursMonth 1-12: 5-20 ng/mLPediatric heart transplant patients 0.3 mg/kg/dayDose at 0.1 mg/kg/day if antibody induction treatment is administered. capsules or oral suspension, divided in two doses, administered every 12 hoursMonth 1-12: 5-20 ng/mLPediatric lung transplant patients0.3 mg/kg/day, Patients with cystic fibrosis may require higher doses due to lower bioavailability[see Clinical Pharmacology (12.3)]. capsules or oral suspension, divided in two doses, administered every 12 hoursWeek 1-2: 10-20 ng/mLWeek to Month 12: 10-15 ng/mLIn lung transplantation, cystic fibrosis patients may have reduced bioavailability of orally administered tacrolimus resulting in the need for higher doses to achieve target tacrolimus trough concentrations. Monitor tacrolimus trough concentrations and adjust the dose accordingly.For conversion of pediatric patients from PROGRAF Granules to PROGRAF capsules or from PROGRAF capsules to PROGRAF Granules, the total daily dose should remain the same. Following conversion from one formulation to another formulation of tacrolimus, therapeutic drug monitoring is recommended [see Dosage and Administration (2.6)]. Intravenous InjectionIf patient is unable to receive an oral formulation, the patient may be started on PROGRAF injection. For pediatric liver transplant patients, the intravenous dose is 0.03-0.05 mg/kg/day.. 2.4 Dosage Adjustment in Patients with Renal Impairment. Due to its potential for nephrotoxicity, consider dosing PROGRAF at the lower end of the therapeutic dosing range in patients who have received liver, heart, or lung transplant, and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required.In kidney transplant patients with post-operative oliguria, the initial dose of PROGRAF should be administered no sooner than hours and within 24 hours of transplantation, but may be delayed until renal function shows evidence of recovery [see Dosage and Administration (2.2), Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].. 2.5 Dosage Adjustment in Patients with Hepatic Impairment. Due to the reduced clearance and prolonged half-life, patients with severe hepatic impairment (Child-Pugh >= 10) may require lower doses of PROGRAF. Close monitoring of blood concentrations is warranted. The use of PROGRAF in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood concentrations of tacrolimus. These patients should be monitored closely, and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration (2.2), Warnings and Precautions (5.5), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)]. 2.6 Therapeutic Drug Monitoring. Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments, and compliance. Whole blood trough concentration range can be found in Table 1. Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting drugs and the post-transplant time. Blood concentration monitoring is not replacement for renal and liver function monitoring and tissue biopsies. Data from clinical trials show that tacrolimus whole blood concentrations were most variable during the first week post-transplantation.The relative risks of toxicity and efficacy failure are related to tacrolimus whole blood trough concentrations. Therefore, monitoring of whole blood trough concentrations is recommended to assist in the clinical evaluation of toxicity and efficacy failure.Methods commonly used for the assay of tacrolimus include high-performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) and immunoassays. Immunoassays may react with metabolites as well as parent compound. Therefore, assay results obtained with immunoassays may have positive bias relative to results of HPLC/MS. The bias may depend upon the specific assay and laboratory. Comparison of the concentrations in published literature to patient concentrations using the current assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anticoagulant. Heparin anticoagulation is not recommended because of the tendency to form clots on storage. Samples which are not analyzed immediately should be stored at room temperature or in refrigerator and assayed within days; see assay instructions for specifics. If samples are to be kept longer, they should be deep frozen at -20C. One study showed drug recovery 90% for samples stored at -20C for months, with reduced recovery observed after months. 2.7 Preparation and Administration Instructions of PROGRAF Injection for Pharmacists. Tacrolimus can cause fetal harm. Follow applicable special handling and disposal procedures1 [see How Supplied/ Storage and Handling (16.4)].PROGRAF injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to concentration between 0.004 mg/mL and 0.02 mg/mL prior to use. Diluted infusion solution should be stored in glass or polyethylene containers and should be discarded after 24 hours. The diluted infusion solution should not be stored in polyvinyl chloride (PVC) container due to decreased stability and the potential for extraction of phthalates. In situations where more dilute solutions are utilized (e.g., pediatric dosing, etc.), PVC-free tubing should likewise be used to minimize the potential for significant drug adsorption onto the tubing. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Due to the chemical instability of tacrolimus in alkaline media, PROGRAF injection should not be mixed or co-infused with solutions of pH or greater (e.g., ganciclovir or acyclovir).. 2.8 Preparation and Administration Instructions of PROGRAF Granules. Tacrolimus can cause fetal harm. Follow applicable special handling and disposal procedures1 [see How Supplied/ Storage and Handling (16.4)].The required dose for PROGRAF Granules is calculated based on the weight of the patient. Use the minimum whole number of packets that corresponds to the required morning or evening dose. If the morning or evening dose is not covered by the whole number of packets, use one additional 0.2 mg packet to round up the dose. Do not use tubing, syringes and other equipment (cups) containing PVC to prepare or administer tacrolimus products. Do not sprinkle PROGRAF Granules on food. Prepare and administer PROGRAF Granules as follows: To prepare the dose, empty the entire contents of each PROGRAF Granules packet into glass cup. Check for any remaining granules in the packet(s) and empty these into the cup. Add to tablespoons (15 to 30 milliliters) of room temperature drinking water to the cup containing the PROGRAF Granules. Mix and administer the entire contents of the cup. The granules will not completely dissolve. The suspension should be given immediately after preparation. For younger patients, the suspension can be drawn up via non-PVC oral syringe that will be dispensed with the prescription. The cup or syringe should be rinsed with the same quantity of water (15 to 30 milliliters) and given to the patient to ensure all of the medication is taken. The pharmacy must dispense with the Instructions for Use. Alert the patient to read the Instructions for Use.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. PROGRAF is available in the following dosage forms and strengths:CapsulesOblong, 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 bodyInjection1 mL ampule for intravenous infusion contains anhydrous tacrolimus USP, mg/mL For Oral SuspensionUnit-dose packets with white granules for oral suspension contains anhydrous tacrolimus USP:o0.2 mgo1 mg. o0.2 mg. o1 mg. oCapsules: 0.5 mg, mg and mg (3)oInjection: mg/mL (3)oFor oral suspension: 0.2 mg, mg unit-dose packets containing granules (3). oCapsules: 0.5 mg, mg and mg (3). oInjection: mg/mL (3). oFor oral suspension: 0.2 mg, mg unit-dose packets containing granules (3). Letter logo. Letter logo. Letter logo.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oMycophenolic 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)oNelfinavir and Grapefruit Juice: Increased tacrolimus concentrations via CYP3A inhibition; avoid concomitant use. (7.2)oCYP3A Inhibitors: Increased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed. (5.11, 7.2)oCYP3A4 Inducers: Decreased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed. (5.11, 7.2). oMycophenolic 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). oNelfinavir and Grapefruit Juice: Increased tacrolimus concentrations via CYP3A inhibition; avoid concomitant use. (7.2). oCYP3A Inhibitors: Increased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed. (5.11, 7.2). oCYP3A4 Inducers: Decreased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed. (5.11, 7.2). 7.1 Mycophenolic Acid. When PROGRAF is prescribed with given dose of 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 PROGRAFPROGRAF dosage adjustment recommendation based on observed effect of coadministered drug on tacrolimus exposures [see Clinical Pharmacology (12.3)], literature reports of altered tacrolimus exposures, or the other drugs known CYP3A inhibitor/inducer status. Drug/Substance Class or NameDrug Interaction EffectRecommendationsGrapefruit or grapefruit juiceHigh dose or double strength grapefruit juice is strong CYP3A inhibitor; low dose or single strength grapefruit juice is 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 InducersStrong 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 Johns WortMay 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 extractsMay increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation). 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 omeprazoleMay 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 MetoclopramideMay 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, prednisoneMay decrease tacrolimus 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) TherapyThe 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)].. Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St Johns Wort. 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. Clotrimazole, antibiotics (e.g., erythromycin, fluconazole), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole. Magnesium and aluminum hydroxide antacids. Metoclopramide. Methylprednisolone, prednisone.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential ContraceptionPROGRAF can cause fetal harm when administered to pregnant women. Advise female and male patients of reproductive potential to speak to their healthcare provider on family planning options including appropriate contraception prior to starting treatment with PROGRAF [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)].InfertilityBased on findings in animals, male and female fertility may be compromised by treatment with PROGRAF [see Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.

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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 PROGRAF (tacrolimus) Capsules, USP. Strength0.5 mg(containing the equivalent of 0.5 mg anhydrous tacrolimus USP)1 mg(containing the equivalent of mg anhydrous tacrolimus USP)5 mg(containing the equivalent of mg anhydrous tacrolimus USP) Shape/coloroblong/light yellowoblong/whiteoblong/grayish red Branding on capsule cap/body607617657 100 count bottleNDC 0469-0607-73NDC 0469-0617-73NDC 0469-0657-73 10 blister cards of 10 capsulesNDC 0469-0617-11NDC 0469-0657-11Note: PROGRAF capsules USP are not filled to maximum capsule capacity. Capsule contains labeled amount. Store and DispenseStore at 20C to 25C (68F to 77F); excursions permitted 15C to 30C (59F to 86F) [See USP Controlled Room Temperature].. f. f. f. 16.2 PROGRAF (tacrolimus) Injection. (for Intravenous infusion only)NDC 0469-3016-01 Product Code 3016015 mg/mL (equivalent of mg of anhydrous tacrolimus USP per mL) supplied as sterile solution in 1 mL ampule, in boxes of 10 ampulesStore and DispenseStore between 5C and 25C (41F and 77F).. 16.3 PROGRAF Granules (tacrolimus for oral suspension) Strength0.2 mg(containing the equivalent of 0.2 mg anhydrous tacrolimus USP)1 mg(containing the equivalent of mg anhydrous tacrolimus USP)Shape/colorWhite granulesWhite granules1 carton containing 50 packetsNDC 0469-1230-50NDC 0469-1330-50Store and DispenseStore at 20C to 25C (68F to 77F); excursions permitted 15C to 30C (59F to 86F) [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 spill occurs, wipe the surface with wet paper towel. Follow applicable special handling and disposal procedures1.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. PROGRAF is 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(R) 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING 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: oInspect their PROGRAF medicine when they receive 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.oTake PROGRAF at the same 12-hour intervals every day to achieve consistent blood concentrations.oTake PROGRAF consistently either with or without food because the presence and composition of food decreases the bioavailability of PROGRAF.oNot to eat grapefruit or drink grapefruit juice in combination with PROGRAF [see Drug Interactions (7.2)].oIf 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.. oInspect their PROGRAF medicine when they receive 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.. oTake PROGRAF at the same 12-hour intervals every day to achieve consistent blood concentrations.. oTake PROGRAF consistently either with or without food because the presence and composition of food decreases the bioavailability of PROGRAF.. oNot to eat grapefruit or drink grapefruit juice in combination with PROGRAF [see Drug Interactions (7.2)].. oIf 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 broad spectrum sunscreen with high protection factor [see Warnings and Precautions (5.1)].. 17.3 Increased Risk of Infection. Inform patients they are at increased risk of developing 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 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)]. 17.10 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 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)]. 17.11 Myocardial Hypertrophy Inform patients to report symptoms of tiredness, swelling, and/or shortness of breath (heart failure).. 17.12 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)].Capsules and Intravenous Injection manufactured by: Astellas Ireland Co., Ltd. Killorglin, County Kerry, IrelandGranules for oral suspension manufactured by: Astellas Pharma Tech Co., Ltd. Toyama, JapanMarketed by: Astellas Pharma US, Inc. Northbrook, IL 60062PROGRAF(R) is registered trademark of Astellas Pharma Inc. All other trademarks and registered trademarks are the property of their respective owners.291762-PRG.

INSTRUCTIONS FOR USE SECTION.

Instructions for Use PROGRAF(R) Granules(PRO-graf)(tacrolimus for oral suspension)Your healthcare provider has prescribed PROGRAF(R) Granules, which comes in individual packets that will need to be mixed with water before giving the medicine to your child.Read this Instructions for Use and the Patient Information for the first time and each time you get refill of PROGRAF Granules (tacrolimus for oral suspension). There may be new information. This Instructions for Use does not take the place of talking to your childs healthcare provider about their medical condition or treatment. Ask the healthcare provider if you have any questions about how to mix or give dose of PROGRAF Granules the right way.Important information: These instructions are for preparing PROGRAF Granules only.These instructions should not be used for PROGRAF capsules.oMix PROGRAF Granules in water to make an oral suspension.oGive all of the prepared oral suspension to your child right away after preparing. Do not save the prepared oral suspension for later use.oUse glass or metal materials to prepare your childs dose of PROGRAF Granules. oDo not use any plastic (PVC) materials to prepare PROGRAF Granules. The granules will stick to plastic container and your child may not receive their full dose. oDo not breathe in (inhale) or let the granules in PROGRAF or the prepared oral suspension come in contact with your skin or eyes. oIf you get the granules or the prepared oral suspension on your skin, wash the area well with soap and water. oIf you get the granules or the prepared oral suspension in your eyes, rinse with plain water. If you spill the granules, wipe the surface with wet paper towel. If you spill the prepared oral suspension, dry the area with dry paper towel and then wipe the area with wet paper towel. Throw away the paper towels in the trash and wash your hands well with soap and water.For each dose of PROGRAF Granules mixed with water that will be given using glass cup, you will need the following supplies (See Figure A):oCarton containing PROGRAF Granules packets. Follow the instructions on the carton for the number of packets your childs healthcare provider has prescribed for each dose.opaper towelsopair of scissorsometal stirring spoonomeasuring deviceo1 small clean glass cup (plastic containers should not be used)ocontainer with drinking water Figure AStep 1Choose clean flat work surface. Place clean paper towel on the work surface. Place the supplies to prepare the dose on the paper towel. Step 2Wash and dry your hands.Step 3Remove the prescribed number of PROGRAF Granules packets from the carton.Step 4Using pair of scissors, cut along the dotted line on PROGRAF Granules packet to open it.Step 5Empty all of the granules in the packet into the glass cup. Check for any remaining granules in the packet and empty these into the glass cup.Step 6If more than packet of PROGRAF Granules is needed for your childs prescribed dose, repeat Steps and using the number of packets needed for the prescribed dose.Step 7Add to tablespoons (15 to 30 milliliters) of room temperature drinking water to the glass cup containing the granules.Step 8Gently stir the granules and water in the glass cup with metal stirring spoon. The granules will not completely dissolve. You will see granules that are suspended in the water.Step 9Give the granules and water suspension in the glass cup to your child. Make sure your child drinks all of the medicine in the cup.Give all of the medicine to your child right away after preparing. Do not save the medicine for later use.Step 10To make sure all of the medicine is given to your child, refill the glass cup with the same amount of water used in Step 7.Step 11Gently swirl the glass cup to mix any remaining granules.Step 12Give all of the medicine in the cup to the child.Step 13Wash the glass cup. Throw away the paper towel and clean the work surface. Wash your hands.For each dose of PROGRAF Granules (tacrolimus for oral suspension) mixed with water that will be drawn up and given using an oral syringe, you will need the following supplies (See Figure B):oCarton containing PROGRAF Granules packets. Follow the instructions on the carton for the number of packets your childs healthcare provider has prescribed for each dose.opaper towelsopair of scissorsometal stirring spoonomeasuring deviceo1 small clean glass cup (plastic containers should not be used)ocontainer with drinking water o1 non-PVC oral syringe (ask your pharmacist for the oral syringe you should use)Figure BStep 1Choose clean flat work surface. Place clean paper towel on the work surface. Place the supplies to prepare the dose on the paper towel.Step 2Wash and dry your hands.Step 3Remove the prescribed number of PROGRAF Granules packets from the carton.Step 4Using pair of scissors, cut along the dotted line on PROGRAF Granules packet to open it.Step Empty all of the granules in the packet into the glass cup. Check for any remaining granules in the packet and empty these into the glass cup. Step 6If more than packet of PROGRAF Granules is needed for your childs prescribed dose, repeat Steps and using the number of packets needed for the prescribed dose.Step 7Add to tablespoons (15 to 30 milliliters) of room temperature drinking water to the glass cup containing the granules.Step 8Gently stir the granules and drinking water in the glass cup with metal stirring spoon. The granules will not completely dissolve. You will see granules that are suspended in the drinking water.Step 9Insert the tip of the oral syringe into the glass cup.Pull back on the plunger of the oral syringe to draw up the suspension.Step 10Place the tip of the oral syringe in your childs mouth along the inner cheek. Slowly push the plunger all the way down to give your child all of the medicine in the oral syringe.Repeat Steps and 10 until the glass cup is empty.Give all of the medicine to your child right away after preparing. Do not save the medicine for later use.Step 11To make sure all of the medicine is given to your child, refill the glass cup with the same amount of drinking water used in Step 7.Step 12Gently swirl the glass cup to mix any remaining granules. Step 13Repeat Steps and 10 until the glass cup is empty.Step 14Rinse the plunger and barrel of the syringe well with drinking water and dry well before storing the oral syringe.Step 15Wash the glass cup. Throw away the paper towel and clean the work surface. Wash your hands.How should store PROGRAF Granules packetsStore PROGRAF Granules packets at room temperature between 68F to 77F (20C to 25C).Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use.Keep PROGRAF Granules and all medicine out of the reach of children. This Instructions for Use has been approved by the U.S. Food and Drug Administration. PROGRAF Granules manufactured by: Astellas Pharma Tech Co., Ltd. Toyama, JapanMarketed by: Astellas Pharma US, Inc. Northbrook, IL 60062PROGRAF(R) is registered trademark of Astellas Pharma Inc. 291762-PRG Revised: July 2021 oMix PROGRAF Granules in water to make an oral suspension.. oGive all of the prepared oral suspension to your child right away after preparing. Do not save the prepared oral suspension for later use.. oUse glass or metal materials to prepare your childs dose of PROGRAF Granules. oDo not use any plastic (PVC) materials to prepare PROGRAF Granules. The granules will stick to plastic container and your child may not receive their full dose. oDo not use any plastic (PVC) materials to prepare PROGRAF Granules. The granules will stick to plastic container and your child may not receive their full dose. oDo not breathe in (inhale) or let the granules in PROGRAF or the prepared oral suspension come in contact with your skin or eyes. oIf you get the granules or the prepared oral suspension on your skin, wash the area well with soap and water. oIf you get the granules or the prepared oral suspension in your eyes, rinse with plain water. oIf you get the granules or the prepared oral suspension on your skin, wash the area well with soap and water. oIf you get the granules or the prepared oral suspension in your eyes, rinse with plain water. oCarton containing PROGRAF Granules packets. Follow the instructions on the carton for the number of packets your childs healthcare provider has prescribed for each dose.. opaper towels. opair of scissors. ometal stirring spoon. omeasuring device. o1 small clean glass cup (plastic containers should not be used). ocontainer with drinking water oCarton containing PROGRAF Granules packets. Follow the instructions on the carton for the number of packets your childs healthcare provider has prescribed for each dose.. opaper towels. opair of scissors. ometal stirring spoon. omeasuring device. o1 small clean glass cup (plastic containers should not be used). ocontainer with drinking water o1 non-PVC oral syringe (ask your pharmacist for the oral syringe you should use). Figure A. Step 3. Step 4. Step 5. Step 7. Step 8. Step 9. Figure B. Step 3. Step 4. Step 5. Step 7. Step 8. Step 9. Step 10.

LACTATION SECTION.

8.2 Lactation Risk SummaryControlled 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 [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)]. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for PROGRAF and any potential adverse effects on the breastfed child from PROGRAF or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Tacrolimus binds to an intracellular protein, FKBP-12. 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-B).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).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCarcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3.0 mg/kg/day (0.9 to 2.2 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) and in the rat was 5.0 mg/kg/day (0.265 to 0.65 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) [see Warnings and Precautions (5.1)]. 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% 3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m2/day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high-dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at daily dose of 3.5 mg/kg (0.1% tacrolimus ointment). No drug-related tumors were noted in the mouse dermal carcinogenicity study at daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown.The implications of these carcinogenicity studies to the human condition are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune systems ability to inhibit unrelated carcinogenesis.MutagenesisNo evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.Impairment of FertilityTacrolimus, subcutaneously administered to male rats at paternally toxic doses of mg/kg/day (1.6 to 4.3 times the recommended clinical dose range [0.2 to 0.075 mg/kg/day] on mg/m2 basis) or mg/kg/day (2.4 to 6.4 times the recommended clinical dose range), resulted in dose-related decrease in sperm count. Tacrolimus, administered orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by higher rate of pre- and post-implantation loss and increased numbers of undelivered and nonviable pups. When administered at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.

OVERDOSAGE SECTION.

10 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. 0.5 mg Individual Carton 0.5 mg Individual Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness have been established in pediatric liver, kidney, heart, and lung transplant patients.Liver TransplantationSafety 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 TransplantationUse 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 TransplantationThe 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean +- S.D.) of tacrolimus have been determined following intravenous (IV) and/or oral (PO) administration in healthy volunteers, and in kidney transplant, liver transplant, and heart transplant patients (Table 17). Table 17. Pharmacokinetics Parameters (mean +- S.D.) of Tacrolimus in Healthy Volunteers and PatientsPopulationNRoute(Dose)ParametersCmax (ng/mL)Tmax (hr)AUC(ngohr/mL)t1/2 (hr)CL(L/hr/kg)V(L/kg) Healthy Volunteers 8IV (0.025 mg/kg/4 hr)Not applicable652AUC0-inf +- 15634.2 +- 7.70.040 +- 0.0091.91 +- 0.3130PO (5 mg) (granules)35.6 +- 10.91.3 +- 0.5320 +- 16432.1 +- 5.9Not availablePO (5 mg) (capsules)28.8 +- 8.91.5 +- 0.7266 +- 9532.3 +- 8.8 Kidney Transplant Patients26IV (0.02 mg/kg/12 hr)294 +- 26218.8 +- 16.70.083 +- 0.0501.41 +- 0.66PO (0.2 mg/kg/day)19.2 +- 10.33.0203 +- 42PO (0.3 mg/kg/day)24.2 +- 15.81.5288 +- 93 Liver Transplant Patients17IV (0.05 mg/kg/12 hr)3300 +- 213011.7 +- 3.90.053 +- 0.0170.85 +- 0.30PO (0.3 mg/kg/day)68.5 +- 30.02.3 +- 1.5519 +- 179 Heart Transplant Patients11IV (0.01 mg/kg/day as continuous infusion)954AUC0-t +- 33423.6 +- 9.220.051 +- 0.01511PO (0.075 mg/kg/day)Determined after the first dose 14.7 +- 7.792.1 [0.5-6.0]Median [range] 82.7AUC0-12 +- 63.214PO (0.15 mg/kg/day) 24.5 +- 13.71.5 [0.4-4.0] 142 +- 116Due to intersubject variability in tacrolimus pharmacokinetics, individualization of the dosing regimen is necessary for optimal therapy [see Dosage and Administration 2.6 )]. Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics.AbsorptionAbsorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability of tacrolimus was 17 +- 10% in adult kidney transplant patients (N 26), 22 +- 6% in adult liver transplant patients (N 17), 23 +- 9% in adult heart transplant patients (N 11) and 18 +- 5% in healthy volunteers (N 16).A single dose trial conducted in 32 healthy volunteers established the bioequivalence of the mg and mg capsules. Another single dose trial in 32 healthy volunteers established the bioequivalence of the 0.5 mg and mg capsules. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in dose-proportional fashion in 18 fasted healthy volunteers receiving single oral dose of 3, 7, and 10 mg.In 18 kidney transplant patients, tacrolimus trough concentrations from to 30 ng/mL measured at 10-12 hours post-dose (Cmin) correlated well with the AUC (correlation coefficient 0.93). In 24 liver transplant patients over concentration range of 10 to 60 ng/mL, the correlation coefficient was 0.94. In 25 heart transplant patients over concentration range of to 24 ng/mL, the correlation coefficient was 0.89 after an oral dose of 0.075 or 0.15 mg/kg/day at steady-state.In healthy volunteer adult study, the systemic exposure to tacrolimus (AUC) for PROGRAF Granules was approximately 16% higher than that for PROGRAF capsules when administered as single doses. If pediatric patients are converted between formulations, therapeutic drug monitoring must be performed and dose adjustments made to ensure that systemic exposure to tacrolimus is maintained. Food EffectsThe rate and extent of tacrolimus absorption were greatest under fasted conditions. The presence and composition of food decreased both the rate and extent of tacrolimus absorption when administered to 15 healthy volunteers.The effect was most pronounced with high-fat meal (848 kcal, 46% fat): mean AUC and Cmax were decreased 37% and 77%, respectively; Tmax was lengthened 5-fold. high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean Cmax by 28% and 65%, respectively.In healthy volunteers (N 16), the time of the meal also affected tacrolimus bioavailability. When given immediately following the meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition.In 11 liver transplant patients, PROGRAF administered 15 minutes after high fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC (27 +- 18%) and Cmax (50 +- 19%), as compared to fasted state.PROGRAF capsules should be taken consistently every day either with or without food because the presence and composition of food decreases the bioavailability of PROGRAF [see Dosage and Administration (2.1)].DistributionThe plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In U.S. trial, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).EliminationMetabolismTacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). metabolic pathway leading to the formation of possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, 31-demethyl metabolite has been reported to have the same activity as tacrolimus.ExcretionThe mean clearance following IV administration of tacrolimus is 0.040, 0.083, 0.053, and 0.051 L/hr/kg in healthy volunteers, adult kidney transplant patients, adult liver transplant patients, and adult heart transplant patients, respectively. In man, less than 1% of the dose administered is excreted unchanged in urine.In mass balance study of IV-administered radiolabeled tacrolimus to healthy volunteers, the mean recovery of radiolabel was 77.8 +- 12.7%. Fecal elimination accounted for 92.4 +- 1.0% and the elimination half-life based on radioactivity was 48.1 +- 15.9 hours whereas it was 43.5 +- 11.6 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.029 +- 0.015 L/hr/kg and clearance of tacrolimus was 0.029 +- 0.009 L/hr/kg. When administered PO, the mean recovery of the radiolabel was 94.9 +- 30.7%. Fecal elimination accounted for 92.6 +- 30.7%, urinary elimination accounted for 2.3 +- 1.1% and the elimination half-life based on radioactivity was 31.9 +- 10.5 hours whereas it was 48.4 +- 12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226 +- 0.116 L/hr/kg and clearance of tacrolimus was 0.172 +- 0.088 L/hr/kg.Specific PopulationsPediatric PatientsPROGRAF capsules Pharmacokinetics in Pediatric PatientsPharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following IV administration of 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 11.5 +- 3.8 hours, 2.6 +- 2.1 L/kg and 0.138 +- 0.071 L/hr/kg, respectively. Following oral administration to patients, mean AUC and Cmax were 337 +- 167 ng.hr/mL and 48.4 +- 27.9 ng/mL, respectively. The absolute bioavailability was 31 +- 24%.Pharmacokinetics of tacrolimus have also been studied in kidney transplantation patients, 8.2 +- 2.4 years of age. Following IV infusion of 0.06 mg/kg/day to 12 pediatric patients (8 male and female), mean terminal half-life and clearance were 10.2 +- 5.0 hours and 0.12 +- 0.04 L/hr/kg, respectively. Following oral administration to the same patients, mean AUC and Cmax were 181 +- 65 ng.hr/mL and 30 +- 11 ng/mL, respectively. The absolute bioavailability was 19 +- 14%.Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations [see Dosage and Administration 2.3 )]. PROGRAF Granules Pharmacokinetics in Pediatric PatientsA multicenter, open-label, single arm, pharmacokinetic study (OPTION, NCT01371331) was conducted using tacrolimus granules for oral suspension in pediatric patients undergoing de novo liver, kidney, or heart transplant. After an initial 24-hour continuous IV infusion of tacrolimus (0.025 mg/kg/hour) for 12 hours to days, oral PROGRAF Granules were dosed at 0.3 mg/kg/day in divided doses twice daily. Tacrolimus whole blood trough concentrations ranged from 5-15 ng/mL for the first month post-transplant, and 5-10 ng/mL thereafter. Two pharmacokinetic (PK) profiles, AUC, Cmax, Tmax and Ctrough, were taken after the first oral dose (Day 1) and at steady state (Day 7). Subsequent oral doses of PROGRAF Granules were adjusted based on clinical evidence of efficacy, the whole-blood trough levels, and/or occurrence of adverse events. Of 52 patients enrolled, thirty-eight (38) had an evaluable PK profile. The mean pediatric age was 6.1 years for heart transplant, 1.1 years for liver transplant and 3.6 years for kidney transplant. Summary results of PK parameters are presented in Table 18.Table 18. Summary of Whole Blood PK Parameters of Tacrolimus after Administration of PROGRAF Granules in Pediatric PatientsPopulationN(age range)ParametersAUCtau [hrng/mL]mean +- SDCmax [ng/mL]mean +- SDTmax [hr]mean +- SDCtrough [ng/mL]mean +- SDHeart Transplant Patients12 (0.58-13 years)Day 1Day 7224.13 +- 114.30165.17 +- 39.1245.61 +- 19.5532.69 +- 9.782.95 +- 4.330.84 +- 0.4412.60 +- 13.407.57 +- 1.80Liver Transplant Patients14 (0.33-12 years)Day 1Day 7210.56 +- 84.01195.08 +- 94.6325.11 +- 10.7830.52 +- 19.352.73 +- 1.841.71 +- 1.1213.41 +- 7.119.71 +- 4.03Kidney Transplant Patients12 (2.42-11 years)Day 1Day 797.40 +- 36.77208.32 +- 68.7518.04 +- 8.1036.63 +- 13.971.78 +- 0.881.09 +- 0.613.54 +- 1.458.92 +- 3.59Renal and Hepatic Impaired PatientsThe mean pharmacokinetic parameters for tacrolimus following single administrations to adult patients with renal and hepatic impairment are given in Table 19. Table 19. Pharmacokinetics in Renal and Hepatic Impaired Adult PatientsPopulation(No. of Patients)DoseAUC0-t (ng.hr/mL)t1/2 (hr)V(L/kg)CI(L/hr/kg) Renal Impairment (n 12)0.02mg/kg/4 hrIV393 +- 123(t 60 hr)26.3 +- 9.21.07 +- 0.200.038 +- 0.014 Mild Hepatic Impairment (n 6)0.02mg/kg/4 hrIV367 +- 107(t 72 hr)60.6 +- 43.8Range: 27.8 1413.1 +- 1.60.042 +- 0.027.7 mgPO488 +- 320(t 72 hr)66.1 +- 44.8Range: 29.5 1383.7 +- 4.7Corrected for bioavailability 0.034 +- 0.019 Severe Hepatic Impairment (n 6, IV)0.02 mg/kg/4 hrIV (n 2) 0.01 mg/kg/8 hrIV (n 4)762 +- 204(t 120 hr) 289 +- 117(t 144 hr)198 +- 158Range: 81 4363.9 +- 1.00.017 +- 0.013 (n 5, PO)1 patient did not receive the PO dose mg PO(n 1) mg PO(n 4)4 mg PO(n 1)658(t 120 hr) 533 +- 156(t 144 hr)119 +- 35Range: 85 178 0.016 +- 0.011 Patients with Renal ImpairmentTacrolimus pharmacokinetics, following single IV administration, were determined in 12 patients (7 not on dialysis and on dialysis, serum creatinine of 3.9 +- 1.6 and 12.0 +- 2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers (Table 19) [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].Patients with Hepatic ImpairmentTacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in patients with severe hepatic dysfunction (mean Pugh score: 10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [see Dosage and Administration (2.5) and Use in Specific Populations (8.7)].Patients with Cystic FibrosisLower bioavailability of tacrolimus has been reported in patients with cystic fibrosis [see Dosage and Administration (2.2, 2.3)].Racial or Ethnic GroupsThe pharmacokinetics of tacrolimus have been studied following single IV and oral administration of PROGRAF to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following 4-hour IV infusion of 0.015 mg/kg. However, after single oral administration of mg, mean (+- SD) tacrolimus Cmax in African-Americans (23.6 +- 12.1 ng/mL) was significantly lower than in Caucasians (40.2 +- 12.6 ng/mL) and the Latino-Americans (36.2 +- 15.8 ng/mL) (p 0.01). Mean AUC0-inf tended to be lower in African-Americans (203 +- 115 ng.hr/mL) than Caucasians (344 +- 186 ng.hr/mL) and Latino-Americans (274 +- 150 ng.hr/mL). The mean (+- SD) absolute oral bioavailability (F) in African-Americans (12 +- 4.5%) and Latino-Americans (14 +- 7.4%) was significantly lower than in Caucasians (19 +- 5.8%, = 0.011). There was no significant difference in mean terminal T1/2 among the three ethnic groups (range from approximately 25 to 30 hours). retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see Dosage and Administration (2.2)]. Male and Female PatientsA formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in dosing by gender in the kidney transplant trial. retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney, liver, and heart transplant patients indicated no gender-based differences.Drug Interaction StudiesFrequent monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when concomitant use of the following drugs with tacrolimus is initiated or discontinued [see Drug Interactions (7)].oTelaprevir: In single-dose study in healthy volunteers, co-administration of tacrolimus (0.5 mg single dose) with telaprevir (750 mg three times daily for 13 days) increased the tacrolimus dose-normalized Cmax by 9.3-fold and AUC by 70-fold compared to tacrolimus alone [see Drug Interactions (7.2)].oBoceprevir: In single-dose study in 12 subjects, co-administration of tacrolimus (0.5 mg single dose) with boceprevir (800 mg three times daily for 11 days) increased tacrolimus Cmax by 9.9-fold and AUC by 17-fold compared to tacrolimus alone [see Drug Interactions (7.2)].oNelfinavir: Based on clinical study of liver transplant recipients, co-administration of tacrolimus with nelfinavir increased blood concentrations of tacrolimus significantly and, as result, reduction in the tacrolimus dose by an average of 16-fold was needed to maintain mean trough tacrolimus blood concentrations of 9.7 ng/mL. It is recommended to avoid concomitant use of PROGRAF and nelfinavir unless the benefits outweigh the risks [see Drug Interactions (7.2)]. oRifampin: In study of normal volunteers, significant decrease in tacrolimus oral bioavailability (14 +- 6% vs. +- 3%) was observed with concomitant rifampin administration (600 mg). In addition, there was significant increase in tacrolimus clearance (0.036 +- 0.008 L/hr/kg vs. 0.053 +- 0.010 L/hr/kg) with concomitant rifampin administration [see Drug Interactions (7.2)]. oMagnesium and Aluminum-hydroxide: In single-dose crossover study in healthy volunteers, co-administration of tacrolimus and magnesium-aluminum-hydroxide resulted in 21% increase in the mean tacrolimus AUC and 10% decrease in the mean tacrolimus Cmax relative to tacrolimus administration alone [see Drug Interactions (7.2)]. oKetoconazole: In study of normal volunteers, significant increase in tacrolimus oral bioavailability (14 +- 5% vs. 30 +- 8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430 +- 0.129 L/hr/kg vs. 0.148 +- 0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients [see Drug Interactions (7.2)]. oVoriconazole (see complete prescribing information for VFEND): Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for days) increased tacrolimus (0.1 mg/kg single dose) Cmax and AUC in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see Drug Interactions (7.2)].oPosaconazole (see complete prescribing information for Noxafil): Repeat oral administration of posaconazole (400 mg twice daily for days) increased tacrolimus (0.05 mg/kg single dose) Cmax and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [see Drug Interactions (7.2)].oCaspofungin (see complete prescribing information for CANCIDAS): Caspofungin reduced the blood AUC0-12 of tacrolimus by approximately 20%, peak blood concentration (Cmax) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS 70 mg daily, as compared to results from control period in which tacrolimus was administered alone [see Drug Interactions (7.2)].. oTelaprevir: In single-dose study in healthy volunteers, co-administration of tacrolimus (0.5 mg single dose) with telaprevir (750 mg three times daily for 13 days) increased the tacrolimus dose-normalized Cmax by 9.3-fold and AUC by 70-fold compared to tacrolimus alone [see Drug Interactions (7.2)].. oBoceprevir: In single-dose study in 12 subjects, co-administration of tacrolimus (0.5 mg single dose) with boceprevir (800 mg three times daily for 11 days) increased tacrolimus Cmax by 9.9-fold and AUC by 17-fold compared to tacrolimus alone [see Drug Interactions (7.2)].. oNelfinavir: Based on clinical study of liver transplant recipients, co-administration of tacrolimus with nelfinavir increased blood concentrations of tacrolimus significantly and, as result, reduction in the tacrolimus dose by an average of 16-fold was needed to maintain mean trough tacrolimus blood concentrations of 9.7 ng/mL. It is recommended to avoid concomitant use of PROGRAF and nelfinavir unless the benefits outweigh the risks [see Drug Interactions (7.2)]. oRifampin: In study of normal volunteers, significant decrease in tacrolimus oral bioavailability (14 +- 6% vs. +- 3%) was observed with concomitant rifampin administration (600 mg). In addition, there was significant increase in tacrolimus clearance (0.036 +- 0.008 L/hr/kg vs. 0.053 +- 0.010 L/hr/kg) with concomitant rifampin administration [see Drug Interactions (7.2)]. oMagnesium and Aluminum-hydroxide: In single-dose crossover study in healthy volunteers, co-administration of tacrolimus and magnesium-aluminum-hydroxide resulted in 21% increase in the mean tacrolimus AUC and 10% decrease in the mean tacrolimus Cmax relative to tacrolimus administration alone [see Drug Interactions (7.2)]. oKetoconazole: In study of normal volunteers, significant increase in tacrolimus oral bioavailability (14 +- 5% vs. 30 +- 8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430 +- 0.129 L/hr/kg vs. 0.148 +- 0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients [see Drug Interactions (7.2)]. oVoriconazole (see complete prescribing information for VFEND): Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for days) increased tacrolimus (0.1 mg/kg single dose) Cmax and AUC in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see Drug Interactions (7.2)].. oPosaconazole (see complete prescribing information for Noxafil): Repeat oral administration of posaconazole (400 mg twice daily for days) increased tacrolimus (0.05 mg/kg single dose) Cmax and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [see Drug Interactions (7.2)].. oCaspofungin (see complete prescribing information for CANCIDAS): Caspofungin reduced the blood AUC0-12 of tacrolimus by approximately 20%, peak blood concentration (Cmax) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS 70 mg daily, as compared to results from control period in which tacrolimus was administered alone [see Drug Interactions (7.2)].

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy registry that monitors pregnancy outcomes in women exposed to PROGRAF during pregnancy.The Transplantation Pregnancy Registry International (TPRI) is 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 SummaryTacrolimus can cause fetal harm when administered to pregnant woman. Data from postmarketing surveillance and TPRI suggest that infants exposed to tacrolimus in utero are at 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 mg/m2 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 mg/m2 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 mg/m2 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 to 4% and 15 to 20%, respectively.Clinical ConsiderationsDisease-Associated Maternal and/or Embryo-Fetal RiskRisks 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 ReactionsPROGRAF 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 ReactionsRenal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at the time of delivery in infants of mothers taking PROGRAF. Labor or DeliveryThere is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to PROGRAF. DataHuman DataThere 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 TacrolimusKidneyLiverPregnancy OutcomesIncludes multiple births and terminations.462253 Miscarriage 24.5%25% Live births 331180 Pre-term delivery (< 37 weeks)49%42% Low birth weight (< 2500 g)42%30% Birth defects8%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 DataAdministration 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 mg/m2 basis). At mg/kg (1.6 to 4.3 times the recommended clinical dose range), 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 to 6.9 times the recommended clinical dose range) 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 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 to 6.9 times the recommended clinical dose range); 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 to 2.2 times the recommended clinical dose range).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 to 6.9 times the 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 mg/kg (0.8 to 2.2 times the recommended clinical dose range) [see Nonclinical Toxicology (13.1)].

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1.1) 7/2021Dosage and Administration (2.2, 2.3) 7/2021Warnings and Precautions (5.11) 12/2020.

REFERENCES SECTION.

15 REFERENCES 1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationPROGRAF(R) (PRO-graf) (tacrolimus) capsules, for oral usePROGRAF(R) (PRO-graf) Granules (tacrolimus for oral suspension)Read this Patient Information before you start taking PROGRAF and each time you get refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is the most important information should know about PROGRAFPROGRAF can cause serious side effects, including:oIncreased risk of cancer. People who take PROGRAF have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma).oIncreased risk of infection. PROGRAF is medicine that affects your immune system. PROGRAF can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving PROGRAF that can cause death. Call your healthcare provider right away if you have any symptoms of an infection, including:ofeverosweats or chillsocough or flu-like symptomsomuscle achesowarm, red, or painful areas on your skinWhat is PROGRAFoPROGRAF is prescription medicine used with other medicines to help prevent organ rejection in people who have had kidney, liver, heart, or lung transplant. oPROGRAF capsules and PROGRAF GRANULES are types of tacrolimus immediate-release drugs and they are not the same as tacrolimus extended-release tablets or tacrolimus extended-release capsules. Your healthcare provider should decide what medicine is right for you.Who should not take PROGRAFDo not take PROGRAF if you:oare allergic to tacrolimus or any of the ingredients in PROGRAF. See the end of this leaflet for complete list of ingredients in PROGRAF.What should tell my healthcare provider before taking PROGRAFBefore taking PROGRAF, tell your healthcare provider about all of your medical conditions, including if you:oplan to receive any vaccines. People taking PROGRAF should not receive live vaccines. ohave or have had liver, kidney, or heart problems.oare pregnant or plan to become pregnant. PROGRAF can harm your unborn baby.oIf you are able to become pregnant, you should use effective birth control before and during treatment with PROGRAF. Talk to your healthcare provider before starting treatment with PROGRAF about birth control methods that may be right for you.oMales who have female partners who are able to become pregnant should also use effective birth control before and during treatment with PROGRAF. Talk to your healthcare provider before starting treatment with PROGRAF about birth control methods that may be right for you. oThere is pregnancy registry for females who become pregnant and males who have fathered pregnancy during treatment with PROGRAF. The purpose of this registry is to collect information about the health of you and your baby. To enroll in this voluntary registry, call 1-877-955-6877 or go to https://www.transplantpregnancyregistry.org/.oare breastfeeding or plan to breastfeed. PROGRAF passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking PROGRAF.oplan to have children. PROGRAF may affect the ability to have children in females and males (fertility problems).Tell your healthcare provider about all the medicines you take, and when you start new medicine or stop taking medicine, including prescription and over-the-counter medicines, vitamins, natural, herbal, or nutritional supplements.Especially tell your healthcare provider if you take:osirolimus (RAPAMUNE): You should not take PROGRAF if you take sirolimus. ocyclosporine (GENGRAF, NEORAL, and SANDIMMUNE)omedicines called aminoglycosides that are used to treat bacterial infectionsoganciclovir (CYTOVENE IV, VALCYTE)oamphotericin (ABELCET, AMBISOME)ocisplatinoantiviral medicines called nucleoside reverse transcriptase inhibitors oantiviral medicines called protease inhibitors owater pill (diuretic)omedicine to treat high blood pressure onelfinavir (VIRACEPT)otelaprevir (INCIVEK)oboceprevir oritonavir (KALETRA, NORVIR, TECHNIVIE, VIEKIRA PAK, VIEKIRA XR)oletermovir (PREVYMIS)oketoconazole oitraconazole (ONMEL, SPORANOX)ovoriconazole (VFEND)oclarithromycin (BIAXIN, BIAXIN XL, PREVPAC)orifampin (RIFADIN, RIFAMATE, RIFATER, RIMACTANE)orifabutin (MYCOBUTIN) oamiodarone (NEXTERONE, PACERONE)Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above.PROGRAF may affect the way other medicines work, and other medicines may affect how PROGRAF works.Know the medicines you take. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine.How should take PROGRAFoTake PROGRAF exactly as your healthcare provider tells you to take it.oYour healthcare provider will tell you how much PROGRAF to take and when to take it. Your healthcare provider may change your PROGRAF dose if needed. Do not stop taking or change your dose of PROGRAF without talking to your healthcare provider.PROGRAF capsules:oDo not open or crush PROGRAF capsules.PROGRAF Granules:oChildren who have trouble swallowing capsules can be given PROGRAF Granules.oGive the dose of PROGRAF Granules right after preparing. Do not save prepared PROGRAF Granules as liquid to take at later time. oSee the Instructions for Use at the end of this Patient Information for detailed instructions about how to mix and give PROGRAF Granules as liquid in glass cup or oral syringe.oIf you get the granules or prepared oral suspension on your skin, wash the area well with soap and water. oIf you get the granules or prepared oral suspension in your eyes, rinse with plain water.What should avoid while taking PROGRAFoWhile you take PROGRAF you should not receive any live vaccines. oLimit the amount of time you spend in sunlight and avoid exposure to ultraviolet (UV) light, such as tanning machines. Wear protective clothing and use sunscreen with high sun protection factor (SPF).oDo not eat grapefruit or drink grapefruit juice during treatment with PROGRAF.What are the possible side effects of PROGRAFPROGRAF may cause serious side effects, including:oSee What is the most important information should know about PROGRAFoproblems from medicine errors. People who take PROGRAF have sometimes been given the wrong type of tacrolimus product. Tacrolimus extended-release medicines are not the same as PROGRAF capsules or granules and cannot be substituted for each other. Check your PROGRAF when you get new prescription and before you take it to make sure you have received PROGRAF capsules or PROGRAF Granules.oCheck with the pharmacist and call your healthcare provider if you think you were given the wrong medicine. ohigh blood sugar (diabetes). Your healthcare provider may do blood tests to check for diabetes while you take PROGRAF. Call your healthcare provider right away if you have any symptoms of high blood sugar, including:ofrequent urinationoincreased thirst or hungeroblurred visionoconfusionodrowsinessoloss of appetiteofruity smell on your breathonausea, vomiting, or stomach painokidney problems. Kidney problems are serious and common side effect of PROGRAF. Your healthcare provider may do blood tests to check your kidney function while you take PROGRAF. onervous system problems. Nervous system problems are serious and common side effect of PROGRAF. Call your healthcare provider right away if you get any of these symptoms while taking PROGRAF. These could be signs of serious nervous system problem:oheadacheoconfusionoseizuresochanges in your visionochanges in behaviorocomaotremorsonumbness and tinglingohigh levels of potassium in your blood. Your healthcare provider may do blood tests to check your potassium level while you take PROGRAF.ohigh blood pressure. High blood pressure is serious and common side effect of PROGRAF. Your healthcare provider will monitor your blood pressure while you take PROGRAF and may prescribe blood pressure medicine for you, if needed. Your healthcare provider may instruct you to check your blood pressure at home.ochanges in the electrical activity of your heart (QT prolongation).oheart problems (myocardial hypertrophy). Tell your healthcare provider right away if you get any of these symptoms of heart problems while taking PROGRAF:oshortness of breathochest painofeel lightheadedofeel faintosevere low red blood cell count (anemia).The most common side effects of PROGRAF in people who have received kidney, liver, heart, or lung transplant are:oinfections in general, including cytomegalovirus (cmv) infectionotremors (shaking of the body)oconstipationodiarrheaoheadacheostomach painotrouble sleepingonauseaohigh blood sugar (diabetes)olow levels of magnesium in your bloodolow levels of phosphate in your bloodoswelling of the hands, legs, ankles, or feetoweaknessopainohigh levels of fat in your bloodohigh levels of potassium in your bloodolow red blood cell count (anemia)olow white blood cell countofeveronumbness or tingling in your hands and feetoinflammation of your airway (bronchitis)ofluid around your heartTell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of PROGRAF. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store PROGRAFPROGRAF capsulesoStore PROGRAF capsules at room temperature between 68F to 77F (20C to 25C). PROGRAF GranulesoStore PROGRAF Granules packets at room temperature between 68F to 77F (20C to 25C).Keep PROGRAF and all medicines out of the reach of children.General information about the safe and effective use of PROGRAF.oMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use PROGRAF for condition for which it was not prescribed. Do not give PROGRAF to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about PROGRAF that is written for health professionals. oThis Patient Information leaflet summarizes the most important information about PROGRAF. If you would like more information, talk to your healthcare provider.What are the ingredients in PROGRAFActive ingredient: tacrolimusInactive ingredients:PROGRAF capsules: croscarmellose sodium, hypromellose, lactose monohydrate, and magnesium stearate. The 0.5 mg capsule shell contains ferric oxide, gelatin, and titanium dioxide. The mg capsule shell contains gelatin and titanium dioxide. The mg capsule shell contains ferric oxide, gelatin, and titanium dioxide.PROGRAF Granules: croscarmellose sodium, hypromellose, and lactose monohydrate.Capsules manufactured by: Astellas Ireland Co., Ltd. Killorglin, County Kerry, IrelandPROGRAF Granules manufactured by: Astellas Pharma Tech Co., Ltd. Toyama, JapanMarketed by: Astellas Pharma US, Inc. Northbrook, IL 60062PROGRAF(R) is registered trademark of Astellas Pharma Inc. All other trademarks and registered trademarks are the property of their respective owners.291762-PRG For more information, go to www.astellas.com/us or call 1-800-727-7003.This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 07-2021. oIncreased risk of cancer. People who take PROGRAF have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma).. oIncreased risk of infection. PROGRAF is medicine that affects your immune system. PROGRAF can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving PROGRAF that can cause death. Call your healthcare provider right away if you have any symptoms of an infection, including:. ofever. osweats or chills. ocough or flu-like symptoms. omuscle aches. owarm, red, or painful areas on your skin. oPROGRAF is prescription medicine used with other medicines to help prevent organ rejection in people who have had kidney, liver, heart, or lung transplant. oPROGRAF capsules and PROGRAF GRANULES are types of tacrolimus immediate-release drugs and they are not the same as tacrolimus extended-release tablets or tacrolimus extended-release capsules. Your healthcare provider should decide what medicine is right for you.. oare allergic to tacrolimus or any of the ingredients in PROGRAF. See the end of this leaflet for complete list of ingredients in PROGRAF.. oplan to receive any vaccines. People taking PROGRAF should not receive live vaccines. ohave or have had liver, kidney, or heart problems.. oare pregnant or plan to become pregnant. PROGRAF can harm your unborn baby.. oIf you are able to become pregnant, you should use effective birth control before and during treatment with PROGRAF. Talk to your healthcare provider before starting treatment with PROGRAF about birth control methods that may be right for you.. oMales who have female partners who are able to become pregnant should also use effective birth control before and during treatment with PROGRAF. Talk to your healthcare provider before starting treatment with PROGRAF about birth control methods that may be right for you. oThere is pregnancy registry for females who become pregnant and males who have fathered pregnancy during treatment with PROGRAF. The purpose of this registry is to collect information about the health of you and your baby. To enroll in this voluntary registry, call 1-877-955-6877 or go to https://www.transplantpregnancyregistry.org/.. oare breastfeeding or plan to breastfeed. PROGRAF passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking PROGRAF.. oplan to have children. PROGRAF may affect the ability to have children in females and males (fertility problems).. osirolimus (RAPAMUNE): You should not take PROGRAF if you take sirolimus. ocyclosporine (GENGRAF, NEORAL, and SANDIMMUNE). omedicines called aminoglycosides that are used to treat bacterial infections. oganciclovir (CYTOVENE IV, VALCYTE). oamphotericin (ABELCET, AMBISOME). ocisplatin. oantiviral medicines called nucleoside reverse transcriptase inhibitors oantiviral medicines called protease inhibitors owater pill (diuretic). omedicine to treat high blood pressure onelfinavir (VIRACEPT). otelaprevir (INCIVEK). oboceprevir oritonavir (KALETRA, NORVIR, TECHNIVIE, VIEKIRA PAK, VIEKIRA XR). oletermovir (PREVYMIS). oketoconazole oitraconazole (ONMEL, SPORANOX). ovoriconazole (VFEND). oclarithromycin (BIAXIN, BIAXIN XL, PREVPAC). orifampin (RIFADIN, RIFAMATE, RIFATER, RIMACTANE). orifabutin (MYCOBUTIN) oamiodarone (NEXTERONE, PACERONE). oTake PROGRAF exactly as your healthcare provider tells you to take it.. oYour healthcare provider will tell you how much PROGRAF to take and when to take it.. Your healthcare provider may change your PROGRAF dose if needed. Do not stop taking or change your dose of PROGRAF without talking to your healthcare provider.. oDo not open or crush PROGRAF capsules.. oChildren who have trouble swallowing capsules can be given PROGRAF Granules.. oGive the dose of PROGRAF Granules right after preparing. Do not save prepared PROGRAF Granules as liquid to take at later time. oSee the Instructions for Use at the end of this Patient Information for detailed instructions about how to mix and give PROGRAF Granules as liquid in glass cup or oral syringe.. oIf you get the granules or prepared oral suspension on your skin, wash the area well with soap and water. oIf you get the granules or prepared oral suspension in your eyes, rinse with plain water.. oWhile you take PROGRAF you should not receive any live vaccines. oLimit the amount of time you spend in sunlight and avoid exposure to ultraviolet (UV) light, such as tanning machines. Wear protective clothing and use sunscreen with high sun protection factor (SPF).. oDo not eat grapefruit or drink grapefruit juice during treatment with PROGRAF.. oSee What is the most important information should know about PROGRAF. oproblems from medicine errors. People who take PROGRAF have sometimes been given the wrong type of tacrolimus product. Tacrolimus extended-release medicines are not the same as PROGRAF capsules or granules and cannot be substituted for each other. Check your PROGRAF when you get new prescription and before you take it to make sure you have received PROGRAF capsules or PROGRAF Granules.. oCheck with the pharmacist and call your healthcare provider if you think you were given the wrong medicine. ohigh blood sugar (diabetes). Your healthcare provider may do blood tests to check for diabetes while you take PROGRAF. Call your healthcare provider right away if you have any symptoms of high blood sugar, including:. ofrequent urination. oincreased thirst or hunger. oblurred vision. oconfusion. odrowsiness. oloss of appetite. ofruity smell on your breath. onausea, vomiting, or stomach pain. okidney problems. Kidney problems are serious and common side effect of PROGRAF. Your healthcare provider may do blood tests to check your kidney function while you take PROGRAF. onervous system problems. Nervous system problems are serious and common side effect of PROGRAF. Call your healthcare provider right away if you get any of these symptoms while taking PROGRAF. These could be signs of serious nervous system problem:. oheadache. oconfusion. oseizures. ochanges in your vision. ochanges in behavior. ocoma. otremors. onumbness and tingling. ohigh levels of potassium in your blood. Your healthcare provider may do blood tests to check your potassium level while you take PROGRAF.. ohigh blood pressure. High blood pressure is serious and common side effect of PROGRAF. Your healthcare provider will monitor your blood pressure while you take PROGRAF and may prescribe blood pressure medicine for you, if needed. Your healthcare provider may instruct you to check your blood pressure at home.. ochanges in the electrical activity of your heart (QT prolongation).. oheart problems (myocardial hypertrophy). Tell your healthcare provider right away if you get any of these symptoms of heart problems while taking PROGRAF:. oshortness of breath. ochest pain. ofeel lightheaded. ofeel faint. osevere low red blood cell count (anemia).. oinfections in general, including cytomegalovirus (cmv) infection. otremors (shaking of the body). oconstipation. odiarrhea. oheadache. ostomach pain. otrouble sleeping. onausea. ohigh blood sugar (diabetes). olow levels of magnesium in your blood. olow levels of phosphate in your blood. oswelling of the hands, legs, ankles, or feet. oweakness. opain. ohigh levels of fat in your blood. ohigh levels of potassium in your blood. olow red blood cell count (anemia). olow white blood cell count. ofever. onumbness or tingling in your hands and feet. oinflammation of your airway (bronchitis). ofluid around your heart. oStore PROGRAF capsules at room temperature between 68F to 77F (20C to 25C). oStore PROGRAF Granules packets at room temperature between 68F to 77F (20C to 25C).. oMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use PROGRAF for condition for which it was not prescribed. Do not give PROGRAF to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about PROGRAF that is written for health professionals. oThis Patient Information leaflet summarizes the most important information about PROGRAF. If you would like more information, talk to your healthcare provider.

SPL UNCLASSIFIED SECTION.

1.1 Prophylaxis of Organ Rejection in Kidney, Liver, Heart, or Lung Transplant. PROGRAF(R) 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Can cause fetal harm. Advise pregnant women of the potential risk to the fetus. (8.1, 8.3). Pregnancy: Can cause fetal harm. Advise pregnant women of the potential risk to the fetus. (8.1, 8.3). 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy registry that monitors pregnancy outcomes in women exposed to PROGRAF during pregnancy.The Transplantation Pregnancy Registry International (TPRI) is 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 SummaryTacrolimus can cause fetal harm when administered to pregnant woman. Data from postmarketing surveillance and TPRI suggest that infants exposed to tacrolimus in utero are at 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 mg/m2 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 mg/m2 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 mg/m2 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 to 4% and 15 to 20%, respectively.Clinical ConsiderationsDisease-Associated Maternal and/or Embryo-Fetal RiskRisks 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 ReactionsPROGRAF 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 ReactionsRenal dysfunction, transient neonatal hyperkalemia and low birth weight have been reported at the time of delivery in infants of mothers taking PROGRAF. Labor or DeliveryThere is an increased risk for premature delivery (< 37 weeks) following transplantation and maternal exposure to PROGRAF. DataHuman DataThere 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 TacrolimusKidneyLiverPregnancy OutcomesIncludes multiple births and terminations.462253 Miscarriage 24.5%25% Live births 331180 Pre-term delivery (< 37 weeks)49%42% Low birth weight (< 2500 g)42%30% Birth defects8%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 DataAdministration 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 mg/m2 basis). At mg/kg (1.6 to 4.3 times the recommended clinical dose range), 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 to 6.9 times the recommended clinical dose range) 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 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 to 6.9 times the recommended clinical dose range); 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 to 2.2 times the recommended clinical dose range).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 to 6.9 times the 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 mg/kg (0.8 to 2.2 times the recommended clinical dose range) [see Nonclinical Toxicology (13.1)]. 8.2 Lactation Risk SummaryControlled 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 [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)]. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for PROGRAF and any potential adverse effects on the breastfed child from PROGRAF or from the underlying maternal condition.. 8.3 Females and Males of Reproductive Potential ContraceptionPROGRAF can cause fetal harm when administered to pregnant women. Advise female and male patients of reproductive potential to speak to their healthcare provider on family planning options including appropriate contraception prior to starting treatment with PROGRAF [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)].InfertilityBased on findings in animals, male and female fertility may be compromised by treatment with PROGRAF [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use. Safety and effectiveness have been established in pediatric liver, kidney, heart, and lung transplant patients.Liver TransplantationSafety 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 TransplantationUse 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 TransplantationThe 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. 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.. 8.6 Renal Impairment. The pharmacokinetics of PROGRAF in patients with renal impairment was similar to that in healthy volunteers with normal renal function. However, consideration should be given to dosing PROGRAF at the lower end of the therapeutic dosing range in patients who have received liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].. 8.7 Hepatic Impairment. The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: 10) compared to healthy volunteers with normal hepatic function. Close monitoring of tacrolimus trough concentrations is warranted in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. The use of PROGRAF in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood trough concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration 2.5 and Clinical Pharmacology (12.3)]. 8.8 Race or Ethnicity African-American patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to Caucasian patients [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. African-American and Hispanic patients are at increased risk for new onset diabetes after transplant. Monitor blood glucose concentrations and treat appropriately [see Warnings and Precautions (5.4)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oNot Interchangeable with Extended-Release Tacrolimus Products Medication Errors: Instruct patients or caregivers to recognize the appearance of PROGRAF capsules. (5.3)oNew Onset Diabetes After Transplant: Monitor blood glucose. (5.4)oNephrotoxicity (acute and/or chronic): Reduce the dose; use caution with other nephrotoxic drugs. (5.5)oNeurotoxicity: Including risk of Posterior Reversible Encephalopathy Syndrome (PRES); monitor for neurologic abnormalities; reduce or discontinue PROGRAF. (5.6)oHyperkalemia: Monitor serum potassium levels. Consider carefully before using with other agents also associated with hyperkalemia. (5.7)oHypertension: May require antihypertensive therapy. Monitor relevant drug-drug interactions. (5.8)oAnaphylactic Reactions with IV formulation: Observe patients receiving PROGRAF injection for signs and symptoms of anaphylaxis. (5.9)oNot recommended for use with sirolimus: Not recommended in liver and heart transplant due to increased risk of serious adverse reactions. (5.10)oMyocardial Hypertrophy: Consider dose reduction/discontinuation. (5.13)oImmunizations: Avoid live vaccines. (5.14)oPure Red Cell Aplasia: Consider discontinuation of PROGRAF. (5.15). oNot Interchangeable with Extended-Release Tacrolimus Products Medication Errors: Instruct patients or caregivers to recognize the appearance of PROGRAF capsules. (5.3). oNew Onset Diabetes After Transplant: Monitor blood glucose. (5.4). oNephrotoxicity (acute and/or chronic): Reduce the dose; use caution with other nephrotoxic drugs. (5.5). oNeurotoxicity: Including risk of Posterior Reversible Encephalopathy Syndrome (PRES); monitor for neurologic abnormalities; reduce or discontinue PROGRAF. (5.6). oHyperkalemia: Monitor serum potassium levels. Consider carefully before using with other agents also associated with hyperkalemia. (5.7). oHypertension: May require antihypertensive therapy. Monitor relevant drug-drug interactions. (5.8). oAnaphylactic Reactions with IV formulation: Observe patients receiving PROGRAF injection for signs and symptoms of anaphylaxis. (5.9). oNot recommended for use with sirolimus: Not recommended in liver and heart transplant due to increased risk of serious adverse reactions. (5.10). oMyocardial Hypertrophy: Consider dose reduction/discontinuation. (5.13). oImmunizations: Avoid live vaccines. (5.14). oPure Red Cell Aplasia: Consider discontinuation of PROGRAF. (5.15). 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 broad-spectrum sunscreen with 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, 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:oPolyomavirus-associated nephropathy (PVAN), mostly due to BK virus infection oJC virus-associated progressive multifocal leukoencephalopathy (PML) oCytomegalovirus infections: CMV seronegative transplant patients who receive an organ from 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)]. oPolyomavirus-associated nephropathy (PVAN), mostly due to BK virus infection oJC virus-associated progressive multifocal leukoencephalopathy (PML) oCytomegalovirus infections: CMV seronegative transplant patients who receive an organ from CMV seropositive donor disease are at higher risk of developing CMV viremia and CMV disease.. 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 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. PROGRAF, like other calcineurin inhibitors, can cause acute or chronic nephrotoxicity. Nephrotoxicity was reported in clinical trials [see Adverse Reactions (6.1)]. Consider dosage reduction in patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range. The risk for nephrotoxicity may increase when PROGRAF is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors) [see Drug Interactions (7.2)]. Monitor renal function and consider dosage reduction if nephrotoxicity occurs.. 5.6 Neurotoxicity. PROGRAF may cause 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 (6.1, 6.2)]. As symptoms may be associated with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of PROGRAF if neurotoxicity occurs.. 5.7 Hyperkalemia. Hyperkalemia has been reported with PROGRAF use. Serum potassium levels should be monitored. Careful consideration should be given prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) during PROGRAF therapy [see Adverse Reactions (6.1)]. Monitor serum potassium levels periodically during treatment.. 5.8 Hypertension. Hypertension is common adverse effect of PROGRAF therapy and may require antihypertensive therapy [see Adverse Reactions (6.1)]. The control of blood pressure can be accomplished with any of the common antihypertensive agents, though careful consideration should be given prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) [see Warnings and Precautions (5.7)]. Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of PROGRAF [see Drug Interactions (7.2)]. 5.9 Anaphylactic Reactions with PROGRAF Injection. Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including PROGRAF, in small percentage of patients (0.6%). The exact cause of these reactions is not known. PROGRAF injection should be reserved for patients who are unable to take PROGRAF orally. Monitor patients for anaphylaxis when using the intravenous route of administration [see Dosage and Administration (2.1)]. 5.10 Not Recommended for Use with Sirolimus PROGRAF is not recommended for use with sirolimus: oThe use of sirolimus with PROGRAF in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT), and is not recommended.oThe use of sirolimus (2 mg per day) with PROGRAF in heart transplant patients in U.S. trial was associated with increased risk of renal function impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Clinical Studies (14.3)].. oThe use of sirolimus with PROGRAF in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT), and is not recommended.. oThe use of sirolimus (2 mg per day) with PROGRAF in heart transplant patients in U.S. trial was associated with increased risk of renal function impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Clinical Studies (14.3)].. 5.11 Interactions with CYP3A4 Inhibitors and Inducers When co-administering PROGRAF with strong CYP3A4 inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin), adjustments in the dosing regimen of PROGRAF and subsequent frequent monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions are recommended. rapid, sharp rise in tacrolimus levels has been reported after co-administration with strong CYP3A4 inhibitor, clarithromycin, despite an initial reduction of tacrolimus dose. Early and frequent monitoring of tacrolimus whole blood trough levels is recommended [see Drug Interactions (7.2)].. 5.12 QT Prolongation. PROGRAF may prolong the QT/QTc interval and may cause Torsade de Pointes. Avoid PROGRAF in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment. When co-administering PROGRAF with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, reduction in PROGRAF dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. Use of PROGRAF with amiodarone has been reported to result in increased tacrolimus whole blood concentrations with or without concurrent QT prolongation [see Drug Interactions (7.2)].. 5.13 Myocardial Hypertrophy. Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving PROGRAF therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of PROGRAF should be considered [see Adverse Reactions (6.2)].. 5.14 Immunizations. Whenever possible, administer the complete complement of vaccines before transplantation and treatment with PROGRAF.The use of live vaccines should be avoided during treatment with tacrolimus; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with PROGRAF.. 5.15 Pure Red Cell Aplasia. Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. mechanism for tacrolimus-induced PRCA has not been elucidated. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. If PRCA is diagnosed, discontinuation of PROGRAF should be considered [see Adverse Reactions (6.2)].