Mycophenolate Suspension

Allergic reactions to mycophenolate mofetil have been observed; therefore, mycophenolate mofetil is contraindicated in patients with a hypersensitivity to mycophenolate mofetil, mycophenolic acid or any component of the drug product.

Pregnancy Exposure Prevention and Planning

Females of reproductive potential must be made aware of the increased risk of first trimester pregnancy loss and congenital malformations and must be counseled regarding pregnancy prevention and planning.
Females of reproductive potential include girls who have entered puberty and all women who have a uterus and have not passed through menopause. Menopause is the permanent end of menstruation and fertility. Menopause should be clinically confirmed by a patient’s healthcare practitioner. Some commonly used diagnostic criteria include 1) 12 months of spontaneous amenorrhea (not amenorrhea induced by a medical condition or medical therapy) or 2) postsurgical from a bilateral oophorectomy.

Pregnancy Testing
To prevent unplanned exposure during pregnancy, 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, females should be counseled with regard to whether the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in certain situations.

Contraception
Females of reproductive potential taking mycophenolate mofetil must receive contraceptive counseling and use acceptable contraception (see Table 8 for acceptable contraception methods). Patients must use acceptable birth control during entire mycophenolate mofetil therapy, and for 6 weeks after stopping mycophenolate mofetil, unless the patient chooses abstinence (she chooses to avoid heterosexual intercourse completely).
Patients should be aware that mycophenolate mofetil reduces blood levels of the hormones in the oral contraceptive pill and could theoretically reduce its effectiveness (see PRECAUTIONS: Information for Patientsand PRECAUTIONS: Drug Interactions: Oral Contraceptives)

Table 8 Acceptable Contraception Methods for Females of Reproductive Potential
Pick from the following birth control options:

OR

OR

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

Gastrointestinal Disorders
Gastrointestinal bleeding (requiring hospitalization) has been observed in approximately 3% of renal, in 1.7% of cardiac, and in 5.4% of hepatic transplant patients treated with mycophenolate mofetil 3 g daily. In pediatric renal transplant patients, 5/148 cases of gastrointestinal bleeding (requiring hospitalization) were observed.

Gastrointestinal perforations have rarely been observed. Most patients receiving mycophenolate mofetil were also receiving other drugs known to be associated with these complications. Patients with active peptic ulcer disease were excluded from enrollment in studies with mycophenolate mofetil. Because mycophenolate mofetil has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, hemorrhage, and perforation, mycophenolate mofetil should be administered with caution in patients with active serious digestive system disease.

Patients with Renal Impairment
Subjects with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) who have received single doses of mycophenolate mofetil showed higher plasma MPA and MPAG AUCs relative to subjects with lesser degrees of renal impairment or normal healthy volunteers. No data are available on the safety of long-term exposure to these levels of MPAG. Doses of mycophenolate mofetil greater than 1 g administered twice a day to renal transplant patients should be avoided and they should be carefully observed (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND ADMINISTRATION).

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

In patients with delayed renal graft function posttransplant, mean MPA AUC0-12h was comparable, but MPAG AUC0-12h was 2-fold to 3-fold higher, compared to that seen in posttransplant patients without delayed renal graft function. In the three controlled studies of prevention of renal rejection, there were 298 of 1483 patients (20%) with delayed graft function. Although patients with delayed graft function have a higher incidence of certain adverse events (anemia, thrombocytopenia, hyperkalemia) than patients without delayed graft function, these events were not more frequent in patients receiving mycophenolate mofetil than azathioprine or placebo. No dose adjustment is recommended for these patients; however, they should be carefully observed (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND ADMINISTRATION).

Infections in Cardiac Transplant Patients
In cardiac transplant patients, the overall incidence of opportunistic infections was approximately 10% higher in patients treated with mycophenolate mofetil than in those receiving azathioprine therapy, but this difference was not associated with excess mortality due to infection/sepsis among patients treated with mycophenolate mofetil (see ADVERSE REACTIONS).

There were more herpes virus (H. simplex, H. zoster, and cytomegalovirus) infections in cardiac transplant patients treated with mycophenolate mofetil compared to those treated with azathioprine (see ADVERSE REACTIONS).

Concomitant Medications
It is recommended that mycophenolate mofetil not be administered concomitantly with azathioprine because both have the potential to cause bone marrow suppression and such concomitant administration has not been studied clinically.

In view of the significant reduction in the AUC of MPA by cholestyramine, caution should be used in the concomitant administration of mycophenolate mofetil with drugs that interfere with enterohepatic recirculation because of the potential to reduce the efficacy of mycophenolate mofetil (see PRECAUTIONS: Drug Interactions).

Patients with HGPRT Deficiency
Mycophenolate mofetil is an IMPDH (inosine monophosphate dehydrogenase) inhibitor, therefore it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.

Immunizations
During treatment with mycophenolate mofetil, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective (see PRECAUTIONS: Drug Interactions: Live Vaccines).

Phenylketonurics
Mycophenolate mofetil oral suspension contains aspartame, a source of phenylalanine (0.56 mg phenylalanine/mL suspension). Therefore, care should be taken if mycophenolate mofetil oral suspension is administered to patients with phenylketonuria.

Information for Patients

See Medication Guide

• Inform females of reproductive potential that use of mycophenolate mofetil during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations, and advise them as to the appropriate steps to manage these risks, including that they must use acceptable contraception (see WARNINGS: Embryofetal Toxicity, PRECAUTIONS: Pregnancy Exposure Prevention and Planning).
• Discuss pregnancy testing, pregnancy prevention and planning with females of reproductive potential. In the event of a positive pregnancy test, females should be counseled with regard to whether the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in certain situations.
• Females of reproductive potential must use acceptable birth control during entire mycophenolate mofetil therapy and for 6 weeks after stopping mycophenolate mofetil, unless the patient chooses to avoid heterosexual intercourse completely (abstinence) (see PRECAUTIONS: Pregnancy Exposure Prevention and Planning, Table 8).
• For patients who are considering pregnancy, discuss appropriate alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of mycophenolate mofetil should be discussed with the patient.
• Give patients complete dosage instructions and inform them about the increased risk of lymphoproliferative disease and certain other malignancies.
• Inform patients that they need repeated appropriate laboratory tests while they are taking mycophenolate mofetil.
• Advise patients that they should not breastfeed during mycophenolate mofetil therapy.

Laboratory Tests

Complete blood counts should be performed weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year (see WARNINGS, ADVERSE REACTIONSand DOSAGE AND ADMINISTRATION).

Drug Interactions

Drug interaction studies with mycophenolate mofetil have been conducted with acyclovir, antacids, cholestyramine, cyclosporine, ganciclovir, oral contraceptives, sevelamer, trimethoprim/sulfamethoxazole, norfloxacin, and metronidazole. Drug interaction studies have not been conducted with other drugs that may be commonly administered to renal, cardiac or hepatic transplant patients. Mycophenolate mofetil has not been administered concomitantly with azathioprine.


Acyclovir
Coadministration of mycophenolate mofetil (1 g) and acyclovir (800 mg) to 12 healthy volunteers resulted in no significant change in MPA AUC and Cmax. However, MPAG and acyclovir plasma AUCs were increased 10.6% and 21.9%, respectively. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are acyclovir concentrations, the potential exists for mycophenolate and acyclovir or its prodrug (eg, valacyclovir) to compete for tubular secretion, further increasing the concentrations of both drugs.

Antacids With Magnesium and Aluminum Hydroxides
Absorption of a single dose of mycophenolate mofetil (2 g) was decreased when administered to ten rheumatoid arthritis patients also taking Maalox® TC (10 mL qid). The Cmax and AUC0-24h for MPA were 33% and 17% lower, respectively, than when mycophenolate mofetil was administered alone under fasting conditions. Mycophenolate mofetil may be administered to patients who are also taking antacids containing magnesium and aluminum hydroxides; however, it is recommended that mycophenolate mofetil and the antacid not be administered simultaneously.

Proton Pump Inhibitors (PPIs)
Coadministration of PPIs (e.g., lansoprazole, pantoprazole) in single doses to healthy volunteers and multiple doses to transplant patients receiving mycophenolate mofetil has been reported to reduce the exposure to mycophenolic acid (MPA). An approximate reduction of 30 to 70% in the Cmax and 25% to 35% in the AUC of MPA has been observed, possibly due to a decrease in MPA solubility at an increased gastric pH. The clinical impact of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and mycophenolate mofetil. Because clinical relevance has not been established, PPIs should be used with caution when coadministered to transplant patients being treated with mycophenolate mofetil.

Cholestyramine
Following single-dose administration of 1.5 g mycophenolate mofetil to 12 healthy volunteers pretreated with 4 g tid of cholestyramine for 4 days, MPA AUC decreased approximately 40%. This decrease is consistent with interruption of enterohepatic recirculation which may be due to binding of recirculating MPAG with cholestyramine in the intestine. Some degree of enterohepatic recirculation is also anticipated following intravenous administration of mycophenolate mofetil. Therefore, mycophenolate mofetil is not recommended to be given with cholestyramine or other agents that may interfere with enterohepatic recirculation.

Cyclosporine
Cyclosporine (Sandimmune®) pharmacokinetics (at doses of 275 to 415 mg/day) were unaffected by single and multiple doses of 1.5 g bid of mycophenolate mofetil in 10 stable renal transplant patients. The mean (±SD) AUC0-12h and Cmax of cyclosporine after 14 days of multiple doses of mycophenolate mofetil were 3290 (±822) ng•h/mL and 753 (±161) ng/mL, respectively, compared to 3245 (±1088) ng•h/mL and 700 (±246) ng/mL, respectively, 1 week before administration of mycophenolate mofetil.

Cyclosporine A interferes with MPA enterohepatic recirculation. In renal transplant patients, mean MPA exposure (AUC0-12h) was approximately 30-50% greater when mycophenolate mofetil is administered without cyclosporine compared with when mycophenolate mofetil is coadministered with cyclosporine. This interaction is due to cyclosporine inhibition of multidrug-resistance-associated protein 2 (MRP-2) transporter in the biliary tract, thereby preventing the excretion of MPAG into the bile that would lead to enterohepatic recirculation of MPA. This information should be taken into consideration when MMF is used without cyclosporine; changes in MPA exposure should be expected when switching patients from cyclosporine A to one of the immunosuppressants which do not interfere with MPA’s enterohepatic cycle (e.g., tacrolimus; belatacept).

Telmisartan
Concommitant administration of telmisartan and mycophenolate mofetil resulted in an approximately 30% decrease in mycophenolic acid (MPA) concentrations. Telmisartan changes MPA’s elimination by enhancing PPAR gamma (peroxisome proliferator-activated receptor gamma) expression, which in turn results in an enhanced UGT1A9 expression and activity

Ganciclovir

Following single-dose administration to 12 stable renal transplant patients, no pharmacokinetic interaction was observed between mycophenolate mofetil (1.5 g) and intravenous ganciclovir (5 mg/kg). Mean (±SD) ganciclovir AUC and Cmax (n=10) were 54.3 (±19.0) mcg•h/mL and 11.5 (±1.8) mcg/mL, respectively, after coadministration of the two drugs, compared to 51.0 (±17.0) mcg•h/mL and 10.6 (±2.0) mcg/mL, respectively, after administration of intravenous ganciclovir alone. The mean (±SD) AUC and Cmax of MPA (n=12) after coadministration were 80.9 (±21.6) mcg•h/mL and 27.8 (±13.9) mcg/mL, respectively, compared to values of 80.3 (±16.4) mcg•h/mL and 30.9 (±11.2) mcg/mL, respectively, after administration of mycophenolate mofetil alone. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are ganciclovir concentrations, the two drugs will compete for tubular secretion and thus further increases in concentrations of both drugs may occur. In patients with renal impairment in which MMF and ganciclovir or its prodrug (eg, valganciclovir) are coadministered, patients should be monitored carefully.


Oral Contraceptives
A study of coadministration of mycophenolate mofetil (1 g bid) and combined oral contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.20 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) was conducted in 18 women with psoriasis over 3 consecutive menstrual cycles. Mean AUC0-24h was similar for ethinylestradiol and 3-keto desogestrel; however, mean levonorgestrel AUC0-24h significantly decreased by about 15%. There was large inter-patient variability (%CV in the range of 60% to 70%) in the data, especially for ethinylestradiol. Mean serum levels of LH, FSH and progesterone were not significantly affected. Mycophenolate mofetil may not have any influence on the ovulation-suppressing action of the studied oral contraceptives. It is recommended to co-administer mycophenolate mofetil with hormonal contraceptives (eg, birth control pill, transdermal patch, vaginal ring, injection, and implant) with caution, and additional barrier contraceptive methods must be used (see PRECAUTIONS: Pregnancy Exposure Prevention and Planning).

Sevelamer
Concomitant administration of sevelamer and mycophenolate mofetil in adult and pediatric patients decreased the mean MPA Cmax and AUC0-12h by 36% and 26% respectively. This data suggest that sevelamer and other calcium free phosphate binders should not be administered simultaneously with mycophenolate mofetil. Alternatively, it is recommended that sevelamer and other calcium free phosphate binders preferentially could be given 2 hours after mycophenolate mofetil intake to minimize the impact on the absorption of MPA.

Trimethoprim/sulfamethoxazole
Following single-dose administration of mycophenolate mofetil (1.5 g) to 12 healthy male volunteers on day 8 of a 10 day course of trimethoprim 160 mg/sulfamethoxazole 800 mg administered bid, no effect on the bioavailability of MPA was observed. The mean (±SD) AUC and Cmax of MPA after concomitant administration were 75.2 (±19.8) mcg•h/mL and 34.0 (±6.6) mcg/mL, respectively, compared to 79.2 (±27.9) mcg•h/mL and 34.2 (±10.7) mcg/mL, respectively, after administration of mycophenolate mofetil alone.

Norfloxacin and Metronidazole
Following single-dose administration of mycophenolate mofetil (1 g) to 11 healthy volunteers on day 4 of a 5 day course of a combination of norfloxacin and metronidazole, the mean MPA AUC0-48h was significantly reduced by 33% compared to the administration of mycophenolate mofetil alone (p<0.05). Therefore, mycophenolate mofetil is not recommended to be given with the combination of norfloxacin and metronidazole. There was no significant effect on mean MPA AUC0-48h when mycophenolate mofetil was concomitantly administered with norfloxacin or metronidazole separately. The mean (±SD) MPA AUC0-48h after coadministration of mycophenolate mofetil with norfloxacin or metronidazole separately was 48.3 (±24) mcg•h/mL and 42.7 (±23) mcg•h/mL, respectively, compared with 56.2 (±24) mcg•h/mL after administration of mycophenolate mofetil alone.

Ciprofloxacin and Amoxicillin plus Clavulanic Acid
A total of 64 mycophenolate mofetil-treated renal transplant recipients received either oral ciprofloxacin 500 mg bid or amoxicillin plus clavulanic acid 375 mg tid for 7 or at least 14 days. Approximately 50% reductions in median trough MPA concentrations (pre-dose) from baseline (Mycophenolate mofetil alone) were observed in 3 days following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. These reductions in trough MPA concentrations tended to diminish within 14 days of antibiotic therapy and ceased within 3 days after discontinuation of antibiotics. The postulated mechanism for this interaction is an antibiotic-induced reduction in glucuronidase-possessing enteric organisms leading to a decrease in enterohepatic recirculation of MPA. The change in trough level may not accurately represent changes in overall MPA exposure; therefore, clinical relevance of these observations is unclear.

Rifampin
In a single heart-lung transplant patient, after correction for dose, a 67% decrease in MPA exposure (AUC0-12h) has been observed with concomitant administration of mycophenolate mofetil and rifampin. Therefore, mycophenolate mofetil is not recommended to be given with rifampin concomitantly unless the benefit outweighs the risk.

Other Interactions
The measured value for renal clearance of MPAG indicates removal occurs by renal tubular secretion as well as glomerular filtration. Consistent with this, coadministration of probenecid, a known inhibitor of tubular secretion, with mycophenolate mofetil in monkeys results in a 3-fold increase in plasma MPAG AUC and a 2-fold increase in plasma MPA AUC. Thus, other drugs known to undergo renal tubular secretion may compete with MPAG and thereby raise plasma concentrations of MPAG or the other drug undergoing tubular secretion.

Drugs that alter the gastrointestinal flora may interact with mycophenolate mofetil by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption.

Live Vaccines
During treatment with mycophenolate mofetil, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective (see PRECAUTIONS: Immunizations). Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.

Carcinogenesis & Mutagenesis & Impairment Of Fertility

In a 104-week oral carcinogenicity study in mice, mycophenolate mofetil in daily doses up to 180 mg/kg was not tumorigenic. The highest dose tested was 0.5 times the recommended clinical dose (2 g/day) in renal transplant patients and 0.3 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, mycophenolate mofetil in daily doses up to 15 mg/kg was not tumorigenic. The highest dose was 0.08 times the recommended clinical dose in renal transplant patients and 0.05 times the recommended clinical dose in cardiac 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).

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

Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. This dose represents 0.1 times the recommended clinical dose in renal transplant patients and 0.07 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 0.02 times the recommended clinical dose in renal transplant patients and 0.01 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.

Pregnancy

Pregnancy Category D. See WARNINGS section.
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. In animal studies, congenital malformations and pregnancy loss occurred when pregnant rats and rabbits received mycophenolic acid at dose multiples similar to and less than clinical doses. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Risks and benefits of mycophenolate mofetil should be discussed with the patient. When appropriate, consider alternative immunosuppressants with less potential for embryofetal toxicity. In certain situations, the patient and her healthcare practitioner may decide that the maternal benefits outweigh the risks to the fetus. For those females using mycophenolate mofetil at any time during pregnancy and those becoming pregnant within 6 weeks of discontinuing therapy, the healthcare practitioner should report the pregnancy to the Mycophenolate Pregnancy Registry (1-800-617-8191). The healthcare practitioner should strongly encourage the patient to enroll in the pregnancy registry. The information provided to the registry will help the healthcare community better understand the effects of mycophenolate in pregnancy.
In the National Transplantation Pregnancy Registry (NTPR), there were data on 33 MMF-exposed pregnancies in 24 transplant patients; there were 15 spontaneous abortions (45%) and 18 live-born infants. Four of these 18 infants had structural malformations (22%). In postmarketing data (collected 1995-2007) on 77 females exposed to systemic MMF during pregnancy, 25 had spontaneous abortions and 14 had a malformed infant or fetus. Six of 14 malformed offspring had ear abnormalities. Because these postmarketing data are reported voluntarily, it is not always possible to reliably estimate the frequency of particular adverse outcomes. These malformations are similar to findings in animal reproductive toxicology studies. For comparison, the background rate for congenital anomalies in the United States is about 3%, and NTPR data show a rate of 4-5% among babies born to organ transplant patients using other immunosuppressive drugs.
In animal reproductive toxicology studies, there were increased rates of fetal resorptions and malformations in the absence of maternal toxicity. Female rats and rabbits received mycophenolate mofetil (MMF) doses equivalent to 0.02 to 0.9 times the recommended human dose for renal and cardiac transplant patients, based on body surface area conversions. In rat offspring, malformations included anophthalmia, agnathia, and hydrocephaly. In rabbit offspring, malformations included ectopia cordis, ectopic kidneys, diaphragmatic hernia, and umbilical hernia.

Nursing Mothers

Studies in rats treated with mycophenolate mofetil have shown mycophenolic acid to be excreted in milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from mycophenolate mofetil, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Based on pharmacokinetic and safety data in pediatric patients after renal transplantation, the recommended dose of mycophenolate mofetil oral suspension is 600 mg/m2 bid (up to a maximum of 1 g bid). Also see CLINICAL PHARMACOLOGY, CLINICAL STUDIES, ADVERSE REACTIONS, andDOSAGE AND ADMINISTRATION.

Safety and effectiveness in pediatric patients receiving allogeneic cardiac or hepatic transplants have not been established.

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 the elderly and younger patients. In general dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant or other drug therapy. Elderly patients may be at an increased risk of adverse reactions compared with younger individuals (see ADVERSE REACTIONS).

The principal adverse reactions associated with the administration of mycophenolate mofetil include diarrhea, leukopenia, sepsis, vomiting, and there is evidence of a higher frequency of certain types of infections eg, opportunistic infection (see WARNINGS: Serious Infectionsand WARNINGS: New or Reactivated Viral Infections). The adverse event profile associated with the administration of mycophenolate mofetil Intravenous has been shown to be similar to that observed after administration of oral dosage forms of mycophenolate mofetil.

Mycophenolate mofetil Oral
The incidence of adverse events for mycophenolate mofetil was determined in randomized, comparative, double-blind trials in prevention of rejection in renal (2 active, 1 placebo-controlled trials), cardiac (1 active-controlled trial), and hepatic (1 active-controlled trial) transplant patients.

Geriatrics
Elderly patients (≥65 years), particularly those who are receiving mycophenolate mofetil as part of a combination immunosuppressive regimen, may be at increased risk of certain infections (including cytomegalovirus [CMV] tissue invasive disease) and possibly gastrointestinal hemorrhage and pulmonary edema, compared to younger individuals (see PRECAUTIONS).
Safety data are summarized below for all active-controlled trials in renal (2 trials), cardiac (1 trial), and hepatic (1 trial) transplant patients. Approximately 53% of the renal patients, 65% of the cardiac patients, and 48% of the hepatic patients have been treated for more than 1 year. Adverse events reported in ≥20% of patients in the mycophenolate mofetil treatment groups are presented below.

The placebo-controlled renal transplant study generally showed fewer adverse events occurring in ≥20% of patients. In addition, those that occurred were not only qualitatively similar to the azathioprine-controlled renal transplant studies, but also occurred at lower rates, particularly for infection, leukopenia, hypertension, diarrhea and respiratory infection.

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

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

Sepsis, which was generally CMV viremia, was slightly more common in renal transplant patients treated with mycophenolate mofetil compared to patients treated with azathioprine. The incidence of sepsis was comparable in mycophenolate mofetil and in azathioprine-treated patients in cardiac and hepatic studies.

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

Patients receiving mycophenolate mofetil alone or as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see WARNINGS: Lymphoma and Malignancy). The incidence of malignancies among the 1483 patients treated in controlled trials for the prevention of renal allograft rejection who were followed for ≥1 year was similar to the incidence reported in the literature for renal allograft recipients.

Lymphoproliferative disease or lymphoma developed in 0.4% to 1% of patients receiving mycophenolate mofetil (2 g or 3 g daily) with other immunosuppressive agents in controlled clinical trials of renal, cardiac, and hepatic transplant patients followed for at least 1 year (see WARNINGS: Lymphoma and Malignancy). Non-melanoma skin carcinomas occurred in 1.6% to 4.2% of patients, other types of malignancy in 0.7% to 2.1% of patients. Three-year safety data in renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data.

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

Severe neutropenia (ANC <0.5 x 103/mcL) developed in up to 2.0% of renal transplant patients, up to 2.8% of cardiac transplant patients and up to 3.6% of hepatic transplant patients receiving mycophenolate mofetil 3 g daily (see WARNINGS: Neutropenia ,PRECAUTIONS: Laboratory Tests and DOSAGE AND ADMINISTRATION).

All transplant patients are at increased risk of opportunistic infections. The risk increases with total immunosuppressive load (see WARNINGS: Serious Infections and WARNINGS: New or Reactivated Viral Infections). Table 10 shows the incidence of opportunistic infections that occurred in the renal, cardiac, and hepatic transplant populations in the azathioprine-controlled prevention trials:

The following other opportunistic infections occurred with an incidence of less than 4% in mycophenolate mofetil patients in the above azathioprine-controlled studies: Herpes zoster, visceral disease; Candida, urinary tract infection, fungemia/disseminated disease, tissue invasive disease; Cryptococcosis; Aspergillus/Mucor; Pneumocystis carinii.

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

In patients receiving mycophenolate mofetil (2 g or 3 g) in controlled studies for prevention of renal, cardiac or hepatic rejection, fatal infection/sepsis occurred in approximately 2% of renal and cardiac patients and in 5% of hepatic patients (see WARNINGS: Serious Infections). In cardiac transplant patients, the overall incidence of opportunistic infections was approximately 10% higher in patients treated with mycophenolate mofetil than in those receiving azathioprine, but this difference was not associated with excess mortality due to infection/sepsis among patients treated with mycophenolate mofetil.

The following adverse events were reported with 3% to <20% incidence in renal, cardiac, and hepatic transplant patients treated with mycophenolate mofetil, in combination with cyclosporine and corticosteroids.
  
Table 11 Adverse Events Reported in 3% to <20% of Patients Treated With Mycophenolate Mofetil in Combination With Cyclosporine and Corticosteroids

Pediatrics
The type and frequency of adverse events in a clinical study in 100 pediatric patients 3 months to 18 year of age doses with mycophenolate mofetil oral suspension 600 mg/m2 (up to 1 g bid) were generally similar to those observed in adult patient dosed with mycophenolate mofetil capsules at a dose of 1 g bid with the exception of abdominal pain, fever, infection, pain, sepsis, diarrhea, vomiting, pharingitis, respiratory tract infection, hypertension, leukopenia, and anemia, which were observed in a higher proportion in pediatric patients.

Mycophenolate mofetil intravenous
The adverse event 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 renal transplant patients in the immediate posttransplant period (administered for the first 5 days). The potential venous irritation of mycophenolate mofetil intravenous was evaluated by comparing the adverse events attributable to peripheral venous infusion of mycophenolate mofetil intravenous with those observed in the intravenous placebo group; patients in this group received active medication by the oral route.

Adverse events attributable to peripheral venous infusion were phlebitis and thrombosis, both observed at 4% in patients treated with mycophenolate mofetil intravenous.

In the active controlled study in hepatic transplant patients, 2 g/day of mycophenolate mofetil intravenous were administered in the immediate posttransplant period (up to 14 days). The safety profile of intravenous mycophenolate mofetil was similar to that of intravenous azathioprine.

Postmarketing Experience

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

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

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

Infections (see WARNINGS: Serious Infections, New or Reactivated Viral Infections):
 Infections

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

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

• Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with mycophenolate mofetil. The reported cases generally had risk factors for PML, including treatment with immunosuppressant therapies and impairment of immune function.

• Polyomavirus associated neuropathy (PVAN), especially due to BK virus infection, has been observed in patients receiving immunosuppressants, including mycophenolate mofetil. This infection is associated with serious outcomes, including deteriorating renal function and renal graft loss.

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

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

The experience with overdose of mycophenolate mofetil in humans is very limited. The events received from reports of overdose fall within the known safety profile of the drug. The highest dose administered to renal transplant patients in clinical trials has been 4 g/day. In limited experience with cardiac and hepatic transplant patients in clinical trials, the highest doses used were 4 g/day or 5 g/day. At doses of 4 g/day or 5 g/day, there appears to be a higher rate, compared to the use of 3 g/day or less, of gastrointestinal intolerance (nausea, vomiting, and/or diarrhea), and occasional hematologic abnormalities, principally neutropenia, leading to a need to reduce or discontinue dosing.

In acute oral toxicity studies, no deaths occurred in adult mice at doses up to 4000 mg/kg or in adult monkeys at doses up to 1000 mg/kg; these were the highest doses of mycophenolate mofetil tested in these species. These doses represent 11 times the recommended clinical dose in renal transplant patients and approximately 7 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. In adult rats, deaths occurred after single-oral doses of 500 mg/kg of mycophenolate mofetil. The dose represents approximately 3 times the recommended clinical dose in cardiac transplant patients when corrected for BSA.

MPA and MPAG are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (>100 mcg/mL), small amounts of MPAG are removed. By increasing excretion of the drug, MPA can be removed by bile acid sequestrants, such as cholestyramine (see CLINICAL PHARMACOLOGY: Pharmacokinetics). 

Mycophenolate mofetil for oral suspension USP 200 mg/ml 

Supplied as white to off white powder blend for constitution to white to off white mixed fruit flavor suspension. Supplied in the following presentations:


NDCNumber               Size
NDC67877-230-22     225 mL bottle with bottle adapter and 2 oral dispensers

Storage and Dispensing Information

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.

Revised: September,2016

Ascend Laboratories, LLC

NDC67877-230-22

Mycophenolate Mofetil For Oral Suspension USP

200 mg/ml

Rx Only