Mycophenolate Mofetil (Page 3 of 10)

5.8 Immunizations

During treatment with mycophenolate mofetil for oral suspension, the use of live attenuated vaccines should be avoided (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines) and patients should be advised that vaccinations may be less effective. Advise patients to discuss with the physician before seeking any immunizations.

5.10 Risks in Patients with Phenylketonuria

Phenylalanine can be harmful to patients with phenylketonuria (PKU). Mycophenolate mofetil for oral suspension contains aspartame, a source of phenylalanine (0.58 mg phenylalanine/mL suspension). Before prescribing mycophenolate mofetil for oral suspension to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including mycophenolate mofetil for oral suspension.

5.11 Blood Donation

Patients should not donate blood during therapy and for at least 6 weeks following discontinuation of mycophenolate mofetil for oral suspension because their blood or blood products might be administered to a female of reproductive potential or a pregnant woman.

5.12 Semen Donation

Based on animal data, men should not donate semen during therapy and for 90 days following discontinuation of mycophenolate mofetil for oral suspension [see Use in Specific Populations (8.3)].

5.13 Effect of Concomitant Medications on Mycophenolic Acid Concentrations

A variety of drugs have potential to alter systemic MPA exposure when coadministered with mycophenolate mofetil. Therefore, determination of MPA concentrations in plasma before and after making any changes to immunosuppressive therapy, or when adding or discontinuing concomitant medications, may be appropriate to ensure MPA concentrations remain stable.

5.14 Potential Impairment of Ability to Drive or Operate Machinery

Mycophenolate mofetil for oral suspension may impact the ability to drive and use machines. Patients should avoid driving or using machines if they experience somnolence, confusion, dizziness, tremor, or hypotension during treatment with mycophenolate mofetil for oral suspension [see Adverse Reactions (6.1)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:

  • Embryofetal Toxicity [see Warnings and Precautions (5.1)]
  • Lymphomas and Other Malignancies [see Warnings and Precautions (5.2)]
  • Serious Infections [see Warnings and Precautions (5.3)]
  • Blood Dyscrasias: Neutropenia, Pure Red Cell Aplasia [see Warnings and Precautions (5.4)]
  • Gastrointestinal Complications [see Warnings and Precautions (5.5)]
  • Acute Inflammatory Syndrome Associated with Mycophenolate Products [see Warnings and Precautions (5.7)]

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.

An estimated total of 1557 patients received mycophenolate mofetil during pivotal clinical trials in the prevention of acute organ rejection. Of these, 991 were included in the three renal studies, 277 were included in one hepatic study, and 289 were included in one cardiac study. Patients in all study arms also received cyclosporine and corticosteroids.

The data described below primarily derive from five randomized, active-controlled double-blind 12-month trials of mycophenolate mofetil in de novo kidney (3) heart (1) and liver (1) transplant patients [see Clinical Studies (14.1, 14.2, 14.3)].

Mycophenolate Mofetil Oral

The incidence of adverse reactions for mycophenolate mofetil was determined in five randomized, comparative, double-blind trials in the prevention of rejection in kidney, heart and liver transplant patients (two active- and one placebo-controlled trials, one active-controlled trial, and one active-controlled trial, respectively) [see Clinical Studies (14.1, 14.2 and 14.3)].

The three de novo kidney studies with 12-month duration compared two dose levels of oral mycophenolate mofetil (1 gram twice daily and 1.5 grams twice daily) with azathioprine (2 studies) or placebo (1 study) when administered in combination with cyclosporine (Sandimmune®) and corticosteroids to prevent acute rejection episodes. One study also included anti-thymocyte globulin (ATGAM®) induction therapy.

In the de novo heart transplantation study with 12-month duration, patients received mycophenolate mofetil 1.5 grams twice daily (n=289) or azathioprine 1.5 to 3 mg/kg/day (n=289), in combination with cyclosporine (Sandimmune® or Neoral®) and corticosteroids as maintenance immunosuppressive therapy.

In the de novo liver transplantation study with 12-month duration, patients received mycophenolate mofetil 1 gram twice daily intravenously for up to 14 days followed by mycophenolate mofetil 1.5 grams twice daily orally or azathioprine 1 to 2 mg/kg/day intravenously followed by azathioprine 1 to 2 mg/kg/day orally, in combination with cyclosporine (Neoral®) and corticosteroids as maintenance immunosuppressive therapy. The total number of patients enrolled was 565.

Approximately 53% of the kidney transplant patients, 65% of the heart transplant patients, and 48% of the liver transplant patients were treated for more than 1 year. Adverse reactions reported in ≥20% of patients in the mycophenolate mofetil treatment groups are presented below. The safety data of three kidney transplantation studies are pooled together.

Table 3: Adverse Reactions in Controlled Studies of De Novo Kidney, Heart or Liver Transplantation Reported in ≥20% of Patients in the Mycophenolate Mofetil Group

Kidney Studies

Heart Study

Liver Study

Adverse drug reaction

( M edDRA)

S y s tem Organ Class

Mycophenolate

Mofetil

2 grams/day

(n=501)

or 3 grams/day

(n=490)

AZA

1 to 2

mg/kg/day

or 100 to

150

mg/day

Placebo

Mycophenolate

Mofetil

3 grams/day

AZA

1 .5 to 3 mg/kg/day

Mycophenolate

Mofetil

3 grams /d ay

AZA

1 to 2

m g / k g / d ay

(n=991)

(n=326)

(n=166 )

(n=289)

(n=289)

(n=277)

(n=287)

%

%

%

%

%

%

%

In fections and infestations

Bacterial infections

39.9

33.7

37.3

27.4

26.5

Viral infections

a

31.1

24.9

B l oo d and lymphatic system disorders

Anemia

20.0

23.6

2.4

45.0

47.1

43.0

53.0

Ecchymosis

20.1

9.7

Leukocytosis

42.6

37.4

22.4

21.3

Leukopenia

28.6

24.8

4.2

34.3

43.3

45.8

39.0

Thrombocytopenia

24.2

28.0

38.3

42.2

M e tabolism and nutrition disorders

Hypercholesterolemia

46.0

43.9

Hyperglycemia

48.4

53.3

43.7

48.8

Hyperkalemia

22.0

23.7

Hypocalcemia

30.0

30.0

Hypokalemia

32.5

26.3

37.2

41.1

Hypomagnesemia

20.1

14.2

39.0

37.6

Psychiatric disorders

Depression

20.1

15.2

Insomnia

43.3

39.8

52.3

47.0

Nervous system disorders

Dizziness

34.3

33.9

Headache

58.5

55.4

53.8

49.1

Tremor

26.3

25.6

33.9

35.5

Cardiac disorders

Tachycardia

22.8

21.8

22.0

15.7

Vascular disorders

Hypertension

27.5

32.2

19.3

78.9

74.0

62.1

59.6

Hypotension

34.3

40.1

Respiratory, thoracic and mediastinal disorders

Cough

40.5

32.2

Dyspnea

44.3

44.3

31.0

30.3

Pleural effusion

34.3

35.9

G a s trointestinal disorders

Abdominal pain

22.4

23.0

11.4

41.9

39.4

62.5

51.2

Constipation

43.6

38.8

37.9

38.3

Decreased appetite

25.3

17.1

Diarrhea

30.4

20.9

13.9

52.6

39.4

51.3

49.8

Dyspepsia

22.1

22.1

22.4

20.9

Nausea

56.1

60.2

54.5

51.2

Vomiting

39.1

34.6

32.9

33.4

H epatobiliary disorders

Blood lactate dehydrogenase increased

23.5

18.3

Hepatic enzyme increased

24.9

19.2

S k i n and subcutaneous tissues disorders

Rash

26.0

20.8

Renal and urinary disorders

Blood creatinine increased

42.2

39.8

Blood urea increased

36.7

34.3

G eneral disorders and administration site conditions

Asthenia

49.1

41.2

35.4

33.8

Edema b

21.0

28.2

8.4

67.5

55.7

48.4

47.7

Pain c

24.8

32.2

9.6

79.2

77.5

74.0

77.5

Pyrexia

56.4

53.6

52.3

56.1

a “-” Indicates that the incidence was below the cutoff value of 20% for inclusion in the table.

b “Edema” includes peripheral edema, facial edema, scrotal edema.

c “Pain” includes musculoskeletal pain (myalgia, neck pain, back pain).

In the three de novo kidney studies, patients receiving 2 grams/day of mycophenolate mofetil had an overall better safety profile than did patients receiving 3 grams/day of mycophenolate mofetil.

Post-transplant lymphoproliferative disease (PTLD, pseudolymphoma) developed in 0.4% to 1% of patients receiving mycophenolate mofetil (2 grams or 3 grams daily) with other immunosuppressive agents in controlled clinical trials of kidney, heart and liver transplant patients followed for at least 1 year [see Warnings and Precautions (5.2)]. Non-melanoma skin carcinomas occurred in 1.6% to 4.2% of patients, other types of malignancy in 0.7% to 2.1% of patients. Three-year safety data in kidney and heart transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. In pediatric patients, PTLD was observed in 1.35% (2/148) by 12 months post-transplant.

Cytopenias, including leukopenia, anemia, thrombocytopenia and pancytopenia are a known risk associated with mycophenolate and may lead or contribute to the occurrence of infections and hemorrhages [see Warnings and Precautions (5.3)]. Severe neutropenia (ANC <0.5 x 103 /μL) developed in up to 2% of kidney transplant patients, up to 2.8% of heart transplant patients and up to 3.6% of liver transplant patients receiving mycophenolate mofetil 3 grams daily [see Warnings and Precautions (5.4) and Dosage and Administration (2.5)].

The most common opportunistic infections in patients receiving mycophenolate mofetil with other immunosuppressants were mucocutaneous candida, CMV viremia/syndrome, and herpes simplex. The proportion of patients with CMV viremia/syndrome was 13.5%. In patients receiving mycophenolate mofetil (2 grams or 3 grams) in controlled studies for prevention of kidney, heart or liver rejection, fatal infection/sepsis occurred in approximately 2% of kidney and heart patients and in 5% of liver patients [see Warnings and Precautions (5.3)].

The most serious gastrointestinal disorders reported were ulceration and hemorrhage, which are known risks associated with mycophenolate mofetil. Mouth, esophageal, gastric, duodenal, and intestinal ulcers often complicated by hemorrhage, as well as hematemesis, melena, and hemorrhagic forms of gastritis and colitis were commonly reported during the pivotal clinical trials, while the most common gastrointestinal disorders were diarrhea, nausea and vomiting. Endoscopic investigation of patients with mycophenolate mofetil-related diarrhea revealed isolated cases of intestinal villous atrophy [see Warnings and Precautions (5.5)].

The following adverse reactions were reported with 3% to <20% incidence in kidney, heart, and liver transplant patients treated with mycophenolate mofetil, in combination with cyclosporine and corticosteroids.

Table 4: Adverse Reactions in Controlled Studies of De Novo Kidney, Heart or Liver Transplantation Reported in 3% to <20% of Patients Treated with Mycophenolate Mofetil in Combination with Cyclosporine and Corticosteroids

System Organ Class

A dverse Reactions

Body as a Whole

cellulitis, chills, hernia, malaise

Infections and Infestations

fungal infections

Hematologic and Lymphatic

coagulation disorder, ecchymosis, pancytopenia

Urogenital

hematuria

Cardiovascular

hypotension

Metabolic and Nutritional

acidosis, alkaline phosphatase increased, hyperlipemia, hypophosphatemia, weight loss

Digestive

esophagitis, flatulence, gastritis, gastrointestinal hemorrhage, hepatitis, ileus, nausea and vomiting, stomach ulcer, stomatitis

Neoplasm benign, malignant and unspecified

neoplasm

Skin and Appendages

skin benign neoplasm, skin carcinoma

Psychiatric

confusional state

Nervous

hypertonia, paresthesia, somnolence

Musculoskeletal

arthralgia, myasthenia

Pediatric Study

The type and frequency of adverse events in a clinical study for prevention of kidney allograft rejection in 100 pediatric patients 3 months to 18 years of age dosed with mycophenolate mofetil for oral suspension 600 mg/m2 twice daily (up to 1 gram twice daily) were generally similar to those observed in adult patients dosed with mycophenolate mofetil capsules at a dose of 1 gram twice daily with the exception of abdominal pain, fever, infection, pain, sepsis, diarrhea, vomiting, pharyngitis, respiratory tract infection, hypertension, leukopenia, and anemia, which were observed in a higher proportion in pediatric patients.

Geriatrics

Geriatric patients (≥65 years), particularly those who are receiving mycophenolate mofetil as part of a combination immunosuppressive regimen, may be at increased risk of certain infections (including cytomegalovirus [CMV] tissue invasive disease) and possibly gastrointestinal hemorrhage and pulmonary edema, compared to younger individuals [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

Mycophenolate Mofetil Intravenous

The safety profile of mycophenolate mofetil intravenous was determined from a single, double-blind, controlled comparative study of the safety of 2 grams/day of intravenous and oral mycophenolate mofetil in kidney transplant patients in the immediate post-transplant period (administered for the first 5 days). The potential venous irritation of mycophenolate mofetil intravenous was evaluated by comparing the adverse reactions attributable to peripheral venous infusion of mycophenolate mofetil intravenous with those observed in the intravenous placebo group; patients in the placebo group received active medication by the oral route.

Adverse reactions attributable to peripheral venous infusion were phlebitis and thrombosis, both observed at 4% in patients treated with mycophenolate mofetil intravenous.

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