Mycophenolate Mofetil (Page 3 of 11)

5.4 Blood Dyscrasias: Neutropenia and Pure Red Cell Aplasia (PRCA)

Severe neutropenia [absolute neutrophil count (ANC) less than 0.5 x 10 3 /mcL] developed in transplant patients receiving mycophenolate mofetil 3 g daily [see Adverse Reactions ( 6.1)]. Patients receiving mycophenolate mofetil should be monitored for neutropenia . Neutropenia has been observed most frequently in the period from 31 to 180 days post-transplant in patients treated for prevention of kidney, heart and liver rejection. The development of neutropenia may be related to mycophenolate mofetil itself, concomitant medications, viral infections, or a combination of these causes. If neutropenia develops (ANC less than 1.3 x 10 3 /mcL), dosing with mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately [see Dosage and Administration ( 2.5)].

Patients receiving mycophenolate mofetil should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.

Consider monitoring with complete blood counts weekly for the first month, twice monthly for the second and third months, and monthly for the remainder of the first year.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressive agents. In some cases, PRCA was found to be reversible with dose reduction or cessation of mycophenolate mofetil therapy. In transplant patients, however, reduced immunosuppression may place the graft at risk.

5.5 Gastrointestinal Complications

Gastrointestinal bleeding requiring hospitalization, ulceration and perforations were observed in clinical trials. Physicians should be aware of these serious adverse effects particularly when administering mycophenolate mofetil to patients with a gastrointestinal disease.

5.6 Patients with Hypoxanthine-Guanine Phosphoribosyl-Transferase Deficiency (HGPRT)

Mycophenolate mofetil is an inosine monophosphate dehydrogenase (IMPDH) inhibitor; therefore it should be avoided in patients with hereditary deficiencies of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndromes because it may cause an exacerbation of disease symptoms characterized by the overproduction and accumulation of uric acid leading to symptoms associated with gout such as acute arthritis, tophi, nephrolithiasis or urolithiasis and renal disease including renal failure.

5.7 Acute Inflammatory Syndrome Associated with Mycophenolate Products

Acute inflammatory syndrome (AIS) has been reported with the use of MMF and mycophenolate products, and some cases have resulted in hospitalization. AIS is a paradoxical pro-inflammatory reaction characterized by fever, arthralgias, arthritis, muscle pain and elevated inflammatory markers including, C-reactive protein and erythrocyte sedimentation rate, without evidence of infection or underlying disease recurrence. Symptoms occur within weeks to months of initiation of treatment or a dose increase. After discontinuation, improvement of symptoms and inflammatory markers are usually observed within 24 to 48 hours.

Monitor patients for symptoms and laboratory parameters of AIS when starting treatment with mycophenolate products or when increasing the dosage. Discontinue treatment and consider other treatment alternatives based on the risk and benefit for the patient.

5.8 Immunizations

During treatment with mycophenolate mofetil, 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.

5.9 Local Reactions with Rapid Intravenous Administration

Mycophenolate mofetil intravenous solution must not be administered by rapid or bolus intravenous injection as rapid infusion increases the risk of local adverse reactions such as phlebitis and thrombosis [see Adverse Reactions ( 6.1)] .

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 (0.56 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.

5.11 Blood Donation

Patients should not donate blood during therapy and for at least 6 weeks following discontinuation of mycophenolate mofetil 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 [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 co-administered 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 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 [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 Trials 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 1,557 adult 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, and 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 ( 14.1,14.2and14.3)] .

The three de novo kidney studies with 12-month duration compared two dose levels of oral mycophenolate mofetil (1 g twice daily and 1.5 g 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 g 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 g twice daily intravenously for up to 14 days followed by mycophenolate mofetil 1.5 g 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 5 Adverse Reactions in Controlled Studies of De Novo Kidney, Heart or Liver Transplantation Reported in ≥20% of Patients in the Mycophenolate Mofetil Group

Adverse drug reaction Kidney Studies Heart Study Liver Study
Mycophenolate mofetil 2g/day (n=501) or 3g/day (n=490) AZA 1 to 2 mg/kg/day or 100 to 150 mg/day Placebo Mycophenolate mofetil 3g/day AZA 1.5 to 3 mg/kg/day Mycophenolate mofetil 3g/day AZA 1 to 2 mg/kg/day
(n=991) (n=326) (n=166) (n=289) (n=289) (n=277) (n=287)
System Organ Class % % % % % % %
Infections and infestations
Bacterial infections 39.9 33.7 37.3 27.4 26.5
Viral infections a 31.1 24.9
Blood 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
Metabolism 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
Gastrointestinal 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
Hepatobiliary disorders
Blood lactate dehydrogenase increased 23.5 18.3
Hepatic enzyme increased 24.9 19.2
Skin 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
General 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 g/day of mycophenolate mofetil had an overall better safety profile than did patients receiving 3 g/day of mycophenolate mofetil.

Post-transplant lymphoproliferative disease (PTLD, pseudolymphoma) developed in 0.4% to 1% of patients receiving mycophenolate mofetil (2 g or 3 g 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 10 3 /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 g 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 g or 3 g) 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 6 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 Adverse 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

Pediatrics

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/m 2 twice daily (up to 1 g twice daily) were generally similar to those observed in adult patients dosed with mycophenolate mofetil capsules at a dose of 1 g 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.

Safety information in pediatric heart transplant or pediatric liver transplant patients treated with mycophenolate mofetil is supported by an open-label study in pediatric liver transplant patients and publications; the type and frequency of the reported adverse reactions are consistent with those observed in pediatric patients following renal transplant and in adults.

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 g/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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