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Mycophenolate

Pronunciation

Class: Immunosuppressive Agents
Chemical Name: 6-(1,3-Dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-2-(4-morpholinyl)ethyl ester hexenoic acid
Molecular Formula: C23H31NO7C23H31NO7•HClC17H19NaO6C17H20O6
CAS Number: 116680-01-4
Brands: CellCept, Myfortic

Warning(s)

  • Immunosuppression
  • Immunosuppression may result in increased susceptibility to infection and possible development of lymphoma.1 27 43 44

  • Only clinicians experienced in immunosuppressive therapy and management of renal, cardiac, or hepatic transplant patients should prescribe mycophenolate.1 27

  • Patients should be managed in facilities equipped and staffed with appropriate laboratory and supportive resources; the clinician responsible for maintenance therapy should have complete information for patient follow-up.1 27

  • Fetotoxicity
  • May cause fetal harm; potential risk of congenital malformations and loss of pregnancy.1 27 43 44 Women of childbearing potential must use contraception.1 27 43 44 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Introduction

Immunosuppressive agent.1 2 3 4 5 6 7 Mycophenolate mofetil is a prodrug that is hydrolyzed in vivo to mycophenolic acid, the pharmacologically active metabolite.1 2 7 12 Mycophenolate sodium delayed-release tablets release the active moiety, mycophenolic acid, in the small intestine.27 28

Uses for Mycophenolate

Renal Allotransplantation

Prevention of rejection of renal allografts.1 3 4 5 6 12 27

Cardiac Allotransplantation

Prevention of rejection of cardiac allografts.1 7

Slideshow: Multiple Sclerosis: What's New in Treatment Options?

Hepatic Allotransplantation

Prevention of rejection of liver allografts.1 9

Crohn’s Disease

Has been used in the management of Crohn’s Disease.13 14 15 16 18 20 21 22 23 24 25 Not a first-line agent; reserved for patients who are refractory to or intolerant of other agents (e.g., azathioprine, mercaptopurine, methotrexate, infliximab).14 23

Mycophenolate Dosage and Administration

General

Distribute medication guide each time mycophenolate is dispensed.41 42 43 44

Administration

Administer mycophenolate mofetil and mycophenolate sodium orally;1 27 administer mycophenolate mofetil hydrochloride by IV infusion.1

In patients undergoing allotransplantation, the drug is used with cyclosporine and corticosteroids; other immunosuppressive agents (e.g., antithymocyte globulin, antilymphocyte globulin, muromonab-CD3, basiliximab, daclizumab) also have been used.1 3 4 5 6 27 28 29 30 31 Safety and efficacy of concomitant use with immunosuppressive drugs other than these agents not determined.1 32 (See Specific Drugs under Interactions.)

Handle with care.1

Mycophenolate mofetil: Do not crush tablets; do not open or crush capsules.1 43

Mycophenolate sodium: Do not crush, chew, or cut tablets.27 44 Tablets should be swallowed whole to maintain integrity of enteric coating.27

Avoid inhalation of powder in capsules or oral suspension (before and after reconstitution) and contact with skin or mucous membranes.1

Avoid contact with IV solution.1 In case of skin or mucous membrane contact, wash affected area with soap and water.1

If contact with eyes occurs, wash with water.1

Wipe up any spilled drug with a wet paper towel.1

Oral Administration

Mycophenolate mofetil: Administer orally as soon as possible following renal, cardiac, or hepatic transplantation.1

Mycophenolate mofetil: Administer preferably on an empty stomach, 1 hour before or 2 hours after food.1 43 May be given with food, if necessary, in stable renal transplant recipients.1 43 (See Food under Pharmacokinetics.) If a dose is missed, take the missed dose as soon as it is remembered unless it is almost time for the next dose.43 Do not take a double dose.43

Mycophenolate sodium: Administer as soon as possible following renal transplantation in adults.27 If a dose is missed, take the missed dose as soon as it is remembered unless it is almost time for the next dose.44 Do not take a double dose.44

Mycophenolate sodium: Administer in stable pediatric renal transplant recipients; safety and efficacy in de novo pediatric renal transplant recipients not established.27

Mycophenolate sodium: Administer on an empty stomach, 1 hour before or 2 hours after food.27 44 (See Food under Pharmacokinetics.)

Reconstitution

Mycophenolate mofetil for oral suspension: Reconstitute at time of dispensing by adding 94 mL of water (about 47 mL initially followed by another 47 mL after vigorous shaking for 1 minute) to provide a suspension containing 200 mg/mL.1 12 Shake bottle well again for 1 minute.1

Mycophenolate mofetil for oral suspension: Do not admix with other drugs.1

NG Tube

Mycophenolate mofetil for oral suspension: Can administer by nasogastric tube (minimum 1.7 mm in interior diameter; minimum French size number 8).1

IV Administration

Mycophenolate mofetil hydrochloride injection: Initiate within 24 hours following transplantation.1

Reserve IV administration for patients who cannot tolerate or are unable to take an oral dosage form.1

Administer IV for up to 14 days.1

Switch from parenteral to oral therapy as soon as possible.1

Do not mix or administer concurrently via the same infusion catheter with any other IV drugs or infusion admixtures.1

Reconstitution

Mycophenolate mofetil hydrochloride injection: Add 14 mL of 5% dextrose injection to a vial containing 500 mg of mycophenolate mofetil; shake vial gently.1

Use strict aseptic technique; drug contains no preservative.1

Dilution

For a 1-g infusion dose, add contents of 2 reconstituted vials to 140 mL of 5% dextrose injection to provide a solution containing 6 mg/mL.1

For a 1.5-g infusion dose, add the contents of 3 reconstituted vials to 210 mL of 5% dextrose injection to provide a solution containing 6 mg/mL.1

Start IV administration within 4 hours of reconstitution and dilution.1

Rate of Administration

Infuse over ≥ 2 hours by either a peripheral or central vein; do not administer by rapid IV (“bolus”) injection or rapid IV infusion.1

Dosage

Available as mycophenolate mofetil (oral capsules, tablets, for oral suspension) and mycophenolate mofetil hydrochloride (injection); dosage expressed in terms of mycophenolate mofetil.1

Available as mycophenolate sodium (delayed-release tablets); dosage expressed in terms of mycophenolic acid.27

Mycophenolate sodium delayed-release tablets should not be used interchangeably with mycophenolate mofetil tablets, capsules, or oral suspension without clinician supervision.27

If neutropenia (ANC <1300/mm3) develops, temporarily discontinue or reduce dosage.1 27 (See Hematologic Effects under Cautions.)

Pediatric Patients

Renal Allotransplantation
Mycophenolate mofetil capsules, tablets, and oral suspension
Oral

Children 3 months to 18 years of age: 600 mg/m2 as the oral suspension twice daily (maximum 1 g twice daily).1

Children with a body surface area of 1.25–1.5 m2: 750 mg as capsules twice daily.1

Children with a body surface area >1.5 m2: 1 g as capsules or tablets twice daily.1

Mycophenolate sodium delayed-release tablets
Oral

Children 5–16 years of age: 400 mg/m2 twice daily (maximum 720 mg twice daily).27

Children 5–16 years of age with a body surface area <1.19 m2: accurate dosage cannot be administered using commercially available tablets.27

Children 5–16 years of age with a body surface area of 1.19–1.58 m2: 1080 mg daily (given as three 180-mg tablets twice daily or as one 180-mg tablet and one 360-mg tablet twice daily).27

Children 5–16 years of age with a body surface >1.58 m2: 1440 mg daily (given as four 180-mg tablets twice daily or two 360-mg tablets twice daily).27

Adults

Renal Allotransplantation
Mycophenolate mofetil capsules, tablets, and oral suspension
Oral

1 g twice daily.1 No efficacy advantage with dosage of 1.5 g twice daily;1 2-g daily dosage associated with a superior safety profile compared with the 3-g daily dosage.1

Mycophenolate sodium delayed-release tablets
Oral

720 mg twice daily.27

Mycophenolate mofetil hydrochloride for injection
IV

1 g twice daily.1 No efficacy advantage with dosage of 1.5 g twice daily;1 2-g daily dosage associated with a superior safety profile compared with the 3-g daily dosage.1

Cardiac Allotransplantation
Mycophenolate mofetil capsules, tablets, and oral suspension
Oral

1.5 g twice daily.1

Mycophenolate mofetil hydrochloride for injection
IV

1.5 g twice daily.1

Hepatic Allotransplantation
Mycophenolate mofetil capsules, tablets, and oral suspension
Oral

1.5 g twice daily.1

Mycophenolate mofetil hydrochloride for injection
IV

1 g twice daily.1

Crohn’s Disease
Mycophenolate mofetil capsules, tablets, and oral suspension
Oral

Dosages of 1–2 g daily have been used.14 15 19 21 23 24

Prescribing Limits

Pediatric Patients

Renal Allotransplantation
Mycophenolate mofetil capsules, tablets, and oral suspension
Oral

Children 3 months to 18 years of age: Maximum 1 g twice daily.1

Mycophenolate sodium delayed-release tablets
Oral

Children 5–16 years of age: Maximum 720 mg twice daily.27

Special Populations

Hepatic Impairment

Renal Allotransplantation

No dosage adjustment necessary in renal transplant recipients with severe hepatic parenchymal disease; not known whether dosage adjustment is needed for other hepatic diseases.1 27

Cardiac Allotransplantation

No data available for cardiac transplant recipients with severe hepatic parenchymal disease.1

Renal Impairment

Renal Allotransplantation

Dosage adjustment not necessary in renal transplant recipients experiencing postoperative delayed graft function.1 27

Mycophenolate mofetil capsules, tablets, or oral suspension or mycophenolate mofetil hydrochloride for injection: Avoid dosages >1 g twice daily in renal transplant recipients with severe chronic renal impairment (GFR <25 mL/minute per 1.73 m2) beyond the immediate posttransplant period.1

Cardiac Allotransplantation

No data available for cardiac transplant recipients with severe chronic renal impairment.1

Hepatic Allotransplantation

No data available for hepatic transplant recipients with severe chronic renal impairment.1

Geriatric Patients

Mycophenolate mofetil capsules, tablets, or oral suspension or mycophenolate mofetil hydrochloride for injection: Select dosage carefully.1 Dosage adjustment based solely on age is not necessary in geriatric patients ≥65 years of age.1

Mycophenolate sodium delayed-release tablets: Maximum 720 mg twice daily.27

Cautions for Mycophenolate

Contraindications

  • Known hypersensitivity to mycophenolate mofetil, mycophenolate sodium, mycophenolic acid, or any ingredient in the formulation.1 27

  • IV formulation contraindicated in patients with known severe hypersensitivity to IV polysorbate (Tween) 80.1

Warnings/Precautions

Warnings

Carcinogenicity

Increased risk of lymphoma and other malignancies, particularly of the skin in patients receiving immunosuppressive regimens.1 27 Risk appears to be related to the intensity and duration of immunosuppression rather than to any specific immunosuppressive agent.1 27

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm when administered to pregnant women.1 27 33 35 36 40 Congenital malformations and increased incidence of spontaneous abortions reported during postmarketing surveillance and from the National Transplantation Pregnancy Registry (NTPR); teratogenicity and embryolethality demonstrated in animals.1 27 33 35 40

Use not recommended during pregnancy unless potential benefits justify risks to the fetus.1 27 33 Women of childbearing potential should have a negative blood or urine pregnancy test (i.e., sensitivity of at least 25 mIU/mL for human chorionic gonadotropin [HCG]) within 1 week prior to beginning therapy.1 27 40 Do not initiate therapy until a report of the pregnancy test is available indicating that results are negative.1 27 40

Women of childbearing potential should use 2 reliable forms of contraception 4 weeks prior to, during, and for 6 weeks following discontinuance of mycophenolate mofetil.1 27 40 If used during pregnancy or patient becomes pregnant while receiving the drug, apprise of potential fetal hazard and risk for loss of pregnancy; encourage patient to enroll in the NTPR.1 27

Infectious Complications

Increased susceptibility to infection (i.e., opportunistic infections, sepsis, life-threatening/fatal infections).1 27

Incidence of opportunistic infections in cardiac allograft recipients receiving mycophenolate was about 10% higher than in those receiving azathioprine; the difference was not associated with excess mortality due to infection or sepsis in patients receiving mycophenolate.1 Viral infections (e.g., cytomegalovirus [CMV] infections, herpes simplex, herpes zoster) reported more frequently in cardiac transplant recipients receiving mycophenolate than in those receiving azathioprine.1

Latent Viral Infections

Increased risk of reactivation of latent viral infections, including BK virus-associated nephropathy (BKVN).1 27 484 485 486 487 488 489 490 492 Principally observed in renal transplant patients (usually within the first year posttransplantation); may result in severe allograft dysfunction and/or graft loss.1 27 484 485 486 487 488 489 490 491 492 Reported in patients receiving immunosuppressive regimens containing mycophenolate mofetil.1 486 488 489 490 491 492 Risk appears to correlate with degree of overall immunosuppression rather than use of specific immunosuppressant.485 486 487 488 489 490 491 492 Monitor closely for signs of BKVN (e.g., deterioration in renal function);1 27 484 485 486 488 if BKVN develops, institute early treatment, and consider reducing immunosuppressive therapy.1 27 484 485 486 487 488 490 491 492

Progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain caused by the JC virus, reported in at least 17 patients receiving mycophenolate mofetil (CellCept); death occurred in at least 7 patients.37 38 39 These patients had concomitant exposure to other immunosuppressive agents (i.e., azathioprine, corticosteroids, cyclophosphamide, cyclosporine, tacrolimus) or had compromised immune function.1 27 37 38 Not reported to date with mycophenolate sodium (Myfortic).37 However, risk of PML with mycophenolate sodium expected to be the same as with mycophenolate mofetil; both drugs are metabolized to the same active metabolite (mycophenolic acid).37

Consider possible diagnosis of PML in any immunocompromised patient who develops neurologic manifestations.1 27 37 38 Refer patient to a neurologist as clinically indicated.1 27 37 38 If PML develops, consider decreasing total immunosuppression; weigh benefits of reduced immunosuppression against risk of potential graft rejection in organ transplant recipients.1 27 37 38

Hematologic Effects

Severe neutropenia (ANC <500/mm3) reported; observed most frequently between 31–180 days posttransplant.1 27 Neutropenia may be related to mycophenolate, concomitant therapies, viral infection, or a combination of these causes.1 27

Perform CBC weekly during the first month of therapy, twice monthly during the second and third months, and then monthly thereafter during the first year.1 27

Discontinue or adjust dosage if neutropenia develops, perform suitable diagnostic tests, and initiate appropriate patient management.1 27

Pure red cell aplasia (PRCA), a condition in which RBC precursors in the bone marrow are absent or nearly absent, reported in at least 41 patients receiving mycophenolate mofetil.1 27 495 496 497 498 Some of these patients also were receiving other immunosuppressive agents (e.g., alemtuzumab, azathioprine, tacrolimus); relative contribution of mycophenolate mofetil to development of PRCA not known.1 27 495 498 Consider risk of PRCA also in patients receiving mycophenolate sodium; both drugs converted to the same active metabolite (mycophenolic acid).27 495

PRCA may be reversible in some cases with dosage reduction or discontinuance.1 27 495 496 497 498 Consider possibility of graft rejection if immunosuppression reduced in transplant patients; implement any changes to immunosuppressive therapy under appropriate medical supervision.1 27 495 496

Major Toxicities

GI Effects

Severe GI bleeding (requiring hospitalization) has occurred; increased incidence of adverse GI effects (e.g., ulceration, hemorrhage, perforation) reported.1 3 4 27 Caution in patients with serious active GI disease.1 3 4 27

General Precautions

Hypoxanthine Phosphoribosyltransferase Deficiency

Avoid (on theoretical grounds) in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), including Kelley-Seegmiller or Lesch-Nyhan syndrome.1 27 Mycophenolic acid inhibits inosine monophosphate dehydrogenase.1

Phenylketonuria

Oral suspension contains aspartame (Nutrasweet), which is metabolized in the GI tract to provide about 0.56 mg of phenylalanine per 5 mL of the suspension.1

Specific Populations

Pregnancy

Category D.1 27 33 34 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 27 Discontinue nursing or the drug.1 27 Avoid breast-feeding for at least 6 weeks after discontinuing mycophenolate sodium.27

Pediatric Use

Mycophenolate mofetil: Safety for the prevention of rejection of renal allografts in children 3 months to 18 years of age based on data from a pediatric pharmacokinetic and safety study.1

Mycophenolate mofetil: Safety and efficacy not established in pediatric patients <3 months of age receiving renal allografts.1

Mycophenolate mofetil: Safety and efficacy not established in pediatric patients <18 years of age receiving allogenic cardiac or hepatic transplants.1 12

Mycophenolate sodium: Safety and efficacy in stable renal transplant recipients 5–16 years of age based on data from a pediatric pharmacokinetic study and clinical studies in adults.27 Safety and efficacy not established in children <5 years of age; a mycophenolate sodium dosage form appropriate for pediatric patients with body surface area <1.19 m2 currently not available.27

Mycophenolate sodium: Safety and efficacy not established in de novo renal transplant patients.27

Mycophenolate mofetil: Safety profile in children generally is similar to that in adults; 10 11 however, the incidence of abdominal pain,1 fever,1 infection,1 pain,1 sepsis,1 diarrhea,1 vomiting,1 pharyngitis,1 respiratory tract infection,1 hypertension,1 and anemia1 higher in pediatric patients than in adults.1 10 Lymphoproliferative malignancies reported rarely; other types of malignancies not reported.1 Severe GI bleeding (requiring hospitalization) reported.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 27 Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant diseases and drug therapy.1 27

Possible increased risk of developing GI hemorrhage, pulmonary edema, or certain infections (e.g., invasive CMV infection).1 27

Renal Impairment

Mycophenolate mofetil: No data available in cardiac or hepatic transplant recipients with severe chronic renal impairment; may use if potential benefits outweigh potential risks.1

Mycophenolate sodium: Follow patients with severe chronic renal impairment (GFR <25 mL/minute per 1.73m2) for adverse effects due to increased concentrations of free (unbound) mycophenolic acid and total mycophenolic acid glucuronide concentrations.27

Common Adverse Effects

Mycophenolate mofetil: Diarrhea,1 3 4 leukopenia,1 3 sepsis,1 vomiting,1 3 higher frequency of infections, including opportunistic infections1 3 4 (e.g., CMV infections,1 3 4 herpes zoster,3 herpes simplex,1 3 candidal infections,1 3 aspergillosis,3 4 Pneumocystis carinii pneumonia).1 3

Mycophenolate sodium: Constipation, diarrhea, nausea, urinary tract infection, nasopharyngitis.27

Interactions for Mycophenolate

Drugs That Alter Intestinal Flora

Possible disruption of enterohepatic recirculation; less mycophenolic acid available for absorption.1 27

Drugs That Interfere with Enterohepatic Recirculation

Possible decreased plasma concentrations of mycophenolic acid.1 27 Concomitant use not recommended.1 27

Drugs That Undergo Renal Tubular Secretion

Possible increased plasma concentrations of phenolic glucuronide of mycophenolic acid or other drugs that undergo renal tubular secretion.1

Vaccines

Vaccines may be less effective; avoid use of live virus vaccines.1 27 43 Influenza virus vaccine inactivated may be of value.1 27

Specific Drugs

Drug

Interaction

Comments

Acyclovir

Mycophenolate mofetil: Increased plasma concentrations of acyclovir and the phenolic glucuronide of mycophenolic acid1

Can be used concomitantly1 27

If used with mycophenolate sodium, monitor CBC27

Monitor patients with renal impairment1

Amoxicillin and clavulanic acid

Mycophenolate mofetil: Decreased trough concentrations of mycophenolic acid.1 493 May reduce glucuronidase-possessing enteric bacteria resulting in decreased enterohepatic recirculation of mycophenolic acid1 493

Clinical importance not clear1 493

Antacids (aluminum- and magnesium- containing)

Decreased mycophenolic acid plasma concentrations and AUC when administered with Maalox TC 1 27

May be used with antacids; do not administer simultaneously1 27 43 44

Azathioprine

Increased risk of bone marrow suppression1

Concomitant use not recommended1 27

Cholestyramine

Decreased mycophenolic acid AUC1 27

Concomitant use not recommended 1 27

Ciprofloxacin

Mycophenolate mofetil: Decreased trough concentrations of mycophenolic acid.1 493 May reduce glucuronidase-possessing enteric bacteria resulting in decreased enterohepatic recirculation of mycophenolic acid1 493

Clinical importance not clear1 493

Co-trimoxazole

Pharmacokinetic interaction unlikely1

Cyclosporine

Use of mycophenolate mofetil without cyclosporine results in increased systemic exposure to mycophenolic acid compared with use of mycophenolate mofetil in conjunction with cyclosporine;1 plasma cyclosporine concentrations not affected1 27

Mycophenolate mofetil: Consider possibility of increased mycophenolic acid concentrations if drug is used without cyclosporine1

Ganciclovir

Possible increased plasma concentrations of the metabolites of both drugs in patients with renal impairment1 27

Can be used concomitantly1 27

Monitor patients with renal impairment1

If used with mycophenolate sodium, monitor CBC27

Hormonal contraceptives (ethinyl estradiol, levonorgestrel, desogestrel, gestodene)

Mycophenolate mofetil: Decreased plasma levonorgestrel concentrations; no changes in ethinyl estradiol and 3-keto desogestrel concentrations1

Mycophenolate sodium: Pharmacokinetic interaction unlikely27

Caution; use additional contraceptive methods1 27

Metronidazole

Mycophenolate mofetil: Possible decreased exposure to mycophenolic acid when administered concomitantly with metronidazole and norfloxacin; no substantial effect when administered with metronidazole1

Concomitant use with norfloxacin and metronidazole not recommended1

Norfloxacin

Mycophenolate mofetil: Possible decreased exposure to mycophenolic acid when administered concomitantly with norfloxacin and metronidazole; no substantial effect when administered with norfloxacin1

Concomitant use with norfloxacin and metronidazole not recommended1

Probenecid

Possible increased concentrations of mycophenolic acid and the phenolic glucuronide of mycophenolic acid 1

Rifampin

Mycophenolate mofetil: Possible decreased systemic exposure to mycophenolic acid1

Concomitant use not recommended unless benefit outweighs risk1

Salicylates

Possible increased free fraction of mycophenolic acid 1

Sevelamer

Mycophenolate mofetil: Possible decreased plasma concentrations of mycophenolic acid1

Concurrent administration not recommended; give sevelamer or other non-calcium-containing phosphate binders 2 hours after mycophenolate mofetil1

Sirolimus

Following use of an immunosuppressive regimen (i.e., mycophenolate mofetil, cyclosporine or tacrolimus, and a corticosteroid) for 12 weeks, switching from cyclosporine or tacrolimus to sirolimus associated with higher than expected incidence of acute rejection in cardiac transplant patients32

Safety and efficacy of mycophenolate mofetil in combination with sirolimus after withdrawal of initial cyclosporine or tacrolimus therapy not established32

Valganciclovir

Possible increased plasma concentrations of the metabolites of both drugs in patients with renal impairment8

Monitor patients with renal impairment1

Mycophenolate Pharmacokinetics

Absorption

Bioavailability

Mycophenolate mofetil: Rapidly absorbed following oral administration; bioavailability is 94%.1

Following oral and IV administration, mycophenolate mofetil undergoes rapid and complete metabolism to mycophenolic acid, the active metabolite.1

Mycophenolate sodium: Following oral administration of the delayed-release tablets, mycophenolic acid is released in the small intestine; bioavailability is 72%.27

Mycophenolate mofetil tablets, capsules, and oral suspension are bioequivalent.1 12

Mycophenolate sodium delayed-release tablets cannot be used interchangeably with mycophenolate mofetil tablets, capsules, or oral suspension without clinician supervision.27 Single oral doses of mycophenolate sodium delayed-release tablets (mycophenolic acid 720 mg) and mycophenolate mofetil 1 g result in bioequivalent mycophenolic acid exposure.28

Food

Food decreases peak plasma concentrations of mycophenolic acid (by 33–40%); no effect on the mycophenolic acid AUC.1 27

Special Populations

Plasma concentrations of free (unbound) mycophenolic acid and total mycophenolic acid glucuronide have increased in nontransplant individuals with severe chronic renal impairment (GFR <25 mL/minute per 1.73 m2).1 Plasma mycophenolic acid concentrations in patients with delayed graft function similar to values in patients not experiencing delayed graft function.1

Pharmacokinetic parameters, including AUC, in children 1–18 years of age receiving mycophenolate mofetil 600 mg/m2 (oral suspension) twice daily following renal transplantation similar to values in adult renal transplant recipients receiving 1 g twice daily.1

Peak plasma concentrations and AUC of mycophenolic acid in stable pediatric renal transplant patients 5–16 years of age receiving a single dose of mycophenolate sodium (mycophenolic acid 450 mg/m2) increased (33 and 18%, respectively) relative to adults receiving the same dose based on body surface area.27 Clinical importance not determined.27

Distribution

Plasma Protein Binding

Mycophenolic acid: ≥97–98% (mainly albumin).1 27

Elimination

Metabolism

Mycophenolate mofetil undergoes complete metabolism to mycophenolic acid; metabolism occurs presystemically following oral administration.1 Mycophenolic acid is metabolized by glucuronyl transferase to the phenolic glucuronide of mycophenolic acid.1 27 The phenolic glucuronide is converted to mycophenolic acid via enterohepatic recirculation.1 27

Elimination Route

Mycophenolate mofetil: Excreted in urine (93%) as the phenolic glucuronide of mycophenolic acid (87%) and in feces (6%).1

Mycophenolate sodium: Excreted principally in urine as phenolic glucuronide of mycophenolic acid (>60%) and as unchanged mycophenolic acid (3%).27

Half-life

Mycophenolic acid: 8–17.9 hours.1 27

Special Populations

Plasma concentrations of mycophenolic acid glucuronide higher in nontransplant subjects with severe renal impairment than in those with mild impairment or normal renal function.1 27

Plasma concentrations of mycophenolic acid glucuronide higher in transplant patients with delayed renal graft function than in patients not experiencing delayed graft function.1

Dialysis does not remove mycophenolic acid.1 27

Pharmacokinetic studies in patients with alcoholic cirrhosis indicate that hepatic mycophenolic acid glucuronidation is not affected by hepatic parenchymal disease; hepatic disease with other etiologies (e.g., biliary cirrhosis) may show a different effect.1

Stability

Storage

Oral

Capsules and Tablets

25°C (may be exposed to 15–30°C).1 27

Mycophenolate mofetil: Dispense in light-resistant containers (e.g., original container).1

Mycophenolate sodium: Dispense in tight containers.27

Suspension

25°C (may be exposed to 15–30°C).1 Store reconstituted suspension at 25°C (may be exposed to 15–30°C) for up to 60 days.1 Reconstituted suspension may be refrigerated; do not freeze.1

Parenteral

Powder for Injection

25°C (may be exposed to 15–30°C).1 Store reconstituted solution and solution for infusion at 25°C (may be exposed to 15–30°C).1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Dextrose 5% in water

Actions

  • Differs structurally and pharmacologically from other immunosuppressive agents.1 27

  • Prolongs survival of allogenic transplants in animal models.1 27 Has reversed ongoing acute rejection in animal allograph models.1 27

  • A potent, selective, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), an essential enzyme in de novo guanosine synthesis.1 2 7 27 Because T- and B-cells are dependent on de novo synthesis of purines (e.g., guanosine), mycophenolic acid has potent cytostatic effects on lymphocytes.1 2 4 5 27

  • Inhibits proliferative responses of T- and B-cells to both mitogenic and allospecific stimulation1 2 27 and suppresses antibody formation by B-cells.1 2 4 27 By preventing glycosylation of lymphocyte and monocyte glycoproteins involved in intercellular adhesion to endothelial cells, mycophenolic acid may inhibit recruitment of leukocytes to sites of inflammation and graft rejection.1 2 27

Advice to Patients

  • Importance of reading the manufacturer’s patient information (medication guide) prior to initiating therapy and each time prescription is refilled.1 43 44

  • Importance of taking mycophenolate as directed.1 27 43 44 Importance of following instructions for administration, handling, and storage of the oral suspension.1 43 44

  • Risk of lymphoproliferative disease and other malignancies (e.g., skin cancer).1 27 43 44 Limit sunlight or other UV light exposure by wearing protective clothing and using sunscreens with a high protection factor.1 27 43 44 Avoid use of tanning beds or sunlamps.43 44

  • Importance of informing clinician of any unexplained fever, prolonged tiredness, weight loss, swelling of lymph nodes, or unusual skin changes (e.g., new lesions or bumps, discoloration, brown or black lesions with uneven borders).43 44

  • Necessity of routine laboratory testing (e.g., CBC).1 27 43 44

  • Importance of informing a clinician immediately of any evidence of infection (e.g., temperature ≥100.5°F, cold or flu symptoms, earache, headache, pain on urination, white patches in mouth or throat), unexpected bruising, bleeding, or other manifestations of bone marrow depression.1 27 43 44 Importance of informing clinicians of any unusual tiredness, lack of energy, dizziness, or fainting.43 44

  • Importance of informing women of childbearing potential of possible risks to fetus prior to initiating therapy.40 43 44 Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed; importance of advising women to avoid pregnancy and to use 2 reliable methods of contraception 4 weeks before, during, and for 6 weeks after discontinuance of the drug.1 27 33 43 44 Advise patients that mycophenolate may decrease effectiveness of certain oral contraceptives.1 27 40 43 44 Warn of potential hazard to the fetus and potential risk for loss of pregnancy in cases of inadvertent exposure to mycophenolate during pregnancy.1 27 43 44

  • Importance of patients informing clinician if they plan on receiving any vaccines; instruct patients to avoid live vaccines while taking mycophenolate.43 44

  • Women receiving mycophenolate sodium should avoid breast feeding for at least 6 weeks after discontinuance of the drug.27

  • Importance of informing clinicians of concomitant conditions (e.g., ulcers, Lesch-Nyhan or Kelley-Seegmiller syndrome, phenylketonuria) and existing or contemplated therapy, including prescription or OTC drugs.1 27 43 44

  • Importance of informing patients of other important precautionary information.1 27 43 44 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Mycophenolate Mofetil

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

250 mg

CellCept

Roche

For oral suspension

200 mg/mL

CellCept

Roche

Tablets

500 mg

CellCept

Roche

Mycophenolate Mofetil Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion only

500 mg (of mycophenolate mofetil)

CellCept Intravenous

Roche

Mycophenolate Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, delayed-release, (enteric-coated) film-coated

180 mg (of mycophenolic acid)

Myfortic

Novartis

360 mg (of mycophenolic acid)

Myfortic

Novartis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

CellCept 200MG/ML Suspension (GENENTECH): 160/$909.96 or 480/$2,705.93

CellCept 250MG Capsules (GENENTECH): 30/$166.00 or 100/$529.98

CellCept 500MG Tablets (GENENTECH): 100/$951.33 or 300/$2,822.58

Mycophenolate Mofetil 250MG Capsules (TEVA PHARMACEUTICALS USA): 30/$35.99 or 100/$109.98

Mycophenolate Mofetil 500MG Tablets (ROXANE): 100/$129.99 or 300/$339.96

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions May 1, 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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4. Sollinger HW for the US Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation. 1995; 60:225-32. (IDIS 352830) [IDIS 352830] [PubMed 7645033]

5. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation. 1996; 61:1029-37. (IDIS 367784) [PubMed 8623181]

6. Johnson C, Ahsan N, Gonwa T et al. Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation. Transplantation. 2000; 69:834-41. [PubMed 10755536]

7. Kobashigawa J, Miller L, Renlund D et al. for the Mycophenolate Mofetil Investigators. A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Transplantation. 1998; 66:507-15. (IDIS 413972) [IDIS 413972] [PubMed 9734496]

8. Roche. Valcyte (valganciclovir hydrochloride) tablets prescribing information (dated 2001 Mar). In: Physician’s desk reference. 56th ed. Montvale, NJ: Medical Economics Company Inc; 2002:3022-6.

9. Wiesner R, Rabkin J, Klintmalm G et al. A randomized double-blind comparative study of mycophenolate mofetil and azathioprine in combination with cyclosporine and corticosteroids in primary liver transplant recipients. Liver Transpl. 2001; 7:442-50. [PubMed 11349266]

10. Jacqz-Aigrain E, Khan Shaghaghi E, Baudouin V et al. Pharmacokinetics and tolerance of mycophenolate mofetil in renal transplant children. Pediatr Nephrol. 2000; 14:95-9.

11. Jungraithmayr T, Staskewitz A, Kirste G et al. Pediatric renal transplantation with mycophenolate mofetil-based immunosuppression without induction: results after three years. Transplantation. 2003; 75:454-61. [IDIS 493515] [PubMed 12605109]

12. Roche Laboratories, Nutley, NJ: Personal Communication.

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17. Hafraoui S, Dewit O, Marteau P et al. Mycophenolate mofetil in refractory Crohn’s disease after failure of treatments by azathioprine or methotrexate. Gastroenterol Clin Biol. 2002; 26:17-22. [PubMed 11938035]

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19. Skelly MM, Logan RF, Jenkins D et al. Toxicity of mycophenolate mofetil in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2002; 8:93-7. [PubMed 11854606]

20. Miehsler W, Reinisch W, Moser G et al. Is mycophenolate mofetil an effective alternative in azathioprine-intolerant patients with chronic active Crohn’s disease? Am J Gastroenterol. 2001; 96:782-7.

21. Neurath MF, Wanitschke R, Peters M et al. Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn’s disease. Gut. 1999; 44:625-8. [IDIS 429065] [PubMed 10205197]

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23. Fickert P, Hinterleitner TA, Wenzl HH et al. Mycophenolate mofetil in patients with Crohn’s disease. Am J Gastroenterol. 1998; 93:2529-32. [IDIS 420391] [PubMed 9860419]

24. Fellermann K, Steffen M, Stein J et al. Mycophenolate mofetil: lack of efficacy in chronic active inflammatory bowel disease. Aliment Pharmacol Ther. 2000; 14:171-6. [PubMed 10651657]

25. Hassard PV, Vasiliauskas EA, Kam LY et al. Efficacy of mycophenolate mofetil in patients failing 6-mercaptopurine or azathioprine therapy for Crohn’s disease. Inflamm Bowel Dis. 2000; 6:16-20. [PubMed 10701145]

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27. Novartis. Myfortic (mycophenolate sodium) delayed-release tablets prescribing information. East Hanover, NJ: 2009 Oct.

28. Budde K, Glander P, Diekmann F et al. Review of the immunosuppressant enteric-coated mycophenolate sodium. Expert Opin Pharmacother. 2004; 5:1333-45. [PubMed 15163278]

29. Nashan B, Ivens K, Suwelack B et al. Conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in maintenance renal transplant patients: preliminary results from the myfortic prospective multicenter study. Transplant Proc. 2004; 36(Suppl 2S):521-3S.

30. Budde K, Curtis J, Knoll G et al. Enteric-coated mycophenolate sodium can be safely administered in maintenance renal transplant patients: results of a 1-year study. Am J Transplantation. 2003; 4:237-43.

31. Salvadori M, Holzer H, de Mattos A et al. Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplantation. 2003; 4:231-6.

32. Birgerson LE. Dear Health Care Professional: Important safety information regarding higher than expected incidence of acute rejection in cardiac transplant patients switched from calcineurin inhibitors in combination with CellCept (mycophenolate mofetil) to Rapamune (sirolimus) in combination with CellCept at 12 weeks post heart transplantation. Nutley, NJ: Wyeth Pharmaceuticals Inc; 2007 Feb 1. From FDA website.

33. Birgerson LE. Dear health care professional letter regarding important drug warning for CellCept (mycophenolate mofetil) . Nutley, NJ; 2007 Oct.

34. Novartis, East Hanover, NJ: Personal communication.

35. Sifontis NM, Coscia LA, Constantinescu S et al. Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus. Transplantation. 2006; 82:1698-702. [PubMed 17198262]

36. Armenti VT, Radomski JS, Moritz MJ et al. Report from the National Transplantation Pregnancy Registry (NTPR); outcomes of pregnancy after transplantation. Clin Transpl. 2004; 103-14.

37. Cunningham S. Dear healthcare professional letter regarding important prescribing information about Myfortic (mycophenolic acid) delayed-release tablet. East Hanover, NJ: Novartis; 2008 June.

38. Birgerson LE. Dear healthcare professional letter regarding important changes in the CellCept (mycophenolate mofetil) prescribing information; reports of progressive multifocal leukoencephalopathy (PML) in patients treated with CellCept. Nutley, NJ: Roche; 2008 June.

39. US Food and Drug Administration. Communication about an ongoing safety review of Cellcept (mycophenolate mofetil) and Myfortic (mycophenolic acid). Rockville, MD; 2008 June 4. From FDA website.

40. US Food and Drug Administration. Information for healthcare professionals; mycophenolate mofetil (marketed as Cellcept) and mycophenolic acid (marketed as Myfortic). FDA Alert. Rockville, MD; 2008 May 16. From FDA website.

41. Food and Drug Administration. Medwatch safety information 2009. Cellcept (mycophenolate mofetil). From FDA website.

42. Birgerson LE. Dear healthcare professional letter regarding new CellCept (mycophenolate mofetil) medication guide to be distributed by pharmacists information. Nutley, NJ; 2009 Jan.

43. Roche Laboratories, Inc. Cellcept (mycophenolate mofetil) medication guide. Nutley, NJ; 2009 Oct.

44. Novartis. Myfortic (mycophenolic acid) medication guide. East Hanover, NJ; 2009 Oct.

484. Food and Drug Administration. Information for healthcare professionals: immunosuppressant drugs, required labeling changes [sirolimus (marketed as Rapamune), cyclosporine (marketed as Sandimmune and generics), cyclosporine modified (marketed as Neoral and generics), mycophenolate mofetil (marketed as Cellcept and generic), mycophenolic acid (marketed as Myfortic)]. Rockville, MD; July 14, 2009. From FDA website.

485. Wiseman AC. Polyomavirus nephropathy: a current perspective and clinical considerations. Am J Kidney Dis. 2009; 54:131-42. [PubMed 19394729]

486. Bonvoisin C, Weekers L, Xhignesse P et al. Polyomavirus in renal transplantation: a hot problem. Transplantation. 2008; 85 (suppl 7):S42-8.

487. Mannon RB. Polyomavirus nephropathy: what have we learned?. Transplantation. 2004; 77:1313-8. [PubMed 15167583]

488. Ziedina I, Folkmane I, Chapenko S et al. Reactivation of BK Virus in the Early Period After Kidney Transplantation. Transplant Proc. 2009; 41:766-8. [PubMed 19328975]

489. Dharnidharka VR, Cherikh WS, Abbott KC. An OPTN analysis of national registry data on treatment of BK virus allograft nephropathy in the United States. Transplantation. 2009; 87:1019-26. [PubMed 19352121]

490. Alméras C, Foulongne V, Garrigue V et al. Does reduction in immunosuppression in viremic patients prevent BK virus nephropathy in de novo renal transplant recipients? A prospective study. Transplantation. 2008; 85:1099-104. [PubMed 18431228]

491. Hirsch HH, Brennan DC, Drachenberg CB et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation. 2005; 79:1277-86. [PubMed 15912088]

492. Benavides CA, Pollard VB, Mauiyyedi S et al. BK virus-associated nephropathy in sirolimus-treated renal transplant patients: incidence, course, and clinical outcomes. Transplantation. 2007; 84:83-8. [PubMed 17627242]

493. Borrows R, Chusney G, Loucaidou M et al. The magnitude and time course of changes in mycophenolic acid 12-hour predose levels during antibiotic therapy in mycophenolate mofetil-based renal transplantation. Ther Drug Monit. 2007; 29:122-6. [PubMed 17304160]

495. Orloff J. Dear healthcare professional letter regarding important prescribing information about Myfortic (mycophenolic acid) delayed-release tablet. East Hanover, NJ; 2009 Aug.

496. Birgerson LE. Dear healthcare professional letter regarding important changes in the CellCept (mycophenolate mofetil) prescribing information: reports of pure red cell aplasia (PRCA) in patients treated with CellCept. Nutley, NJ; 2009 Aug.

497. Engelen W, Verpooten GA, Van der Planken M et al. Four cases of red blood cell aplasia in association with the use of mycophenolate mofetil in renal transplant patients. Clin Nephrol. 2003; 60:119-24. [PubMed 12940614]

498. Elimelakh M, Dayton V, Park KS et al. Red cell aplasia and autoimmune hemolytic anemia following immunosuppression with alemtuzumab, mycophenolate, and daclizumab in pancreas transplant recipients. Haematologica. 2007; 92:1029-36. [PubMed 17640860]

HID. Trissel LA. Handbook on injectable drugs. 14th ed; Bethesda, MD: American Society of Health-System Pharmacists; 2007:1187-8.

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