Tacrolimus (Page 5 of 17)

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 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 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 (≥ 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. These all occur with oral 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. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 40% and 36% of liver transplantation patients receiving tacrolimus in the U.S. and European randomized trials.

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

U.S. TRIAL

EUROPEAN TRIAL

Tacrolimus (N = 250)

Cyclosporine/AZA (N = 250)

Tacrolimus

(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%

Vomiting

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 liver transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.”

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