16) ] The most common adverse reactions (≥ 15%) were abnormal renal function, hypertension, diabetes mellitus, fever, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, constipation, diarrhea, headache, abdominal pain, insomnia, paresthesia, peripheral edema, nausea, hyperkalemia, hypomagnesemia, and hyperlipemia.
1) To report SUSPECTED ADVERSE REACTIONS, contact Dr. 1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below. Kidney Transplantation The incidence of adverse reactions was determined in three randomized kidney transplant trials.
One of the trials used azathioprine (AZA) and corticosteroids and two of the trials used mycophenolate mofetil (MMF) and corticosteroids concomitantly for maintenance immunosuppression. Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a trial where 205 patients received tacrolimus-based immunosuppression and 207 patients received cyclosporine-based immunosuppression.
The trial population had a mean age of 43 years (mean±SD was 43±13 years on tacrolimus 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 tacrolimus-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 tacrolimus in conjunction with azathioprine are presented below: Table 4.
Kidney Transplantation:
Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA) Tacrolimus/AZA (N=205) Cyclosporine/AZA (N=207) Nervous System Tremor Headache Insomnia Paresthesia Dizziness 54% 44% 32% 23% 19% 34% 38% 30% 16% 16% Gastrointestinal Diarrhea Nausea Constipation Vomiting Dyspepsia 44% 38% 35% 29% 28% 41% 36% 43% 23% 20% Cardiovascular Hypertension Chest Pain 50% 19% 52% 13% Urogenital Creatinine Increased Urinary Tract Infection 45% 34% 42% 35% Metabolic and Nutritional Hypophosphatemia Hypomagnesemia Hyperlipemia Hyperkalemia Diabetes Mellitus Hypokalemia Hyperglycemia Edema 49% 34% 31% 31% 24% 22% 22% 18% 53% 17% 38% 32% 9% 25% 16% 19% Hemic and Lymphatic Anemia Leukopenia 30% 15% 24% 17% Miscellaneous Infection 45% 49% Peripheral Edema Asthenia Abdominal Pain Pain Fever Back Pain 36% 34% 33% 32% 29% 24% 48% 30% 31% 30% 29% 20% Respiratory System Dyspnea Cough Increased 22% 18% 18% 15% Musculoskeletal Arthralgia 25% 24% Skin Rash Pruritus 17% 15% 12% 7% Two trials were conducted for tacrolimus-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 tacrolimus (Group C, n=403), or one of two cyclosporine (CsA) regimens (Group A, n=384 and Group B, n=408) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab.
The trial population had a mean age of 46 years (range 17 to 76); the distribution was 65% male, and the composition was 93% Caucasian. The 12 month post-transplant information from this trial is presented below. Adverse reactions that occurred in ≥ 10% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 1 [Note: This trial was conducted entirely outside of the United States.
S. trials] are presented below: Table 5. S. trial (Study 2) with tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received tacrolimus (n=212) or cyclosporine (n=212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids.
The trial population had a 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 tacrolimus in conjunction with MMF in Study 2 are presented below: Table 6. ” Liver Transplantation There were two randomized comparative liver transplant trials.
S. trial, 263 adult and pediatric patients received tacrolimus and steroids and 266 patients received cyclosporine-based immunosuppressive regimen (CsA/AZA). 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. 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.
S. trial to that in the European trial. 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 (≥ 38%) observed in tacrolimus-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.
, tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting. S. and European randomized trials. Table 7. S. ” Heart Transplantation The incidence of adverse reactions was determined based on two trials in primary orthotopic heart transplantation.
In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine (AZA) in combination with tacrolimus (n=157) or cyclosporine (n=157) for 18 months. The trial population had a 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 tacrolimus-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.
, 5 to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm. S. trial, the incidence of adverse reactions was based on 331 heart transplant patients that received corticosteroids and tacrolimus in combination with sirolimus (n=109), tacrolimus in combination with MMF (n=107) or cyclosporine modified in combination with MMF (n=115) for 1 year.
The trial population had a 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%). S. heart transplantation trial. 2 mEq/L (24%), platelet count <75,000 cells/mcL (19%), and other opportunistic infections (15%).
Other targeted treatment-emergent adverse reactions in tacrolimus-treated patients occurred at a rate of less than 15%, and include the following: Cushingoid features, impaired wound healing, hyperkalemia, Candida infection, and CMV infection/syndrome.
” New Onset Diabetes After Transplant Kidney Transplantation New Onset Diabetes After Transplant (NODAT) is defined as a composite of fasting plasma glucose ≥126 mg/dL, HbA 1C ≥ 6%, insulin use ≥ 30 days, or oral hypoglycemic use. 1) ].
Table 10. Incidence of New Onset Diabetes After Transplant at 1 year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2) Parameter Treatment Group Tacrolimus/MMF (N = 212) NEORAL/MMF (N = 212) NODAT 112/150 (75%) 93/152 (61%) Fasting Plasma Glucose ≥ 126 mg/dL 96/150 (64%) 80/152 (53%) HbA 1C ≥ 6% 59/150 (39%) 28/152 (18%) Insulin Use ≥ 30 days 9/150 (6%) 4/152 (3%) Oral Hypoglycemic Use 15/150 (10%) 5/152 (3%) In early trials of tacrolimus, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criterion of “use of insulin for 30 or more consecutive days with < 5 day gap” in patients without a 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 Tacrolimus/Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in a Phase 3 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 2 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 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA) Status of PTDM * Tacrolimus/AZA CsA/AZA Patients without pre-transplant history of diabetes mellitus 151 151 New onset PTDM * , 1 st Year 30/151 (20%) 6/151 (4%) Still insulin-dependent at one year in those without prior history of diabetes 25/151 (17%) 5/151 (3%) New onset PTDM * post 1 year 1 0 Patients with PTDM * at 2 years 16/151 (11%) 5/151 (3%) * Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.
Table 12. Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial Patient Race Patients Who Developed PTDM * Tacrolimus Cyclosporine African-American 15/41 (37%) 3 (8%) Hispanic 5/17 (29%) 1 (6%) Caucasian 10/82 (12%) 1 (1%) Other 0/11 (0%) 1 (10%) Total 30/151 (20%) 6 (4%) * Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.
S. and European randomized trials, respectively, (Table 13). S. 1) ]. Table 13. S. Trial European Trial Tacrolimus Cyclosporine Tacrolimus Cyclosporine Patients at risk † 239 236 239 249 New Onset PTDM * 42 (18%) 30 (13%) 26 (11%) 12 (5%) Patients still on insulin at 1 year 23 (10%) 19 (8%) 18 (8%) 6 (2%) * Use of insulin for 30 or more consecutive days, with < 5-day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.
† Patients without pre-transplant history of diabetes mellitus. S. and European randomized trials, respectively (Table 14). S. 1 ) ]. Table 14. S. Trial European Trial Tacrolimus/ MMF Cyclosporine/MMF Tacrolimus/ AZA Cyclosporine/ AZA Patients at risk † 75 83 132 138 New Onset PTDM * 10 (13%) 6 (7%) 29 (22%) 5 (4%) Patients still on insulin at 1 year ‡ 7 (9%) 1 (1%) 24 (18%) 4 (3%) * Use of insulin for 30 or more consecutive days without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.
† Patients without pre-transplant history of diabetes mellitus. S. trial. Less Frequently Reported Adverse Reactions (>3% and <15%) in Liver, Kidney, and Heart Transplant Studies The following adverse reactions were reported in either liver, kidney, and/or heart transplant recipients who were treated with tacrolimus in clinical trials.
’s Prograf (tacrolimus) products. 2 Postmarketing Experience The following adverse reactions have been reported from worldwide marketing experience with tacrolimus. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a 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:
Cardiovascular: Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischemia, pericardial effusion, QT prolongation, Torsades de pointes , venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation, myocardial hypertrophy Gastrointestinal: Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastrooesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis hemorrhagic, pancreatitis necrotizing, stomach ulcer, veno-occlusive liver disease Hemic/Lymphatic: Agranulocytosis, disseminated intravascular coagulation, hemolytic anemia, neutropenia, febrile neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pure red cell aplasia thrombotic microangiopathy Infections: Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal; -polyoma virus-associated nephropathy (PVAN) including graft loss Metabolic/Nutritional: Glycosuria, increased amylase including pancreatitis, weight decreased Miscellaneous: Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction Musculoskeletal and Connective Tissue Disorders: Pain in extremity including Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) Nervous System: Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), quadriplegia, speech disorder, syncope Respiratory: Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure Skin: Stevens-Johnson syndrome, toxic epidermal necrolysis Special Senses: Blindness, optic neuropathy, blindness cortical, hearing loss including deafness, photophobia Urogenital: Acute renal failure, cystitis hemorrhagic, hemolytic-uremic syndrome