Home > Medical Reference > Complementary Medicine

Mycophenolate


Pronunciation

 (mye koe FEN oh late)


U.S. Brand Names

 CellCept®; Myfortic®


Synonyms

 MMF; MPA; Mycophenolate Mofetil; Mycophenolate Sodium; Mycophenolic Acid


Generic Available

 No


Canadian Brand Names

 CellCept®


Use

 Prophylaxis of organ rejection concomitantly with cyclosporine and corticosteroids in patients receiving allogenic renal (CellCept®, Myfortic®), cardiac (CellCept®), or hepatic (CellCept®) transplants


Use - Unlabeled/Investigational

 Treatment of rejection in liver transplant patients unable to tolerate tacrolimus or cyclosporine due to neurotoxicity; mild rejection in heart transplant patients; treatment of moderate-severe psoriasis; treatment of proliferative lupus nephritis


Pregnancy Risk Factor

 C (manufacturer)


Pregnancy Implications

 There are no adequate and well-controlled studies using mycophenolate in pregnant women, however, it may cause fetal harm. Women of childbearing potential should have a negative pregnancy test prior to beginning therapy. Two reliable forms of contraception should be used prior to, during, and for 6 weeks after therapy.


Lactation

 Excretion in breast milk unknown/not recommended


Contraindications

 Hypersensitivity to mycophenolate mofetil, mycophenolic acid, mycophenolate sodium, or any component of the formulation; intravenous formulation is contraindicated in patients who are allergic to polysorbate 80


Warnings/Precautions

 Risk for infection and development of lymphoproliferative disorders is increased. Patients should be monitored appropriately and given supportive treatment should these conditions occur. Toxicity may be increased in patients with renal impairment. Use caution with active peptic ulcer disease.

Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, tablets should not be crushed, and capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in the capsules and the powder for oral suspension. Caution should be exercised in the handling and preparation of solutions of intravenous mycophenolate. Avoid skin contact with the intravenous solution and reconstituted suspension. If such contact occurs, wash thoroughly with soap and water, rinse eyes with plain water.

Theoretically, use should be avoided in patients with the rare hereditary deficiency of hypoxanthine-guanine phosphoribosyltransferase (such as Lesch-Nyhan or Kelley-Seegmiller syndrome). Intravenous solutions should be given over at least 2 hours; never administer intravenous solution by rapid or bolus injection.

CellCept® and Myfortic® dosage forms should not be used interchangeably due to differences in absorption.


Adverse Reactions

 As reported in adults following oral dosing of CellCept® alone in renal, cardiac, and hepatic allograft rejection studies. In general, lower doses used in renal rejection patients had less adverse effects than higher doses. Rates of adverse effects were similar for each indication, except for those unique to the specific organ involved. The type of adverse effects observed in pediatric patients was similar to those seen in adults; abdominal pain, anemia, diarrhea, fever, hypertension, infection, pharyngitis, respiratory tract infection, sepsis, and vomiting were seen in higher proportion; lymphoproliferative disorder was the only type of malignancy observed. Percentages of adverse reactions were similar in studies comparing CellCept® to Myfortic® in patients following renal transplant.

>20%:

Cardiovascular: Hypertension (28% to 77%), peripheral edema (27% to 64%), edema (27% to 28%), tachycardia (20% to 22%)

Central nervous system: Pain (31% to 76%), headache (16% to 54%), insomnia (41% to 52%), fever (21% to 52%), anxiety (28%)

Dermatologic: Rash (22%)

Endocrine & metabolic: Hypercholesterolemia (41%), hypokalemia (32% to 37%)

Gastrointestinal: Abdominal pain (25% to 62%), nausea (20% to 54%), diarrhea (31% to 52%), constipation (18% to 41%), vomiting (33% to 34%), anorexia (25%), dyspepsia (22%)

Genitourinary: Urinary tract infection (37%)

Hematologic: Leukopenia (23% to 46%), leukocytosis (22% to 40%), hypochromic anemia (25%)

Hepatic: Liver function tests abnormal (25%), ascites (24%)

Neuromuscular & skeletal: Back pain (35% to 47%), weakness (35% to 43%), tremor (24% to 34%), paresthesia (21%)

Respiratory: Dyspnea (31% to 37%), respiratory tract infection (22% to 37%), cough (31%), lung disorder (22% to 30%)

Miscellaneous: Infection (18% to 27%), Candida (11% to 22%), herpes simplex (10% to 21%)

3% to <20%:

Cardiovascular: Angina, arrhythmia, arterial thrombosis, atrial fibrillation, atrial flutter, bradycardia, cardiac arrest, cardiac failure, CHF, extrasystole, facial edema, hypervolemia, hypotension, pallor, palpitation, pericardial effusion, peripheral vascular disorder, postural hypotension, supraventricular extrasystoles, supraventricular tachycardia, syncope, thrombosis, vasodilation, vasospasm, venous pressure increased, ventricular extrasystole, ventricular tachycardia

Central nervous system: Agitation, chills with fever, confusion, convulsion, delirium, depression, emotional lability, hallucinations, hypesthesia, malaise, nervousness, psychosis, somnolence, thinking abnormal, vertigo

Dermatologic: Acne, alopecia, bruising, cellulitis, hirsutism, pruritus, skin carcinoma, skin hypertrophy

Endocrine & metabolic: Acidosis, Cushing's syndrome, dehydration, diabetes mellitus, gout, hypercalcemia, hyperlipemia, hyperphosphatemia, hyperuricemia, hypothyroidism, parathyroid disorder

Gastrointestinal: Abdomen enlarged, dry mouth, dysphagia, esophagitis, flatulence, gastritis, gastroenteritis, gastrointestinal hemorrhage, gastrointestinal moniliasis, gingivitis, gum hyperplasia, melena, mouth ulceration, oral moniliasis, stomach disorder, stomatitis

Genitourinary: Impotence, pelvic pain, prostatic disorder, urinary frequency, urinary incontinence, urinary retention, urinary tract disorder

Hematologic: Coagulation disorder, hemorrhage, pancytopenia, polycythemia, prothrombin time increased, thromboplastin increased

Hepatic: Alkaline phosphatase increased, alkalosis, bilirubinemia, cholangitis, cholestatic jaundice, GGT increased, hepatitis, jaundice, liver damage

Local: Abscess, ALT increased, AST increased

Neuromuscular & skeletal: Arthralgia, hypertonia, joint disorder, leg cramps, myalgia, myasthenia, neck pain, neuropathy, osteoporosis

Ocular: Amblyopia, cataract, conjunctivitis, eye hemorrhage, lacrimation disorder, vision abnormal

Otic: Deafness, ear disorder, ear pain, tinnitus

Renal: Albuminuria, creatinine increased, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, oliguria

Respiratory: Apnea, asthma, atelectasis, bronchitis, epistaxis, hemoptysis, hiccup, hyperventilation, hypoxia, respiratory acidosis, lung edema, pharyngitis, pleural effusion, pneumonia, pneumothorax, pulmonary hypertension, respiratory moniliasis, rhinitis, sinusitis, sputum increased, voice alteration

Miscellaneous: CMV viremia/syndrome (12% to 14%), CMV tissue invasive disease (6% to 11%), herpes zoster cutaneous disease (4% to 10%), cyst, diaphoresis, flu-like syndrome, fungal dermatitis, healing abnormal, hernia, ileus infection, lactic dehydrogenase increased, peritonitis, pyelonephritis, scrotal edema, thirst

Postmarketing and/or case reports: Atypical mycobacterial infection, colitis, infectious endocarditis, interstitial lung disorder, intestinal villous atrophy, meningitis, pancreatitis, pulmonary fibrosis (fatal), tuberculosis


Overdosage/Toxicology

 There are no reported overdoses with mycophenolate. At plasma concentrations >100 mcg/mL, small amounts of the inactive metabolite MPAG are removed by hemodialysis. Excretion of the active metabolite, MPA, may be increased by using bile acid sequestrants (cholestyramine).


Drug Interactions

Acyclovir: Levels of both drugs may increase due to competition for tubular secretion; monitor carefully

Antacids (magnesium- and aluminum hydroxide-containing products): Decrease absorption of mycophenolate; do not administer together

Azathioprine: Bone marrow suppression may be caused by both agents; do not administer together

Cholestyramine: Decreases AUC which may lead to decreased efficacy; do not administer together

Ganciclovir: Levels of both drugs may increase due to competition for tubular secretion; monitor carefully

Oral contraceptives: Progesterone levels are not significantly affected, however, effect on estrogen component varies; although the ovulation-suppression action may not be affected, an additional form of contraception should be used

Probenecid: May increase mycophenolate levels due to inhibition of tubular secretion

Vaccines: Avoid use of live vaccines; vaccinations may be less effective. Influenza vaccine may be of value.


Ethanol/Nutrition/Herb Interactions

Food: Decreases Cmax of MPA by 40% following CellCept® administration and 33% following Myfortic® use; the extent of absorption is not changed

Herb/Nutraceutical: Avoid cat's claw, echinacea (have immunostimulant properties)


Stability

Capsules: Store at room temperature of 15°C to 39°C (59°F to 86°F).

Tablets: Store at room temperature of 15°C to 39°C (59°F to 86°F); protect from light.

Oral suspension: Store powder for oral suspension at room temperature of 15°C to 39°C (59°F to 86°F). Should be constituted by a pharmacist prior to dispensing to the patient and not mixed with any other medication. Closed bottle should be tapped to loosen the powder. Add 47 mL of water to the bottle and shake well for ~1 minute. Add another 47 mL of water to the bottle and shake well for an additional minute. Remove child-resistant cap and push bottle adapter into neck of the bottle; close bottle with child-resistant cap tightly to assure proper placement of adapter and status of child-resistant cap. Final concentration is 200 mg/mL of mycophenolate mofetil. Once reconstituted, the oral solution may be stored at room temperature or under refrigeration. Do not freeze. The mixed suspension is stable for 60 days.

Injection: Store intact vials at room temperature 15°C to 30°C (59°F to 86°F). Stability of the infusion solution: 4 hours from reconstitution and dilution of the product. Store solutions at 15°C to 30°C (59°F to 86°F); does not contain an antibacterial preservative; therefore, reconstitution and dilution of the product must be done under aseptic conditions. Preparation of intravenous formulation should take place in a vertical laminar flow hood with the same precautions as antineoplastic agents.

I.V. preparation procedure Step 1:

a. Two vials of mycophenolate injection are used for preparing a 1 g dose, whereas 3 vials are needed for each 1.5 g dose. Reconstitute the contents of each vial by injecting 14 mL of 5% dextrose injection.

b. Gently shake the vial to dissolve the drug

c. Inspect the resulting slightly yellow solution for particulate matter and discoloration prior to further dilution. Discard the vial if particulate matter or discoloration is observed.

I.V. preparation procedure Step 2:

a. To prepare a 1 g dose, further dilute the contents of the two reconstituted vials into 140 mL of 5% dextrose in water. To prepare a 1.5 g dose, further dilute the contents of the three reconstituted vials into 210 mL of 5% dextrose in water. The final concentration of both solutions is 6 mg mycophenolate mofetil per mL.

b. Inspect the infusion solution for particulate matter or discoloration. Discard the infusion solution if particulate matter or discoloration is observed.


Compatibility

 Compatible: Stable in D5W


Mechanism of Action

 MPA exhibits a cytostatic effect on T and B lymphocytes. It is an inhibitor of inosine monophosphate dehydrogenase (IMPDH) which inhibits de novo guanosine nucleotide synthesis. T and B lymphocytes are dependent on this pathway for proliferation.


Pharmacodynamics/Kinetics

Onset of action: Peak effect: Correlation of toxicity or efficacy is still being developed, however, one study indicated that 12-hour AUCs >40 mcg/mL/hour were correlated with efficacy and decreased episodes of rejection

Tmax: Oral: MPA:

CellCept®: 1-1.5 hours

Myfortic®: 1.5-2.5 hours

Absorption: AUC values for MPA are lower in the early post-transplant period versus later (>3 months) post-transplant period. The extent of absorption in pediatrics is similar to that seen in adults, although there was wide variability reported.

Oral: Myfortic®: 93%

Distribution:

CellCept®: MPA: Oral: 4 L/kg; I.V.: 3.6 L/kg

Myfortic®: MPA: Oral: 54 L (at steady state); 112 L (elimination phase)

Protein binding: MPA: 97%, MPAG 82%

Metabolism: Hepatic and via GI tract; CellCept® is completely hydrolyzed in the liver to mycophenolic acid (MPA; active metabolite); enterohepatic recirculation of MPA may occur; MPA is glucuronidated to MPAG (inactive metabolite)

Bioavailability: Oral: CellCept®: 94%; Myfortic®: 72%

Half-life elimination:

CellCept®: MPA: Oral: 18 hours; I.V.: 17 hours

Myfortic®: MPA: Oral: 8-16 hours; MPAG: 13-17 hours

Excretion:

CellCept®: MPA: Urine (<1%), feces (6%); MPAG: Urine (87%)

Myfortic®: MPA: Urine (3%), feces; MPAG: Urine (>60%)


Dosage

Children: Renal transplant: Oral:

CellCept® suspension: 600 mg/m 2 /dose twice daily; maximum dose: 1 g twice daily

Alternatively, may use solid dosage forms according to BSA as follows:

BSA 1.25-1.5 m 2 : 750 mg capsule twice daily

BSA >1.5 m 2 : 1 g capsule or tablet twice daily

Myfortic®:

BSA <1.19 m 2 : Use of this formulation is not recommended

BSA 1.19-1.58 m 2 : 400 mg/m 2 twice daily (maximum: 1080 mg/day)

BSA >1.58 m 2 : 400 mg/m 2 twice daily (maximum: 1440 mg/day)

Adults: The initial dose should be given as soon as possible following transplantation; intravenous solution may be given until the oral medication can be tolerated (up to 14 days)

Renal transplant:

CellCept®:

Oral: 1 g twice daily. Although a dose of 1.5 g twice daily was used in clinical trials and shown to be effective, no efficacy advantage was established. Patients receiving 2 g/day demonstrated an overall better safety profile than patients receiving 3 g/day. Doses >2 g/day are not recommended in these patients because of the possibility for enhanced immunosuppression as well as toxicities.

I.V.: 1 g twice daily

Myfortic®: Oral: 720 mg twice daily (1440 mg/day)

Cardiac transplantation:

Oral (CellCept®): 1.5 g twice daily

I.V. (CellCept®): 1.5 g twice daily

Hepatic transplantation:

Oral (CellCept®): 1.5 g twice daily

I.V. (CellCept®): 1 g twice daily

Dosing adjustment in renal impairment :

Renal transplant: GFR <25 mL/minute in patients outside the immediate post-transplant period:

CellCept®: Doses of >1 g administered twice daily should be avoided; patients should also be carefully observed; no dose adjustments are needed in renal transplant patients experiencing delayed graft function postoperatively

Myfortic®: Clcr<25 mL/minute: Monitor carefully

Cardiac or liver transplant: No data available; mycophenolate may be used in cardiac or hepatic transplant patients with severe chronic renal impairment if the potential benefit outweighs the potential risk

Hemodialysis: Not removed; supplemental dose is not necessary

Peritoneal dialysis: Supplemental dose is not necessary

Dosage adjustment in hepatic impairment: No dosage adjustment is recommended for renal patients with severe hepatic parenchymal disease; however, it is not currently known whether dosage adjustments are necessary for hepatic disease with other etiologies

Elderly: Dosage is the same as younger patients, however, dosing should be cautious due to possibility of increased hepatic, renal or cardiac dysfunction; elderly patients may be at an increased risk of certain infections, gastrointestinal hemorrhage, and pulmonary edema, as compared to younger patients

Dosing adjustment for toxicity (neutropenia) : ANC <1.3 x 10 3 / L: Dosing should be interrupted or the dose reduced, appropriate diagnostic tests performed and patients managed appropriately


Administration

Oral dosage formulations (tablet, capsule, suspension) should be administered as soon as possible following transplantation. Oral dosage forms should be administered on an empty stomach to avoid variability in MPA absorption. The oral solution may be administered via a nasogastric tube (minimum 8 French, 1.7 mm interior diameter) and cannot be mixed with other medications. Delayed release tablets should not be crushed, cut, or chewed.

Intravenous solutions should be administered over at least 2 hours (either peripheral or central vein); do not administer intravenous solution by rapid or bolus injection. Following reconstitution, dilute to a concentration of 6 mg/mL using D5W; mycophenolate is not compatible with other solutions.


Monitoring Parameters

 Complete blood count; signs and symptoms of infection


Dietary Considerations

 Oral dosage formulations should be taken on an empty stomach to avoid variability in MPA absorption. However, in stable renal transplant patients, may be administered with food if necessary. Oral suspension contains 0.56 mg phenylalanine/mL; use caution if administered to patients with phenylketonuria.


Patient Education

 Take oral formulations as directed, preferably 1 hour before or 2 hours after meals. Do not take within 1 hour before or 2 hours after antacids or cholestyramine medications. Do not alter dose and do not discontinue without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) during entire course of therapy unless instructed to restrict fluid intake. You will be susceptible to infection (avoid crowds and exposure to infection). May be at increased risk for skin cancer, wear protective clothing and use sunscreen with high protective factor to help limit exposure to sunlight and UV light. If you have diabetes, monitor glucose levels closely (drug may alter glucose levels). You may experience dizziness or trembling (use caution until response to medication is known); nausea or vomiting (small, frequent meals, frequent mouth care may help); diarrhea (boiled milk, yogurt, or buttermilk may help); sores or white plaques in mouth (frequent rinsing of mouth and frequent mouth care may help); or muscle or back pain (mild analgesics may be recommended). Report chest pain; acute headache or dizziness; symptoms of respiratory infection, cough, or respiratory difficulty; unresolved GI effects; fatigue, chills, fever unhealed sores, white plaques in mouth; irritation in genital area or unusual discharge; unusual bruising or bleeding; or other unusual effects related to this medication. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Two reliable forms of contraception should be used prior to, during, and for 6 weeks after therapy. Breast-feeding is not recommended.


Nursing Implications

 Increased risk for infection and development of lymphoproliferative disorders. Patients should be monitored appropriately and given supportive treatment should these conditions occur. Increased toxicity in patients with renal impairment.


Anesthesia and Critical Care Concerns/Other Considerations

 Avoid inhalation or direct contact with skin or mucous membranes of the powder in CellCept® capsules. If such contact occurs, wash with soap and water; rinse eyes with plain water. Capsules should not be opened or crushed.

Hypertension may accompany the use of mycophenolate in patients post-transplantation. Furthermore, this drug may also induce increases in cholesterol and potassium, and impair glucose tolerance and phosphate and potassium depletion.


Cardiovascular Considerations

 Hypertension may accompany the use of mycophenolate in patients post-transplantation. Furthermore, this drug may also induce increases in cholesterol, increases in serum phosphate, hyperkalemia, and hyperglycemia.


Dental Health: Effects on Dental Treatment

 No significant effects or complications reported


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Effects on Mental Status

 Dizziness and insomnia are common


Mental Health: Effects on Psychiatric Treatment

 Leukopenia is common; avoid clozapine and carbamazepine


Dosage Forms

Capsule, as mofetil (CellCept®): 250 mg

Injection, powder for reconstitution, as mofetil hydrochloride (CellCept®): 500 mg [contains polysorbate 80]

Powder for oral suspension, as mofetil (CellCept®): 200 mg/mL (225 mL) [provides 175 mL suspension following reconstitution; contains phenylalanine 0.56 mg/mL; mixed fruit flavor]

Tablet, as mofetil [film coated] (CellCept®): 500 mg [may contain ethyl alcohol]

Tablet, delayed release, as mycophenolic acid [film coated] (Myfortic®): 180 mg, 360 mg [formulated as a sodium salt]


References

Contreras G, Pardo V, Leclercq B, et al, "Sequential Therapies for Proliferative Lupus Nephritis," N Engl J Med , 2004, 350(10):971-80.

Ettenger R, Warshaw B, Menster M, et al, "Mycophenolate Mofetil in Pediatric Renal Transplantation: A Report of the Ped MMF Study Group." Abstract: 1996, Annual Meeting, ASTP.

Gabardi S, Tran JL, and Clarkson MR, "Enteric-Coated Mycophenolate sodium," Ann Pharmacother , 2003, 37(11):1685-93.

Lipsky JJ, "Mycophenolate Mofetil," Lancet , 1996, 348(9038):1357-9.

Shaw LM, Sollinger HW, Halloran P, et al, "Mycophenolate Mofetil: A Report of the Consensus Panel," Ther Drug Monit , 1995, 17(6):690-9.

Sollinger HW, "Mycophenolate Mofetil for the Prevention of Acute Rejection in Primary Cadaveric Renal Allograft Recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group," Transplantation , 1995, 60:225-32.


International Brand Names

 CellCept® (CA)


A.D.A.M., Inc. is accredited by URAC, also known as the American Accreditation HealthCare Commission (www.urac.org). URAC's accreditation program is the first of its kind, requiring compliance with 53 standards of quality and accountability, verified by independent audit. A.D.A.M. is among the first to achieve this important distinction for online health information and services. Learn more about A.D.A.M.'s editorial process . A.D.A.M. is also a founding member of Hi-Ethics (www.hiethics.com) and subscribes to the principles of the Health on the Net Foundation (www.hon.ch).

The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions. Call 911 for all medical emergencies. Links to other sites are provided for information only -- they do not constitute endorsements of those other sites. © 1997-2007 A.D.A.M., Inc. Any duplication or distribution of the information contained herein is strictly prohibited.
adam.com