MMF

Mycophenolate mofetil, also known as MMF or CellCept, is a prodrug of mycophenolic acid, and classified as a reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH).

This drug is an immunosuppressant combined with drugs such as Cyclosporine and corticosteroids to prevent organ rejection after hepatic, renal, and cardiac transplants.

It is marketed by Roche Pharmaceuticals and was granted FDA approval for the prophylaxis of transplant rejection in 1995.

In addition to the above uses, mycophenolate mofetil has also been studied for the treatment of nephritis and other complications of autoimmune diseases.

Unlike another immunosuppressant class, the calcineurin inhibitors, MMF generally does not cause nephrotoxicity or fibrosis. 2, 3 Previously, mycophenolic acid (MPA) was administered to individuals with autoimmune diseases beginning in the 1970s, but was discontinued due to gastrointestinal effects and concerns over carcinogenicity.

The new semi-synthetic 2-morpholinoethyl ester of MPA was synthesized to avoid the gastrointestinal effects associated with the administration of MPA.

It demonstrates an increased bioavailability, a higher efficacy, and reduced gastrointestinal effects when compared to MPA.

Mycophenolate mofetil is indicated in combination with other immunosuppressants to prevent the rejection of kidney, heart, or liver transplants in adult and pediatric patients ≥3 months old.

Mycophenolate mofetil may also be used off-label as a second-line treatment for autoimmune hepatitis that has not responded adequately to first-line therapy.

Other off-label uses of this drug include lupus-associated nephritis and dermatitis in children.

Mycophenolate mofetil is a prodrug of mycophenolic acid (MPA).

The active form of mycophenolate, MPA, prevents the proliferation of immune cells and the formation of antibodies that cause transplant rejection.

The above effects lead to higher rates of successful transplantation, avoiding the devastating effects of graft rejection.

Inosine-5'-monophosphate dehydrogenase 1 Inhibitor Inducer Inosine-5'-monophosphate dehydrogenase 2 Inhibitor.

Mycophenolate mofetil is rapidly absorbed in the small intestine. 13, 10 The maximum concentration of its active metabolite, MPA, is attained 60-90 minutes following an oral dose.

The average bioavailability of

Oral administered mycophenolate mofetil in a pharmacokinetic study of 12 healthy patients was 94%.

In healthy volunteers, the Cmax of mycophenolate mofetil was 24.5 (±9.5)μg/mL.

In renal transplant patients 5 days post-transplant, Cmax was 12.0 (±3.82) μg/mL, increasing to 24.1 (±12.1)μg/mL 3 months after transplantation.

AUC values were 63.9 (±16.2) μg•h/mL in healthy volunteers after one dose, and 40.8 (±11.4) μg•h/mL, and 65.3 (±35.4)μg•h/mL 5 days and 3 months after a renal transplant, respectively.

The absorption of mycophenolate mofetil is not affected by food.

The volume of distribution of mycophenolate mofetil is 3.6 (±1.5) to 4.0 (±1.2) L/kg.

After both oral and intravenous administration mycophenolate mofetil is entirely metabolized by liver carboxylesterases and 2 to mycophenolic acid (MPA), the active parent drug.

It is then metabolized by the enzyme glucuronyl transferase, producing the inactive phenolic glucuronide of MPA (MPAG).

The glucuronide metabolite is important, as it is then converted to MPA through enterohepatic recirculation.

Mycophenolate mofetil that escapes metabolism in the intestine enters the liver via the portal vein and is transformed to pharmacologically active MPA in the liver cells.

N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide portion of N-(2-hydroxyethyl)-morpholine are additional metabolites of MMF occurring in the intestine as a result of liver carboxylesterase 2 activity. 10, 13 UGT1A9 and UGT2B7 in the liver are the major enzymes contributing to the metabolism of MPA in addition to other UGT enzymes, which also play a role in MPA metabolism.

The four major metabolites of

MPA are 7-O-MPA-β-glucuronide (MPAG, inactive), MPA acyl-glucuronide (AcMPAG), produced by uridine 5ʹ-diphosphate glucuronosyltransferases (UGT) activities, 7-O-MPA glucoside produced via UGT, and small amounts 6-O-des-methyl-MPA (DM-MPA) via CYP3A4/5 and CYP2C8 enzymes.

Hover over products below to view reaction partners Mycophenolate mofetil Mycophenolic acid 7-O-MPA glucoside 6-O-desmethyl-MPA (DM-MPA) Mycophenolic acid glucuronide + Mycophenolic acyl-glucuronide (AcMPAG) N-(2-carboxymethyl)-morpholine N-(2-hydroxyethyl)-morpholine N-(2-hydroxyethyl)-morpholine N-oxide.

A small amount of drug is excreted as MPA in the urine (less than 1%).

When mycophenolate mofetil was given

Oral in a pharmacokinetic study, it was found to be 93% excreted in urine and 6% excreted in feces.

Approximately 87% of the entire administered dose is found to be excreted in the urine as MPAG, an inactive metabolite. 6, 13.

The average apparent half-life of mycophenolate mofetil is 17.9 (±6.5) hours after oral administration and 16.6 (±5.8) hours after intravenous administration.

Plasma clearance of mycophenolate mofetil is 193 mL/min after an oral dose and 177 (±31) mL/min after an intravenous dose.

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LD50 The LD50 of oral mycophenolate mofetil in rats is 250 mg/kg and >4000 mg/kg in mice.

Overdose information

Possible signs and symptoms of acute overdose may consist of hematological abnormalities including leukopenia and neutropenia, and gastrointestinal symptoms. 6, 7, 8.

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

Hypersensitivity to mycophenolate mofetil, mycophenolic acid or any component of the drug product.

Transplant 1 g twice daily, orally Heart Transplant 1.5 g twice daily orally Liver Transplant 1.5 g twice daily orally PEDIATRICS Kidney Transplant 600 mg/m 2 orally twice daily, up to maximum of 2 g daily Heart Transplant 600 mg/m 2 orally twice daily, (starting dose) up to a maximum of 900 mg/m 2 twice daily (3 g) Liver Transplant 600 mg/m 2 orally twice daily,daily (starting dose) up to a maximum of 900 mg/m 2 twice daily (3 g) Reduce or interrupt dosing in the event of neutropenia.

See full prescribing information (FPI) for: adjustments for renal impairment and neutropenia 2.1 Important Administration Instructions Mycophenolate mofetil should not be used without the supervision of a physician with experience in immunosuppressive therapy.

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

Mycophenolate mofetil tablets should not be crushed and mycophenolate mofetil capsules should not be opened or crushed.

Patients should avoid inhalation or contact of the skin or mucous membranes with the powder contained in mycophenolate mofetil capsules and 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 should be given as soon as possible following kidney, heart or liver transplant.

It is recommended that mycophenolate mofetil be administered on an empty stomach.

In stable transplant patients, however, mycophenolate mofetil may be administered with food if necessary.

Patients should be instructed to take a missed dose as soon as they remember, except if it is closer than 2 hours to the next scheduled dose; in this case, they should continue to take mycophenolate mofetil at the usual times. 2.2 Dosage Recommendations for Kidney Transplant Patients Adults The recommended dosage for adult kidney transplant patients is 1 g orally or intravenously infused over no less than 2 hours, twice daily (total daily dose of 2 g).

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

Pediatric patients with

BSA ≥1.25 m 2 may be dosed with capsules or tablets as follows: Table 1 Pediatric Kidney Transplant: Dosage Using Capsules or Tablets Body Surface Area Dosage 1.25 m to <1.5 m 2 Mycophenolate mofetil capsule 750 mg twice daily (1.5 g total daily dose) ≥ 1.5 m 2 Mycophenolate mofetil capsules or tablets 1 g twice daily (2 g total daily dose) 2.3 Dosage Recommendations for Heart Transplant Patients Adults The recommended dosage of mycophenolate mofetil for adult heart transplant patients is 1.5 g orally twice daily (total daily dose of 3 g).

BSA ≥1.25 m 2 may be started on therapy with capsules or tablets as follows: Table 2 Pediatric Heart Transplant: Pediatric Starting Dosage Using Capsules or Tablets Body Surface Area Starting Dosage Maximum maintenance dose: 3 g total daily. 1.25 m to <1.5 m 2 Mycophenolate mofetil capsule 750 mg twice daily (1.5 g total daily dose) ≥ 1.5 m 2 Mycophenolate mofetil capsules or tablets 1 g twice daily (2 g total daily dose) 2.4 Dosage Recommendations for Liver Transplant Patients Adults The recommended dosage of mycophenolate mofetil for adult liver transplant patients is 1.5 g administered orally twice daily (total daily dose of 3 g).

BSA ≥1.25 m 2 may be started on therapy with capsules or tablets as follows: Table 3 Pediatric Liver Transplant: Pediatric Starting Dosage Using Capsules or Tablets Body Surface Area Starting Dosage Maximum maintenance dose: 3 g total daily. 1.25 m to <1.5 m 2 Mycophenolate mofetil capsule 750 mg twice daily (1.5 g total daily dose) ≥ 1.5 m 2 Mycophenolate mofetil capsules or tablets 1 g twice daily (2 g total daily dose) 2.5 Dosage Modifications: Patients with Renal Impairment, Neutropenia Renal Impairment No dosage modifications are needed in kidney transplant patients with delayed graft function postoperatively.

In kidney transplant patients with severe chronic impairment of the graft (GFR <25 mL/min/1.73 m 2 ), do not administer doses of mycophenolate mofetil greater than 1 g twice a day. These patients should be carefully monitored.

If neutropenia develops (ANC <1.3 × 10 3 /µL), dosing with mycophenolate mofetil should be interrupted or reduced, appropriate diagnostic tests performed, and the patient managed appropriately.

Tablets, USP are available containing 500 mg of mycophenolate mofetil, USP.

The 500 mg tablets are purple coloured, capsule shaped, biconvex, film coated tablets debossed ‘AHI’ on one side and ‘500’ on other side.

NDC 63629-9582-1: 120 TABLETs in a BOTTLE Storage and Dispensing Information Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Dispense in light-resistant containers, such as the manufacturer's original containers.

Repackaged/Relabeled by: Bryant Ranch Prepack Burbank, CA 91504.

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 or call 1-800-617-8191.

Use of mycophenolate mofetil (MMF) during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of multiple congenital malformations in multiple organ systems.

Oral administration of mycophenolate to rats and rabbits during the period of organogenesis produced congenital malformations and pregnancy loss at doses less than the recommended clinical dose (0.01 to 0.05 times the recommended clinical doses in kidney and heart transplant patients) .

Consider alternative immunosuppressants with less potential for embryofetal toxicity.

Risks and benefits of mycophenolate mofetil should be discussed with the pregnant woman.

The estimated background risk of pregnancy loss and congenital malformations in organ transplant populations is not clear.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

A spectrum of congenital malformations (including multiple malformations in individual newborns) has been reported in to 27% of live births in MMF exposed pregnancies, based on published data from pregnancy registries.

Malformations that have been documented include external ear, eye, and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, kidney, and nervous system.

Based on published data from pregnancy registries, the risk of first trimester pregnancy loss has been reported at to 49% following MMF exposure.

In animal reproductive toxicology studies, there were increased rates of fetal resorptions and malformations in the absence of maternal toxicity.

Oral administration of MMF to pregnant rats from Gestational Day to Day 16 produced increased embryofetal lethality and fetal malformations including anophthalmia, agnathia, and hydrocephaly at doses equivalent to 0.015 and 0.01 times the recommended human doses for renal and cardiac transplant patients, respectively, when corrected for BSA.

Oral administration of MMF to pregnant rabbits from Gestational Day to Day 19 produced increased embryofetal lethality and fetal malformations included ectopia cordis, ectopic kidneys, diaphragmatic hernia, and umbilical hernia at dose equivalents as low as 0.05 and 0.03 times the recommended human doses for renal and cardiac transplant patients, respectively, when corrected for BSA.

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

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) .

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.

Clinical studies of mycophenolate mofetil did not include sufficient numbers of subjects aged 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.