Mycophenolate Mofetil (mycophenolate mofetil 250 mg) Dailymed

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 [see Clinical Studies (14.1)] , heart [see Clinical Studies (14.2)] or liver transplants [see Clinical Studies (14.3)] , in combination with other immunosuppressants.


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. ( 1)

2 Dosage And Administration

ADULTS	DOSAGE
Kidney Transplant	1 g twice daily orally ( 2.2)
Heart Transplant	1.5 g twice daily orally ( 2.3)
Liver Transplant	1.5 g twice daily orally ( 2.4)
PEDIATRICS
Kidney Transplant	600 mg/m 2orally twice daily, up to maximum of 2 g daily ( 2.2)
Heart Transplant	600 mg/m 2orally twice daily (starting dose) up to a maximum of 900 mg/m 2twice daily (3 g or 15 mL of oral suspension) ( 2.3)
Liver Transplant	600 mg/m 2orally twice daily (starting dose) up to a maximum of 900 mg/m 2twice daily (3 g or 15 mL of oral suspension) ( 2.4)

• Reduce or interrupt dosing in the event of neutropenia. ( 2.5)
• See full prescribing information (FPI) for: adjustments for renal impairment and neutropenia. ( 2.5)

2.1 Important Administration Instructions

Mycophenolate mofetil should not be used without the supervision of a physician with experience in immunosuppressive therapy.

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 therapybecause 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 [see Clinical Pharmacology (12.3)] .

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.

2.2 Dosage Recommendations for Kidney Transplant Patients

The recommended dosage for adult kidney transplant patients is 1 g orally twice daily (total daily dose of 2 g).

Pediatric dosing is based on body surface area (BSA). The recommended dosage of mycophenolate mofetil oral suspension for pediatric kidney transplant patients 3 months and older is 600 mg/m ², administered twice daily (maximum total daily dose of 2 g or 10 mL of the oral suspension). Pediatric patients with BSA ≥ 1.25 m ²may 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 2to < 1.5 m 2	Mycophenolate mofetil capsules 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)

2.3 Dosage Recommendations for Heart Transplant Patients

The recommended dosage of mycophenolate mofetil for adult heart transplant patients is 1.5 g orally twice daily (total daily dose of 3 g).

The recommended starting dose of mycophenolate mofetil oral suspension for pediatric heart transplant patients 3 months and older is 600 mg/m ²administered twice daily. If well tolerated, the dose can be increased to a maintenance dosage of 900 mg/m ²twice daily (maximum total daily dose of 3 g or 15 mL of the oral suspension). The dose may be individualized based on clinical assessment.

Pediatric patients with BSA ≥ 1.25 m ²may 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 Maximum maintenance dose: 3 g total daily.
1.25 m 2to < 1.5 m 2	Mycophenolate mofetil capsules 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)

 

2.4 Dosage Recommendations for Liver Transplant Patients

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).

The recommended starting dosage of mycophenolate mofetil oral suspension for pediatric liver transplant patients 3 months of age and older is 600 mg/m ², administered twice daily. If well tolerated, the dose can be increased to a maintenance dosage of 900 mg/m ²twice daily (maximum total daily dose of 3 g or 15 mL of the oral suspension). The dose may be individualized based on clinical assessment.

Pediatric patients with BSA ≥ 1.25 m ²may 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 Maximum maintenance dose: 3 g total daily.
1.25 m 2to < 1.5 m 2	Mycophenolate mofetil capsules 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)

 

2.5 Dosage Modifications: Patients with Renal Impairment, Neutropenia

No dosage modifications are needed in kidney transplant patients with delayed graft function postoperatively [see Clinical Pharmacology (12.3)] . 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 [see Clinical Pharmacology (12.3)] .

If neutropenia develops (ANC < 1.3 x 10 ³/µL), dosing with mycophenolate mofetil should be interrupted or reduced, appropriate diagnostic tests performed, and the patient managed appropriately [see Warnings and Precautions (5.4)and Adverse Reactions (6.1)] .

• Blood Dyscrasias (Neutropenia, Red Blood Cell Aplasia): Monitor with blood tests; consider treatment interruption or dose reduction. ( 5.4)
• Gastrointestinal Complications: Monitor for complications such as bleeding, ulceration and perforations, particularly in patients with underlying gastrointestinal disorders. ( 5.5)
• Hypoxanthine-Guanine Phosphoribosyl-Transferase Deficiency: Avoid use of mycophenolate mofetil. ( 5.6)
• Acute Inflammatory Syndrome Associated with Mycophenolate Products: Monitor for this paradoxical inflammatory reaction. ( 5.7)
• Immunizations: Avoid live attenuated vaccines. ( 5.8)
• Blood Donation: Avoid during therapy and for 6 weeks thereafter. ( 5.11)
• Semen Donation: Avoid during therapy and for 90 days thereafter. ( 5.12)
• Potential Impairment on Driving and Use of Machinery: Mycophenolate mofetil may affect ability to drive or operate machinery. ( 5.14)

5.1 Embryofetal 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 [see Use in Specific Populations (8.1, 8.3)] .

5.2 Lymphoma and Other Malignancies

Patients receiving immunosuppressants, including mycophenolate mofetil, are at increased risk of developing lymphomas and other malignancies, particularly of the skin [see Adverse Reactions (6.1)] . 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 [see Adverse Reactions (6.1)]. 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 [see Adverse Reactions (6.1)] .

5.3 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. The risk increases with the total immunosuppressive load. These infections may lead to serious outcomes, including hospitalizations and death [see Adverse Reactions (6.1, 6.2)] .

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 [see Adverse Reactions (6.2)] . 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 [see Adverse Reactions (6.2)] . 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.

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

Severe neutropenia [absolute neutrophil count (ANC) < 0.5 x 10 ³/µL] 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 < 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 (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.

5.11 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)]

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. ( 6.1)

 

To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 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 novokidney (3) heart (1) and liver (1) transplant patients [see Clinical Studies (14.1, 14.2, and  14.3)] .

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, 14.2and 14.3)] .

The three de novokidney 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 novoheart 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 novoliver 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       System Organ Class	Kidney Studies			Heart Study		Liver Study
	Mycophenolate Mofetil 2 g/day (n = 501) or 3 g/day (n=490)	AZA 1 to 2 mg/kg/day or 100 to 150 mg/day	Placebo	Mycophenolate Mofetil 3 g/day	AZA 1.5 to 3 mg/kg/day	Mycophenolate Mofetil 3 g/day	AZA 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	26.5
Viral infections	- “-” Indicates that the incidence was below the cutoff value of 20% for inclusion in the table.	-	-	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 “Edema” includes peripheral edema, facial edema, scrotal edema.	21.0	28.2	8.4	67.5	55.7	48.4	47.7
Pain “Pain” includes musculoskeletal pain (myalgia, neck pain, back pain).	24.8	32.2	9.6	79.2	77.5	74.0	77.5
Pyrexia	-	-	-	56.4	53.6	52.3	56.1

In the three de novokidney 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 oral suspension 600 mg/m ²twice 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)] .

6.2 Postmarketing 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 [see Warnings and Precautions (5.1), and Use in Specific Populations (8.1), (8.3)] . 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 [see Warnings and Precautions (5.4)] .
• Immune:  Hypersensitivity, 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 [see Warnings and Precautions (5.3)] .
• 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.