Mycophenolate mofetil capsule

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Description

Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent; inosine monophosphate dehydrogenase (IMPDH) inhibitor.

The chemical name for mycophenolate mofetil (MMF) is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate. It has molecular formula of C 23H 31NO 7, a molecular weight of 433.50, and the following structural formula:

Structured product formula for mycophenolate

Mycophenolate mofetil, USP is a white or almost white crystalline powder. It is slightly soluble in water (43 g/mL at pH 7.4); the solubility increases in acidic medium (4.27 mg/mL at pH 3.6). It is freely soluble in acetone, soluble in methanol, and sparingly soluble in ethanol. The apparent partition coefficient in 1-octanol/water (pH 7.4) buffer solution is 238. The pK avalues for mycophenolate mofetil are 5.6 for the morpholino group and 8.5 for the phenolic group.

Each mycophenolate mofetil capsule intended for oral administration contains 250 mg of mycophenolate mofetil. In addition, each capsule contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, FD&C blue # 1, FD&C red # 3, gelatin, magnesium stearate, povidone (K-90), pregelatinized starch, sodium lauryl sulfate and titanium dioxide. The capsule is printed with black pharmaceutical ink.

Each mycophenolate mofetil tablet intended for oral administration contains 500 mg of mycophenolate mofetil. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc and titanium dioxide. The tablet is printed with black pharmaceutical ink.

Clinical pharmacology

Mechanism of action:

Mycophenolate mofetil has been demonstrated in experimental animal models to prolong the survival of allogeneic transplants (kidney, heart, liver, intestine, limb, small bowel, pancreatic islets, and bone marrow).

Mycophenolate mofetil has also been shown to reverse ongoing acute rejection in the canine renal and rat cardiac allograft models. Mycophenolate mofetil also inhibited proliferative arteriopathy in experimental models of aortic and cardiac allografts in rats, as well as in primate cardiac xenografts. Mycophenolate mofetil was used alone or in combination with other immunosuppressive agents in these studies. Mycophenolate mofetil has been demonstrated to inhibit immunologically mediated inflammatory responses in animal models and to inhibit tumor development and prolong survival in murine tumor transplant models.

Mycophenolate mofetil is rapidly absorbed following oral administration and hydrolyzed to form MPA, which is the active metabolite. MPA is a potent, selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines, whereas other cell types can utilize salvage pathways, MPA has potent cytostatic effects on lymphocytes. MPA inhibits proliferative responses of T- and B-lymphocytes to both mitogenic and allospecific stimulation. Addition of guanosine or deoxyguanosine reverses the cytostatic effects of MPA on lymphocytes. MPA also suppresses antibody formation by B-lymphocytes. 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. Mycophenolate mofetil did not inhibit early events in the activation of human peripheral blood mononuclear cells, such as the production of interleukin-1 (IL-1) and interleukin-2 (IL-2), but did block the coupling of these events to DNA synthesis and proliferation.

Pharmacokinetics:

Following oral and intravenous administration, mycophenolate mofetil undergoes rapid and complete metabolism to MPA, the active metabolite. Oral absorption of the drug is rapid and essentially complete. MPA is metabolized to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. The parent drug, mycophenolate mofetil, can be measured systemically during the intravenous infusion; however, shortly (about 5 minutes) after the infusion is stopped or after oral administration, MMF concentration is below the limit of quantitation (0.4 g/mL).

Clinical studies

Indications and usage

Contraindications

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

Warnings

Precautions

Information for patients:

  • 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 capsules or mycophenolate mofetil tablets.
  • Inform women of childbearing potential that use of mycophenolate mofetil capsules or mycophenolate mofetil tablets in pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of birth defects, and that they must use effective contraception.
  • Discuss pregnancy plans with female patients of childbearing potential.
  • Any female of childbearing potential must use highly effective (two methods) contraception 4 weeks prior to starting mycophenolate mofetil capsules or mycophenolate mofetil tablets therapy and continue contraception until 6 weeks after stopping mycophenolate mofetil capsules or mycophenolate mofetil tablets treatment, unless abstinence is the chosen method (see WARNINGS: Pregnancy).
  • A patient who is planning a pregnancy should not use mycophenolate mofetil capsules or mycophenolate mofetil tablets unless she cannot be successfully treated with other immunosuppressant drugs.

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 REACTIONS and 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 capsules or mycophenolate mofetil tablets have 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 C max. 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 (e.g. 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 C maxand AUC(0-24h) for MPA were 33% and 17% lower, respectively, than when mycophenolate mofetil was administered alone under fasting conditions. Mycophenolate mofetil capsules and mycophenolate mofetil tablets may be administered to patients who are also taking antacids containing magnesium and aluminum hydroxides; however, it is recommended that mycophenolate mofetil capsules and mycophenolate mofetil tablets and the antacid not be administered simultaneously.

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 capsules and mycophenolate mofetil tablets are 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) AUC(0-12h) and C maxof cyclosporine after 14 days of multiple doses of mycophenolate mofetil were 3290 (822) ngh/mL and 753 (161) ng/mL, respectively, compared to 3245 (1088) ngh/mL and 700 (246) ng/mL, respectively, 1 week before administration of mycophenolate mofetil.

In renal transplant patients, mean MPA exposure (AUC 0-12h) 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.

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 C max(n=10) were 54.3 (19.0) gh/mL and 11.5 (1.8) g/mL, respectively, after coadministration of the two drugs, compared to 51.0 (17.0) gh/mL and 10.6 (2.0) g/mL, respectively, after administration of intravenous ganciclovir alone. The mean (SD) AUC and C maxof MPA

(n=12) after coadministration were 80.9 (21.6) gh/mL and 27.8 (13.9) g/mL, respectively, compared to values of 80.3 (16.4) gh/mL and 30.9 (11.2) g/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 (e.g., valganciclovir) are coadministered, patients should be monitored carefully.

Oral Contraceptives:

A study of coadministration of mycophenolate mofetil capsules and mycophenolate mofetil tablets (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 AUC(0-24h) was similar for ethinylestradiol and 3-keto desogestrel; however, mean levonorgestrel AUC(0-24h) 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 capsules and mycophenolate mofetil tablets may not have any influence on the ovulation-suppressing action of the studied oral contraceptives. However, it is recommended that oral contraceptives are coadministered with mycophenolate mofetil capsules and mycophenolate mofetil tablets with caution and additional birth control methods be considered (see WARNINGS: Pregnancy).

Sevelamer:

Concomitant administration of sevelamer and mycophenolate mofetil in adult and pediatric patients decreased the mean MPA C maxand AUC 0-12hby 36% and 26% respectively. This data suggest that sevelamer and other calcium free phosphate binders should not be administered simultaneously with mycophenolate mofetil capsules or mycophenolate mofetil tablets. Alternatively, it is recommended that sevelamer and other calcium free phosphate binders preferentially could be given 2 hours after mycophenolate mofetil capsules or mycophenolate mofetil tablets 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 C maxof MPA after concomitant administration were 75.2 (19.8) gh/mL and 34.0 (6.6) g/mL, respectively, compared to 79.2 (27.9) gh/mL and 34.2 (10.7) gh/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 AUC 0-48hwas significantly reduced by 33% compared to the administration of mycophenolate mofetil alone (p<0.05). Therefore, mycophenolate mofetil capsule or mycophenolate mofetil tablet is not recommended to be given with the combination of norfloxacin and metronidazole. There was no significant effect on mean MPA AUC 0-48hwhen mycophenolate mofetil was concomitantly administered with norfloxacin or metronidazole separately. The mean (SD) MPA AUC 0-48hafter coadministration of mycophenolate mofetil with norfloxacin or metronidazole separately was 48.3 (24) gh/mL and 42.7 (23) gh/mL, respectively, compared with 56.2 (24) gh/mL after administration of mycophenolate mofetil alone.

Ciprofloxacin and Amoxicillin plus Clavulanic Acid

A total of 64 mycophenolate mofetil capsules or mycophenolate mofetil tablets-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 (predose) 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 (AUC 0-12h) has been observed with concomitant administration of mycophenolate mofetil and rifampin. Therefore, mycophenolate mofetil capsule or mycophenolate mofetil tablet 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.

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 vivomouse micronucleus assay. Mycophenolate mofetil was not genotoxic in the 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.

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/m 2bid (up to a maximum of 1 g bid). Also see CLINICAL PHARMACOLOGY, CLINICAL STUDIES, ADVERSE REACTIONS,and DOSAGE 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 capsules and mycophenolate mofetil tablets 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).

Adverse reactions

The principal adverse reactions associated with the administration of mycophenolate mofetil capsules and mycophenolate mofetil tablets include diarrhea, leukopenia, sepsis, vomiting, and there is evidence of a higher frequency of certain types of infections e.g., opportunistic infection (see WARNINGS: Infections and WARNINGS: Latent 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.

The incidence of adverse events for mycophenolate mofetil capsules and mycophenolate mofetil tablets 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.

Overdosage

The experience with overdose of mycophenolate mofetil capsules and mycophenolate mofetil tablets 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 g/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).

Dosage and administration

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HANDLING AND DISPOSAL

Mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits (see WARNINGS: Pregnancy).Mycophenolate mofetil tablets should not be crushed and mycophenolate mofetil capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in mycophenolate mofetil capsules and mycophenolate mofetil Oral Suspension (before or after constitution). If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water. Should a spill occur, wipe up using paper towels wetted with water to remove spilled powder or suspension. Caution should be exercised in the handling and preparation of solutions of mycophenolate mofetil intravenous. Avoid direct contact of the prepared solution of mycophenolate mofetil intravenous with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.

How supplied

Storage and handling

Store at 25C (77F); excursions permitted to 15 to 30C (59 to 86 F). [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP with a child-resistant cap.

Sandimmune is a registered trademark of Novartis Pharmaceuticals Corporation.

ATGAM is a registered trademark of Pharmacia and Upjohn Company.

Neoral is a registered trademark of Novartis Pharmaceuticals Corporation.

Orthoclone OKT is a registered trademark of Ortho Biotech Inc.

Maalox is a registered trademark of Novartis Consumer Health, Inc.

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Mycophenolate Mofetil Capsules

Mycophenolate Mofetil Tablets

Read the Medication Guide that comes with mycophenolate mofetil capsules and mycopheolate mofetil tablets before you start taking it and each time you refill your prescription. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about mycophenolate mofetil?

Mycophenolate mofetil can cause serious side effects:

  • Possible loss of a pregnancy and higher risk of birth defects. Women who take mycophenolate mofetil during pregnancy have a higher risk of losing a pregnancy (miscarriage) during the first 3 months (first trimester), and a higher risk that their baby will be born with birth defects

If you are a female and are able to become pregnant

your healthcare provider must talk with you about effective birth control methods (contraceptive counseling)

you should have a negative pregnancy test within 1 week before you start to take mycophenolate mofetil

you must use 2 different types of effective birth control at the same time, for 4 weeks before you start taking mycophenolate mofetil, during your entire mycophenolate mofetil therapy and for 6 weeks after stopping mycophenolate mofetil, unless you choose to avoid sexual intercourse completely (abstinence). Mycophenolate mofetil decreases blood levels of the hormones in birth control pills that you take by mouth. Birth control pills may not work as well while you take mycophenolate mofetil, and you could become pregnant

If you plan to become pregnant, talk with your healthcare provider. Your healthcare provider will decide if other medicines to prevent rejection may be right for you. In certain situations, you and your healthcare provider may decide that taking mycophenolate mofetil is more important to your health than the possible risks to your unborn baby.

If you get pregnant while taking mycophenolate mofetil, do not stop taking mycophenolate mofetil. Call your healthcare provider right away.You and your healthcare provider should report any cases of pregnancies to

FDA MedWatch at 1-800-FDA-1088.

Zydus Professional Drug Safety at 1-877-993-8779..

Talk to your healthcare provider about joining the National Transplantation Pregnancy Registry at 1-877-955-6877.

Increased risk of getting serious infections. Mycophenolate mofetil weakens the bodys immune system and affects your ability to fight infections. Serious infections can happen with mycophenolate mofetil and can lead to death. Types of infections can include:

  • Viral infections. Certain viruses can live in your body and cause active infections when your immune system is weak. Viral infections that can happen with mycophenolate mofetl capsules and mycophenolate mofetil tablets include:
  • Shingles, other herpes infections, and cytomegalovirus (CMV). CMV can cause serious tissue and blood infections
  • BK virus. BK virus can affect how your kidney works and cause your transplanted kidney to fail.
  • A brain infection called Progressive Multifocal Leukoencephalopathy (PML).In some patients, mycophenolate mofetil may cause an infection of the brain that may cause death. You are at risk for this brain infection because you have a weakened immune system. You should tell your healthcare provider right away if you have any of the following symptoms:

Weakness on one side of the body

You do not care about things that you usually care about (apathy)

You are confused or have problems thinking

You can not control your muscles

Fungal infections.Yeasts and other types of fungal infections can happen with mycophenolate mofetil and can cause serious tissue and blood infections (see "What are the possible side effects of mycophenolate mofetil?")

Call your healthcare provider right away if you have any of the following signs and symptoms of infection:

Temperature of 100.5F or greater

Cold symptoms, such as a runny nose or sore throat

Flu symptoms, such as an upset stomach, stomach pain, vomiting or diarrhea

Earache or headache

Pain during urination

White patches in the mouth or throat

Unexpected bruising or bleeding

Cuts, scrapes or incisions that are red, warm and oozing pus

Increased risk of getting certain cancers. People who take mycophenolate mofetil have a higher risk of getting lymphoma, and other cancers, especially skin cancer. Tell your healthcare provider if you have:

  • unexplained fever, prolonged tiredness, weight loss or lymph node swelling
  • a brown or black skin lesion with uneven borders, or one part of the lesion does not look like the other
  • a change in the size and color of a mole
  • a new skin lesion or bump
  • any other changes to your health

See the section "What are the possible side effects of mycophenolate mofetil?" for information about other serious side effects.

What is mycophenolate mofetil?

Mycophenolate mofetil is a prescription medicine to prevent rejection (antirejection medicine) in people who have received a kidney, heart or liver transplant. Rejection is when the bodys immune system perceives the new organ as a "foreign" threat and attacks it.

Mycophenolate mofetil is used with other medicines called cyclosporine (Sandimmune ®, Gengraf ®, Neoral ®) and corticosteroids. These medicines work together to prevent rejection to your transplanted organ.

Mycophenolate mofetil has been used safely and works in children who received a kidney transplant as it does in adults. It is not known if mycophenolate mofetil is safe and works in children who receive a heart or liver transplant.

Who should not take mycophenolate mofetil?

Do not take mycophenolate mofetil if you are allergic to mycophenolate mofetil or any of the ingredients in mycophenolate mofetil capsules and mycopheolate mofetil tablets. See the end of this Medication Guide for a complete list of ingredients in mycophenolate mofetil capsules and mycopheolate mofetil tablets.

What should I tell my healthcare provider before taking mycophenolate mofetil?

Tell your healthcare provider about all of your medical conditions, if you:

  • have any digestive problems, such as ulcers
  • have Lesch-Nyhan or Kelley-Seegmiller syndrome or another rare inherited deficiency hypoxanthine-guanine phosphoribosyl-transferase (HGPRT).You should not take mycophenolate mofetil if you have one of these disorders
  • plan to receive any vaccines. People taking mycophenolate mofetil should not take live vaccines.Some vaccines may not work as well during treatment with mycophenolate mofetil
  • are pregnant or are planning to become pregnant.See "What is the most important information I should know about mycophenolate mofetil?"
  • are breastfeeding.It is not known if mycophenolate mofetil passes into breast milk. You and your healthcare provider will decide if you will take mycophenolate mofetil or breastfeed. You should not do both without first talking with your healthcare provider

Tell your healthcare provider about all of the medicines you are taking including prescription and nonprescription medicines, vitamins and herbal supplements.

Some medicines may affect the way mycophenolate mofetil works, and mycophenolate mofetil may affect how some medicines work. Especially tell your healthcare provider if you take:

  • birth control pills (oral contraceptives). See "What is the most important information I should know about mycophenolate mofetil?"
  • sevelamer (Renagel ®, Renvela™). These products should be taken 2 hours after taking mycophenolate mofetil
  • acyclovir (Zovirax ®), valacyclovir (Valtrex ®), ganciclovir (Cytovene ®-IV, Vitrasert ®), valganciclovir (Valcyte ®)
  • rifampin (Rifater ®, Rifamate ®, Rimactane ®, Rifadin ®)
  • antacids that contain magnesium and aluminum (mycophenolate mofetil and the antacid should not be taken at the same time)
  • sulfamethoxazole/trimethoprim (Bactrim™, Bactrim DS™)
  • ciprofloxacin (Cipro ®, Cipro ®XR, Ciloxan ®, Proquin ®XR) and amoxicillin plus clavulanic acid (Augmentin ®, Augmentin XR™)
  • azathioprine (Azasan ®, Imuran ®)
  • cholestyramine (Questran Light ®, Questran ®, Locholest Light, Locholest, Prevalite ®)

Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine. Do not take any new medicine without talking with your healthcare provider.

How should I take mycophenolate mofetil?

  • Take mycophenolate mofetil exactly as prescribed
  • Do not stop taking mycophenolate mofetil or change the dose unless your healthcare provider tells you to
  • If you miss a dose of mycophenolate mofetil, or are not sure when you took your last dose, take the regular amount of mycophenolate mofetil prescribed as soon as you remember. If it is time for your next dose, skip the missed dose. Do not take 2 doses at the same time. Call your healthcare provider if you are not sure what to do
  • Take mycophenolate mofetil capsules, mycopheolate mofetil tablets and mycophenolate mofetil oral suspension on an empty stomach, either 1 hour before or 2 hours after a meal, unless your healthcare provider tells you otherwise. With the approval of your healthcare provider, in stable kidney transplant patients, mycophenolate mofetil can be taken with food if necessary. Most people take mycophenolate mofetil by mouth either as blue and orange capsules or lavender tablets. Some people may get mycophenolate mofetil soon after their transplant surgery as an infusion into a vein
  • Do not crush mycophenolate mofetil tablets. Do not open or crush mycophenolate mofetil capsules
  • If you are not able to swallow mycophenolate mofetil capsules or mycopheolate mofetil tablets, your healthcare provider may prescribe mycophenolate mofetil oral suspension. This is a liquid form of mycophenolate mofetil. Your pharmacist will mix the medicine before giving it to you
  • Do not mix mycophenolate mofetil oral suspension with any other medicine
  • If you take too much mycophenolate mofetil, call your healthcare provider or the poison control center right away

What should I avoid while takingmycophenolate mofetil ?

  • Avoid pregnancy.See "What is the most important information I should know about mycophenolate mofetil?"
  • Limit the amount of time you spend in sunlight.Avoid using tanning beds or sunlamps. People who take mycophenolate mofetil have a higher risk of getting skin cancer. (See "What is the most important information I should know about mycophenolate mofetil?")Wear protective clothing when you are in the sun and use a sunscreen with a high protection factor (SPF 30 and above). This is especially important if your skin is very fair or if you have a family history of skin cancer

What are the possible side effects of mycophenolate mofetil?

Mycophenolate mofetil can cause serious side effects:

  • See "What is the most important information I should know about mycophenolate mofetil?"
  • Low blood cell counts. People taking high doses of mycophenolate mofetil each day may have a decrease in blood counts, including

white blood cells, especially neutrophils.Neutrophils fight against bacterial infections. You have a higher chance of getting an infection when your white blood cell count is low. This is most common from 3 months to 6 months after your transplant

red blood cells.Red blood cells carry oxygen to your body tissues.You have a higher chance of getting severe anemia when your red blood cell count is low.

platelets.Platelets help with blood clotting

Your healthcare provider will do blood tests before you start taking mycophenolate mofetil and during treatment with mycophenolate mofetil to check your blood cell counts.

Tell your healthcare provider right away if you have any signs of infection (see "What is the most importantinformation I should know about mycophenolate mofetil?"),or any unexpected bruising or bleeding. Also, tell your healthcare provider if you have unusual tiredness, lack of energy, dizziness or fainting.

  • Stomach problems.Stomach and intestinal bleeding can happen in people who take high doses of mycophenolate mofetil. Bleeding can be severe and you may have to be hospitalized for treatment

Common side effects include:

  • diarrhea. Call your healthcare provider right away if you have diarrhea. Do not stop taking mycophenolate mofetil without first talking with your healthcare provider
  • vomiting
  • pain
  • stomach area pain
  • swelling of the lower legs, ankles and feet
  • high blood pressure

Side effects that happen more often in children than in adults taking mycophenolate mofetil include:

stomach area pain sore throat

fever colds (respiratory tract infections)

infection high blood pressure

pain low white blood cell count

blood infection (sepsis) low red blood cell count

diarrhea

vomiting

These are not all of the possible side effects of mycophenolate mofetil. Tell your healthcare provider about any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. or to Zydus Professional Drug Safety at 1-877-993-8779.

How should I store mycophenolate mofetil?

  • Store at 25C (77F); excursions permitted to 15 to 30C (59 to 86 F). [See USP Controlled Room Temperature]. Keep the container closed tightly
  • Keep mycophenolate mofetil and all medicines out of the reach of children

General Information about Mycophenolate Mofetil

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use mycophenolate mofetil for a condition for which it was not prescribed. Do not give mycophenolate mofetil to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about mycophenolate mofetil. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about mycophenolate mofetil that is written for healthcare professionals. Please address medical inquiries to, (MedicalAffairs@zydususa.com) Tel.: 1-877-993-8779.

What are the ingredients in mycophenolate mofetil capsules and mycopheolate mofetil tablets?

Active Ingredient:mycophenolate mofetil

Inactive Ingredients:

Mycophenolate Mofetil Capsules, 250 mg:

Colloidal silicon dioxide, croscarmellose sodium, FD&C blue # 1, FD&C red # 3, gelatin, magnesium stearate, povidone (K-90), pregelatinized starch, sodium lauryl sulfate and titanium dioxide.

Mycopheolate Mofetil Tablets, 500 mg:

Colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc and titanium dioxide.

This Medication Guide has been approved by the US Food and Drug Administration.

Cytovene-IV, and Valcyte are registered trademarks of Hoffmann-La Roche Inc.

Bactrim and Bactrim DS are trademarks of Hoffmann-La Roche Inc.

Any other trademarks in this document are the property of their respective owners.

Spl unclassified section

Manufactured by:

Cadila Healthcare Ltd.

Ahmedabad, India

Distributed by:

Zydus Pharmaceuticals USA Inc.

Pennington, NJ 08534

Rev.:04/11

Revision Date: 29/04/2011

For additional copies of this Medication Guide, please call 1-877-993-8779 or visit www.zydususa.com.

Ingredients and appearance - Product information

Mycophenolate mofetil capsule- Mycophenolate mofetil

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 68382-130
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Mycophenolate mofetil ( UNII: 9242ECW6R0)( Mycophenolic acid - UNII: HU9DX48N0T ) 250 mgin 1

Inactive Ingredients

Ingredient Name Code
Croscarmellose sodium ( UNII: M28OL1HH48)
Fd&c blue no. 1 ( UNII: H3R47K3TBD)
Fd&c red no. 3 ( UNII: PN2ZH5LOQY)
Magnesium stearate ( UNII: 70097M6I30)
Gelatin ( UNII: 2G86QN327L)
Sodium lauryl sulfate ( UNII: 368GB5141J)
Titanium dioxide ( UNII: 15FIX9V2JP)
Povidone k90 ( UNII: RDH86HJV5Z)
Starch, pregelatinized corn ( UNII: O8232NY3SJ)
Silicon dioxide ( UNII: ETJ7Z6XBU4)

Product Characteristics

Color WHITE (OPAQUE WHITE) Shape CAPSULE (CAPSULE)
Size 19 mm Score 1
Imprint Code 130

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA065433 USA

Labeler - Zydus Pharmaceuticals (USA) Inc.( 156861945)

Establishment

Name ID/FEI Business Operations
Zydus Pharmaceuticals (USA) Inc. 156861945 Analysis(), Manufacture()

Package label.principal display panel

NDC 68382-130-01 in bottle of 100 capsules

Mycophenolate Mofetil Capsules, 250 mg

R xonly

100 capsules

ZYDUS

NDC 68382-131-01 in bottle of 100 tablets

Mycophenolate Mofetil Tablets, 500 mg

R xonly

100 tablets

ZYDUS