Important Administration Instructions

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

Mycophenolate Mofetil for Oral Suspension 

Mycophenolate mofetil for oral suspension 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 for oral suspension and mycophenolic acid delayed-release tablets are not equivalent. 

Patients should avoid inhalation or contact of the skin or mucous membranes with the powder contained in mycophenolate mofetil for oral suspension. 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 for oral suspension should be given as soon as possible following kidney, heart or liver transplant. It is recommended that mycophenolate mofetil for oral suspension be administered on an empty stomach. In stable transplant patients, however, mycophenolate mofetil for oral suspension may be administered with food if necessary [see Clinical Pharmacology (12.3)]. Once reconstituted, mycophenolate mofetil for oral suspension must not be mixed with any liquids prior to dose administration. If needed, mycophenolate mofetil for oral suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter). 

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 for oral suspension at the usual times.

CELLCEPT Intravenous

CELLCEPT Intravenous is recommended for patients unable to take oral mycophenolate mofetil. CELLCEPT Intravenous should be administered within 24 hours following transplant. CELLCEPT Intravenous can be administered for up to 14 days; however, patients should be switched to oral mycophenolate mofetil as soon as they can tolerate oral medication.

Dosage Recommendations for Kidney TransplantPatients

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). The recommended dosage of mycophenolate mofetil for oral suspension for pediatric kidney transplant patients 3 months and older is 600 mg/m2, administered twice daily (maximum total daily dose of 2 g or 10 mL of the oral suspension). Pediatric patients with BSA ≥ 1.25 m2 may be dosed with capsules or tablets as follows: 

Dosage Recommendations for Heart Transplant Patients

Adults

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

Pediatrics (3 months and older)

The recommended starting dosage of mycophenolate mofetil oral suspension for pediatric heart transplant patients 3 months and older is 600 mg/m2, administered twice daily. If well tolerated, the dose can be increased to a maintenance dosage of 900 mg/m2 twice 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 m2 may be started on therapy with capsules or tablets as follows: 

*Maximum maintenance dose: 3 g total daily.

 Dosage Recommendations for Liver Transplant Patients

Adults

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

Pediatrics (3 months and older)

The recommended starting dosage of mycophenolate mofetil oral suspension for pediatric liver transplant patients 3 months of age and older is 600 mg/m2, administered twice daily. If well tolerated, the dose can be increased to a maintenance dosage of 900 mg/m2 twice 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 m2 may be started on therapy with capsules or tablets as follows:

*Maximum maintenance dose: 3 g total daily.

Dosage Modifications: Patients with Renal Impairment, Neutropenia

Renal Impairment 

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 m2), do not administer doses of mycophenolate mofetil for oral suspension greater than 1 g twice a day. These patients should be carefully monitored [see Clinical Pharmacology (12.3)]. 

Neutropenia

If neutropenia develops (ANC <1.3 x 103/µL), dosing with mycophenolate mofetil for oral suspension 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)].

Preparation Instructions of Oral Suspension for Pharmacists

Pregnancy

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 [see Human Data]. 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) [see Animal Data]. 

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 

Lactation

Risk Summary 

There are no data on the presence of mycophenolate in human milk, or the effects on milk production. There are limited data in the National Transplantation Pregnancy Registry on the effects of mycophenolate on a breastfed child [see Data]. Studies in rats treated with MMF have shown mycophenolic acid (MPA) to be present in milk. Because available data are limited, it is not possible to exclude potential risks to a breastfeeding infant.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for mycophenolate mofetil and any potential adverse effects on the breastfed infant from mycophenolate mofetil or from the underlying maternal condition. 

Females and Males of Reproductive Potential 

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. 

Pregnancy Planning 

For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity whenever possible. Risks and benefits of mycophenolate mofetil should be discussed with the patient. 

Pregnancy Testing 

To prevent unplanned exposure during pregnancy, all females of reproductive potential should have a serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL immediately before starting mycophenolate mofetil. Another pregnancy test with the same sensitivity should be done 8 to 10 days later. Repeat pregnancy tests should be performed during routine follow-up visits. Results of all pregnancy tests should be discussed with the patient. In the event of a positive pregnancy test, consider alternative immunosuppressants with less potential for embryofetal toxicity whenever possible. 

Contraception 

Female Patients 

Females of reproductive potential taking mycophenolate mofetil must receive contraceptive counseling and use acceptable contraception (see Table 9 for acceptable contraception methods). Patients must use acceptable birth control during the entire mycophenolate mofetil therapy, and for 6 weeks after stopping mycophenolate mofetil, unless the patient chooses abstinence. 

Patients should be aware that mycophenolate mofetil reduces blood levels of the hormones from the oral contraceptive pill and could theoretically reduce its effectiveness [see Drug Interactions (7.2)]. 

Male Patients 

Genotoxic effects have been observed in animal studies at exposures exceeding the human therapeutic exposures by approximately 1.25 times. Thus, the risk of genotoxic effects on sperm cells cannot be excluded. Based on this potential risk, sexually active male patients and/or their female partners are recommended to use effective contraception during treatment of the male patient and for at least 90 days after cessation of treatment. Also, based on the potential risk of genotoxic effects, male patients should not donate sperm during treatment with mycophenolate mofetil and for at least 90 days after cessation of treatment [see Use in Special Populations (8.1), Nonclinical Toxicology (13.1), Patient Counseling Information (17.9)]. 

Pediatric Use 

Safety and effectiveness have been established in pediatric patients 3 months and older for the prophylaxis of organ rejection of allogeneic kidney, heart or liver transplants.

Kidney Transplant

Use of mycophenolate mofetil in this population is supported by evidence from adequate and well-controlled studies of mycophenolate mofetil in adults with additional data from one open-label, pharmacokinetic and safety study of mycophenolate mofetil in pediatric patients after receiving allogeneic kidney transplant (100 patients, 3 months to 18 years of age) [see Dosage and Administration (2.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3),  Clinical Studies (14.1)]. 

Heart Transplant and Liver Transplant

Use of mycophenolate mofetil in pediatric heart transplant and liver transplant patients is supported by adequate and well- controlled studies and pharmacokinetic data in adult heart transplant and liver transplant patients. Additional supportive data include pharmacokinetic data in pediatric kidney transplant and pediatric liver transplant patients (8 liver transplant patients, 9 months to 5 years of age, in an open-label, pharmacokinetic and safety study) and published evidence of clinical efficacy and safety in pediatric heart transplant and pediatric liver transplant patients [see Dosage and Administration (2.3, 2.4), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1)].

Geriatric Use 

Clinical studies of mycophenolate mofetil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between geriatric and younger patients. In general, dose selection for a geriatric patient should take into consideration the presence of decreased hepatic, renal or cardiac function and of concomitant drug therapies [see Adverse Reactions (6.1), Drug Interactions (7)].

Patients with Renal Impairment

Patients with Kidney Transplant 

No dosage adjustments are needed in kidney transplant patients experiencing delayed graft function postoperatively but patients should be carefully monitored [see Clinical Pharmacology (12.3)]. In kidney transplant patients with severe chronic impairment of the graft (GFR <25 mL/min/1.73 m2), no dose adjustments are necessary; however, doses greater than 1 g administered twice a day should be avoided. 

Patients with Heart and Liver Transplant 

No data are available for heart or liver transplant patients with severe chronic renal impairment. Mycophenolate mofetil may be used for heart or liver transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks. 

Patients with Hepatic Impairment

Patients with Kidney Transplant 

No dosage adjustments are recommended for kidney transplant patients with severe hepatic parenchymal disease. However, it is not known whether dosage adjustments are needed for hepatic disease with other etiologies [see Clinical Pharmacology (12.3)]. 

Patients with Heart Transplant 

No data are available for heart transplant patients with severe hepatic parenchymal disease. 

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)]. 

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)]. 

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. 

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

Severe neutropenia [absolute neutrophil count (ANC) <0.5 x 103/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 103/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. 

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.

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. 

Acute Inflammatory Syndrome Associated withMycophenolate 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.

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. 

Risks in Patients with Phenylketonuria

Phenylalanine can be harmful to patients with phenylketonuria (PKU). Mycophenolate mofetil for oral suspension contains aspartame, a source of phenylalanine (0.56 mg phenylalanine/mL suspension). Before prescribing mycophenolate mofetil for oral suspension to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including mycophenolate mofetil for oral suspension. 

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. 

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)]. 

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. 

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)]. 

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 

An estimated total of 1,557 adult patients received mycophenolate mofetil during pivotal clinical trials in the prevention of acute organ rejection. Of these, 991 were included in the three renal studies, 277 were included in one hepatic study, and 289 were included in one cardiac study. Patients in all study arms also received cyclosporine and corticosteroids. 

The data described below primarily derive from five randomized, active-controlled double-blind 12-month trials of mycophenolate mofetil in de novo kidney (3) heart (1) and liver (1) transplant patients [see Clinical Studies (14.1,  14.2 and  14.3)]. 

Mycophenolate Mofetil Oral 

The incidence of adverse reactions for mycophenolate mofetil was determined in five randomized, comparative, double-blind trials in the prevention of rejection in kidney, heart and liver transplant patients (two active- and one placebo-controlled trials, one active-controlled trial, and one active-controlled trial, respectively) [see Clinical Studies (14.1,  14.2 and 14.3)]. 

The three de novo kidney studies with 12-month duration compared two dose levels of oral mycophenolate mofetil (1 g twice daily and 1.5 g twice daily) with azathioprine (2 studies) or placebo (1 study) when administered in combination with cyclosporine (Sandimmune®) and corticosteroids to prevent acute rejection episodes. One study also included anti-thymocyte globulin (ATGAM®) induction therapy. 

In the de novo heart transplantation study with 12-month duration, patients received mycophenolate mofetil 1.5 g twice daily (n=289) or azathioprine 1.5 to 3 mg/kg/day (n=289), in combination with cyclosporine (Sandimmune® or Neoral®) and corticosteroids as maintenance immunosuppressive therapy. 

In the de novo liver transplantation study with 12-month duration, patients received CellCept 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. 

In the three de novo kidney studies, patients receiving 2 g/day of mycophenolate mofetil had an overall better safety profile than did patients receiving 3 g/day of mycophenolate mofetil. 

Post-transplant lymphoproliferative disease (PTLD, pseudolymphoma) developed in 0.4% to 1% of patients receiving mycophenolate mofetil (2 g or 3 g daily) with other immunosuppressive agents in controlled clinical trials of kidney, heart and liver transplant patients followed for at least 1 year [see Warnings and Precautions (5.2)]. Non-melanoma skin carcinomas occurred in 1.6% to 4.2% of patients, other types of malignancy in 0.7% to 2.1% of patients. Three-year safety data in kidney and heart transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. In pediatric patients, PTLD was observed in 1.35% (2/148) by 12 months post-transplant. 

Cytopenias, including leukopenia, anemia, thrombocytopenia and pancytopenia are a known risk associated with mycophenolate and may lead or contribute to the occurrence of infections and hemorrhages [see Warnings and Precautions (5.3)]. Severe neutropenia (ANC <0.5 x 103/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. 

Pediatrics  

The type and frequency of adverse events in a clinical study for prevention of kidney allograft rejection in 100 pediatric patients 3 months to 18 years of age dosed with mycophenolate mofetil for oral suspension 600 mg/m2 twice daily (up to 1 g twice daily) were generally similar to those observed in adult patients dosed with CellCept 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)]. 

Post-marketing 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 CellCept 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 

Effect of Other Drugs on Mycophenolate Mofetil

Effect of Mycophenolate Mofetil on Other Drugs

Mechanism of Action 

Mycophenolate mofetil (MMF) is absorbed following oral administration and hydrolyzed to mycophenolic acid (MPA), the active metabolite. MPA is a selective uncompetitive inhibitor of the two isoforms (type I and type II) of inosine monophosphate dehydrogenase (IMPDH) leading to inhibition of the de novo pathway of guanosine nucleotide synthesis and blocks DNA synthesis. The mechanism of action of MPA is multifaceted and includes effects on cellular checkpoints responsible for metabolic programming of lymphocytes. MPA shifts transcriptional activities in lymphocytes from a proliferative state to catabolic processes. In vitro studies suggest that MPA modulates transcriptional activities in human CD4+ T-lymphocytes by suppressing the Akt/mTOR and STAT5 pathways that are relevant to metabolism and survival, leading to an anergic state of T-cells whereby the cells become less responsive to antigenic stimulation. Additionally, MPA enhanced the expression of negative co-stimulators such as CD70, PD-1, CTLA-4, and transcription factor FoxP3 as well as decreased the expression of positive co-stimulators CD27 and CD28.

MPA decreases proliferative responses of T- and B-lymphocytes to both mitogenic and allo-antigenic stimulation, antibody responses, as well as the production of cytokines from lymphocytes and monocytes such as GM-CSF, IFN-Ɣ, IL-17, and TNF-α. Additionally, MPA prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved in intercellular adhesion to endothelial cells and may inhibit recruitment of leukocytes into sites of inflammation and graft rejection.

Overall, the effect of MPA is cytostatic and reversible.

Pharmacodynamics

There is a lack of information regarding the pharmacodynamic effects of MMF. 

Pharmacokinetics

Absorption 

Following oral and intravenous administration, MMF undergoes complete conversion to MPA, the active metabolite. In 12 healthy volunteers, the mean absolute bioavailability of oral MMF relative to intravenous MMF was 94%. Two 500 mg CellCept tablets have been shown to be bioequivalent to four 250 mg CellCept capsules. Five mL of the 200 mg/mL constituted mycophenolate mofetil for oral suspension have been shown to be bioequivalent to four 250 mg capsules.

The mean (±SD) pharmacokinetic parameters estimates for MPA following the administration of MMF given as single doses to healthy volunteers, and multiple doses to kidney, heart, and liver transplant patients, are shown in Table 10. The area under the plasma-concentration time curve (AUC) for MPA appears to increase in a dose-proportional fashion in kidney transplant patients receiving multiple oral doses of MMF up to a daily dose of 3 g (1.5 g twice daily) (see Table 10).

In the early post-transplant period (less than 40 days post-transplant), kidney, heart, and liver transplant patients had mean MPA AUCs approximately 20% to 41% lower and mean Cmax approximately 32% to 44% lower compared to the late transplant period (i.e., 3 to 6 months post-transplant) (non-stationarity in MPA pharmacokinetics).

Mean MPA AUC values following administration of 1 g twice daily intravenous CellCept over 2 hours to kidney transplant patients for 5 days were about 24% higher than those observed after oral administration of a similar dose in the immediate post-transplant phase.

In liver transplant patients, administration of 1 g twice daily intravenous CellCept followed by 1.5 g twice daily oral mycophenolate mofetil resulted in mean MPA AUC estimates similar to those found in kidney transplant patients administered 1 g mycophenolate mofetil twice daily.

Effect of Food 

Food (27 g fat, 650 calories) had no effect on the extent of absorption (MPA AUC) of MMF when administered at doses of 1.5 g twice daily to kidney transplant patients. However, MPA Cmax was decreased by 40% in the presence of food [see Dosage and Administration (2.1)]. 

Distribution 

The mean (±SD) apparent volume of distribution of MPA in 12 healthy volunteers was approximately 3.6 (±1.5) L/kg. At clinically relevant concentrations, MPA is 97% bound to plasma albumin. The phenolic glucuronide metabolite of MPA (MPAG) is 82% bound to plasma albumin at MPAG concentration ranges that are normally seen in stable kidney transplant patients; however, at higher MPAG concentrations (observed in patients with kidney impairment or delayed kidney graft function), the binding of MPA may be reduced as a result of competition between MPAG and MPA for protein binding. Mean blood to plasma ratio of radioactivity concentrations was approximately 0.6 indicating that MPA and MPAG do not extensively distribute into the cellular fractions of blood. 

In vitro studies to evaluate the effect of other agents on the binding of MPA to human serum albumin (HSA) or plasma proteins showed that salicylate (at 25 mg/dL with human serum albumin) and MPAG (at ≥ 460 mcg/mL with plasma proteins) increased the free fraction of MPA. MPA at concentrations as high as 100 mcg/mL had little effect on the binding of warfarin, digoxin or propranolol, but decreased the binding of theophylline from 53% to 45% and phenytoin from 90% to 87%. 

Elimination 

Mean (±SD) apparent half-life and plasma clearance of MPA are 17.9 (±6.5) hours and 193 (±48) mL/min following oral administration and 16.6 (±5.8) hours and 177 (±31) mL/min following intravenous administration, respectively. 

Metabolism 

The parent drug, MMF, can be measured systemically during the intravenous infusion; however, approximately 5 minutes after the infusion is stopped or after oral administration, MMF concentrations are below the limit of quantitation (0.4 mcg/mL). 

Metabolism to MPA occurs pre-systemically after oral dosing. MPA is metabolized principally by glucuronyl transferase to form MPAG, which is not pharmacologically active. In vivo, MPAG is converted to MPA during enterohepatic recirculation. The following metabolites of the 2-hydroxyethyl-morpholino moiety are also recovered in the urine following oral administration of MMF to healthy subjects: N-(2-carboxymethyl)­-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine. 

Due to the enterohepatic recirculation of MPAG/MPA, secondary peaks in the plasma MPA concentration-time profile are usually observed 6 to 12 hours post-dose. Bile sequestrants, such as cholestyramine, reduce MPA AUC by interfering with this enterohepatic recirculation of the drug [see Overdosage (10) and  Drug Interaction Studies below].

Excretion 

Negligible amount of drug is excreted as MPA (less than 1% of dose) in the urine. Orally administered radiolabeled MMF resulted in complete recovery of the administered dose, with 93% of the administered dose recovered in the urine and 6% recovered in feces. Most (about 87%) of the administered dose is excreted in the urine as MPAG. At clinically encountered concentrations, MPA and MPAG are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (> 100 mcg/mL), small amounts of MPAG are removed. 

Increased plasma concentrations of MMF metabolites (MPA 50% increase and MPAG about a 3-fold to 6-fold increase) are observed in patients with renal insufficiency [see Specific Populations]. 

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week oral carcinogenicity study in mice, MMF in daily doses up to 180 mg/kg was not tumorigenic. The highest dose tested was 0.2 times the recommended clinical dose (2 g/day) in renal transplant patients and 0.15 times the recommended clinical dose (3 g/day) in cardiac transplant patients when corrected for differences in body surface area (BSA). In a 104-week oral carcinogenicity study in rats, MMF in daily doses up to 15 mg/kg was not tumorigenic. The highest dose was 0.035 times the recommended clinical dose in kidney transplant patients and 0.025 times the recommended clinical dose in heart transplant patients when corrected for BSA. While these animal doses were lower than those given to patients, they were maximal in those species and were considered adequate to evaluate the potential for human risk [see Warnings and Precautions (5.2)].

The genotoxic potential of MMF was determined in five assays. MMF was genotoxic in the mouse lymphoma/thymidine kinase assay and the in vivo mouse micronucleus assay. MMF was not genotoxic in the bacterial mutation assay, the yeast mitotic gene conversion assay or the Chinese hamster ovary cell chromosomal aberration assay. 

MMF had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. This dose represents 0.05 times the recommended clinical dose in renal transplant patients and 0.03 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. In a female fertility and reproduction study conducted in rats, oral doses of 4.5 mg/kg/day caused malformations (principally of the head and eyes) in the first generation offspring in the absence of maternal toxicity. This dose was 0.01 times the recommended clinical dose in renal transplant patients and 0.005 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation. 

Kidney Transplantation

Adults 

The three de novo kidney transplantation studies 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) to prevent acute rejection episodes. One of the two studies with azathioprine (AZA) control arm also included anti-thymocyte globulin (ATGAM®) induction therapy. The geographic location of the investigational sites of these studies are included in Table 13. 

In all three de novo kidney transplantation studies, the primary efficacy endpoint was the proportion of patients in each treatment group who experienced treatment failure within the first 6 months after transplantation. Treatment failure was defined as biopsy-proven acute rejection on treatment or the occurrence of death, graft loss or early termination from the study for any reason without prior biopsy-proven rejection. 

Mycophenolate mofetil, in combination with corticosteroids and cyclosporine, reduced (statistically significant at 0.05 level) the incidence of treatment failure within the first 6 months following transplantation (Table 13). Patients who prematurely discontinued treatment were followed for the occurrence of death or graft loss, and the cumulative incidence of graft loss and patient death combined are summarized in Table 14. Patients who prematurely discontinued treatment were not followed for the occurrence of acute rejection after termination.

No advantage of mycophenolate mofetil at 12 months with respect to graft loss or patient death (combined) was established (Table 14). Numerically, patients receiving mycophenolate mofetil 2 g/day and 3 g/day experienced a better outcome than controls in all three studies; patients receiving mycophenolate mofetil 2 g/day experienced a better outcome than mycophenolate mofetil 3 g/day in two of the three studies. Patients in all treatment groups who terminated treatment early were found to have a poor outcome with respect to graft loss or patient death at 1 year. 

Pediatrics- De Novo Kidney transplantation PK Study with Long Term Follow-Up 

One open-label, safety and pharmacokinetic study of mycophenolate mofetil for oral suspension 600 mg/m2 twice daily (up to 1 g twice daily) in combination with cyclosporine and corticosteroids was performed at centers in the United States (9), Europe (5) and Australia (1) in 100 pediatric patients (3 months to 18 years of age) for the prevention of renal allograft rejection. Mycophenolate mofetil was well tolerated in pediatric patients [see Adverse Reactions (6.1)], and the pharmacokinetics profile was similar to that seen in adult patients dosed with 1 g twice daily CellCept capsules [see Clinical Pharmacology (12.3)]. The rate of biopsy-proven rejection was similar across the age groups (3 months to <6 years, 6 years to <12 years, 12 years to 18 years). The overall biopsy-proven rejection rate at 6 months was comparable to adults. The combined incidence of graft loss (5%) and patient death (2%) at 12 months post-transplant was similar to that observed in adult kidney transplant patients. 

Heart Transplantation

A double-blind, randomized, comparative, parallel-group, multicenter study in primary de novo heart transplant recipients was performed at centers in the United States (20), in Canada (1), in Europe (5) and in Australia (2). The total number of patients enrolled (ITT population) was 650; 72 never received study drug and 578 received study drug (Safety Population). Patients received mycophenolate mofetil 1.5 g twice daily (n=289) or AZA 1.5 to 3 mg/kg/day (n=289), in combination with cyclosporine (Sandimmune® or Neoral®) and corticosteroids as maintenance immunosuppressive therapy. The two primary efficacy endpoints were: (1) the proportion of patients who, after transplantation, had at least one endomyocardial biopsy-proven rejection with hemodynamic compromise, or were re-transplanted or died, within the first 6 months, and (2) the proportion of patients who died or were re-transplanted during the first 12 months following transplantation. Patients who prematurely discontinued treatment were followed for the occurrence of allograft rejection for up to 6 months and for the occurrence of death for 1 year. 

The analyses of the endpoints showed: 

• Rejection: No difference was established between mycophenolate mofetil and AZA with respect to biopsy-proven rejection with hemodynamic compromise. 
• Survival: Mycophenolate mofetil was shown to be at least as effective as AZA in preventing death or re-transplantation at 1 year (see Table 15).

Liver Transplantation

A double-blind, randomized, comparative, parallel-group, multicenter study in primary hepatic transplant recipients was performed at centers in the United States (16), in Canada (2), in Europe (4) and in Australia (1). The total number of patients enrolled was 565. Per protocol, patients received CellCept 1 g twice daily intravenously for up to 14 days followed by mycophenolate mofetil 1.5 g twice daily orally or AZA 1 to 2 mg/kg/day intravenously followed by AZA 1 to 2 mg/kg/day orally, in combination with cyclosporine (Neoral®) and corticosteroids as maintenance immunosuppressive therapy. The actual median oral dose of AZA on study was 1.5 mg/kg/day (range of 0.3 to 3.8 mg/kg/day) initially and 1.26 mg/kg/day (range of 0.3 to 3.8 mg/kg/day) at 12 months. The two primary endpoints were: (1) the proportion of patients who experienced, in the first 6 months post-transplantation, one or more episodes of biopsy-proven and treated rejection or death or re-transplantation, and (2) the proportion of patients who experienced graft loss (death or re-transplantation) during the first 12 months post-transplantation. Patients who prematurely discontinued treatment were followed for the occurrence of allograft rejection and for the occurrence of graft loss (death or re-transplantation) for 1 year. 

In combination with corticosteroids and cyclosporine, mycophenolate mofetil demonstrated a lower rate of acute rejection at 6 months and a similar rate of death or re-transplantation at 1 year compared to AZA (Table 16).

Handling and Disposal

Mycophenolate mofetil (MMF) has demonstrated teratogenic effects in humans [see Warnings and Precautions  (5.1) and  Use in Specific Populations (8.1)]. Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the bottle/cap and the table after reconstitution. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in mycophenolate mofetil for oral suspension, USP (before or after constitution) [see Dosage and Administration (2.6)]. Follow applicable special handling and disposal procedures1.

Mycophenolate Mofetil for Oral Suspension, USP

35 g mycophenolate mofetil, white to off-white powder blend for constitution to a white to off-white mixed-fruit flavor suspension.

It is supplied as follows:

225 mL bottle with bottle adapter and 2 oral dispensers with child-resistant closure:         NDC 69238-1595-2

Storage

• Store dry powder at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
• Store constituted suspension at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) for up to 60 days. Storage in a refrigerator at 2° to 8°C (36° to 46°F) is acceptable. Do not freeze.