Gastrointestinal bleeding (requiring hospitalization), intestinal perforations, gastric ulcers, and duodenal ulcers have been reported in patients treated with mycophenolic acid delayed-release tablets. Mycophenolic acid delayed-release tablets should be administered with caution in patients with active serious digestive system disease.
Acute inflammatory syndrome (AIS) has been reported with the use of 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.
During treatment with mycophenolic acid delayed-release tablets, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Advise patients to discuss with the physician before seeking any immunizations.
Mycophenolic acid delayed-release are inosine monophosphate dehydrogenase inhibitor (IMPDH inhibitor). Mycophenolic acid delayed-release tablets should be avoided in patients with rare hereditary deficiency 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.
Patients should not donate blood during therapy and for at least 6 weeks following discontinuation of mycophenolic acid delayed-release tablets because their blood or blood products might be administered to a female of reproductive potential or a pregnant woman.
Based on animal data, men should not donate semen during therapy and for 90 days following discontinuation of mycophenolic acid delayed-release tablets [see Use in Specific Populations (8.3)].
The following adverse reactions are discussed in greater detail in other sections of the label.
- Embryofetal Toxicity [see Boxed Warning, Warnings and Precautions (5.1)]
- Lymphomas and Other Malignancies [see Boxed Warning, Warnings and Precautions (5.3) ]
- Serious Infections [see Boxed Warning, Warnings and Precautions (5.4) ]
- New or Reactivated Viral Infections [see Warnings and Precautions (5.5)]
- Blood Dyscrasias Including Pure Red Cell Aplasia [ see Warnings and Precautions 5.6 ]
- Serious GI Tract Complications [see Warnings and Precautions (5.7)]
- Acute Inflammatory Syndrome Associated with Mycophenolate Products [see Warnings and Precautions (5.8) ]
- Rare Hereditary Deficiencies [see Warnings and Precautions (5.10)]
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.
The data described below derive from two randomized, comparative, active-controlled, double-blind, double-dummy trials in prevention of acute rejection in de novo and converted stable kidney transplant patients.
In the de novo trial, patients were administered either mycophenolic acid delayed-release tablets 1.44 grams per day (N = 213) or MMF 2 grams per day (N=210) within 48 hours post-transplant for 12 months in combination with cyclosporine, USP MODIFIED and corticosteroids. Forty-one percent of patients also received antibody therapy as induction treatment. In the conversion trial, renal transplant patients who were at least 6 months post-transplant and receiving 2 grams per day MMF in combination with cyclosporine USP MODIFIED, with or without corticosteroids for at least two weeks prior to entry in the trial were randomized to mycophenolic acid delayed-release tablets 1.44 grams per day (N = 159) or MMF 2 grams per day (N = 163) for 12 months.
The average age of patients in both studies was 47 years and 48 years (de novo study and conversion study, respectively), ranging from 22 to 75 years. Approximately 66% of patients were male; 82% were white, 12 % were black, and 6% other races. About 40% of patients were from the United States and 60% from other countries.
In the de novo trial, the overall incidence of discontinuation due to adverse reactions was 18% (39/213) and 17% (35/210) in the mycophenolic acid delayed-release tablets and MMF arms, respectively. The most common adverse reactions leading to discontinuation in the mycophenolic acid delayed-release tablets arm were graft loss (2%), diarrhea (2%), vomiting (1%), renal impairment (1%), CMV infection (1%), and leukopenia (1%). The overall incidence of patients reporting dose reduction at least once during the 0-to 12-month study period was 59% and 60% in the mycophenolic acid delayed-release tablets and MMF arms, respectively. The most frequent reasons for dose reduction in the mycophenolic acid delayed-release tablets arm were adverse reactions (44%), dose reductions according to protocol guidelines (17%), dosing errors (11%) and missing data (2%).
The most common adverse reactions (≥20%) associated with the administration of mycophenolic acid delayed-release tablets were anemia, leukopenia, constipation, nausea, diarrhea, vomiting, dyspepsia, urinary tract infection, CMV infection, insomnia and postoperative pain.
The adverse reactions reported in ≥10% of patients in the de novo trial are presented in Table 2 below.
|de novo Renal Trial **|
|System organ class Adverse drug reactions||Mycophenolic Acid Delayed-Release Tablets 1.44 grams per day (n=213) (%)||Mycophenolate mofetil (MMF) 2 grams per day (n=210) (%)|
|Blood and Lymphatic System Disorders|
|Gastrointestinal System Disorders|
|Abdominal pain upper||14||14|
|General and Administrative Site Disorders|
|Edema lower limb||16||17|
|Increased blood creatinine||15||10|
|Infections and Infestations|
|Urinary tract infection||29||33|
|Metabolism and Nutrition Disorders|
|Musculoskeletal, Connective Tissue and Bone Disorders|
|Nervous System Disorder|
**The trial was not designed to support comparative claims for mycophenolic acid delayed-release tablets for the adverse reactions reported in this table
Table 3 summarizes the incidence of opportunistic infections in de novo transplant patients.
Table 3: Viral and Fungal Infections (%) Reported Over 0 to 12 Months
|de novo Renal Trial|
|Mycophenolic Acid Delayed-Release Tablets 1.44 grams per day (n=213) (%)||Mycophenolate mofetil (MMF) 2 grams per day (n=210) (%)|
|– Cytomegalovirus Disease||5||4|
|Any Fungal Infection||11||12|
|– Candida NOS||6||6|
|– Candida albicans||2||4|
Lymphoma developed in 2 de novo patients (1%), (1 diagnosed 9 days after treatment initiation) and in 2 conversion patients (1%) receiving mycophenolic acid delayed-release tablets with other immunosuppressive agents in the 12-month controlled clinical trials.
Nonmelanoma skin carcinoma occurred in 1% de novo and 12% conversion patients. Other types of malignancy occurred in 1% de novo and 1% conversion patients [see Warnings and Precautions ( 5.4) ].
The adverse reactions reported in less than 10% of de novo or conversion patients treated with mycophenolic acid delayed-release tablets in combination with cyclosporine and corticosteroids are listed in Table 4.
Table 4: Adverse Reactions Reported in <10% of Patients Treated With Mycophenolic Acid Delayed-Release Tablets in Combination With Cyclosporine* and Corticosteroids
|Blood and Lymphatic Disorders||Lymphocele, thrombocytopenia|
|Eye Disorder||Vision blurred|
|Gastrointestinal Disorders||Abdominal pain, abdominal distension, gastroesophageal reflux disease, gingival hyperplasia|
|General Disorders and Administration-Site Conditions||Fatigue, peripheral edema|
|Infections and Infestations||Nasopharyngitis, herpes simplex, upper respiratory infection, oral candidiasis, herpes zoster, sinusitis, influenza, wound infection, implant infection, pneumonia, sepsis|
|Investigations||Hemoglobin decrease, liver function tests abnormal|
|Metabolism and Nutrition Disorders||Hypercholesterolemia, hyperkalemia, hypomagnesemia, diabetes mellitus, hyperglycemia|
|Musculoskeletal and Connective Tissue Disorders||Arthralgia, pain in limb, peripheral swelling, muscle cramps, myalgia|
|Nervous System Disorders||Dizziness (excluding vertigo)|
|Renal and Urinary Disorders||Renal tubular necrosis, renal impairment, hematuria, urinary retention|
|Respiratory, Thoracic and Mediastinal Disorders||Cough, dyspnea, dyspnea exertional|
|Skin and Subcutaneous Tissue Disorders||Acne, pruritus, rash|
|Vascular Disorders||Hypertension aggravated, hypotension|
The following additional adverse reactions have been associated with the exposure to MPA when administered as a sodium salt or as mofetil ester:
Gastrointestinal: Intestinal perforation, gastrointestinal hemorrhage, gastric ulcers, duodenal ulcers [see Warnings and Precautions ( 5.7) ], colitis (including CMV colitis), pancreatitis, esophagitis, and ileus.
Infections: Serious life-threatening infections, such as meningitis and infectious endocarditis, tuberculosis, and atypical mycobacterial infection [see Warnings and Precautions ( 5.4) ].
Respiratory: Interstitial lung disorders, including fatal pulmonary fibrosis.
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