Mycophenolate Mofetil (Capsule)
Renal Transplantation:<br/>Adults: A dose of 1 g administered orally or intravenously (over NO LESS THAN 2 HOURS) 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.<br/>Pediatrics (3 months to 18 years of age): The recommended dose of mycophenolate mofetil oral suspension is 600 mg/madministered twice daily (up to a maximum daily dose of 2 g/10 mL oral suspension). Patients with a body surface area of 1.25 m2 to 1.5 m2 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 mmay be dosed with mycophenolate mofetil capsules or tablets at a dose of 1 g twice daily (2 g daily dose).<br/>Cardiac Transplantation:<br/>Adults: A dose of 1.5 g bid administered intravenously (over NO LESS THAN 2 HOURS) or 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult cardiac transplant patients.<br/>Hepatic Transplantation:<br/>Adults: A dose of 1 g bid administered intravenously (over NO LESS THAN 2 HOURS) or 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult hepatic transplant patients.<br/>Mycophenolate Mofetil Capsules, Tablets, and Oral Suspension: 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 Cby 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.<br/>Note: If required, mycophenolate mofetil oral suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter).<br/>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 . No data are available for cardiac transplant patients with severe hepatic parenchymal disease.<br/>Geriatrics: The recommended oral dose of 1 g bid for renal transplant patients, 1.5 g bid for cardiac transplant patients, and 1 g bid administered intravenously or 1.5 g bid administered orally in hepatic transplant patients is appropriate for elderly patients .<br/>Mycophenolate Mofetil Intravenous:<br/>Adults: Mycophenolate mofetil intravenous is an alternative dosage form to mycophenolate mofetil capsules, tablets and oral suspension recommended for patients unable to take oral mycophenolate mofetil. Mycophenolate mofetil intravenous should be administered within 24 hours following transplantation. Mycophenolate mofetil intravenous can be administered for up to 14 days; patients should be switched to oral mycophenolate mofetil as soon as they can tolerate oral medication. Mycophenolate mofetil intravenous must be reconstituted and diluted to a concentration of 6 mg/mL using 5% Dextrose Injection USP. Mycophenolate mofetil intravenous is incompatible with other intravenous infusion solutions. Following reconstitution, mycophenolate mofetil intravenous must be administeredby slow intravenous infusion over a period of NO LESS THAN 2 HOURS by either peripheral or central vein. CAUTION: MYCOPHENOLATE MOFETIL INTRAVENOUS SOLUTION SHOULD NEVER BE ADMINISTERED BY RAPID OR BOLUS INTRAVENOUS INJECTION (see WARNINGS).<br/>Dosage Adjustments: In renal transplant patients with severe chronic renal impairment (GFR<25 mL/min/1.73 m) 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 . 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��10/��L), dosing with mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately .
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 (MMF) is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate. It has a molecular formula of CHNO, a molecular weight of 433.50, and the following structural formula: Mycophenolate mofetil is a white to off-white crystalline powder. It is slightly soluble in water (43��g/mL at pH 7.4); the solubility increases in acidic medium (4.27 mg/mL at pH 3.6). It is freely soluble in acetone, soluble in methanol, and sparingly soluble in ethanol. The apparent partition coefficient in 1-octanol/water (pH 7.4) buffer solution is 238. The pKa values for 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. In addition, each capsule contains the following inactive ingredients: croscarmellose sodium, FD&C blue #2, gelatin, magnesium stearate, povidone (K-90), pregelatinized starch and titanium dioxide. The capsule is printed with edible black ink. The black ink is comprised of butyl alcohol, black iron oxide, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac and strong ammonia solution.
Mechanism of Action: Mycophenolate mofetil has been demonstrated in experimental animal models to prolong the survival of allogeneic transplants (kidney, heart, liver, intestine, limb, small bowel, pancreatic islets, and bone marrow). Mycophenolate mofetil has also been shown to reverse ongoing acute rejection in the canine renal and rat cardiac allograft models. Mycophenolate mofetil also inhibited proliferative arteriopathy in experimental models of aortic and cardiac allografts in rats, as well as in primate cardiac xenografts. Mycophenolate mofetil was used alone or in combination with other immunosuppressive agents in these studies. Mycophenolate mofetil has been demonstrated to inhibit immunologically mediated inflammatory responses in animal models and to inhibit tumor development and prolong survival in murine tumor transplant models. Mycophenolate mofetil is rapidly absorbed following oral administration and hydrolyzed to form MPA, which is the active metabolite. MPA is a potent, selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines, whereas other cell types can utilize salvage pathways, MPA has potent cytostatic effects on lymphocytes. MPA inhibits proliferative responses of T- and B-lymphocytes to both mitogenic and allospecific stimulation. Addition of guanosine or deoxyguanosine reverses the cytostatic effects of MPA on lymphocytes. MPA also suppresses antibody formation by B-lymphocytes. MPA prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved in intercellular adhesion to endothelial cells and may inhibit recruitment of leukocytes into sites of inflammation and graft rejection. Mycophenolate mofetil did not inhibit early events in the activation of human peripheral blood mononuclear cells, such as the production of interleukin-1 (IL-1) and interleukin-2 (IL-2), but did block the coupling of these events to DNA synthesis and proliferation.<br/>Pharmacokinetics: Following oral and intravenous administration, mycophenolate mofetil undergoes rapid and complete metabolism to MPA, the active metabolite. Oral absorption of the drug is rapid and essentially complete. MPA is metabolized to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. The parent drug, mycophenolate mofetil, can be measured systemically during the intravenous infusion; however, shortly (about 5 minutes) after the infusion is stopped or after oral administration, MMF concentration is below the limit of quantitation (0.4��g/mL).<br/>Absorption: In 12 healthy volunteers, the mean absolute bioavailability of oral mycophenolate mofetil relative to intravenous mycophenolate mofetil (based on MPA AUC) was 94%. The area under the plasma-concentration time curve (AUC) for MPA appears to increase in a dose-proportional fashion in renal transplant patients receiving multiple doses of mycophenolate mofetil up to a daily dose of 3 g (see Table 1). Food (27 g fat, 650 calories) had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g bid to renal transplant patients. However, MPA Cwas decreased by 40% in the presence of food .<br/>Distribution: The mean (��SD) apparent volume of distribution of MPA in 12 healthy volunteers is approximately 3.6 (��1.5) and 4 (��1.2) L/kg following intravenous and oral administration, respectively. MPA, at clinically relevant concentrations, is 97% bound to plasma albumin. MPAG is 82% bound to plasma albumin at MPAG concentration ranges that are normally seen in stable renal transplant patients; however, at higher MPAG concentrations (observed in patients with renal impairment or delayed renal graft function), the binding of MPA may be reduced as a result of competition between MPAG and MPA for protein binding. Mean blood to plasma ratio of radioactivity concentrations was approximately 0.6 indicating that MPA and MPAG do not extensively distribute into the cellular fractions of blood. In vitro studies to evaluate the effect of other agents on the binding of MPA to human serum albumin (HSA) or plasma proteins showed that salicylate (at 25 mg/dL with HSA) and MPAG (at���460��g/mL with plasma proteins) increased the free fraction of MPA. At concentrations that exceeded what is encountered clinically, cyclosporine, digoxin, naproxen, prednisone, propranolol, tacrolimus, theophylline, tolbutamide, and warfarin did not increase the free fraction of MPA. MPA at concentrations as high as 100��g/mL had little effect on the binding of warfarin, digoxin or propranolol, but decreased the binding of theophylline from 53% to 45% and phenytoin from 90% to 87%.<br/>Metabolism: Following oral and intravenous dosing, mycophenolate mofetil undergoes complete metabolism to MPA, the active metabolite. Metabolism to MPA occurs presystemically after oral dosing. MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. In vivo, MPAG is converted to MPA via enterohepatic recirculation. The following metabolites of the 2-hydroxyethyl-morpholino moiety are also recovered in the urine following oral administration of mycophenolate mofetil to healthy subjects: N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine. Secondary peaks in the plasma MPA concentration-time profile are usually observed 6 to 12 hours postdose. The coadministration of cholestyramine (4 g tid) resulted in approximately a 40% decrease in the MPA AUC (largely as a consequence of lower concentrations in the terminal portion of the profile). These observations suggest that enterohepatic recirculation contributes to MPA plasma concentrations. Increased plasma concentrations of mycophenolate mofetil metabolites (MPA 50% increase and MPAG about a 3-fold to 6-fold increase) are observed in patients with renal insufficiency .<br/>Excretion: Negligible amount of drug is excreted as MPA (<1% of dose) in the urine. Orally administered radiolabeled mycophenolate mofetil resulted in complete recovery of the administered dose, with 93% of the administered dose recovered in the urine and 6% recovered in feces. Most (about 87%) of the administered dose is excreted in the urine as MPAG. At clinically encountered concentrations, MPA and MPAG are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (>100��g/mL), small amounts of MPAG are removed. Bile acid sequestrants, such as cholestyramine, reduce MPA AUC by interfering with enterohepatic circulation of the drug . Mean (��SD) apparent half-life and plasma clearance of MPA are 17.9 (��6.5) hours and 193 (��48) mL/min following oral administration. and 16.6 (��5.8) hours and 177 (��31) mL/min following intravenous administration, respectively.<br/>Pharmacokinetics in Healthy Volunteers, Renal, Cardiac, and Hepatic Transplant Patients: Shown below are the mean (��SD) pharmacokinetic parameters for MPA following the administration of mycophenolate mofetil given as single doses to healthy volunteers and multiple doses to renal, cardiac, and hepatic transplant patients. In the early posttransplant period (<40 days posttransplant), renal, cardiac, and hepatic transplant patients had mean MPA AUCs approximately 20% to 41% lower and mean Capproximately 32% to 44% lower compared to the late transplant period (3 to 6 months posttransplant). Mean MPA AUC values following administration of 1 g bid intravenous mycophenolate mofetil over 2 hours to renal transplant patients for 5 days were about 24% higher than those observed after oral administration of a similar dose in the immediate posttransplant phase. In hepatic transplant patients, administration of 1 g bid intravenous mycophenolate mofetil followed by 1.5 g bid oral mycophenolate mofetil resulted in mean MPA AUC values similar to those found in renal transplant patientsadministered 1 g mycophenolate mofetil bid. Table 1 Pharmacokinetic Parameters for MPA [mean (��SD)] Following Administration of Mycophenolate Mofetil to Healthy Volunteers (Single Dose), Renal, Cardiac, and Hepatic Transplant Patients (Multiple Doses) AUCvalues quoted are extrapolated from data from samples collected over 4 hours. Two 500 mg tablets have been shown to be bioequivalent to four 250 mg capsules. Five mL of the 200 mg/mL constituted oral suspension have been shown to be bioequivalent to four 250 mg capsules.<br/>Special Populations: Shown below are the mean (��SD) pharmacokinetic parameters for MPA following the administration of oral mycophenolate mofetil given as single doses to non-transplant subjects with renal or hepatic impairment. Table 2 Pharmacokinetic Parameters for MPA [mean (��SD)] Following Single Doses of Mycophenolate Mofetil Capsules in Chronic Renal and Hepatic Impairment<br/>Renal Insufficiency: In a single-dose study, MMF was administered as capsule or intravenous infusion over 40 minutes. Plasma MPA AUC observed after oral dosing to volunteers with severe chronic renal impairment [glomerular filtration rate (GFR)<25 mL/min/1.73 m] was about 75% higher relative to that observed in healthy volunteers (GFR>80 mL/min/1.73 m). In addition, the single-dose plasma MPAG AUC was 3-fold to 6-fold higher in volunteers with severe renal impairment than in volunteers with mild renal impairment or healthy volunteers, consistent with the known renal elimination of MPAG. No data are available on the safety of long-term exposure to this level of MPAG. Plasma MPA AUC observed after single-dose (1 g) intravenous dosing to volunteers (n=4) with severe chronic renal impairment (GFR<25 mL/min/1.73 m) was 62.4��g��h/mL (��19.3). Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied . In patients with delayed renal graft function posttransplant, mean MPA AUC) was comparable to that seen in posttransplant patients without delayed renal graft function. There is a potential for a transient increase in the free fraction and concentration of plasma MPA in patients with delayed renal graft function. However, dose adjustment does not appear to be necessary in patients with delayed renal graft function. Mean plasma MPAG AUCwas 2-fold to 3-fold higher than in posttransplant patients without delayed renal graft function . In 8 patients with primary graft non-function following renal transplantation, plasma concentrations of MPAG accumulated about 6-fold to 8-fold after multiple dosing for 28 days. Accumulation of MPA was about 1-fold to 2-fold. The pharmacokinetics of mycophenolate mofetil are not altered by hemodialysis. Hemodialysis usually does not remove MPA or MPAG. At high concentrations of MPAG (>100��g/mL), hemodialysis removes only small amounts of MPAG.<br/>Hepatic Insufficiency: In a single-dose (1 g oral) study of 18 volunteers with alcoholic cirrhosis and 6 healthy volunteers, hepatic MPA glucuronidation processes appeared to be relatively unaffected by hepatic parenchymal disease when pharmacokinetic parameters of healthy volunteers and alcoholic cirrhosis patients within this study were compared. However, it should be noted that for unexplained reasons, the healthy volunteers in this study had about a 50% lower AUC as compared to healthy volunteers in other studies, thus making comparisons between volunteers with alcoholic cirrhosis and healthy volunteers difficult. Effectsof hepatic disease on this process probably depend on the particular disease. Hepatic disease with other etiologies, such as primary biliary cirrhosis, may show a different effect. In a single-dose (1 g intravenous) study of 6 volunteers with severe hepatic impairment (aminopyrine breath test less than 0.2% of dose) due to alcoholic cirrhosis, MMF was rapidly converted to MPA. MPA AUC was 44.1��g��h/mL (��15.5).<br/>Pediatrics: The pharmacokinetic parameters of MPA and MPAG have been evaluated in 55 pediatric patients (ranging from 1 year to 18 years of age) receiving mycophenolate mofetil oral suspension at a dose of 600 mg/mbid (up to a maximum of 1 g bid) after allogeneic renal transplantation. The pharmacokinetic data for MPA is provided in Table 3: Table 3 Mean (��SD) Computed Pharmacokinetic Parameters for MPA by Age and Time After Allogeneic Renal Transplantation adjusted to a dose of 600 mg/m ���a subset of 1 to<6 yr ���n=20 n=16 The mycophenolate mofetil oral suspension dose of 600 mg/mbid (up to a maximum of 1 g bid) achieved mean MPA AUC values in pediatric patients similar to those seen in adult renal transplant patients receiving mycophenolate mofetil capsules at a dose of 1 g bid in the early posttransplant period. There was wide variability in the data. As observed in adults, early posttransplant MPA AUC values were approximately 45% to 53% lower than those observed in the later posttransplant period (>3 months). MPA AUC values were similar in the early and late posttransplant period across the 1 year to 18 year age range.<br/>Gender: Data obtained from several studies were pooled to look at any gender-related differences in the pharmacokinetics of MPA (data were adjusted to 1 g oral dose). Mean (��SD) MPA AUCfor males (n=79) was 32.0 (��14.5) and for females (n=41) was 36.5 (��18.8)��g��h/mL while mean (��SD) MPA Cwas 9.96 (��6.19) in the males and 10.6 (��5.64)��g/mL in the females. These differences are not of clinical significance.<br/>Geriatrics: Pharmacokinetics in the elderly have not been studied.
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. Mycophenolate mofetil intravenous is contraindicated in patients who are allergic to Polysorbate 80 (TWEEN).
Mycophenolate mofetil capsules are available as follows: 250 mg, hard gelatin capsules with opaque blue cap and opaque white body. The cap is imprinted���655' with black ink NDC 0781-2067-01, bottle of 100 capsules NDC 0781-2067-05, bottles of 500 capsules<br/>Storage:: Store at 25��C (77��F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight, light-resistant container as defined in the USP with a child-resistant cap. The brands listed are trademarks of their respective owners and are not trademarks of Sandoz Inc. Manufactured in India by Sandoz Private Ltd for Sandoz Inc., Princeton, NJ 08540 Rev. May 2008
WARNING Immunosuppression may lead to increased susceptibility to infection and possible development of lymphoma. Only physicians experienced in immunosuppressive therapy and management of renal, cardiac or hepatic transplant patients should use mycophenolate mofetil. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. Female users of childbearing potential must use contraception. Use of mycophenolate mofetil during pregnancy is associated with increased risk of pregnancy loss and congenital malformations.
General: Gastrointestinal bleeding (requiring hospitalization) has been observed in approximately 3% of renal, in 1.7% of cardiac, and in 5.4% of hepatic transplant patients treated with mycophenolate mofetil 3 g daily. In pediatric renal transplant patients, 5/148 cases of gastrointestinal bleeding (requiring hospitalization) were observed. Gastrointestinal perforations have rarely been observed. Most patients receiving mycophenolate mofetil were also receiving other drugs known to be associated with these complications. Patients with active peptic ulcer disease were excluded from enrollment in studies with mycophenolate mofetil. Because mycophenolate mofetil has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, hemorrhage, and perforation, mycophenolate mofetil should be administered with caution in patients with active serious digestive system disease. Subjects with severe chronic renal impairment (GFR<25 mL/min/1.73 m) who have received single doses of mycophenolate mofetil showed higher plasma MPA and MPAG AUCs relative to subjects with lesser degrees of renal impairment or normal healthy volunteers. No data are available on the safety of long-term exposure to these levels of MPAG. Doses of mycophenolate mofetil greater than 1 g administered twice a day to renal transplant patients should be avoided and they should be carefully observed . 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. In patients with delayed renal graft function posttransplant, mean MPA AUCwas comparable, but MPAG AUCwas 2-fold to 3-fold higher, compared to that seen in posttransplant patients without delayed renal graft function. In the three controlled studies of prevention of renal rejection, there were 298 of 1483 patients (20%) with delayed graft function. Although patients with delayed graft function have a higher incidence of certain adverse events (anemia, thrombocytopenia, hyperkalemia) than patients without delayed graft function, these events were not more frequent in patients receiving mycophenolate mofetil than azathioprine or placebo. No dose adjustment is recommended for these patients; however, they should be carefully observed . 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 therapy, but this difference was not associated with excess mortality due to infection/sepsis among patients treated with mycophenolate mofetil . There were more herpes virus (H. simplex, H. zoster, and cytomegalovirus) infections in cardiac transplant patients treated with mycophenolate mofetil compared to those treated with azathioprine . It is recommended that mycophenolate mofetil not be administered concomitantly with azathioprine because both have the potential to cause bone marrow suppression and such concomitant administration has not been studied clinically. In view of the significant reduction in the AUC of MPA by cholestyramine, caution should be used in the concomitant administration of mycophenolate mofetil with drugs that interfere with enterohepatic recirculation because of the potential to reduce the efficacy of mycophenolate mofetil . On theoretical grounds, because mycophenolate mofetil is an IMPDH (inosine monophosphate dehydrogenase) inhibitor, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome. 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 .<br/>Phenylketonurics: Mycophenolate mofetil oral suspension contains aspartame, a source of phenylalanine (0.56 mg phenylalanine/mL suspension). Therefore, care should be taken if mycophenolate mofetil oral suspension is administered to patients with phenylketonuria.<br/>Information for Patients:<br/>Laboratory Tests: Complete blood counts should be performed weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year .<br/>Drug Interactions: 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.<br/>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. 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.<br/>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 1 TC (10 mL qid). The Cand AUCfor 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.<br/>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. Some degree of enterohepatic recirculation is also anticipated following intravenous administration of mycophenolate mofetil. Therefore, mycophenolate mofetil is not recommended to be given with cholestyramine or other agents that may interfere with enterohepatic recirculation.<br/>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 10 stable renal transplant patients. The mean (��SD) AUC(0���12h) and Cof 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, 1 week before administration of mycophenolate mofetil. In renal transplant patients, mean MPA exposure (AUC) was approximately 30-50% 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 bilethat would lead to enterohepatic recirculation of MPA. This information should be taken into consideration when MMF is used without cyclosporine.<br/>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(n=10) were 54.3 (��19)��g��h/mL and 11.5 (��1.8)��g/mL, respectively, after coadministration of the two drugs, compared to 51 (��17)��g��h/mL and 10.6 (��2)��g/mL, respectively, after administration of intravenous ganciclovir alone. The mean (��SD) AUC and Cof MPA (n=12) after coadministration were 80.9 (��21.6)��g��h/mL and 27.8 (��13.9)��g/mL, respectively, compared to values of 80.3 (��16.4)��g��h/mL and 30.9 (��11.2)��g/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 MMF and ganciclovir or its prodrug (e.g., valganciclovir) are coadministered, patients should be monitored carefully.<br/>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 3 consecutive menstrual cycles. Mean AUCwas similar for ethinylestradiol and 3-keto desogestrel; however, mean levonorgestrel AUCsignificantly 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. However, it is recommended that oral contraceptives are coadministered with mycophenolate mofetil with caution and additional birth control methods be considered .<br/>Sevelamer: Concomitant administration of sevelamer and mycophenolate mofetil in adult and pediatric patients decreased the mean MPA Cand AUCby 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.<br/>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 Cof MPA after concomitant administration were 75.2 (��19.8)��g��h/mL and 34 (��6.6)��g/mL, respectively, compared to 79.2 (��27.9)��g��h/mL and 34.2 (��10.7)��g/mL, respectively, after administration of mycophenolate mofetil alone.<br/>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 AUCwas 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 AUCwhen mycophenolate mofetil was concomitantly administered with norfloxacin or metronidazole separately. The mean (��SD) MPA AUCafter coadministration of mycophenolate mofetil with norfloxcin or metronidazole separately was 48.3 (��24)��g��h/mL and 42.7 (��23)��g��h/mL, respectively, compared with 56.2 (��24)��g��h/mL after administration of mycophenolate mofetil alone.<br/>Rifampin: In a single heart-lung transplant patient, after correction for dose, a 67% decrease in MPA exposure (AUC) 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.<br/>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 tubularsecretion 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.<br/>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 . Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 104-week oral carcinogenicity study in mice, mycophenolate mofetil in daily doses up to 180 mg/kg was not tumorigenic. The highest dose tested was 0.5 times the recommended clinical dose (2 g/day) in renal transplant patients and 0.3 times the recommended clinical dose (3 g/day) in cardiac transplant patients when corrected for differences in body surface area (BSA). In a 104-week oral carcinogenicity study in rats, mycophenolate mofetil in daily doses up to 15 mg/kg was not tumorigenic. The highest dose was 0.08 times the recommended clinical dose in renal transplant patients and 0.05 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. While these animal doses were lower than those given to patients, they were maximal in those species and were considered adequate to evaluate the potential for human risk . The genotoxic potential of mycophenolate mofetil was determined in five assays. Mycophenolate mofetil was genotoxic in the mouse lymphoma/thymidine kinase assay and the in vivo mouse micronucleus assay. Mycophenolate mofetil was not genotoxic in the bacterial mutation assay, the yeast mitotic gene conversion assay or the Chinese hamster ovary cell chromosomal aberration assay. Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. This dose represents 0.1 times the recommended clinical dose in renal transplant patients and 0.07 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. In a female fertility and reproduction study conducted in rats, oral doses of 4.5 mg/kg/day caused malformations (principally of the head and eyes) in the first generation offspring in the absence of maternal toxicity. This dose was 0.02 times the recommended clinical dose in renal transplant patients and 0.01 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation.
The experience with overdose of mycophenolate mofetil in humans is very limited. The events received from reports of overdose fall within the known safety profile of the drug. The highest dose administered to renal transplant patients in clinical trials has been 4 g/day. In limited experience with cardiac and hepatic transplant patients in clinical trials, the highest doses used were 4 g/day or 5 g/day. At doses of 4 g/day or 5 g/day, there appears to be a higher rate, compared to the use of 3 g/day or less, of gastrointestinal intolerance (nausea, vomiting, and/or diarrhea), and occasional hematologicabnormalities, principally neutropenia, leading to a need to reduce or discontinue dosing. In acute oral toxicity studies, no deaths occurred in adult mice at doses up to 4000 mg/kg or in adult monkeys at doses up to 1000 mg/kg; these were the highest doses of mycophenolate mofetil tested in these species. These doses represent 11 times the recommended clinical dose in renal transplant patients and approximately 7 times the recommended clinical dose in cardiac transplant patients whencorrected for BSA. In adult rats, deaths occurred after single-oral doses of 500 mg/kg of mycophenolate mofetil. The dose represents approximately 3 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. MPA and MPAG are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (>100��g/mL), small amounts of MPAG are removed. By increasing excretion of the drug, MPA can be removed by bile acid sequestrants, such as cholestyramine .
Mycophenolate Mofetil (Capsule)
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:Infections and WARNINGS :Progressive Multifocal Leukoencephalopathy (PML). The adverse event profile associated with the administration of mycophenolate mofetil intravenous has been shown to be similar to that observed after administration of oral dosage forms of mycophenolate mofetil.<br/>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 (2 active, 1 placebo-controlled trials), cardiac (1 active-controlled trial), and hepatic (1 active-controlled trial) transplant patients.<br/>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 . Safety data are summarized below for all active-controlled trials in renal (2 trials), cardiac (1 trial), and hepatic (1 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 1 year. Adverse events reported in���20% of patients in the mycophenolate mofetil treatment groups are presented below. Table 8 Adverse Events in Controlled Studies in Prevention of Renal, Cardiac or Hepatic Allograft Rejection (Reported in���20% of Patients in the Mycophenolate Mofetil Group) 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 1483 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 1 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 1-year data. In pediatric patients, no other malignancies besides lymphoproliferative disorder (2/148 patients) have been observed. Severe neutropenia (ANC<0.5��10/��L) 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 . All transplant patients are at increased risk of opportunistic infections. The risk increases with total immunosuppressive load (see WARNING: Infections and WARNINGS: Progressive Multifocal Leukoencephalopathy (PML). Table 9 shows the incidence of opportunistic infections that occurred in the renal, cardiac, and hepatic transplant populations in the azathioprine-controlled prevention trials: Table 9 Viral and Fungal Infections in Controlled Studies in Prevention of Renal, Cardiac or Hepatic Transplant Rejection 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: 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 10 Adverse Events Reported in 3% to<20% of Patients Treated With Mycophenolate Mofetil in Combination With Cyclosporine and Corticosteroids<br/>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/mbid (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.<br/>Mycophenolate Mofetil Intravenous: The adverse event profile of mycophenolate mofetil intravenous was determined from a single, double-blind, controlled comparative study of the safety of 2 g/day of intravenous and oral mycophenolate mofetil in renal transplant patients in the immediate posttransplant period (administered for the first 5 days). The potential venous irritation of mycophenolate mofetil intravenous was evaluated by comparing the adverse events attributable to peripheral venous infusion of mycophenolate mofetil intravenous with those observed in the intravenous placebo group; patients in this group received active medication by the oral route. Adverse events attributable to peripheral venous infusion were phlebitis and thrombosis, both observed at 4% in patients treated with mycophenolate mofetil intravenous. In the active controlled study in hepatic transplant patients, 2 g/day of mycophenolate mofetil intravenous were administered in the immediate posttransplant period (up to 14 days). The safety profile of intravenous mycophenolate mofetil was similar to that of intravenous azathioprine.<br/>Postmarketing Experience:<br/>Congenital Disorders: Congenital malformations including ear malformations have been reported in offspring of patients exposed to mycophenolate mofetil during pregnancy (see WARNINGS: Pregnancy ).<br/>Digestive: Colitis (sometimes caused by cytomegalovirus), pancreatitis, isolated cases of intestinal villous atrophy.<br/>Resistance Mechanism Disorders: Serious life-threatening infections such as meningitis and infectious endocarditis have been reported occasionally and 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.<br/>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.
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. Mycophenolate mofetil intravenous is an alternative dosage form to mycophenolate mofetil capsules, tablets and oral suspension. Mycophenolate mofetil intravenous should be administered within 24 hours following transplantation. Mycophenolate mofetil intravenous can be administered for up to 14 days; patients should be switched to oral mycophenolate mofetil as soon as they can tolerate oral medication.