Prograf: Package Insert and Label Information (Page 5 of 7)

Other Drug Interactions

Immunosuppressants may affect vaccination. Therefore, during treatment with Prograf, vaccination may be less effective. The use of live vaccines should be avoided; live vaccines may include, but are not limited to measles, mumps, rubella, oral polio, BCG, yellow fever, and TY 21a typhoid.1

At a given MMF dose, mycophenolic acid (MPA) exposure is higher with Prograf co-administration than with cyclosporine co-administration due to the differences in the interruption of the enterohepatic recirculation of MPA. Clinicians should be aware that there is also a potential for increased MPA exposure after crossover from cyclosporine to tacrolimus in patients concomitantly receiving MMF or MPA.

Carcinogenesis, Mutagenesis and Impairment of Fertility

An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants. The most common forms of neoplasms are non-Hodgkin’s lymphomas and carcinomas of the skin. As with other immunosuppressive therapies, the risk of malignancies in Prograf recipients may be higher than in the normal, healthy population. Lymphoproliferative disorders associated with Epstein-Barr Virus infection have been seen. It has been reported that reduction or discontinuation of immunosuppression may cause the lesions to regress.

No 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.

Carcinogenicity studies were carried out in male and female rats and mice. In the 80-week mouse study and in the 104-week rat study no relationship of tumor incidence to tacrolimus dosage was found. The highest doses used in the mouse and rat studies were 0.8 – 2.5 times (mice) and 3.5 – 7.1 times (rats) the recommended clinical dose range of 0.1 – 0.2 mg/kg/day when corrected for body surface area.

No impairment of fertility was demonstrated in studies of male and female rats. Tacrolimus, given orally at 1.0 mg/kg (0.7 – 1.4X the recommended clinical dose range of 0.1 – 0.2 mg/kg/day based on body surface area corrections) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and with adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre-implantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (2.3 – 4.6X the recommended clinical dose range based on body surface area correction), 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.

Pregnancy: Category C

In reproduction studies in rats and rabbits, adverse effects on the fetus were observed mainly at dose levels that were toxic to dams. Tacrolimus at oral doses of 0.32 and 1.0 mg/kg during organogenesis in rabbits was associated with maternal toxicity as well as an increase in incidence of abortions; these doses are equivalent to 0.5 – 1X and 1.6 – 3.3X the recommended clinical dose range (0.1 – 0.2 mg/kg) based on body surface area corrections. At the higher dose only, an increased incidence of malformations and developmental variations was also seen. Tacrolimus, at oral doses of 3.2 mg/kg during organogenesis in rats, was associated with maternal toxicity and caused an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally at 1.0 and 3.2 mg/kg (equivalent to 0.7 – 1.4X and 2.3 – 4.6X the recommended clinical dose range based on body surface area corrections) to pregnant rats after organogenesis and during lactation, was associated with reduced pup weights.

No reduction in male or female fertility was evident.

There are no adequate and well-controlled studies in pregnant women. Tacrolimus is transferred across the placenta. The use of tacrolimus during pregnancy has been associated with neonatal hyperkalemia and renal dysfunction. Prograf should be used during pregnancy only if the potential benefit to the mother justifies potential risk to the fetus.

Nursing Mothers

Since tacrolimus is excreted in human milk, nursing should be avoided.

Pediatric Patients

Experience with Prograf in pediatric kidney and heart transplant patients is limited. Successful liver transplants have been performed in pediatric patients (ages up to 16 years) using Prograf. Two randomized active-controlled trials of Prograf in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to Prograf-based and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of Prograf to maintain blood trough concentrations of tacrolimus similar to adult patients (see DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS

Liver Transplantation

The principal adverse reactions of Prograf are tremor, headache, diarrhea, hypertension, nausea, and abnormal renal function. These occur with oral and IV administration of Prograf and may respond to a reduction in dosing. Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting.

Hyperkalemia and hypomagnesemia have occurred in patients receiving Prograf therapy. Hyperglycemia has been noted in many patients; some may require insulin therapy (see WARNINGS).

The incidence of adverse events was determined in two randomized comparative liver transplant trials among 514 patients receiving tacrolimus and steroids and 515 patients receiving a cyclosporine-based regimen (CBIR). The proportion of patients reporting more than one adverse event was 99.8% in the tacrolimus group and 99.6% in the CBIR group. Precautions must be taken when comparing the incidence of adverse events in the U.S. study to that in the European study. The 12-month posttransplant information from the U.S. study and from the European study is presented below. The two studies also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse events reported in ≥ 15% in tacrolimus patients (combined study results) are presented below for the two controlled trials in liver transplantation:

LIVER TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN ≥ 15% OF PROGRAF-TREATED PATIENTS
U.S. STUDY EUROPEAN STUDY

Prograf

CBIR

Prograf

CBIR

Nervous System

Headache (see WARNINGS)

Tremor (see WARNINGS)

Insomnia

Paresthesia

64%

56%

64%

40%

60%

46%

68%

30%

37%

48%

32%

17%

26%

32%

23%

17%

Gastrointestinal

Diarrhea

Nausea

Constipation

LFT Abnormal

Anorexia

Vomiting

72%

46%

24%

36%

34%

27%

47%

37%

27%

30%

24%

15%

37%

32%

23%

6%

7%

14%

27%

27%

21%

5%

5%

11%

Cardiovascular

Hypertension (see PRECAUTIONS)

47%

56%

38%

43%

Urogenital

Kidney Function Abnormal (see WARNINGS)

Creatinine Increased (see WARNINGS)

BUN Increased (see WARNINGS)

Urinary Tract Infection

Oliguria

40%

39%

30%

16%

18%

27%

25%

22%

18%

15%

36%

24%

12%

21%

19%

23%

19%

9%

19%

12%

Metabolic and Nutritional

Hyperkalemia (see WARNINGS)

Hypokalemia

Hyperglycemia (see WARNINGS)

Hypomagnesemia

45%

29%

47%

48%

26%

34%

38%

45%

13%

13%

33%

16%

9%

16%

22%

9%

Hemic and Lymphatic

Anemia

Leukocytosis

Thrombocytopenia

47%

32%

24%

38%

26%

20%

5%

8%

14%

1%

8%

19%

Miscellaneous

Abdominal Pain

Pain

Fever

Asthenia

Back Pain

Ascites

Peripheral Edema

59%

63%

48%

52%

30%

27%

26%

54%

57%

56%

48%

29%

22%

26%

29%

24%

19%

11%

17%

7%

12%

22%

22%

22%

7%

17%

8%

14%

Respiratory System

Pleural Effusion

Atelectasis

Dyspnea

30%

28%

29%

32%

30%

23%

36%

5%

5%

35%

4%

4%

Skin and Appendages

Pruritus

36%

20%

15%

7%

4%

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

Kidney Transplantation

The most common adverse reactions reported were infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain and insomnia.

Adverse events that occurred in ≥ 15% of kidney transplant patients treated with Prograf in conjunction with azathioprine are presented below:

KIDNEY TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN ≥ 15% OF PATIENTS TREATED WITH PROGRAF IN CONJUNCTION WITH AZATHIOPRINE

Prograf

CBIR

Nervous System

Tremor (see WARNINGS)

Headache (see WARNINGS)

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 (see PRECAUTIONS)

Chest pain

50%

19%

52%

13%

Urogenital

Creatinine Increased (see WARNINGS)

Urinary Tract Infection

45%

34%

42%

35%

Metabolic and Nutritional

Hypophosphatemia

Hypomagnesemia

Hyperlipemia

Hyperkalemia (see WARNINGS)

Diabetes Mellitus (see WARNINGS)

Hypokalemia

Hyperglycemia (see WARNINGS)

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

Peripheral Edema

Asthenia

Abdominal Pain

Pain

Fever

Back Pain

45%

36%

34%

33%

32%

29%

24%

49%

48%

30%

31%

30%

29%

20%

Respiratory System

Dyspnea

Cough Increased

22%

18%

18%

15%

Musculoskeletal

Arthralgia

25%

24%

Skin

Rash

17%

12%

Adverse events that occurred in ≥ 10% of kidney transplant patients treated with Prograf in conjunction with MMF in Study 1* are presented below:

*Study 1 was conducted entirely outside of the United States. Such studies often report a lower incidence of adverse events in comparison to US studies.
KIDNEY TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN ≥ 10% OF PROGRAF-TREATED PATIENTS
Prograf (Group C) Cyclosporine (Group A) Cyclosporine (Group B)
(N=403) (N=384) (N=408)
Anemia 17% 19% 17%
Leucopenia 13% 10% 10%
Diarrhea 25% 16% 13%
Edema peripheral 11% 12% 13%
Urinary tract infection 24% 28% 24%
Hyperlipidemia 10% 15% 13%
Hypertension (see PRECAUTIONS) 13% 14% 12%

Adverse events that occurred in ≥15% of kidney transplant patients treated with Prograf in conjunction with MMF in Study 2 are presented below:

KIDNEY TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN ≥ 15% OF PROGRAF-TREATED PATIENTS
Prograf Cyclosporine
(N=212) (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 (see WARNINGS) 26% 19%
Hyperglycemia (see WARNINGS) 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 (see PRECAUTIONS) 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 shown below.

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