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Mycophenolate Mofetil / Mycophenolic Acid

Pronunciation: MYE-koe-FEN-oh-late MOE-fe-til/MYE-koe-fe-NOLE-ik AS-id
Class: Immunosuppressive

Trade Names

CellCept
- Capsules 250 mg
- Tablets 500 mg
- Suspension, powder for reconstitution 200 mg/mL
- Injection, lyophilized powder for solution, concentrate 500 mg as hydrochloride

Myfortic
- Tablets, delayed-release 180 mg as sodium
- Tablets, delayed-release 360 mg as sodium

CellCept I.V. (Canada)

Pharmacology

Inhibits immune-mediated inflammatory responses, but exact mechanism is not known.

Pharmacokinetics

Absorption

Mycophenolate mofetil

Rapidly absorbed following administration. Mean absolute bioavailability of oral mycophenolate relative to IV, based on mycophenolic acid AUC, is 94%. Administration with food decreases C max by 40%, but does not affect the extent of absorption. T max ranges from 0.5 to 1 h.

Mycophenolic sodium

After administration, GI absorption and absolute bioavailability of mycophenolic acid are 93% and 72%, respectively. T max of mycophenolic acid ranges between 1.5 and 2.75 h compared with a range of 0.5 to 1 h, respectively, following administration of mycophenolate mofetil. Administration with food decreases C max and delays T max .

Distribution

Protein binding for mycophenolic acid is more than 98%, and protein binding for the inactive metabolite, mycophenolic acid glucuronide, is 82%. The mean steady-state Vd for mycophenolic acid is 54 L. Mean apparent Vd is 3.6 L/kg and 4 L/kg following IV and oral administration, respectively.

Metabolism

Metabolism is rapid and complete to mycophenolic acid. Mycophenolic acid is metabolized to mycophenolic acid glucuronide by glucuronyl transferase. Mycophenolic acid glucuronide undergoes enterohepatic recycling, in which it is converted to mycophenolic acid.

Elimination

Mycophenolate mofetil

Approximately 93% is recovered in the urine and 6% in the feces. Approximately 87% is excreted in the urine as mycophenolic acid glucuronide. Mean (± standard deviation) apparent half-life and plasma Cl of mycophenolic acid are 17.9 (± 6.5) h and 193 (± 48) mL/min following oral administration, and 16.6 (± 5.8) h and 177 (± 31) mL/min following IV administration, respectively.

Mycophenolic sodium

Mycophenolic acid is eliminated principally in the urine primarily as mycophenolic acid glucuronide (more than 60%) and approximately 3% as unchanged mycophenolic acid. Mean elimination half-life of mycophenolic acid ranged from 8 to 16 h, and the mean elimination half-life of mycophenolic acid glucuronide ranged from 13 to 17 h. The mean renal Cl of mycophenolic acid glucuronide was 15.5 ± 5.9 mL/min.

Special Populations

Renal Function Impairment
Mycophenolate mofetil

Mycophenolic acid AUC increased 75%, and mycophenolic acid glucuronide AUC increased 3- to 6-fold in patients with severe renal impairment (CrCl less than 25 mL/min per 1.73 m 2 ). Hemodialysis usually does not remove mycophenolic acid or mycophenolic acid glucuronide.

Mycophenolate sodium

Based on studies of mycophenolate mofetil, mycophenolic acid glucuronide exposure increased with decreased renal function. Mycophenolic acid glucuronide exposure is approximately 8-fold higher in anuric patients. Dialysis removes the inactive metabolite mycophenolic acid glucuronide, but not the active mycophenolic acid, primarily because of protein binding.

Hepatic Function Impairment

No specific pharmacokinetic studies have been conducted.

Elderly

Pharmacokinetics have not been studied.

Children
Mycophenolate sodium

Based on BSA, mycophenolic acid C max and AUC in children are higher than those in adults. The clinical importance of the increase is unknown.

Gender

No clinically significant difference in pharmacokinetics based on gender.

Indications and Usage

CellCept

In combination with cyclosporine and corticosteroids for prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac, or hepatic transplants.

Myfortic

In combination with cyclosporine and corticosteroids for prophylaxis of organ rejection in patients receiving allogeneic renal transplants.

Unlabeled Uses

Refractory uveitis; second-line therapy for Churg-Strauss syndrome; in combination with prednisolone for treating diffuse proliferative lupus nephritis (mycophenolate mofetil).

Contraindications

Hypersensitivity to mycophenolate mofetil, mycophenolate sodium, mycophenolic acid, or any other component of the product; patients allergic to polysorbate 80 ( Tween ) (IV only).

Dosage and Administration

Renal Transplantation
Adults CellCept

PO/IV 1 g (IV over no less than 2 h) twice daily.

Myfortic

PO 720 mg twice daily on an empty stomach 1 h before or 2 h after food ingestion (max dose in elderly, 720 mg twice daily).

Children CellCept (3 mo to 18 yr of age)

PO 600 mg/m 2 oral suspension twice daily (max daily dose, 2 g per 10 mL). Patients with BSA of 1.25 to 1.5 m 2 may be dosed with 750 mg capsules twice daily. Patients with BSA more than 1.5 m 2 may be dosed with 1 g capsules or tablets twice daily.

Myfortic (5 to 16 yr of age)

PO 400 mg/m 2 twice daily (max dose, 720 mg twice daily). Patients with BSA of 1.19 to 1.58 m 2 may be dosed with 3 Myfortic 180 mg tablets or one 180 mg tablet plus one 360 mg tablet twice daily. Patients with BSA of more than 1.58 m 2 may be dosed either with 4 Myfortic 180 mg tablets or two 360 mg tablets twice daily. Doses for children with BSA less than 1.19 m 2 cannot be accurately administered using currently available formulations of Myfortic tablets.

Cardiac Transplantation
Adults CellCept

PO/IV 1.5 g (IV over no less than 2 h) twice daily.

Hepatic Transplantation
Adults CellCept

PO 1.5 g twice daily. IV 1 g twice daily (over no less than 2 h).

General Advice

  • For use in combination with cyclosporine and corticosteroids.
  • Avoid inhalation and direct contact with skin and mucus membranes of the powder contained in the tablets, capsules, oral suspension, and injection (before and after reconstitution). If accidental skin contact occurs, wash thoroughly with soap and water. If mucus membrane contact occurs, flush thoroughly with water. If eye contact occurs, flush eyes using standard irrigation techniques. If a spill occurs, wipe up using paper towels wetted with water to remove spilled powder or suspension.
  • Oral
  • Two CellCept 500 mg tablets are bioequivalent to 4 CellCept 250 mg capsules; 5 mL of CellCept 200 mg/mL oral suspension is bioequivalent to 4 CellCept 250 mg capsules.
  • Myfortic and CellCept should not be used interchangeably without health care provider supervision because absorption of these products is not equivalent.
  • Myfortic tablets should be swallowed whole and not crushed, chewed, or cut prior to ingesting.
  • Oral suspension contains aspartame, a source of phenylalanine.
  • Administer first dose as soon as possible after transplantation.
  • Administer on an empty stomach, 1 h before or 2 h after food ingestion. May administer CellCept with food if necessary in stable renal transplant patients.
  • Shake suspension well before measuring dose. Measure and administer prescribed dose using supplied oral dispenser. Have patient swallow a glass of water immediately after taking the suspension.
  • Do not mix oral suspension with any other medication.
  • Oral suspension may be administered via nasogastric tube with a minimum size of 8 French.
  • Injection
  • Injection is for patients who are unable to take capsules, tablets, or oral suspension. Injection can be administered for up to 14 days. Switch patients to oral doseform as soon as they can take oral medications.
  • For IV infusion only. Not for intradermal, subcutaneous, IM, IV bolus, or intra-arterial administration.
  • Administer first dose 24 h or less following transplantation.
  • Reconstitute each vial of powder for injection with 14 mL of dextrose 5% injection. Gently shake vial to dissolve drug. Solution should be clear and slightly yellow. Discard vial if particulate matter, cloudiness, or discoloration is noted.
  • For 1 g dose, further dilute contents of 2 reconstituted vials in 140 mL of dextrose 5% injection. For 1.5 g dose, further dilute contents of 3 reconstituted vials in 210 mL of dextrose 5% injection. Final concentration of both solutions is 6 mg/mL.
  • Do not administer if particulate matter, cloudiness, or discoloration noted.
  • Administer reconstituted solution by slow IV infusion over a period of 2 h or more.
  • Discard any unused solution. Do not save for future use.
  • Do not mix with other IV substances or additives, or infuse simultaneously through the same IV line. If the same IV line is used for sequential infusion of different medications, flush line with dextrose 5% injection before and after injection of mycophenolate.

Storage/Stability

Store at 59° to 86°F. Protect from moisture and light. Store reconstituted suspension in refrigerator (36° to 46°F) or at 59° to 86°F. Protect suspension from freezing. Discard any unused suspension after 60 days. Use diluted infusion solution immediately after reconstitution. If not infused immediately after reconstitution, solution may be stored for up to 4 h at room temperature. Discard infusion solution if administration has not been started within 4 h of reconstitution.

Drug Interactions

Acyclovir, ganciclovir, valacyclovir

Possible increased plasma concentrations of each agent, including mycophenolate mofetil. Carefully monitor patients, especially those with renal impairment.

Amoxicillin plus clavulanic acid, ciprofloxacin

Mycophenolic acid concentrations may be reduced 3 days after the start of antibiotic therapy. The decrease tends to diminish within 14 days of starting the antibiotic and ceases within 3 days of stopping the antibiotic. The clinical importance of this change is not known. Monitor the response of the patient. If an interaction is suspected, adjust the mycophenolate dose as needed.

Antacids containing magnesium and aluminum hydroxides

Decreased absorption of mycophenolate; do not administer simultaneously.

Azathioprine

Avoid concomitant use because of potentially increased risk of bone marrow suppression.

Cholestyramine

Decreased mycophenolate plasma concentrations; do not give mycophenolate with cholestyramine or other agents that may interfere with enterohepatic recirculation.

Contraceptives, hormonal

Because hormonal contraceptive efficacy may be decreased, use caution and consider additional birth control methods.

Cyclosporine

Mycophenolic acid trough levels may be decreased because of reduced enterohepatic recirculation. Monitor mycophenolic acid concentrations and response to therapy and adjust the dose as needed.

Drugs that alter GI flora (eg, antibiotics)

May disrupt enterohepatic recirculation and decrease mycophenolic acid absorption.

Iron salts

Following coadministration, mycophenolate absorption and mycophenolic acid AUC were significantly decreased. Avoid coadministration.

Live vaccines

Because vaccinations may be less effective, avoid live attenuated vaccines during mycophenolate treatment.

Metronidazole plus norfloxacin

Mycophenolic acid concentrations may be reduced. Metronidazole plus norfloxacin may have an additive effect on the AUC of mycophenolic acid and mycophenolic acid glucuronide. Avoid coadministration.

Phenytoin

Mycophenolic acid decreased protein binding of phenytoin and may increase free phenytoin levels.

Probenecid

May increase plasma concentrations of mycophenolate.

Rifamycins (eg, rifampin)

Mycophenolic acid plasma concentrations may be reduced, decreasing the efficacy. Closely monitor mycophenolic acid concentrations and adjust the dose as needed. Coadministration of rifampin and mycophenolate is not recommended.

Salicylates

Coadministration increased the free fraction of mycophenolic acid.

Sevelamer

Mycophenolic acid concentrations may be reduced. Administer sevelamer 2 h after mycophenolate mofetil.

Sirolimus, tacrolimus

Mycophenolic acid trough concentrations may be elevated, increasing the risk of adverse reactions. Closely monitor mycophenolic acid concentrations and adjust the dose as needed.

Theophylline

Mycophenolic acid decreased protein binding of theophylline and may increase free theophylline levels.

Adverse Reactions

Cardiovascular

Hypertension (78%); hypotension (33%); CV disorder (26%); tachycardia (22%); angina pectoris, arrhythmia, arterial thrombosis, atrial fibrillation, atrial flutter, bradycardia, CHF, extrasystole, heart arrest, heart failure, increased venous pressure, pallor, palpitation, pericardial effusion, peripheral vascular disorder, postural hypotension, pulmonary hypertension, supraventricular extrasystoles, supraventricular tachycardia, syncope, thrombosis, vasodilatation, vasospasm, ventricular extrasystole, ventricular tachycardia (3% to less than 20%).

CNS

Headache (54%); insomnia (52%); asthenia (43%); tremor (34%); dizziness (29%); anxiety (28%); paresthesia (21%); agitation, confusion, convulsion, delirium, depression, dry mouth, emotional lability, fatigue, hallucinations, hypertonia, hypesthesia, malaise, nervousness, neuropathy, psychosis, somnolence, thinking abnormal, vertigo (3% to less than 20%); progressive multifocal leukoencephalopathy (postmarketing).

Dermatologic

Rash (22%); Candida mucocutaneous (18%); herpes zoster cutaneous disease (10%); acne, alopecia, contusion, cyst, fungal dermatitis, hemorrhage, hirsutism, pruritus, skin benign neoplasm, skin carcinoma, skin disorder, skin hypertrophy, skin ulcer, sweating, vesiculobullous rash (3% to less than 20%); nonmelanoma skin carcinoma (2%).

EENT

Abnormal vision, amblyopia, blurred vision, cataract, conjunctivitis, deafness, ear disorder, ear pain, eye hemorrhage, lacrimation disorder, nasopharyngitis, pharyngitis, pharyngolaryngeal pain, rhinitis, sore throat, tinnitus (3% to less than 20%).

Endocrine

Cushing syndrome, hypothyroidism, parathyroid disorder (3% to less than 20%).

GI

Abdominal pain (63%); nausea (55%); diarrhea (51%); constipation (41%); vomiting (34%); anorexia (25%); dyspepsia (23%); abdominal distension, dysphagia, esophagitis, flatulence, gastritis, gastroenteritis, gastroesophageal reflux disease, GI disorder, GI hemorrhage, GI moniliasis, gingivitis, gum hyperplasia, ileus, infection, loose stool, lower abdominal pain, melena, mouth ulceration, oral moniliasis, peritonitis, rectal disorder, stomach ulcer, stomatitis, upper abdominal pain (3% to less than 20%); colitis, duodenal ulcer, esophagitis, gastric ulcer, intestinal perforation, pancreatitis; intestinal villous atrophy (postmarketing).

Genitourinary

UTI (37%); abnormal kidney function (26%); Candida urinary tract infection (less than 4%); acute kidney failure, albuminuria, bladder spasm, dysuria, hematuria, hydronephrosis, impotence, kidney failure, kidney tubular necrosis, nocturia, oliguria, pain, prostatic disorder, pyelonephritis, renal tubular necrosis, scrotal edema, urinary frequency, urinary incontinence, urinary retention, urinary tract disorder, urine abnormality (3% to less than 20%); BK virus—associated nephropathy (postmarketing).

Hematologic-Lymphatic

Leukopenia (46%); anemia (43%); leukocytosis (41%); thrombocytopenia (38%); hypochromic anemia (25%); leukopenia (21%); severe neutropenia with an absolute neutrophil count (ANC) less than 0.5 × 10 3 /mcL (4%); coagulation disorder, ecchymosis, increased PT and thromboplastin times, lymphocele, pancytopenia, petechia, polycythemia (3% to less than 20%); pure red blood cell aplasia (postmarketing).

Hepatic

Abnormal LFTs (25%); cholangitis, cholestatic jaundice, hepatitis, jaundice, liver damage (3% to less than 20%).

Lab Tests

Increased creatinine (39%); increased BUN (35%); increased lactic dehydrogenase (23%); abnormal lab tests, decreased hemoglobin, (3% to less than 20%).

Local

Phlebitis, thrombosis (4%).

Metabolic-Nutritional

Hyperglycemia (47%); hypercholesterolemia (41%); hypomagnesemia (39%); hypokalemia (37%); hypocalcemia (30%); hyperkalemia (22%); abnormal healing, acidosis, alkaline phosphatase increased, alkalosis, bilirubinemia, dehydration, diabetes mellitus, fluid overload, GGT increased, generalized edema, gout, hypercalcemia, hyperlipidemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypochloremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, hypovolemia, hypoxia, respiratory acidosis, thirst, weight gain, weight loss (3% to less than 20%).

Musculoskeletal

Back pain (47%); arthralgia, joint disorder, limb pain, leg cramps, muscle cramps, myalgia, myasthenia, neck pain, osteoporosis, pelvic pain, peripheral swelling (3% to less than 20%).

Respiratory

Dyspnea, respiratory infection (37%); pleural effusion (34%); increased cough (31%); lung disorder (30%); sinusitis (26%); apnea, asthma, atelectasis, bronchitis, cough, exertional dyspnea, epistaxis, hemoptysis, hiccup, hyperventilation, lung disorder, lung edema, neoplasm, pain, pleural effusion, pneumonia, pneumothorax, respiratory disorder, respiratory moniliasis, sinus congestion, sinusitis, sputum increased, upper respiratory tract infection, voice alteration (3% to less than 20%); interstitial lung disorder including fatal pulmonary fibrosis (postmarketing).

Miscellaneous

Pain (76%); peripheral edema (64%); fever (52%); edema (28%); infection, sepsis (27%); chest pain (26%); ascites, postoperative pain (24%); Candida infection, cytomegalovirus infection (22%); herpes simplex (21%); cytomegalovirus viremia/syndrome (14%); cytomegalovirus tissue invasive disease (12%); fungal infection, herpes zoster (11%); fatal sepsis infection (5%); Aspergillus/Mucor , cryptococcosis, disseminated fungemia, herpes zoster visceral disease, Pneumocystis carinii (less than 4%); Candida albicans infection (2%); lymphoma (1%); abscess, cellulitis, chills with fever, complications of transplant surgery, drug toxicity, enlarged abdomen, face edema, flu syndrome, hemorrhage, hernia, implant infection, lower limb edema, peritonitis, postoperative complications, postoperative wound complication, postprocedural pain, wound infection (3% to less than 20%); atypical mycobacterial infection, congenital malformations, life-threatening infections (eg, infectious carditis, meningitis), tuberculosis (postmarketing)

Precautions

Warnings

Administer under the supervision of a health care provider experienced in immunosuppressive therapy and management of organ transplantation, and in an equipped facility. Increased risk of lymphoma and increased susceptibility to infection may be related to immunosuppression.

Administration is associated with increased risk of pregnancy loss and congenital malformations. Women of childbearing potential must use contraception.


Monitor

Perform CBC weekly during the first month, twice monthly during the second and third months, then monthly through the first year. Monitor patient for signs and symptoms of bacterial, viral, or fungal infections, and for signs and symptoms of organ rejection. Monitor neurological status as needed. Carefully follow patients with severe chronic renal impairment (glomerular filtration rate, less than 25 mL/min per 1.73 m 2 BSA) for potential adverse reactions.


Pregnancy

Category D .

Lactation

Undetermined.

Children

CellCept

Safety and efficacy not established in cardiac or hepatic transplants or in renal transplantation children younger than 3 mo of age.

Myfortic

Safety and efficacy not established in de novo pediatric renal transplant or in stable renal transplant patients younger then 5 yr of age.

Elderly

Use with caution because of the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapy.

Renal Function

CellCept

Do not exceed 2 g/day doses in patients with GFR less than 25 mL/min per 1.73 m 2 ; carefully monitor these patients.

Hepatic Function

No dose adjustments are needed for renal transplant patients with hepatic parenchymal disease. However, it is not known if adjustments are needed for hepatic disease with other etiologies.

Delayed graft function

Occurred in 18.3% of Myfortic -treated patients versus 16.7% of CellCept -treated patients. No dosage adjustment recommended for patients with delayed graft function; however, carefully observe these patients.

GI hemorrhage

GI tract hemorrhage, including perforations, has been observed; administer with caution to patients with active serious digestive system disease.

Hypoxanthine-guanine phosphoribosyl-transferase deficiency

Avoid in patients with hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.

Infection

Oversuppression of the immune system can increase susceptibility to infection, including opportunistic infections, fatal infections, and sepsis. Immunosuppressed patients are at an increased risk for opportunistic infections, including activation of latent viral infections, including progressive multifocal leukoencephalopathy and BK–virus-associated nephropathy. Consider reducing the amount of immunosuppression in patients who develop progressive multifocal leukoencephalopathy and BK–virus-associated nephropathy.

Lymphomas/Malignancies

Patients receiving immunosuppressive regimens involving combinations of drugs are at increased risk of developing lymphomas and other malignancies, particularly of the skin. Risk appears to be related to intensity and duration of immunosuppression rather than to any specific agent.

Neutropenia

Severe neutropenia may occur. If ANC less than 1.3 × 10 3 /mcL develops, interrupt or reduce mycophenolate dose, perform appropriate diagnostic tests, and manage the patient appropriately.

Phenylketonurics

CellCept oral suspension contains aspartame, a source of phenylalanine; use with caution in patient with phenylketonuria.

Pure red cell aplasia

May occur.

Vaccinations

Vaccinations may be less effective; do not administer live attenuated vaccines.

Overdosage

Symptoms

Abdominal pain, diarrhea, dyspepsia, hematological abnormalities (leukopenia, neutropenia), nausea, vomiting.

Patient Information

  • Instruct patients or their caregivers to read the Medication Guide before starting therapy and to reread it with each refill.
  • Advise patient, family, or caregiver that medication will be used in combination with other agents, including cyclosporine and corticosteroids, to achieve maximum benefit.
  • Instruct patient to continue to take other medications prescribed for preventing organ transplant rejection.
  • Instruct patient to notify health care provider immediately if any of the following occur: black, tarry stools; bleeding or unusual bruising; difficulty breathing or unexplained shortness of breath; fever, chills, or other signs of infection; persistent or severe diarrhea; vomiting blood.
  • Advise patient to contact health care provider if bothersome adverse reactions or any unusual problems occur.
  • Instruct patient with increased risk of skin cancer to limit exposure to sunlight and ultraviolet light (eg, tanning beds) by wearing protective clothing and using effective sunscreen.
  • Caution patient that drug may cause drowsiness or dizziness and to use caution while driving or performing other tasks requiring mental alertness or coordination until tolerance is determined.
  • Instruct women of childbearing potential to use 2 effective forms of contraception before starting therapy, during therapy, and for 6 wk following discontinuation of treatment.
  • Ensure that women of childbearing potential have a negative pregnancy test within 1 wk prior to beginning therapy. Do not initiate therapy until negative pregnancy test has been documented.
  • Injection
  • Advise patient or caregiver that medication will be prepared and administered by health care provider until patient can take oral medication.
  • Advise patient that vaccinations may be less effective.
  • Oral
  • Caution patient to avoid inhalation and direct contact with skin and mucus membranes of the powder contained in the tablets and capsules. If accidental skin contact occurs, advise patient to wash thoroughly with soap and water. If mucus membrane contact occurs, advise patient to flush thoroughly with water. If eye contact occurs, advise patient to flush eyes thoroughly with water. If capsules are opened or tablets crushed, advise patient to wipe up using paper towels wetted with water to remove spilled powder or tablet particles.
  • Advise patient to take prescribed dose on an empty stomach, 1 h before or 2 h after food intake.
  • Instruct patient to take Myfortic tablets whole and not crush, chew, or cut the tablets.
  • Advise patient or caregiver using oral suspension to shake suspension well before measuring dose and to use the supplied oral dispenser for measuring and taking dose. Advise patient to follow dose of suspension with a full glass of water to wash all medication into stomach. Caution patient or caregiver not to mix suspension with any other medication.
  • Advise phenylketonuric patients that the oral suspension contains aspartame, a source of phenylalanine (phenylalanine 0.56 mg/mL of suspension).
  • Advise patient that if a dose is missed to take it as soon as remembered. If it is almost time for the next dose, advise patient to skip the missed dose and take the next dose at the regularly scheduled time. Caution patient not to double the dose to catch up.

Copyright © 2009 Wolters Kluwer Health.

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