INDICATIONS AND USAGE Renal, Cardiac, and Hepatic Transplant Mycophenolate mofetil is indicated for the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants.

Mycophenolate mofetil should be used concomitantly with cyclosporine and corticosteroids.

WARNINGS (see boxed WARNING ) Embryofetal Toxicity Mycophenolate mofetil can cause fetal harm when administered to a pregnant female.

Use of mycophenolate mofetil during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations, especially external ear and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, kidney and nervous system (see PRECAUTIONS: Pregnancy ).

Pregnancy Exposure Prevention and Planning Females of reproductive potential must be made aware of the increased risk of first trimester pregnancy loss and congenital malformations and must be counseled regarding pregnancy prevention and planning.

For recommended pregnancy testing and contraception methods (see PRECAUTIONS: Pregnancy Exposure Prevention and Planning ).

Lymphoma and Malignancy Patients receiving immunosuppressive regimens involving combinations of drugs, including mycophenolate mofetil, as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see ADVERSE REACTIONS ).

The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.

As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Lymphoproliferative disease or lymphoma developed in 0.4% to 1% of patients receiving mycophenolate mofetil (2 g or 3 g) with other immunosuppressive agents in controlled clinical trials of renal, cardiac, and hepatic transplant patients (see ADVERSE REACTIONS ).

In pediatric patients, no other malignancies besides lymphoproliferative disorder (2/148 patients) have been observed (see ADVERSE REACTIONS ).

Combination with Other Immunosuppressive Agents Mycophenolate mofetil has been administered in combination with the following agents in clinical trials: antithymocyte globulin (ATGAM ®† ), OKT3 (Orthoclone OKT ®† 3), cyclosporine (Sandimmune ®† , Neoral ®† ) and corticosteroids.

The efficacy and safety of the use of mycophenolate mofetil in combination with other immunosuppressive agents have not been determined.

Serious Infections Patients receiving immunosuppressants, including mycophenolate mofetil, are at increased risk of developing bacterial, fungal, protozoal and new or reactivated viral infections, including opportunistic infections.

These infections may lead to serious, including fatal outcomes.

Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution (see ADVERSE REACTIONS ).

New or Reactivated Viral Infections Polyomavirus associated nephropathy (PVAN), JC virus associated progressive multifocal leukoencephalopathy (PML), cytomegalovirus (CMV) infections, reactivation of hepatitis B (HBV) or hepatitis C (HCV) have been reported in patients treated with immunosuppressants, including mycophenolate mofetil.

Reduction in immunosuppression should be considered for patients who develop evidence of new or reactivated viral infections.

Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft.

PVAN, especially due to BK virus infection, is associated with serious outcomes, including deteriorating renal function and renal graft loss (see ADVERSE REACTIONS: Postmarketing Experience ).

Patient monitoring may help detect patients at risk for PVAN.

PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies, and ataxia.

Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function (see ADVERSE REACTIONS: Postmarketing Experience ).

In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.

The risk of CMV viremia and CMV disease is highest among transplant recipients seronegative for CMV at time of transplant who receive a graft from a CMV seropositive donor.

Therapeutic approaches to limiting CMV disease exist and should be routinely provided.

Patient monitoring may help detect patients at risk for CMV disease.

Viral reactivation has been reported in patients infected with HBV or HCV.

Monitoring infected patients for clinical and laboratory signs of active HBV or HCV infection is recommended.

Neutropenia Severe neutropenia [absolute neutrophil count (ANC) < 0.5 x 10 3 /µL] developed in up to 2% of renal, up to 2.8% of cardiac, and up to 3.6% of hepatic transplant patients receiving mycophenolate mofetil 3 g daily (see ADVERSE REACTIONS ).

Patients receiving mycophenolate mofetil should be monitored for neutropenia (see PRECAUTIONS: Laboratory Tests ).

The development of neutropenia may be related to mycophenolate mofetil itself, concomitant medications, viral infections, or some combination of these causes.

If neutropenia develops (ANC < 1.3 x 10 3 /µL), dosing with mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately (see DOSAGE AND ADMINISTRATION ).

Neutropenia has been observed most frequently in the period from 31 to 180 days posttransplant in patients treated for prevention of renal, cardiac, and hepatic rejection.

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.

Pure Red Cell Aplasia (PRCA) Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressive agents.

The mechanism for mycophenolate mofetil induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppression regimen are also unknown.

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.

ADVERSE REACTIONS The principal adverse reactions associated with the administration of mycophenolate mofetil include diarrhea, leukopenia, sepsis, vomiting, and there is evidence of a higher frequency of certain types of infections e.g., opportunistic infection (see WARNINGS: Serious Infections and WARNINGS: New or Reactivated Viral Infections ).

Mycophenolate Mofetil Oral The incidence of adverse events for mycophenolate mofetil was determined in randomized, comparative, double-blind trials in prevention of rejection in renal (two active, one placebo-controlled trials), cardiac (one active-controlled trial), and hepatic (one active-controlled trial) transplant patients.

Geriatrics Elderly 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 PRECAUTIONS ).

Safety data are summarized below for all active-controlled trials in renal (two trials), cardiac (one trial), and hepatic (one trial) transplant patients.

Approximately 53% of the renal patients, 65% of the cardiac patients, and 48% of the hepatic patients have been treated for more than one year.

Adverse events reported in ≥ 20% of patients in the mycophenolate mofetil treatment groups are presented below.

Table 9: Adverse Events in Controlled Studies in Prevention of Renal, Cardiac or Hepatic Allograft Rejection (Reported in ≥ 20% of Patients in the Mycophenolate Mofetil Group) Renal Studies Cardiac Study Hepatic Study Mycophenolate Mofetil 2 g/day Mycophenolate Mofetil 3 g/day Azathioprine 1 to 2 mg/kg/day or 100 to 150 mg/day Mycophenolate Mofetil 3 g/day Azathioprine 1.5 to 3 mg/kg/day Mycophenolate Mofetil 3 g/day Azathioprine 1 to 2 mg/kg/day (n = 336) (n = 330) (n = 326) (n = 289) (n = 289) (n = 277) (n = 287) % % % % % % % Body as a Whole Pain 33 31.2 32.2 75.8 74.7 74 77.7 Abdominal pain 24.7 27.6 23 33.9 33.2 62.5 51.2 Fever 21.4 23.3 23.3 47.4 46.4 52.3 56.1 Headache 21.1 16.1 21.2 54.3 51.9 53.8 49.1 Infection 18.2 20.9 19.9 25.6 19.4 27.1 25.1 Sepsis - - - - - 27.4 26.5 Asthenia - - - 43.3 36.3 35.4 33.8 Chest pain - - - 26.3 26 - - Back pain - - - 34.6 28.4 46.6 47.4 Ascites - - - - - 24.2 22.6 Hematologic and Lymphatic Anemia 25.6 25.8 23.6 42.9 43.9 43 53 Leukopenia 23.2 34.5 24.8 30.4 39.1 45.8 39 Thrombocytopenia - - - 23.5 27 38.3 42.2 Hypochromic anemia - - - 24.6 23.5 - - Leukocytosis - - - 40.5 35.6 22.4 21.3 Urogenital Urinary tract infection 37.2 37 33.7 - - - - Kidney function abnormal - - - 21.8 26.3 25.6 28.9 Cardiovascular Hypertension 32.4 28.2 32.2 77.5 72.3 62.1 59.6 Hypotension - - - 32.5 36 - - Cardiovascular disorder - - - 25.6 24.2 - - Tachycardia - - - 20.1 18 22 15.7 Metabolic and Nutritional Peripheral edema 28.6 27 28.2 64 53.3 48.4 47.7 Hypercholesteremia - - - 41.2 38.4 - - Edema - - - 26.6 25.6 28.2 28.2 Hypokalemia - - - 31.8 25.6 37.2 41.1 Hyperkalemia - - - - - 22 23.7 Hyperglycemia - - - 46.7 52.6 43.7 48.8 Creatinine increased - - - 39.4 36 - - BUN increased - - - 34.6 32.5 - - Lactic dehydrogenase increased - - - 23.2 17 - - Hypomagnesemia - - - - - 39 37.6 Hypocalcemia - - - - - 30 30 Digestive Diarrhea 31 36.1 20.9 45.3 34.3 51.3 49.8 Constipation 22.9 18.5 22.4 41.2 37.7 37.9 38.3 Nausea 19.9 23.6 24.5 54 54.3 54.5 51.2 Dyspepsia - - - - - 22.4 20.9 Vomiting - - - 33.9 28.4 32.9 33.4 Anorexia - - - - - 25.3 17.1 Liver function tests abnormal - - - - - 24.9 19.2 Respiratory Infection 22 23.9 19.6 37 35.3 - - Dyspnea - - - 36.7 36.3 31 30.3 Cough increased - - - 31.1 25.6 - - Lung disorder - - - 30.1 29.1 22 18.8 Sinusitis - - - 26 19 - - Pleural effusion - - - - - 34.3 35.9 Skin and Appendages Rash - - - 22.1 18 - - Nervous System Tremor - - - 24.2 23.9 33.9 35.5 Insomnia - - - 40.8 37.7 52.3 47 Dizziness - - - 28.7 27.7 - - Anxiety - - - 28.4 23.9 - - Paresthesia - - - 20.8 18 - - The placebo-controlled renal transplant study generally showed fewer adverse events occurring in ≥ 20% of patients.

In addition, those that occurred were not only qualitatively similar to the azathioprine-controlled renal transplant studies, but also occurred at lower rates, particularly for infection, leukopenia, hypertension, diarrhea and respiratory infection.

The above data demonstrate that in three controlled trials for prevention of renal rejection, patients receiving 2 g/day of mycophenolate mofetil had an overall better safety profile than did patients receiving 3 g/day of mycophenolate mofetil.

The above data demonstrate that the types of adverse events observed in multicenter controlled trials in renal, cardiac, and hepatic transplant patients are qualitatively similar except for those that are unique to the specific organ involved.

Sepsis, which was generally CMV viremia, was slightly more common in renal transplant patients treated with mycophenolate mofetil compared to patients treated with azathioprine.

The incidence of sepsis was comparable in mycophenolate mofetil and in azathioprine-treated patients in cardiac and hepatic studies.

In the digestive system, diarrhea was increased in renal and cardiac transplant patients receiving mycophenolate mofetil compared to patients receiving azathioprine, but was comparable in hepatic transplant patients treated with mycophenolate mofetil or azathioprine.

Patients receiving mycophenolate mofetil alone or as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see WARNINGS: Lymphoma and Malignancy ).

The incidence of malignancies among the 1,483 patients treated in controlled trials for the prevention of renal allograft rejection who were followed for ≥ 1 year was similar to the incidence reported in the literature for renal allograft recipients.

Lymphoproliferative disease or lymphoma 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 renal, cardiac, and hepatic transplant patients followed for at least one year (see WARNINGS: Lymphoma and Malignancy ).

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 renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the one year data.

In pediatric patients, no other malignancies besides lymphoproliferative disorder (2/148 patients) have been observed.

Severe neutropenia (ANC < 0.5 x 10 3 /µL) developed in up to 2% of renal transplant patients, up to 2.8% of cardiac transplant patients and up to 3.6% of hepatic transplant patients receiving mycophenolate mofetil 3 g daily (see WARNINGS: Neutropenia , PRECAUTIONS: Laboratory Tests and DOSAGE AND ADMINISTRATION ).

All transplant patients are at increased risk of opportunistic infections.

The risk increases with total immunosuppressive load (see WARNINGS: Serious Infections and WARNINGS: New or Reactivated Viral Infections ).

Table 10 shows the incidence of opportunistic infections that occurred in the renal, cardiac, and hepatic transplant populations in the azathioprine-controlled prevention trials.

Table 10: Viral and Fungal Infections in Controlled Studies in Prevention of Renal, Cardiac or Hepatic Transplant Rejection Renal Studies Cardiac Study Hepatic Study Mycophenolate Mofetil 2 g/day Mycophenolate Mofetil 3 g/day Azathioprine 1 to 2 mg/kg/day or 100 to 150 mg/day Mycophenolate Mofetil 3 g/day Azathioprine 1.5 to 3 mg/kg/day Mycophenolate Mofetil 3 g/day Azathioprine 1 to 2 mg/kg/day (n = 336) (n = 330) (n = 326) (n = 289) (n = 289) (n = 277) (n = 287) % % % % % % % Herpes simplex 16.7 20 19 20.8 14.5 10.1 5.9 CMV - Viremia/syndrome 13.4 12.4 13.8 12.1 10 14.1 12.2 - Tissue invasive disease 8.3 11.5 6.1 11.4 8.7 5.8 8 Herpes zoster 6 7.6 5.8 10.7 5.9 4.3 4.9 - Cutaneous disease 6 7.3 5.5 10 5.5 4.3 4.9 Candida 17 17.3 18.1 18.7 17.6 22.4 24.4 - Mucocutaneous 15.5 16.4 15.3 18 17.3 18.4 17.4 The following other opportunistic infections occurred with an incidence of less than 4% in mycophenolate mofetil patients in the above azathioprine-controlled studies: Herpes zoster, visceral disease; Candida, urinary tract infection, fungemia/disseminated disease, tissue invasive disease; Cryptococcosis; Aspergillus/Mucor; Pneumocystis carinii.

In the placebo-controlled renal transplant study, the same pattern of opportunistic infection was observed compared to the azathioprine-controlled renal studies, with a notably lower incidence of the following: Herpes simplex and CMV tissue-invasive disease.

In patients receiving mycophenolate mofetil (2 g or 3 g) in controlled studies for prevention of renal, cardiac or hepatic rejection, fatal infection/sepsis occurred in approximately 2% of renal and cardiac patients and in 5% of hepatic patients (see WARNINGS: Serious Infections ).

In cardiac transplant patients, the overall incidence of opportunistic infections was approximately 10% higher in patients treated with mycophenolate mofetil than in those receiving azathioprine, but this difference was not associated with excess mortality due to infection/sepsis among patients treated with mycophenolate mofetil.

The following adverse events were reported with 3% to < 20% incidence in renal, cardiac, and hepatic transplant patients treated with mycophenolate mofetil, in combination with cyclosporine and corticosteroids.

Table 11: Adverse Events Reported in 3% to < 20% of Patients Treated With Mycophenolate Mofetil in Combination With Cyclosporine and Corticosteroids Body System Body as a Whole abdomen enlarged, abscess, accidental injury, cellulitis, chills occurring with fever, cyst, face edema, flu syndrome, hemorrhage, hernia, lab test abnormal, malaise, neck pain, pelvic pain, peritonitis Hematologic and Lymphatic coagulation disorder, ecchymosis, pancytopenia, petechia, polycythemia, prothrombin time increased, thromboplastin time increased Urogenital acute kidney failure, albuminuria, dysuria, hydronephrosis, hematuria, impotence, kidney failure, kidney tubular necrosis, nocturia, oliguria, pain, prostatic disorder, pyelonephritis, scrotal edema, urine abnormality, urinary frequency, urinary incontinence, urinary retention, urinary tract disorder Cardiovascular angina pectoris, arrhythmia, arterial thrombosis, atrial fibrillation, atrial flutter, bradycardia, cardiovascular disorder, congestive heart failure, extrasystole, heart arrest, heart failure, hypotension, pallor, palpitation, pericardial effusion, peripheral vascular disorder, postural hypotension, pulmonary hypertension, supraventricular tachycardia, supraventricular extrasystoles, syncope, tachycardia, thrombosis, vasodilatation, vasospasm, ventricular extrasystole, ventricular tachycardia, venous pressure increased Metabolic and Nutritional abnormal healing, acidosis, alkaline phosphatase increased, alkalosis, bilirubinemia, creatinine increased, dehydration, gamma glutamyl transpeptidase increased, generalized edema, gout, hypercalcemia, hypercholesteremia, hyperlipemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypochloremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, hypovolemia, hypoxia, lactic dehydrogenase increased, respiratory acidosis, SGOT increased, SGPT increased, thirst, weight gain, weight loss Digestive anorexia, cholangitis, cholestatic jaundice, dysphagia, esophagitis, flatulence, gastritis, gastroenteritis, gastrointestinal disorder, gastrointestinal hemorrhage, gastrointestinal moniliasis, gingivitis, gum hyperplasia, hepatitis, ileus, infection, jaundice, liver damage, liver function tests abnormal, melena, mouth ulceration, nausea and vomiting, oral moniliasis, rectal disorder, stomach ulcer, stomatitis Respiratory apnea, asthma, atelectasis, bronchitis, epistaxis, hemoptysis, hiccup, hyperventilation, lung edema, lung disorder, neoplasm, pain, pharyngitis, pleural effusion, pneumonia, pneumothorax, respiratory disorder, respiratory moniliasis, rhinitis, sinusitis, sputum increased, voice alteration Skin and Appendages acne, alopecia, fungal dermatitis, hemorrhage, hirsutism, pruritus, rash, skin benign neoplasm, skin carcinoma, skin disorder, skin hypertrophy, skin ulcer, sweating, vesiculobullous rash Nervous agitation, anxiety, confusion, convulsion, delirium, depression, dry mouth, emotional lability, hallucinations, hypertonia, hypesthesia, nervousness, neuropathy, paresthesia, psychosis, somnolence, thinking abnormal, vertigo Endocrine Cushing’s syndrome, diabetes mellitus, hypothyroidism, parathyroid disorder Musculoskeletal arthralgia, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis Special Senses abnormal vision, amblyopia, cataract (not specified), conjunctivitis, deafness, ear disorder, ear pain, eye hemorrhage, tinnitus, lacrimation disorder Pediatrics The type and frequency of adverse events in a clinical study in 100 pediatric patients 3 months to 18 years of age dosed with mycophenolate mofetil oral suspension 600 mg/m 2 bid (up to 1 g bid) were generally similar to those observed in adult patients dosed with mycophenolate mofetil capsules at a dose of 1 g bid 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.

Postmarketing Experience Congenital Disorders Embryofetal Toxicity Congenital malformations, including ear, facial, cardiac and nervous system malformations and an increased incidence of first trimester pregnancy loss have been reported following exposure to mycophenolate mofetil during pregnancy (see PRECAUTIONS: Pregnancy ).

Digestive Colitis (sometimes caused by cytomegalovirus), pancreatitis, isolated cases of intestinal villous atrophy.

Hematologic and Lymphatic Cases of pure red cell aplasia (PRCA) and hypogammaglobulinemia have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressive agents.

Infections (see WARNINGS: Serious Infections and WARNINGS: New or Reactivated Viral Infections ).

Serious life-threatening infections such as meningitis and infectious endocarditis have been reported occasionally.

There is evidence of a higher frequency of certain types of serious infections such as tuberculosis and atypical mycobacterial infection.

Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with mycophenolate mofetil.

The reported cases generally had risk factors for PML, including treatment with immunosuppressant therapies and impairment of immune function.

Polyomavirus associated neuropathy (PVAN), especially due to BK virus infection, has been observed in patients receiving immunosuppressants, including mycophenolate mofetil.

This infection is associated with serious outcomes, including deteriorating renal function and renal graft loss.

Viral reactivation has been reported in patients infected with HBV or HCV.

Respiratory Interstitial lung disorders, including fatal pulmonary fibrosis, have been reported rarely and should be considered in the differential diagnosis of pulmonary symptoms ranging from dyspnea to respiratory failure in posttransplant patients receiving mycophenolate mofetil.