Mycophenolate Mofetil

Mycophenolate mofetil is an antimetabolite immunosuppressant indicated for the prophylaxis of organ rejection in adult and pediatric recipients 3 months of age and older of allogeneic kidney, heart or liver transplants, in combination with other immunosuppressants. Mycophenolate mofetil (MMF) is indicated for the prophylaxis of organ rejection, in adult and pediatric recipients 3 months of age and older of allogeneic kidney , heart or liver transplants , in combination with other immunosuppressants.

Kidney Transplant 1 g twice daily, orally Heart Transplant 1.5 g twice daily orally Liver Transplant 1.5 g twice daily orally PEDIATRICS Kidney Transplant 600 mg/m 2 orally twice daily, up to maximum of 2 g daily Heart Transplant 600 mg/m2 orally twice daily (starting dose) up to a maximum of 900 mg/m2 twice daily (3 g or 15 mL of oral suspension) Liver Transplant 600 mg/m2 orally twice daily (starting dose) up to a maximum of 900 mg/m2 twice daily (3 g or 15 mL of oral suspension) MYCOPHENOLATE MOFETIL Intravenous is an alternative when patients cannot tolerate oral medication. Administer within 24 hours following transplantation, until patients can tolerate oral medication, up to 14 days. Reduce or interrupt dosing in the event of neutropenia. See full prescribing information (FPI) for: adjustments for renal impairment and neutropenia.

2.1Important Administration Instructions Mycophenolate

mofetil should not be used without the supervision of a physician with experience in immunosuppressive therapy. Mycophenolate mofetil capsules and tablets Mycophenolate mofetil oral dosage forms (capsules or tablets) should not be used interchangeably with mycophenolic acid delayed-release tablets without supervision of a physician with experience in immunosuppressive therapy because the rates of absorption following the administration of Mycophenolate mofetil oral dosage forms and mycophenolic acid delayed-release tablets are not equivalent. Mycophenolate mofetil tablets should not be crushed and mycophenolate mofetil capsules should not be opened or crushed.

Patients should avoid inhalation or contact of the skin or mucous membranes with the powder contained in Mycophenolate mofetil capsules. If such contact occurs, they must wash the area of contact thoroughly with soap and water. In case of ocular contact, rinse eyes with plain water.

The initial oral dose of Mycophenolate mofetil should be given as soon as possible following kidney, heart or liver transplant. It is recommended that Mycophenolate mofetil be administered on an empty stomach. In stable transplant patients, however Mycophenolate mofetil may be administered with food if necessary . Patients should be instructed to take a missed dose as soon as they remember, except if it is closer than 2 hours to the next scheduled dose; in this case, they should continue to take Mycophenolate mofetil at the usual times.

2.2Dosage Recommendations for Kidney Transplant Patients

Adults The recommended dosage for adult kidney transplant patients is 1 g orally, twice daily (total daily dose of 2 g). Pediatrics (3 months and older) Pediatric dosing is based on body surface area (BSA). Pediatric patients with BSA ≥1.25 m 2 may be dosed with capsules or tablets as follows: Table 1 Pediatric Kidney Transplant: Dosage Using Capsules or Tablets Body Surface Area Dosage 1.25 m 2 to <1.5 m 2 Mycophenolate mofetil capsule 750 mg twice daily (1.5 g total daily dose) ≥ 1.5 m 2 Mycophenolate mofetil capsules or tablets 1 g twice daily (2 g total daily dose)

2.3Dosage Recommendations for Heart Transplant Patients

Adults The recommended dosage of Mycophenolate mofetil for adult heart transplant patients is 1.5 g orally administered twice daily (total daily dose of 3 g). Pediatrics (3 months and older) Pediatric patients with BSA ≥1.25 m 2 may be started on therapy with capsules or tablets as follows: Table 2 Pediatric Heart Transplant: Pediatric Starting Dosage Using Capsules or Tablets Body Surface Area Starting Dosage* 1.25 m 2 to <1.5 m 2 Mycophenolate mofetil capsule 750 mg twice daily (1.5 g total daily dose) ≥ 1.5 m 2 Mycophenolate mofetil capsules or tablets 1 g twice daily (2 g total daily dose) *Maximum maintenance dose: 3 g total daily.

2.4Dosage Recommendations for Liver Transplant Patients

Adults The recommended dosage of Mycophenolate mofetil for adult liver transplant patients is 1.5 g administered orally twice daily (total daily dose of 3 g). Pediatrics (3 months and older) Pediatric patients with BSA ≥1.25 m 2 may be started on therapy with capsules or tablets as follows: Table 3 Pediatric Liver Transplant: Pediatric Starting Dosage Using Capsules or Tablets Body Surface Area Starting Dosage* 1.25 m 2 to <1.5 m 2 Mycophenolate mofetil capsule 750 mg twice daily (1.5 g total daily dose) ≥ 1.5 m 2 Mycophenolate mofetil capsules or tablets 1 g twice daily (2 g total daily dose) *Maximum maintenance dose: 3 g total daily.

2.5Dosage Modifications: Patients with Renal Impairment,

Neutropenia Renal Impairment No dosage modifications are needed in kidney transplant patients with delayed graft function postoperatively . In kidney transplant patients with severe chronic impairment of the graft (GFR <25 mL/min/1.73 m 2 ), do not administer doses of Mycophenolate mofetil greater than 1 g twice a day. These patients should be carefully monitored . Neutropenia If neutropenia develops (ANC <1.3 × 10 3 /µL), dosing with Mycophenolate mofetil should be interrupted or reduced, appropriate diagnostic tests performed, and the patient managed appropriately .

Blood Dyscrasias (Neutropenia, Red Blood Cell Aplasia): Monitor with blood tests; consider treatment interruption or dose reduction. Gastrointestinal Complications: Monitor for complications such as bleeding, ulceration and perforations, particularly in patients with underlying gastrointestinal disorders. Hypoxanthine-Guanine Phosphoribosyl-Transferase Deficiency: Avoid use of MYCOPHENOLATE MOFETIL. Acute Inflammatory Syndrome Associated with Mycophenolate Products: Monitor for this paradoxical inflammatory reaction. Hypersensitivity Reactions: Discontinue MYCOPHENOLATE MOFETIL; treat and monitor until signs and symptoms resolve. Immunizations: Avoid live attenuated vaccines. Blood Donation: Avoid during therapy and for 6 weeks thereafter. Semen Donation: Avoid during therapy and for 90 days thereafter. Potential Impairment on Driving and Use of Machinery: MYCOPHENOLATE MOFETIL may affect ability to drive or operate machinery.

5.1Embryofetal Toxicity Use of

MMF 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. Females of reproductive potential must be made aware of these risks and must be counseled regarding pregnancy prevention and planning. Avoid use of MMF during pregnancy if safer treatment options are available .

5.2Lymphoma and Other Malignancies Patients

receiving immunosuppressants, including Mycophenolate mofetil, are at increased risk of developing lymphomas and other malignancies, particularly of the skin . The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. For patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor. Post-transplant lymphoproliferative disorder (PTLD) 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 kidney, heart and liver transplant patients . The majority of PTLD cases appear to be related to Epstein Barr Virus (EBV) infection.

The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children. In pediatric patients, no other malignancies besides PTLD were observed in clinical trials .

5.3Serious 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. The risk increases with the total immunosuppressive load. These infections may lead to serious outcomes, including hospitalizations and death . Serious viral infections reported include: Polyomavirus-associated nephropathy (PVAN), especially due to BK virus infection JC virus-associated progressive multifocal leukoencephalopathy (PML), and Cytomegalovirus (CMV) infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at highest risk of CMV viremia and CMV disease.

Viral reactivation in patients infected with Hepatitis B and C COVID-19 Consider dose reduction or discontinuation of Mycophenolate mofetil in patients who develop new infections or reactivate viral infections, weighing 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 . 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 . In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms. 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.

5.4Blood Dyscrasias: Neutropenia and Pure Red

Cell Aplasia (PRCA) Severe neutropenia [absolute neutrophil count (ANC) <0.5 × 10 3 /µL] developed in transplant patients receiving Mycophenolate mofetil 3 g daily . 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 <1.3 × 10 3 /µL), dosing with Mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately . 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.

5.5Gastrointestinal 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.

5.6Patients 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.

5.7Acute 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.

5.8Hypersensitivity Reactions Postmarketing

cases of hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with mycophenolate mofetil. These reactions generally occurred within hours to the next day after initiating mycophenolate mofetil. If signs or symptoms of hypersensitivity reaction occur, discontinue mycophenolate mofetil; treat and monitor until symptoms resolve .

5.9Immunizations 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.

5.12Blood 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.

5.13Semen Donation Based on

animal data, men should not donate semen during therapy and for 90 days following discontinuation of Mycophenolate mofetil .

5.14Effect 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.

5.15Potential 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 .

Mycophenolate mofetil is contraindicated in patients with history of a hypersensitivity, including anaphylaxis, to mycophenolate mofetil (MMF), mycophenolic acid (MPA) or any component of the drug product . History of hypersensitivity, including anaphylaxis, to mycophenolate mofetil, mycophenolic acid or any component of the drug product

8.1Pregnancy Pregnancy Exposure Registry There

is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to mycophenolate during pregnancy and those becoming pregnant within 6 weeks of discontinuing Mycophenolate mofetil treatment. To report a pregnancy or obtain information about the registry, visit www.mycophenolateREMS.com or call 1-800-617-8191. Risk Summary Use of mycophenolate mofetil (MMF) during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of multiple congenital malformations in multiple organ systems . Oral administration of mycophenolate to rats and rabbits during the period of organogenesis produced congenital malformations and pregnancy loss at doses less than the recommended clinical dose (0.01 to 0.05 times the recommended clinical doses in kidney and heart transplant patients) . Consider alternative immunosuppressants with less potential for embryofetal toxicity.

Risks and benefits of Mycophenolate mofetil should be discussed with the pregnant woman. The estimated background risk of pregnancy loss and congenital malformations in organ transplant populations is not clear. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data Human Data A spectrum of congenital malformations (including multiple malformations in individual newborns) has been reported in 23 to 27% of live births in MMF exposed pregnancies, based on published data from pregnancy registries. Malformations that have been documented include external ear, eye, and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, kidney, and nervous system. Based on published data from pregnancy registries, the risk of first trimester pregnancy loss has been reported at 45 to 49% following MMF exposure.

Animal Data In animal reproductive toxicology studies, there were increased rates of fetal resorptions and malformations in the absence of maternal toxicity. Oral administration of MMF to pregnant rats from Gestational Day 7 to Day 16 produced increased embryofetal lethality and fetal malformations including anophthalmia, agnathia, and hydrocephaly at doses equivalent to 0.015 and 0.01 times the recommended human doses for renal and cardiac transplant patients, respectively, when corrected for BSA. Oral administration of MMF to pregnant rabbits from Gestational Day 7 to Day 19 produced increased embryofetal lethality and fetal malformations included ectopia cordis, ectopic kidneys, diaphragmatic hernia, and umbilical hernia at dose equivalents as low as 0.05 and 0.03 times the recommended human doses for renal and cardiac transplant patients, respectively, when corrected for BSA.

The most common adverse reactions in clinical trials (20 % or greater) include diarrhea, leukopenia, infection, vomiting, and there is evidence of a higher frequency of certain types of infections e.g., opportunistic infection. To report SUSPECTED ADVERSE REACTIONS, contact Concord Biotech Limited at Telephone : 1-855-407-0586 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.com. The following adverse reactions are discussed in greater detail in other sections of the label: Embryofetal Toxicity Lymphomas and Other Malignancies Serious Infections Blood Dyscrasias: Neutropenia, Pure Red Cell Aplasia Gastrointestinal Complications Acute Inflammatory Syndrome Associated with Mycophenolate Products Hypersensitivity Reactions

6.1Clinical 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 1557 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 heart and liver transplant patients . 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) . 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 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). Adverse drug reaction Kidney Studies Heart Study Liver Study Mycophenolate mofetil AZA Placebo Mycophenolate mofetil AZA Mycophenolate mofetil AZA System Organ Class 2g/day (n=501) or 3g/day (n=490) 1 to 2 mg/kg/day or 100 to 150 mg/day 3g/day 1.5 to 3 mg/kg/day 3g/day 1 to 2 mg/kg/day (n=991) (n=326) (n=166) (n=289) (n=289) (n=277) (n=287) % % % % % % % Infections and infestations Bacterial infections 39.9 33.7 37.3 - - 27.4

26.5Viral

infections - a - - 31.1 24.9 - - Blood and lymphatic system disorders Anemia 20.0 23.6 2.4 45.0 47.1 43.0

53.0Ecchymosis

- - - 20.1 9.7 - - Leukocytosis - - - 42.6 37.4 22.4

21.3Leukopenia

28.6 24.8 4.2 34.3 43.3 45.8

39.0Thrombocytopenia

- - - 24.2 28.0 38.3

42.2Metabolism and

nutrition disorders Hypercholesterolemia - - - 46.0 43.9 - - Hyperglycemia - - - 48.4 53.3 43.7

48.8Hyperkalemia

- - - - - 22.0

23.7Hypocalcemia

- - - - - 30.0

30.0Hypokalemia

- - - 32.5 26.3 37.2

41.1Hypomagnesemia

- - - 20.1 14.2 39.0

37.6Psychiatric

disorders Depression - - - 20.1 15.2 - - Insomnia - - - 43.3 39.8 52.3

47.0Nervous

system disorders Dizziness - -- - 34.3 33.9 - - Headache - - - 58.5 55.4 53.8

49.1Tremor

- - - 26.3 25.6 33.9

35.5Cardiac

disorders Tachycardia - - - 22.8 21.8 22.0

15.7Vascular

disorders Hypertension 27.5 32.2 19.3 78.9 74.0 62.1

59.6Hypotension

- - - 34.3 40.1 - -- Respiratory, thoracic and mediastinal disorders Cough - - - 40.5 32.2 - - Dyspnea - - - 44.3 44.3 31.0

30.3Pleural

effusion - - - - - 34.3

35.9Gastrointestinal

disorders Abdominal pain 22.4 23.0 11.4 41.9 39.4 62.5

51.2Constipation

- - - 43.6 38.8 37.9

38.3Decreased

appetite - - - - - 25.3

17.1Diarrhea

30.4 20.9 13.9 52.6 39.4 51.3

49.8Dyspepsia

- - - 22.1 22.1 22.4

20.9Nausea

- - - 56.1 60.2 54.5

51.2Vomiting

- - - 39.1 34.6 32.9

33.4Hepatobiliary

disorders Blood lactate dehydrogenase increased - - - 23.5 18.3 - - Hepatic enzyme increased - - - - - 24.9

19.2Skin 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

33.8Edema

b 21.0 28.2 8.4 67.5 55.7 48.4

47.7Pain

c 24.8 32.2 9.6 79.2 77.5 74.0

77.5Pyrexia

- - - 56.4 53.6 52.3

56.1In 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 . 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 . Severe neutropenia (ANC <0.5 × 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 . 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 . 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 . 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 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 . 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.

6.2Postmarketing Experience The

following adverse reactions have been identified during post-approval use of Mycophenolate mofetil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Embryo-Fetal Toxicity: Congenital malformations and spontaneous abortions, mainly in the first trimester, have been reported following exposure to mycophenolate mofetil (MMF) in combination with other immunosuppressants during pregnancy . Congenital malformations include: Facial malformations: cleft lip, cleft palate, micrognathia, hypertelorism of the orbits Abnormalities of the ear and eye: abnormally formed or absent external/middle ear, coloboma, microphthalmos Malformations of the fingers: polydactyly, syndactyly, brachydactyly Cardiac abnormalities: atrial and ventricular septal defects Esophageal malformations: esophageal atresia Nervous system malformations: such as spina bifida . Cardiovascular: Venous thrombosis has been reported in patients treated with mycophenolate mofetil administered intravenously . Digestive: Colitis, pancreatitis Hematologic and Lymphatic: Bone marrow failure, cases of pure red cell aplasia (PRCA) and hypogammaglobulinemia have been reported in patients treated with Mycophenolate mofetil in combination with other immunosuppressive agents . Immune : Hypersensitivity reactions, including anaphylaxis and angioedema , , hypogammaglobinemia. Infections : Meningitis, infectious endocarditis, tuberculosis, atypical mycobacterial infection, progressive multifocal leukoencephalopathy, BK virus infection, viral reactivation of hepatitis B and hepatitis C, protozoal infections . Respiratory : Bronchiectasis, interstitial lung disease, 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 post-transplant patients receiving Mycophenolate mofetil.

Vascular: Lymphocele