Tacrolimus: Package Insert and Label Information (Page 3 of 11)
6.1 Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.
Kidney Transplant
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 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%), Black (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.
Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with azathioprine are presented below:
| Tacrolimus/AZA (N = 205) | Cyclosporine/AZA (N = 207) | |
| Nervous System | ||
| Tremor | 54% | 34% |
| Headache | 44% | 38% |
| Insomnia | 32% | 30% |
| Paresthesia | 23% | 16% |
| Dizziness | 19% | 16% |
| Gastrointestinal | ||
| Diarrhea | 44% | 41% |
| Nausea | 38% | 36% |
| Constipation | 35% | 43% |
| Vomiting | 29% | 23% |
| Dyspepsia | 28% | 20% |
| Cardiovascular | ||
| Hypertension | 50% | 52% |
| Chest Pain | 19% | 13% |
| Urogenital | ||
| Creatinine Increased | 45% | 42% |
| Urinary Tract Infection | 34% | 35% |
| Metabolic and Nutritional | ||
| Hypophosphatemia | 49% | 53% |
| Hypomagnesemia | 34% | 17% |
| Hyperlipemia | 31% | 38% |
| Hyperkalemia | 31% | 32% |
| Diabetes Mellitus | 24% | 9% |
| Hypokalemia | 22% | 25% |
| Hyperglycemia | 22% | 16% |
| Edema | 18% | 19% |
| Hemic and Lymphatic | ||
| Anemia | 30% | 24% |
| Leukopenia | 15% | 17% |
| Miscellaneous | ||
| Infection | 45% | 49% |
| Peripheral Edema | 36% | 48% |
| Asthenia | 34% | 30% |
| Abdominal Pain | 33% | 31% |
| Pain | 32% | 30% |
| Fever | 29% | 29% |
| Back Pain | 24% | 20% |
| Respiratory System | ||
| Dyspnea | 22% | 18% |
| Cough Increased | 18% | 15% |
| Musculoskeletal | ||
| Arthralgia | 25% | 24% |
| Skin | ||
| Rash | 17% | 12% |
| Pruritus | 15% | 7% |
Two trials were conducted for tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids. In the non-US trial (Study 1), the incidence of adverse reactions was based on 1,195 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. Such trials often report a lower incidence of adverse reactions in comparison to U.S. trials] are presented below:
| Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil | ||||||
| Tacrolimus (Group C) (N = 403) | Cyclosporine (Group A) (N = 384) | Cyclosporine (Group B) (N = 408) | ||||
| Diarrhea | 25% | 16% | 13% | |||
| Urinary Tract Infection | 24% | 28% | 24% | |||
| Anemia | 17% | 19% | 17% | |||
| Hypertension | 13% | 14% | 12% | |||
| Leukopenia | 13% | 10% | 10% | |||
| Edema Peripheral | 11% | 12% | 13% | |||
| Hyperlipidemia | 10% | 15% | 13% | |||
In the U.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%), Black (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:
| Tacrolimus/MMF (N = 212) | Cyclosporine/MMF (N = 212) | |
| Gastrointestinal Disorders | ||
| Diarrhea | 44% | 26% |
| Nausea | 39% | 47% |
| Constipation | 36% | 41% |
| Vomiting | 26% | 25% |
| Dyspepsia | 18% | 15% |
| Injury, Poisoning, and Procedural Complications | ||
| Post-Procedural Pain | 29% | 27% |
| Incision Site Complication | 28% | 23% |
| Graft Dysfunction | 24% | 18% |
| Metabolism and Nutrition Disorders | ||
| Hypomagnesemia | 28% | 22% |
| Hypophosphatemia | 28% | 21% |
| Hyperkalemia | 26% | 19% |
| Hyperglycemia | 21% | 15% |
| Hyperlipidemia | 18% | 25% |
| Hypokalemia | 16% | 18% |
| Nervous System Disorders | ||
| Tremor | 34% | 20% |
| Headache | 24% | 25% |
| Blood and Lymphatic System Disorders | ||
| Anemia | 30% | 28% |
| Leukopenia | 16% | 12% |
| Miscellaneous | ||
| Edema Peripheral | 35% | 46% |
| Hypertension | 32% | 35% |
| Insomnia | 30% | 21% |
| Urinary Tract Infection | 26% | 22% |
| Blood Creatinine Increased | 23% | 23% |
Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions.
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