Tacrolimus: Package Insert and Label Information (Page 3 of 10)

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:

Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)

Tacrolimus Capsules USP/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%
Leucopenia 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 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. Such trials often report a 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 Tacrolimus in Conjunction with MMF (Study 1)

DiarrheaUrinary tract infectionAnemiaHypertensionLeucopeniaEdema peripheralHyperlipidemia Tacrolimus Capsules USP (group C) (N=403) 25%24%17%13%13%11%10% Cyclosporine(Group A)(N=384) 16%28%19%14%10%12%15% Cyclosporine(Group B) (N=408) 13%24%17%12%10%13%13%
Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/DaclizumabCsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil

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:

Table 6. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 2)

Tacrolimus Capsules USP / MMF (N=212) Cyclosporine / MMF (N=212)
Gastrointestinal Disorder
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 Disorder
Hypomagnesemia 28% 22%
Hypophosphatemia 28% 21%
Hyperkalemia 26% 19%
Hyperglycemia 21% 15%
Hyperlipidemia 18% 25%
Hypokalemia 16% 18%
Nervous System Disorder
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.

Liver Transplantation

There 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 a mean age of 44 years (range 0.4 to70), the distribution was 52% male, and the composition was White (78%), Black (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 a 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 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. These all occur with oral and IV administration of Tacrolimus and some may respond to a reduction in dosing (e.g., tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting.

Table 7. Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus

U.S. TRIAL EUROPEAN TRIAL
Tacrolimus Capsules USP (N=250) Cyclosporine/AZA (N=250) Tacrolimus Capsules USP (N=264) Cyclosporine/AZA (N=265)
Nervous system
Headache 64% 60% 37% 26%
Insomnia 64% 68% 32% 23%
Tremor 56% 46% 48% 32%
Paresthesia 40% 30% 17% 17%
Gastrointestinal
Diarrhea 72% 47% 37% 27%
Nausea 46% 37% 32% 27%
LFT Abnormal 36% 30% 6% 5%
Anorexia 34% 24% 7% 5%
Vomitting 27% 15% 14% 11%
Constipation 24% 27% 23% 21%
Cardiovascular
Hypertension 47% 56% 38% 43%
Urogenital
Kidney function abnormal 40% 27% 36% 23%
Creatinine increased 39% 25% 24% 19%
BUN increased 30% 22% 12% 9%
Oliguria 18% 15% 19% 12%
Urinary Tract Infection 16% 18% 21% 19%
Metabolic and Nutritional
Hypomagnesemia 48% 45% 16% 9%
Hyperglycemia 47% 38% 33% 22%
Hyperkalemia 45% 26% 13% 9%
Hypokalemia 29% 34% 13% 16%
Hemic and Lymphatic
Anemia 47% 38% 5% 1%
Leukocytosis 32% 26% 8% 8%
Thrombocytopenia 24% 20% 14% 19%
Miscellaneous
Pain 63% 57% 24% 22%
Abdominal Pain 59% 54% 29% 22%
Asthenia 52% 48% 11% 7%
Fever 48% 56% 19% 22%
Back pain 30% 29% 17% 17%
Ascites 27% 22% 7% 8%
Peripheral edema 26% 26% 12% 14%
Respiratory System
Pleural effusion 30% 32% 36% 35%
Dyspnea 29% 23% 5% 4%
Atelectasis 28% 30% 5% 4%
Skin and Appendages
Pruritus 36% 20% 15% 7%
Rash 24% 19% 10% 4%

Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions.

DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.

As the leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. Our material is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2022. All Rights Reserved.