CELLCEPT® (mycophenolate mofetil)

CELLCEPT® (mycophenolate mofetil)

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CELLCEPT® (mycophenolate mofetil)

CELLCEPT (mycophenolate mofetil) is an antimetabolite immunosuppressant. It 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 an empirical formula of C23H31NO7, a molecular weight of 433.50

MMF is a white to off-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 pKa values for MMF are 5.6 for the morpholino group and 8.5 for the phenolic group.

MMF hydrochloride has a solubility of 65.8 mg/mL in 5% Dextrose Injection USP (D5W). The pH of the reconstituted solution is 2.4 to 4.1.

CELLCEPT is available for oral administration as capsules containing 250 mg of MMF, tablets containing 500 mg of MMF, and as a powder for oral suspension which, when reconstituted, contains 200 mg/mL of MMF.

Indications and usage

CELLCEPT is an antimetabolite immunosuppressant indicated for the prophylaxis of organ rejection in recipients of allogeneic kidney, heart or liver transplants, and should be used in combination with other immunosuppressants.

Mechanism of Action

Mycophenolate mofetil (MMF) is absorbed following oral administration and hydrolyzed to mycophenolic acid (MPA), the active metabolite. MPA is a selective, uncompetitive, 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. MMF 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.

Dosage and administration

Important Administration Instructions

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

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

CELLCEPT tablets should not be crushed and CELLCEPT capsules should not be opened or crushed. Patients should avoid inhalation or contact of the skin or mucous membranes with the powder contained in CELLCEPT 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 CELLCEPT should be given as soon as possible following kidney, heart or liver transplant. It is recommended that CELLCEPT be administered on an empty stomach. In stable transplant patients, however, CELLCEPT may be administered with food if necessary. Once reconstituted, CELLCEPT Oral Suspension must not be mixed with any liquids prior to dose administration. If needed, CELLCEPT Oral Suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter).

Patients should be instructed to take a missed dose as soon as they remember, except if it is closer than 2 hours to the next scheduled dose; in this case, they should continue to take CELLCEPT at the usual times.

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

CELLCEPT Intravenous must not be administered as a bolus. Following reconstitution, CELLCEPT Intravenous must be administered by slow intravenous infusion over a period of no less than 2 hours by either peripheral or central vein, as rapid infusion increases the risk of local adverse reactions such as phlebitis and thrombosis

AdultDosing
Kidney Transplant1 g twice daily, orally or intravenously (IV) over no less than 2 h
Heart Transplant1.5 g twice daily orally or IV, over no less than 2 h
Liver Transplant1.5 g twice daily orally or1 g twice daily IV over no less than 2 h
PEDIATRICS
Kidney Transplant600 mg/m2 orally twice daily, up to maximum of 2 g daily
  • CELLCEPT Intravenous is an alternative when patients cannot tolerate oral medication. Administer within 24 hours following transplantation, until patients can tolerate oral medication, up to 14 days.
  • Reduce or interrupt dosing in the event of neutropenia.

Contraindications

  • Hypersensitivity to mycophenolate mofetil, MPA acid or any component of the drug product
  • Patients allergic to Polysorbate 80 (present in CELLCEPT IV)

Warnings and precautions

  • Blood Dyscrasias (Neutropenia, Red Blood Cell Aplasia): Monitor with blood tests; consider treatment interruption or dose reduction.
  • Gastrointestinal Complications: Monitor for complications such as bleeding, ulceration and perforations, particularly in patients with underlying gastrointestinal disorders.
  • Hypoxanthine-Guanine Phosphoribosyl-Transferase Deficiency: Avoid use of CELLCEPT.
  • Immunizations: Avoid live attenuated vaccines.
  • Local Reactions with Rapid Intravenous Administration: CELLCEPT Intravenous must not be administered by rapid or bolus intravenous injection.
  • Phenylketonurics: Oral suspension contains aspartame.
  • Blood Donation: Avoid during therapy and for 6 weeks thereafter.
  • Semen Donation: Avoid during therapy and for 90 days thereafter.
  • Potential Impairment on Driving and Use of Machinery: CELLCEPT may affect ability to drive or operate machinery.

Adverse reactions

The most common adverse reactions in clinical trials (20 % or greater) include diarrhea, leukopenia, infection, vomiting, and there is evidence of a higher frequency of certain types of infections e.g., opportunistic infection.

Drug interactions

Antacids with Magnesium or Aluminum Hydroxide: Concomitant use with an antacid containing magnesium or aluminum hydroxide decreases Mycophenolic Acid (MPA) systemic exposure , which may reduce CELLCEPT efficacy.

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Proton Pump Inhibitors (PPIs): Concomitant use with PPIs decreases Mycophenolic Acid (MPA) systemic exposure , which may reduce CELLCEPT efficacy. Examples are Lansoprazole, pantoprazole

Drugs that Interfere with Enterohepatic Recirculation: Concomitant use with drugs that directly interfere with enterohepatic recirculation, or indirectly interfere with enterohepatic recirculation by altering the gastrointestinal flora, can decrease Mycophenolic Acid (MPA) systemic exposure , which may reduce CELLCEPT efficacy. Examples are Trimethoprim/sulfamethoxazole, bile acid sequestrants (cholestyramine), rifampin as well as aminoglycoside, cephalosporin, fluoroquinolone and penicillin classes of antimicrobials

Drugs Modulating Glucuronidation: Concomitant use with drugs inducing glucuronidation decreases MPA systemic exposure, potentially reducing CELLCEPT efficacy, while use with drugs inhibiting glucuronidation increases MPA systemic exposure, which may increase the risk of CELLCEPT related adverse reactions. Examples are Telmisartan (induces glucuronidation); isavuconazole (inhibits glucuronidation).

Calcium Free Phosphate Binders: Concomitant use with calcium free phosphate binders decrease MPA systemic exposure, which may reduce CELLCEPT efficacy. Examples; Sevelamer

Drugs that Undergo Renal Tubular Secretion: When concomitantly used with CELLCEPT, its metabolite MPAG, may compete with drugs eliminated by renal tubular secretion which may increase plasma concentrations and/or adverse reactions associated with these drugs. Examples; Acyclovir, ganciclovir, probenecid, valacyclovir, valganciclovir.

Combination Oral Contraceptives: Concomitant use with CELLCEPT decreased the systemic exposure to levonorgestrel, but did not affect the systemic exposure to ethinylestradiol, which may result in reduced combination oral contraceptive effectiveness.

Use in specific populations

Pregnancy: 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 (0.02 to 0.1 times the recommended clinical doses in kidney and heart transplant patients)

Consider alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of CELLCEPT should be discussed with the pregnant woman.

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

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

Females and Males of Reproductive Potential

Females of reproductive potential must be made aware of the increased risk of first trimester pregnancy loss and congenital malformations and must be counseled regarding pregnancy prevention and planning.

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

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

Contraception: Patients Females of reproductive potential taking CELLCEPT must receive contraceptive counseling and use acceptable contraception methods. Patients must use acceptable birth control during the entire CELLCEPT therapy, and for 6 weeks after stopping CELLCEPT, unless the patient chooses abstinence.

Male Patients: Genotoxic effects have been observed in animal studies at exposures exceeding the human therapeutic exposures by approximately 2.5 times. Thus, the risk of genotoxic effects on sperm cells cannot be excluded. Based on this potential risk, sexually active male patients and/or their female partners are recommended to use effective contraception during treatment of the male patient and for at least 90 days after cessation of treatment. Also, based on the potential risk of genotoxic effects, male patients should not donate sperm during treatment with CELLCEPT and for at least 90 days after cessation of treatment.

Pediatric Use: Safety and effectiveness of CELLCEPT have been established in pediatric patients 3 months and older for the prophylaxis of kidney rejection after allogeneic kidney transplant. Use of CELLCEPT in this population is supported by evidence from adequate and well-controlled studies of CELLCEPT in adults with additional data from one open-label, pharmacokinetic and safety study of CELLCEPT in pediatric patients after receiving allogeneic kidney transplant.

Safety and effectiveness in pediatric patients receiving allogeneic heart or liver transplants have not been established.

Overdosage

Possible signs and symptoms of acute overdose include hematological abnormalities such as leukopenia and neutropenia, and gastrointestinal symptoms such as abdominal pain, diarrhea, nausea, vomiting, and dyspepsia.

The experience with overdose of CELLCEPT in humans is limited. The reported effects associated with overdose fall within the known safety profile of the drug. The highest dose administered to kidney transplant patients in clinical trials has been 4 g/day. In limited experience with heart and liver 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, particularly neutropenia.

Treatment and Management

MPA and the phenolic glucuronide metabolite of MPA (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

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