MYCOPHENOLATE MOFETIL

Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent; inosine monophosphate dehydrogenase (IMPDH) inhibitor. The chemical name for mycophenolate mofetil is 2-Morpholinoethyl ( E )-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-5-phthalanyl)-4-methyl-4-hexenoate. It has a molecular formula of C 23 H 31 NO 7 , a molecular weight of 433.5, and the following structural formula: Mycophenolate mofetil, USP is a white to almost white crystalline powder. It is practically insoluble in water (43 mcg/mL at pH 7.4); the solubility increases in acidic medium (4.27 mg/mL at pH 3.6). It is freely soluble in acetone, soluble in methanol, and sparingly soluble in anhydrous ethanol. The apparent partition coefficient in 1-octanol/water (pH 7.4) buffer solution is 238. The pKa values for mycophenolate mofetil are 5.6 for the morpholino group and 8.5 for the phenolic group. Mycophenolate mofetil is available for oral administration as capsules containing 250 mg of mycophenolate mofetil and tablets containing 500 mg of mycophenolate mofetil. Mycophenolate Mofetil Capsules USP, 250 mg contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn), and sodium lauryl sulfate. The empty gelatin capsule shells contain black iron oxide, FD&C Blue No. 2, gelatin, red iron oxide, titanium dioxide, and yellow iron oxide. In addition, the imprinting ink contains the following: ammonium hydroxide, black iron oxide, propylene glycol, and shellac glaze. Mycophenolate Mofetil Tablets USP, 500 mg contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone, pregelatinized starch (corn), red iron oxide, sodium lauryl sulfate, talc, titanium dioxide and yellow iron oxide. Chemical Structure-Mycophenolate mofetil

Renal, Cardiac, and Hepatic Transplant Mycophenolate mofetil is indicated for the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants. Mycophenolate mofetil should be used concomitantly with cyclosporine and corticosteroids.

Renal Transplantation Adults A dose of 1 g administered orally twice a day (daily dose of 2 g) is recommended for use in renal transplant patients. Although a dose of 1.5 g administered twice daily (daily dose of 3 g) was used in clinical trials and was shown to be safe and effective, no efficacy advantage could be established for renal transplant patients. Patients receiving 2 g/day of mycophenolate mofetil demonstrated an overall better safety profile than did patients receiving 3 g/day of mycophenolate mofetil. Pediatrics (3 Months to 18 years of Age) The recommended dose of mycophenolate mofetil oral suspension is 600 mg/m 2 administered twice daily (up to a maximum daily dose of 2 g/10 mL oral suspension). Patients with a body surface area of 1.25 m 2 to 1.5 m 2 may be dosed with mycophenolate mofetil capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a body surface area > 1.5 m 2 may be dosed with mycophenolate mofetil capsules or tablets at a dose of 1 g twice daily (2 g daily dose). Cardiac Transplantation Adults A dose of 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult cardiac transplant patients. Hepatic Transplantation Adults A dose of 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult hepatic transplant patients. Mycophenolate Mofetil Capsules and Tablets The initial oral dose of mycophenolate mofetil should be given as soon as possible following renal, cardiac or hepatic transplantation. Food had no effect on MPA AUC, but has been shown to decrease MPA C max by 40%. Therefore, it is recommended that mycophenolate mofetil be administered on an empty stomach. However, in stable renal transplant patients, mycophenolate mofetil may be administered with food if necessary. Patients should be instructed to take a missed dose as soon as they remember, except if it is near the next scheduled dose, and then continue to take mycophenolate mofetil at the usual times. Patients with Hepatic Impairment No dose adjustments are recommended for renal patients with severe hepatic parenchymal disease. However, it is not known whether dose adjustments are needed for hepatic disease with other etiologies (see CLINICAL PHARMACOLOGY: Pharmacokinetics ). No data are available for cardiac transplant patients with severe hepatic parenchymal disease. Geriatrics The recommended oral dose of 1 g bid for renal transplant patients, 1.5 g bid for cardiac transplant patients, and 1.5 g bid administered orally in hepatic transplant patients is appropriate for elderly patients (see PRECAUTIONS: Geriatric Use ). Dosage Adjustments In renal transplant patients with severe chronic renal impairment (GFR < 25 mL/min/1.73 m 2 ) outside the immediate posttransplant period, doses of mycophenolate mofetil greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in renal transplant patients experiencing delayed graft function postoperatively (see CLINICAL PHARMACOLOGY: Pharmacokinetics and PRECAUTIONS: Patients with Renal Impairment ). No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment. Mycophenolate mofetil may be used for cardiac or hepatic transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks. If neutropenia develops (ANC < 1.3 x 10 3 /µL), dosing with mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately (see WARNINGS: Neutropenia , ADVERSE REACTIONS , and PRECAUTIONS: Laboratory Tests ).

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

The principal adverse reactions associated with the administration of mycophenolate mofetil include diarrhea, leukopenia, sepsis, vomiting, and there is evidence of a higher frequency of certain types of infections e.g., opportunistic infection (see WARNINGS: Serious Infections and WARNINGS: New or Reactivated Viral Infections ). Mycophenolate Mofetil Oral The incidence of adverse events for mycophenolate mofetil was determined in randomized, comparative, double-blind trials in prevention of rejection in renal (two active, one placebo-controlled trials), cardiac (one active-controlled trial), and hepatic (one active-controlled trial) transplant patients. Geriatrics Elderly patients (≥ 65 years), particularly those who are receiving mycophenolate mofetil as part of a combination immunosuppressive regimen, may be at increased risk of certain infections (including cytomegalovirus [CMV] tissue invasive disease) and possibly gastrointestinal hemorrhage and pulmonary edema, compared to younger individuals (see PRECAUTIONS ). Safety data are summarized below for all active-controlled trials in renal (two trials), cardiac (one trial), and hepatic (one trial) transplant patients. Approximately 53% of the renal patients, 65% of the cardiac patients, and 48% of the hepatic patients have been treated for more than one year. Adverse events reported in ≥ 20% of patients in the mycophenolate mofetil treatment groups are presented below. Table 9: Adverse Events in Controlled Studies in Prevention of Renal, Cardiac or Hepatic Allograft Rejection (Reported in ≥ 20% of Patients in the Mycophenolate Mofetil Group) Renal Studies Cardiac Study Hepatic Study Mycophenolate Mofetil 2 g/day Mycophenolate Mofetil 3 g/day Azathioprine 1 to 2 mg/kg/day or 100 to 150 mg/day Mycophenolate Mofetil 3 g/day Azathioprine 1.5 to 3 mg/kg/day Mycophenolate Mofetil 3 g/day Azathioprine 1 to 2 mg/kg/day (n = 336) (n = 330) (n = 326) (n = 289) (n = 289) (n = 277) (n = 287) % % % % % % % Body as a Whole Pain 33 31.2 32.2 75.8 74.7 74 77.7 Abdominal pain 24.7 27.6 23 33.9 33.2 62.5 51.2 Fever 21.4 23.3 23.3 47.4 46.4 52.3 56.1 Headache 21.1 16.1 21.2 54.3 51.9 53.8 49.1 Infection 18.2 20.9 19.9 25.6 19.4 27.1 25.1 Sepsis - - - - - 27.4 26.5 Asthenia - - - 43.3 36.3 35.4 33.8 Chest pain - - - 26.3 26 - - Back pain - - - 34.6 28.4 46.6 47.4 Ascites - - - - - 24.2 22.6 Hematologic and Lymphatic Anemia 25.6 25.8 23.6 42.9 43.9 43 53 Leukopenia 23.2 34.5 24.8 30.4 39.1 45.8 39 Thrombocytopenia - - - 23.5 27 38.3 42.2 Hypochromic anemia - - - 24.6 23.5 - - Leukocytosis - - - 40.5 35.6 22.4 21.3 Urogenital Urinary tract infection 37.2 37 33.7 - - - - Kidney function abnormal - - - 21.8 26.3 25.6 28.9 Cardiovascular Hypertension 32.4 28.2 32.2 77.5 72.3 62.1 59.6 Hypotension - - - 32.5 36 - - Cardiovascular disorder - - - 25.6 24.2 - - Tachycardia - - - 20.1 18 22 15.7 Metabolic and Nutritional Peripheral edema 28.6 27 28.2 64 53.3 48.4 47.7 Hypercholesteremia - - - 41.2 38.4 - - Edema - - - 26.6 25.6 28.2 28.2 Hypokalemia - - - 31.8 25.6 37.2 41.1 Hyperkalemia - - - - - 22 23.7 Hyperglycemia - - - 46.7 52.6 43.7 48.8 Creatinine increased - - - 39.4 36 - - BUN increased - - - 34.6 32.5 - - Lactic dehydrogenase increased - - - 23.2 17 - - Hypomagnesemia - - - - - 39 37.6 Hypocalcemia - - - - - 30 30 Digestive Diarrhea 31 36.1 20.9 45.3 34.3 51.3 49.8 Constipation 22.9 18.5 22.4 41.2 37.7 37.9 38.3 Nausea 19.9 23.6 24.5 54 54.3 54.5 51.2 Dyspepsia - - - - - 22.4 20.9 Vomiting - - - 33.9 28.4 32.9 33.4 Anorexia - - - - - 25.3 17.1 Liver function tests abnormal - - - - - 24.9 19.2 Respiratory Infection 22 23.9 19.6 37 35.3 - - Dyspnea - - - 36.7 36.3 31 30.3 Cough increased - - - 31.1 25.6 - - Lung disorder - - - 30.1 29.1 22 18.8 Sinusitis - - - 26 19 - - Pleural effusion - - - - - 34.3 35.9 Skin and Appendages Rash - - - 22.1 18 - - Nervous System Tremor - - - 24.2 23.9 33.9 35.5 Insomnia - - - 40.8 37.7 52.3 47 Dizziness - - - 28.7 27.7 - - Anxiety - - - 28.4 23.9 - - Paresthesia - - - 20.8 18 - - The placebo-controlled renal transplant study generally showed fewer adverse events occurring in ≥ 20% of patients. In addition, those that occurred were not only qualitatively similar to the azathioprine-controlled renal transplant studies, but also occurred at lower rates, particularly for infection, leukopenia, hypertension, diarrhea and respiratory infection. The above data demonstrate that in three controlled trials for prevention of renal rejection, patients receiving 2 g/day of mycophenolate mofetil had an overall better safety profile than did patients receiving 3 g/day of mycophenolate mofetil. The above data demonstrate that the types of adverse events observed in multicenter controlled trials in renal, cardiac, and hepatic transplant patients are qualitatively similar except for those that are unique to the specific organ involved. Sepsis, which was generally CMV viremia, was slightly more common in renal transplant patients treated with mycophenolate mofetil compared to patients treated with azathioprine. The incidence of sepsis was comparable in mycophenolate mofetil and in azathioprine-treated patients in cardiac and hepatic studies. In the digestive system, diarrhea was increased in renal and cardiac transplant patients receiving mycophenolate mofetil compared to patients receiving azathioprine, but was comparable in hepatic transplant patients treated with mycophenolate mofetil or azathioprine. Patients receiving mycophenolate mofetil alone or as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see WARNINGS: Lymphoma and Malignancy ). The incidence of malignancies among the 1,483 patients treated in controlled trials for the prevention of renal allograft rejection who were followed for ≥ 1 year was similar to the incidence reported in the literature for renal allograft recipients. Lymphoproliferative disease or lymphoma developed in 0.4% to 1% of patients receiving mycophenolate mofetil (2 g or 3 g daily) with other immunosuppressive agents in controlled clinical trials of renal, cardiac, and hepatic transplant patients followed for at least one year (see WARNINGS: Lymphoma and Malignancy ). Non-melanoma skin carcinomas occurred in 1.6% to 4.2% of patients, other types of malignancy in 0.7% to 2.1% of patients. Three-year safety data in renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the one year data. In pediatric patients, no other malignancies besides lymphoproliferative disorder (2/148 patients) have been observed. Severe neutropenia (ANC < 0.5 x 10 3 /µL) developed in up to 2% of renal transplant patients, up to 2.8% of cardiac transplant patients and up to 3.6% of hepatic transplant patients receiving mycophenolate mofetil 3 g daily (see WARNINGS: Neutropenia , PRECAUTIONS: Laboratory Tests and DOSAGE AND ADMINISTRATION ). All transplant patients are at increased risk of opportunistic infections. The risk increases with total immunosuppressive load (see WARNINGS: Serious Infections and WARNINGS: New or Reactivated Viral Infections ). Table 10 shows the incidence of opportunistic infections that occurred in the renal, cardiac, and hepatic transplant populations in the azathioprine-controlled prevention trials. Table 10: Viral and Fungal Infections in Controlled Studies in Prevention of Renal, Cardiac or Hepatic Transplant Rejection Renal Studies Cardiac Study Hepatic Study Mycophenolate Mofetil 2 g/day Mycophenolate Mofetil 3 g/day Azathioprine 1 to 2 mg/kg/day or 100 to 150 mg/day Mycophenolate Mofetil 3 g/day Azathioprine 1.5 to 3 mg/kg/day Mycophenolate Mofetil 3 g/day Azathioprine 1 to 2 mg/kg/day (n = 336) (n = 330) (n = 326) (n = 289) (n = 289) (n = 277) (n = 287) % % % % % % % Herpes simplex 16.7 20 19 20.8 14.5 10.1 5.9 CMV - Viremia/syndrome 13.4 12.4 13.8 12.1 10 14.1 12.2 - Tissue invasive disease 8.3 11.5 6.1 11.4 8.7 5.8 8 Herpes zoster 6 7.6 5.8 10.7 5.9 4.3 4.9 - Cutaneous disease 6 7.3 5.5 10 5.5 4.3 4.9 Candida 17 17.3 18.1 18.7 17.6 22.4 24.4 - Mucocutaneous 15.5 16.4 15.3 18 17.3 18.4 17.4 The following other opportunistic infections occurred with an incidence of less than 4% in mycophenolate mofetil patients in the above azathioprine-controlled studies: Herpes zoster, visceral disease; Candida, urinary tract infection, fungemia/disseminated disease, tissue invasive disease; Cryptococcosis; Aspergillus/Mucor; Pneumocystis carinii. In the placebo-controlled renal transplant study, the same pattern of opportunistic infection was observed compared to the azathioprine-controlled renal studies, with a notably lower incidence of the following: Herpes simplex and CMV tissue-invasive disease. In patients receiving mycophenolate mofetil (2 g or 3 g) in controlled studies for prevention of renal, cardiac or hepatic rejection, fatal infection/sepsis occurred in approximately 2% of renal and cardiac patients and in 5% of hepatic patients (see WARNINGS: Serious Infections ). In cardiac transplant patients, the overall incidence of opportunistic infections was approximately 10% higher in patients treated with mycophenolate mofetil than in those receiving azathioprine, but this difference was not associated with excess mortality due to infection/sepsis among patients treated with mycophenolate mofetil. The following adverse events were reported with 3% to < 20% incidence in renal, cardiac, and hepatic transplant patients treated with mycophenolate mofetil, in combination with cyclosporine and corticosteroids. Table 11: Adverse Events Reported in 3% to < 20% of Patients Treated With Mycophenolate Mofetil in Combination With Cyclosporine and Corticosteroids Body System Body as a Whole abdomen enlarged, abscess, accidental injury, cellulitis, chills occurring with fever, cyst, face edema, flu syndrome, hemorrhage, hernia, lab test abnormal, malaise, neck pain, pelvic pain, peritonitis Hematologic and Lymphatic coagulation disorder, ecchymosis, pancytopenia, petechia, polycythemia, prothrombin time increased, thromboplastin time increased Urogenital acute kidney failure, albuminuria, dysuria, hydronephrosis, hematuria, impotence, kidney failure, kidney tubular necrosis, nocturia, oliguria, pain, prostatic disorder, pyelonephritis, scrotal edema, urine abnormality, urinary frequency, urinary incontinence, urinary retention, urinary tract disorder Cardiovascular angina pectoris, arrhythmia, arterial thrombosis, atrial fibrillation, atrial flutter, bradycardia, cardiovascular disorder, congestive heart failure, extrasystole, heart arrest, heart failure, hypotension, pallor, palpitation, pericardial effusion, peripheral vascular disorder, postural hypotension, pulmonary hypertension, supraventricular tachycardia, supraventricular extrasystoles, syncope, tachycardia, thrombosis, vasodilatation, vasospasm, ventricular extrasystole, ventricular tachycardia, venous pressure increased Metabolic and Nutritional abnormal healing, acidosis, alkaline phosphatase increased, alkalosis, bilirubinemia, creatinine increased, dehydration, gamma glutamyl transpeptidase increased, generalized edema, gout, hypercalcemia, hypercholesteremia, hyperlipemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypochloremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, hypovolemia, hypoxia, lactic dehydrogenase increased, respiratory acidosis, SGOT increased, SGPT increased, thirst, weight gain, weight loss Digestive anorexia, cholangitis, cholestatic jaundice, dysphagia, esophagitis, flatulence, gastritis, gastroenteritis, gastrointestinal disorder, gastrointestinal hemorrhage, gastrointestinal moniliasis, gingivitis, gum hyperplasia, hepatitis, ileus, infection, jaundice, liver damage, liver function tests abnormal, melena, mouth ulceration, nausea and vomiting, oral moniliasis, rectal disorder, stomach ulcer, stomatitis Respiratory apnea, asthma, atelectasis, bronchitis, epistaxis, hemoptysis, hiccup, hyperventilation, lung edema, lung disorder, neoplasm, pain, pharyngitis, pleural effusion, pneumonia, pneumothorax, respiratory disorder, respiratory moniliasis, rhinitis, sinusitis, sputum increased, voice alteration Skin and Appendages acne, alopecia, fungal dermatitis, hemorrhage, hirsutism, pruritus, rash, skin benign neoplasm, skin carcinoma, skin disorder, skin hypertrophy, skin ulcer, sweating, vesiculobullous rash Nervous agitation, anxiety, confusion, convulsion, delirium, depression, dry mouth, emotional lability, hallucinations, hypertonia, hypesthesia, nervousness, neuropathy, paresthesia, psychosis, somnolence, thinking abnormal, vertigo Endocrine Cushing’s syndrome, diabetes mellitus, hypothyroidism, parathyroid disorder Musculoskeletal arthralgia, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis Special Senses abnormal vision, amblyopia, cataract (not specified), conjunctivitis, deafness, ear disorder, ear pain, eye hemorrhage, tinnitus, lacrimation disorder Pediatrics The type and frequency of adverse events in a clinical study in 100 pediatric patients 3 months to 18 years of age dosed with mycophenolate mofetil oral suspension 600 mg/m 2 bid (up to 1 g bid) were generally similar to those observed in adult patients dosed with mycophenolate mofetil capsules at a dose of 1 g bid with the exception of abdominal pain, fever, infection, pain, sepsis, diarrhea, vomiting, pharyngitis, respiratory tract infection, hypertension, leukopenia, and anemia, which were observed in a higher proportion in pediatric patients. Postmarketing Experience Congenital Disorders Embryofetal Toxicity Congenital malformations, including ear, facial, cardiac and nervous system malformations and an increased incidence of first trimester pregnancy loss have been reported following exposure to mycophenolate mofetil during pregnancy (see PRECAUTIONS: Pregnancy ). Digestive Colitis (sometimes caused by cytomegalovirus), pancreatitis, isolated cases of intestinal villous atrophy. Hematologic and Lymphatic Cases of pure red cell aplasia (PRCA) and hypogammaglobulinemia have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressive agents. Infections (see WARNINGS: Serious Infections and WARNINGS: New or Reactivated Viral Infections ). Serious life-threatening infections such as meningitis and infectious endocarditis have been reported occasionally. There is evidence of a higher frequency of certain types of serious infections such as tuberculosis and atypical mycobacterial infection. Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with mycophenolate mofetil. The reported cases generally had risk factors for PML, including treatment with immunosuppressant therapies and impairment of immune function. Polyomavirus associated neuropathy (PVAN), especially due to BK virus infection, has been observed in patients receiving immunosuppressants, including mycophenolate mofetil. This infection is associated with serious outcomes, including deteriorating renal function and renal graft loss. Viral reactivation has been reported in patients infected with HBV or HCV. Respiratory Interstitial lung disorders, including fatal pulmonary fibrosis, have been reported rarely and should be considered in the differential diagnosis of pulmonary symptoms ranging from dyspnea to respiratory failure in posttransplant patients receiving mycophenolate mofetil.

Drug interaction studies with mycophenolate mofetil have been conducted with acyclovir, antacids, cholestyramine, cyclosporine, ganciclovir, oral contraceptives, sevelamer, trimethoprim/sulfamethoxazole, norfloxacin, and metronidazole. Drug interaction studies have not been conducted with other drugs that may be commonly administered to renal, cardiac or hepatic transplant patients. Mycophenolate mofetil has not been administered concomitantly with azathioprine. Acyclovir Coadministration of mycophenolate mofetil (1 g) and acyclovir (800 mg) to 12 healthy volunteers resulted in no significant change in MPA AUC and C max . However, MPAG and acyclovir plasma AUCs were increased 10.6% and 21.9%, respectively. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are acyclovir concentrations, the potential exists for mycophenolate and acyclovir or its prodrug (e.g., valacyclovir) to compete for tubular secretion, further increasing the concentrations of both drugs. Antacids with Magnesium and Aluminum Hydroxides Absorption of a single dose of mycophenolate mofetil (2 g) was decreased when administered to ten rheumatoid arthritis patients also taking Maalox ®† TC (10 mL qid). The C max and AUC (0-24h) for MPA were 33% and 17% lower, respectively, than when mycophenolate mofetil was administered alone under fasting conditions. Mycophenolate mofetil may be administered to patients who are also taking antacids containing magnesium and aluminum hydroxides; however, it is recommended that mycophenolate mofetil and the antacid not be administered simultaneously. Proton Pump Inhibitors (PPIs) Coadministration of PPIs (e.g., lansoprazole, pantoprazole) in single doses to healthy volunteers and multiple doses to transplant patients receiving mycophenolate mofetil has been reported to reduce the exposure to mycophenolic acid (MPA). An approximate reduction of 30% to 70% in the C max and 25% to 35% in the AUC of MPA has been observed, possibly due to a decrease in MPA solubility at an increased gastric pH. The clinical impact of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and mycophenolate mofetil. Because clinical relevance has not been established, PPIs should be used with caution when coadministered to transplant patients being treated with mycophenolate mofetil. Cholestyramine Following single-dose administration of 1.5 g mycophenolate mofetil to 12 healthy volunteers pretreated with 4 g tid of cholestyramine for 4 days, MPA AUC decreased approximately 40%. This decrease is consistent with interruption of enterohepatic recirculation which may be due to binding of recirculating MPAG with cholestyramine in the intestine. Therefore, mycophenolate mofetil is not recommended to be given with cholestyramine or other agents that may interfere with enterohepatic recirculation. Cyclosporine Cyclosporine (Sandimmune ®† ) pharmacokinetics (at doses of 275 to 415 mg/day) were unaffected by single and multiple doses of 1.5 g bid of mycophenolate mofetil in ten stable renal transplant patients. The mean (± SD) AUC (0-12h) and C max of cyclosporine after 14 days of multiple doses of mycophenolate mofetil were 3290 (± 822) ng•h/mL and 753 (± 161) ng/mL, respectively, compared to 3245 (± 1088) ng•h/mL and 700 (± 246) ng/mL, respectively, one week before administration of mycophenolate mofetil. Cyclosporine A interferes with MPA enterohepatic recirculation. In renal transplant patients, mean MPA exposure (AUC 0-12h ) was approximately 30% to 50% greater when mycophenolate mofetil is administered without cyclosporine compared with when mycophenolate mofetil is coadministered with cyclosporine. This interaction is due to cyclosporine inhibition of multidrug-resistance-associated protein 2 (MRP-2) transporter in the biliary tract, thereby preventing the excretion of MPAG into the bile that would lead to enterohepatic recirculation of MPA. This information should be taken into consideration when mycophenolate mofetil is used without cyclosporine; changes in MPA exposure should be expected when switching patients from cyclosporine A to one of the immunosuppressants which do not interfere with MPA’s enterohepatic cycle (e.g., tacrolimus; belatacept). Telmisartan Concommitant administration of telmisartan and mycophenolate mofetil resulted in an approximately 30% decrease in mycophenolic acid (MPA) concentrations. Telmisartan changes MPA’s elimination by enhancing PPAR gamma (peroxisome proliferator-activated receptor gamma) expression, which in turn results in an enhanced UGT1A9 expression and activity. Ganciclovir Following single-dose administration to 12 stable renal transplant patients, no pharmacokinetic interaction was observed between mycophenolate mofetil (1.5 g) and intravenous ganciclovir (5 mg/kg). Mean (± SD) ganciclovir AUC and C max (n = 10) were 54.3 (± 19) mcg•h/mL and 11.5 (± 1.8) mcg/mL, respectively, after coadministration of the two drugs, compared to 51 (± 17) mcg•h/mL and 10.6 (± 2) mcg/mL, respectively, after administration of intravenous ganciclovir alone. The mean (± SD) AUC and C max of MPA (n = 12) after coadministration were 80.9 (± 21.6) mcg•h/mL and 27.8 (± 13.9) mcg/mL, respectively, compared to values of 80.3 (± 16.4) mcg•h/mL and 30.9 (± 11.2) mcg/mL, respectively, after administration of mycophenolate mofetil alone. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are ganciclovir concentrations, the two drugs will compete for tubular secretion and thus further increases in concentrations of both drugs may occur. In patients with renal impairment in which mycophenolate mofetil and ganciclovir or its prodrug (e.g., valganciclovir) are coadministered, patients should be monitored carefully. Oral Contraceptives A study of coadministration of mycophenolate mofetil (1 g bid) and combined oral contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.20 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) was conducted in 18 women with psoriasis over three consecutive menstrual cycles. Mean AUC (0-24h) was similar for ethinylestradiol and 3-keto desogestrel; however, mean levonorgestrel AUC (0-24h) significantly decreased by about 15%. There was large inter-patient variability (% CV in the range of 60% to 70%) in the data, especially for ethinylestradiol. Mean serum levels of LH, FSH and progesterone were not significantly affected. Mycophenolate mofetil may not have any influence on the ovulation-suppressing action of the studied oral contraceptives. It is recommended to coadminister mycophenolate mofetil with hormonal contraceptives (e.g., birth control pill, transdermal patch, vaginal ring, injection, and implant) with caution and additional barrier contraceptive methods must be used (see PRECAUTIONS: Pregnancy Exposure Prevention and Planning ). Sevelamer Concomitant administration of sevelamer and mycophenolate mofetil in adult and pediatric patients decreased the mean MPA C max and AUC 0-12h by 36% and 26% respectively. This data suggest that sevelamer and other calcium free phosphate binders should not be administered simultaneously with mycophenolate mofetil. Alternatively, it is recommended that sevelamer and other calcium free phosphate binders preferentially could be given 2 hours after mycophenolate mofetil intake to minimize the impact on the absorption of MPA. Trimethoprim/Sulfamethoxazole Following single-dose administration of mycophenolate mofetil (1.5 g) to 12 healthy male volunteers on day 8 of a 10 day course of trimethoprim 160 mg/sulfamethoxazole 800 mg administered bid, no effect on the bioavailability of MPA was observed. The mean (± SD) AUC and C max of MPA after concomitant administration were 75.2 (± 19.8) mcg•h/mL and 34 (± 6.6) mcg/mL, respectively, compared to 79.2 (± 27.9) mcg•h/mL and 34.2 (± 10.7) mcg/mL, respectively, after administration of mycophenolate mofetil alone. Norfloxacin and Metronidazole Following single-dose administration of mycophenolate mofetil (1 g) to 11 healthy volunteers on day 4 of a 5 day course of a combination of norfloxacin and metronidazole, the mean MPA AUC 0-48h was significantly reduced by 33% compared to the administration of mycophenolate mofetil alone (p< 0.05). Therefore, mycophenolate mofetil is not recommended to be given with the combination of norfloxacin and metronidazole. There was no significant effect on mean MPA AUC 0-48h when mycophenolate mofetil was concomitantly administered with norfloxacin or metronidazole separately. The mean (± SD) MPA AUC 0-48h after coadministration of mycophenolate mofetil with norfloxacin or metronidazole separately was 48.3 (± 24) mcg•h/mL and 42.7 (± 23) mcg•h/mL, respectively, compared with 56.2 (± 24) mcg•h/mL after administration of mycophenolate mofetil alone. Ciprofloxacin and Amoxicillin plus Clavulanic Acid A total of 64 mycophenolate mofetil-treated renal transplant recipients received either oral ciprofloxacin 500 mg bid or amoxicillin plus clavulanic acid 375 mg tid for 7 days or at least 14 days. Approximately 50% reductions in median trough MPA concentrations (pre-dose) from baseline (mycophenolate mofetil alone) were observed in 3 days following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. These reductions in trough MPA concentrations tended to diminish within 14 days of antibiotic therapy and ceased within 3 days after discontinuation of antibiotics. The postulated mechanism for this interaction is an antibiotic-induced reduction in glucuronidase-possessing enteric organisms leading to a decrease in enterohepatic recirculation of MPA. The change in trough level may not accurately represent changes in overall MPA exposure; therefore, clinical relevance of these observations is unclear. Rifampin In a single heart-lung transplant patient, after correction for dose, a 67% decrease in MPA exposure (AUC 0-12h ) has been observed with concomitant administration of mycophenolate mofetil and rifampin. Therefore, mycophenolate mofetil is not recommended to be given with rifampin concomitantly unless the benefit outweighs the risk. Other Interactions The measured value for renal clearance of MPAG indicates removal occurs by renal tubular secretion as well as glomerular filtration. Consistent with this, coadministration of probenecid, a known inhibitor of tubular secretion, with mycophenolate mofetil in monkeys results in a 3-fold increase in plasma MPAG AUC and a 2-fold increase in plasma MPA AUC. Thus, other drugs known to undergo renal tubular secretion may compete with MPAG and thereby raise plasma concentrations of MPAG or the other drug undergoing tubular secretion. Drugs that alter the gastrointestinal flora may interact with mycophenolate mofetil by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. Live Vaccines During treatment with mycophenolate mofetil, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective (see PRECAUTIONS: Immunizations ). Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.

Storage and Handling Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Dispense a Medication Guide with each prescription.