CellCept (Mycophenolate Mofetil)

CellCept®

Roche

Mycophenolate Mofetil

Immunosuppressant Agent

Manufacturers’ Warnings In Clinical States: Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of solid organ 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.

Action And Clinical Pharmacology: 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 heart 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.

Pharmacokinetics: Following oral administration, mycophenolate mofetil undergoes rapid and extensive absorption and complete presystemic metabolism to MPA, the active metabolite. Mycophenolate mofetil is not measurable systemically in plasma following oral administration.

Absorption: In 12 healthy volunteers, the mean absolute bioavailability of oral mycophenolate mofetil relative to i.v. 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.

Effect of Food: 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 b.i.d. to renal transplant patients. However, MPA Cmax was decreased by 40% in the presence of food (see Dosage).

Distribution: The mean (±SD) apparent volume of distribution of MPA in 12 healthy volunteers is approximately 3.6 (±1.5) and 4.0 (±1.2) L/kg following i.v. 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 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 ³460 µg/mL with plasma proteins) increased the free fraction of MPA. At concentrations exceeding those 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 µg/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%.

Metabolism: Mycophenolate mofetil undergoes complete presystemic metabolism to MPA, the active metabolite. MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. 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 t.i.d.) 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.

Excretion: Negligible amount of drug is excreted as MPA (100 µg/mL), small amounts of this metabolite are removed.

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 i.v. administration, respectively.

Pharmacokinetics in Healthy Volunteers and Renal Transplant Patients: Shown in Table I are the mean (±SD) pharmacokinetic parameters for MPA following the administration of oral mycophenolate mofetil given as single doses to healthy volunteers and multiple doses to renal transplant patients.
It has been demonstrated that the 500 mg tablet (´2) is bioequivalent to the 250 mg capsule (´4) with respect to the extent of absorption (AUC), and with respect to the rate of absorption (Cmax). Shown in Table II are the pharmacokinetic parameters for MPA following the administration of oral mycophenolate mofetil in renal transplant patients.

Renal Insufficiency: In a single-dose study (6 volunteers/group), the mean plasma MPA AUC observed in volunteers with severe chronic renal impairment [glomerular filtration rate (GFR) 80 mL/min/1.73 m. However, the mean single dose plasma MPAG AUC was 3- 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. Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied. No data are available on the safety of long-term exposure to this level of MPAG (see Precautions, General, and Dosage).

In patients with delayed graft function post-transplant, mean MPA AUC0-12 was comparable to that seen in post-transplant patients without delayed graft function. Mean plasma MPAG AUC0-12 was 2- to 3-fold higher than in post-transplant patients without delayed graft function (see Precautions, General, and Dosage).

Hemodialysis: At clinically encountered concentrations, MPA is not removed by hemodialysis. Similary, MPAG concentrations normally encountered are unaffected by hemodialysis, however, at high MPAG concentrations (>100 µg/mL), hemodialysis removes only small amounts of MPAG.

Hepatic Insufficiency: In a single dose (1 g) 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. Effects of hepatic disease on this process probably depend on the particular disease. Hepatic disease with other etiologies may show a different effect.

Children: Very limited pharmacokinetic data are available for pediatric renal transplant recipients. Data on these patients collected on day 21 post-transplant are presented in Table IV.

Gender: Data obtained from several studies were pooled to examine any gender-related differences in the pharmacokinetics of MPA (data were adjusted to 1 g dose). Mean (±SD) MPA AUC0-12 for males (n=79) was 32.0 (±14.5) and for females (n=41) was 36.5 (±18.8) µg•h/mL while mean (±SD) MPA Cmax was 9.96 (±6.19) in the males and 10.6 (±5.64) µg/mL in the females. These differences are not of clinical significance.

Clinical Studies: The safety and efficacy of mycophenolate mofetil as adjunctive therapy for the prevention of organ rejection following allogeneic renal transplants was assessed in 3 randomized, double-blind, multicenter trials.

Prevention of Rejection: These studies compared 2 dose levels of mycophenolate mofetil (1.0 g b.i.d. and 1.5 g b.i.d.) with azathioprine (two studies) or placebo (one study) when administered in combination with cyclosporine and corticosteroids to prevent acute rejection episodes. One study also included antithymocyte globulin (Atgam) induction therapy. The three studies are described by geographic location of the investigational sites. One study was conducted in the U.S. at 14 sites, one study was conducted in Europe at 20 sites, and one study was conducted in Europe, Canada, and Australia at a total of 21 sites.

The primary efficacy endpoint was the proportion of patients in each treatment group who experienced biopsy-proven acute rejection or treatment failure (defined as early termination from the study for any reason without prior biopsy-proven rejection) within the first 6 months after transplantation. Mycophenolate mofetil, when administered with antithymocyte globulin (Atgam) induction (1 study) and with cyclosporine and corticosteroids (all 3 studies), was shown to be superior to the following three therapeutic regimens: (1) antithymocyte globulin (Atgam) induction/azathioprine/cyclosporine/corticosteroids, (2) azathioprine/cyclosporine/corticosteroids, and (3) cyclosporine/corticosteroids.

Cumulative incidence of 12-month graft loss and patient death are presented in Table VI. No advantage of mycophenolate mofetil with respect to graft loss and patient death was established. Numerically, patients receiving mycophenolate mofetil 2 g/day and 3 g/day experienced a better outcome than controls in all three studies; patients receiving mycophenolate mofetil 2 g/day experienced a better outcome than mycophenolate mofetil 3 g/day in 2 of the 3 studies. Patients in all treatment groups who terminated treatment early were found to have a poor outcome with respect to graft loss and patient death at 1 year.

Indications And Clinical Uses: For the prophylaxis of organ rejection in patients receiving allogeneic renal transplants. Mycophenolate mofetil should be used concomitantly with cyclosporine and corticosteroids.

Contra-Indications: 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 (see Supplied).

Manufacturers’ Warnings In Clinical States: Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of solid organ 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.

Patients receiving immunosuppressive regimes involving combinations of drugs, including mycophenolate mofetil, as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. Oversuppression of the immune system can also increase susceptibility to infection. Mycophenolate mofetil has been administered in combination with the following agents in clinical trials: antithymocyte globulin (Atgam) induction, cyclosporine, and corticosteroids. The efficacy and safety of the use of mycophenolate mofetil in combination with other immunosuppressive agents has not been determined. The long-term risk of mycophenolate mofetil is unknown.

Lymphoproliferative disease or lymphoma developed in patients receiving mycophenolate mofetil with other immunosuppressive agents in approximately 1% of patients in the pivotal studies of prevention of rejection (see Adverse Effects).

Up to 2.0% of patients receiving mycophenolate mofetil for prevention of rejection have developed severe neutropenia [absolute neutrophil count (ANC)
Patients receiving mycophenolate mofetil should be monitored for neutropenia (see Precautions, Laboratory Tests). The development of neutropenia may be related to mycophenolate mofetil itself, concomitant medications, viral infections, or some combination of these causes.

Pregnancy: Adverse effects on fetal development (including resorptions and malformations) occurred when pregnant rats and rabbits were dosed during organogenesis. These responses occurred at doses (6 mg/kg/day in rat and 90 mg/kg/day in rabbit) lower than those associated with maternal toxicity, and at doses 0.03 to 0.92 times the recommended clinical dose on a BSA basis. 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 when corrected for BSA.

There are no adequate and well-controlled studies in pregnant women. However, as mycophenolate mofetil has been shown to have teratogenic effects in animals, it may cause fetal harm when administered to a pregnant woman. Therefore, mycophenolate mofetil should not be used in pregnant women unless the potential benefit justifies the potential risk to the fetus.

Women of childbearing potential should have a negative serum or urine pregnancy test with a sensitivitiy of at least 50 mIU/mL within 1 week prior to beginning therapy. It is recommended that mycophenolate mofetil therapy should not be initiated by the physician until a report of a negative pregnancy test has been obtained.

Effective contraception must be used before beginning mycophenolate mofetil therapy, during therapy, and for 6 weeks following discontinuation of therapy, even where there has been a history of infertility, unless due to hysterectomy. Two reliable forms of contraception must be used simultaneously unless abstinence is the chosen method. If pregnancy does occur during treatment, the physician and patient should discuss the desirability of continuing the pregnancy (see Precautions, Information for the Patient and Blue Section – Information for the Patient).

Lactation : Studies in rats have shown mycophenolate mofetil is excreted in milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from mycophenolate mofetil, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother (see Blue Section – Information for the Patient).

Precautions: Mycophenolate mofetil should be administered with caution in patients with active serious digestive system disease. Gastrointestinal tract hemorrhage has been observed in approximately 3% of patients treated with mycophenolate mofetil. Mycophenolate mofetil has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, and rarely perforation. Most patients receiving mycophenolate mofetil were also receiving other drugs that are known to be associated with these complications. Patients with active peptic ulcer disease were excluded from enrollment in studies with mycophenolate mofetil.

Subjects with severe chronic renal impairment who have received single doses of mycophenolate mofetil showed higher mean plasma MPA and MPAG AUCs relative to subjects with lesser degrees of renal impairment or normal healthy subjects.

In patients with delayed graft function post-transplant, mean MPA AUC0-12 was comparable, but MPAG AUC0-12 was 2- to 3-fold higher, compared to that seen in post-transplant patients without delayed graft function. In the three pivotal studies of prevention of rejection, 298 of 1 483 patients (20%) experienced 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 (see Pharmacology, Pharmacokinetics).

It is recommended that mycophenolate mofetil not be administered concomitantly with azathioprine because 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 (see Drug Interactions).

Information for the Patient: Patients should be informed of the need for repeated appropriate laboratory tests while they are receiving mycophenolate mofetil. Patients should be given complete dosage instructions and informed of the increased risk of lymphoproliferative disease and certain other malignancies. Women of childbearing potential should be instructed of the potential risks during pregnancy, and that they should use effective contraception before beginning mycophenolate mofetil therapy, during therapy and for 6 weeks after mycophenolate mofetil has been stopped (see Warnings, Pregnancy and Blue Section – Information for the Patient).

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 (see Warnings and Dosage).

Drug Interactions: Drug interaction studies with mycophenolate mofetil have been conducted with acyclovir, antacids, cholestyramine, cyclosporine A, ganciclovir, oral contraceptives, and trimethoprim/sulfamethoxazole. Drug interaction studies have not been conducted with other drugs that may be commonly administered to renal 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 Cmax. 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 the 2 drugs 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 (2.0 g) was decreased when administered to rheumatoid arthritis patients also taking Maalox TC (10 mL q.i.d.). The Cmax and AUC values for MPA were 38% 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.

Cholestyramine: Following single dose administration of 1.5 g mycophenolate mofetil to normal healthy subjects pretreated with 4 g t.i.d. of cholestyramine for 4 days, there was a mean 40% reduction in the AUC of MPA. This decrease is consistent with interruption of enterohepatic recirculation by irreversible binding, in the intestine, of recirculating MPAG with cholestyramine. Mycophenolate mofetil is not recommended to be given with cholestyramine or other agents that may interfere with enterohepatic recirculation.

Cyclosporine: Mycophenolate mofetil has been investigated with Sandimmune but not with the Neoral formulation. Cyclosporine (Sandimmune) pharmacokinetics (at doses of 275 to 415 mg/day) were unaffected by single and multiple doses of 1.5 g b.i.d. of mycophenolate mofetil in 10 stable renal transplant patients. The mean (±SD) AUC0-12 and Cmax of cyclosporine after 14 days of multiple doses of mycophenolate mofetil were 3 290 (±822) ng•h/mL and 753 (±161) ng/mL, respectively, compared to 3 245 (±1 088) ng•h/mL and 700 (±246) ng/mL, respectively, 1 week before administration of mycophenolate mofetil. The effect of cyclosporine on mycophenolate mofetil pharmacokinetics could not be evaluated in this study, however, plasma concentrations of MPA were similar to that for healthy volunteers.

Ganciclovir: Following single-dose administration to 12 stable renal transplant patients, no pharmacokinetic interaction was observed between mycophenolate mofetil (1.5 g) and i.v. ganciclovir (5 mg/kg). Mean (±SD) ganciclovir AUC and Cmax (n=10) were 54.3 (±19.0) µg•h/mL and 11.5 (±1.8) µg/mL, respectively after coadministration of the 2 drugs, compared to 51.0 (±17.0) µg•h/mL and 10.6 (±2.0) µg/mL, respectively after administration of i.v. ganciclovir alone. The mean (±SD) AUC and Cmax of MPA (n=12) after coadministration were 80.9 (±21.6) µg•h/mL and 27.8 (±13.9) µg/mL, respectively compared to values of 80.3 (±16.4) µg•h/mL and 30.9 (±11.2) µg/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 potential exists for the 2 drugs to compete for tubular secretion and thus further increases in concentrations of both drugs may occur.

Oral Contraceptives: Following single dose administration to healthy women, no pharmacokinetic interaction was observed between mycophenolate mofetil (1.0 g) and 2 tablets of Ortho-Novum 7/7/7 (1 mg norethindrone and 35 µg ethinyl estradiol). This single dose study demonstrates the lack of a gross pharmacokinetic interaction, but cannot exclude the possibility of changes in the pharmacokinetics of the oral contraceptive under long-term dosing conditions with mycophenolate mofetil which might adversely affect the efficacy of the oral contraceptive.

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 Bactrim DS (trimethoprim 160 mg/sulfamethoxazole 800 mg) administered b.i.d., no effect on the bioavailability of MPA was observed. The mean (±SD) AUC and Cmax of MPA after concomitant administration were 75.2 (±19.8) µg•h/mL and 34.0 (±6.6) µg/mL, respectively compared to 79.2 (±27.9) and 34.2 (±10.7), respectively after administration of mycophenolate mofetil alone.

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 raises plasma AUC of MPAG by 3-fold. 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.

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) 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 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 (see Warnings).

Mycophenolate mofetil was not genotoxic, with or without metabolic activation, in several assays: the bacterial mutation assay, the yeast mitotic gene conversion assay, the mouse micronucleus aberration assay, or the Chinese hamster ovary cell (CHO) 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 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 when corrected for BSA. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation.

Children: Safety and efficacy in children have not been established. Very limited pharmacokinetic data are available in pediatric patients (see Pharmacology, Pharmacokinetics).

Adverse Reactions: The adverse event profile associated with the use of immunosuppressive drugs is often difficult to establish owing to the presence of underlying disease and the concurrent use of many other medications. The principal adverse reactions associated with the administration of mycophenolate mofetil include diarrhea, leukopenia, sepsis and vomiting, and there is evidence of a higher frequency of certain types of infections.

The incidence of adverse events for mycophenolate mofetil was determined in three randomized comparative double-blind trials in prevention of rejection in renal transplant patients. Because of the lower overall reporting of events in the European placebo-controlled prevention of rejection study, these data were not combined with the other 2 active-controlled prevention trials, but are instead presented separately.

Safety data are summarized below for all patients in the double-blind prevention studies while receiving treatment; approximately 53% of these patients have been treated for more than 1 year. Adverse events, whether or not deemed to be causally associated with the study medication, which were reported in ³10% of patients in any treatment group are presented in Table VII for the 2 active-controlled studies combined (U.S. and Europe/Canada/Australia) and for the 1 European placebo-controlled study. Opportunistic infections are summarized separately.

The incidence of malignancies among the 1 483 patients enrolled in controlled trials for the prevention of rejection who were followed for ³1 year was similar to the incidence reported in the literature for renal allograft recipients. There was a slight increase in the incidence of lymphoproliferative disease in the mycophenolate mofetil treatment groups compared to the placebo and azathioprine groups (see Warnings).

The following adverse events, not mentioned in any of the tables above, were reported with ³3% incidence in patients treated with mycophenolate mofetil.

Body As a Whole: abdomen enlarged, accidental injury, chills and fever, cyst, face edema, flu syndrome, hemorrhage, hernia, malaise, pelvic pain.

Hemic and Lymphatic: ecchymosis, polycythemia.

Urogenital: albuminuria, dysuria, hydronephrosis, impotence, pain, pyelonephritis, urinary frequency, urinary tract disorder.

Cardiovascular: angina pectoris, atrial fibrillation, cardiovascular disorder, hypotension, palpitation, peripheral vascular disorder, postural hypotension, tachycardia, thrombosis, vasodilatation.

Metabolic and Nutritional: acidosis, alkaline phosphatase increased, creatinine increased, dehydration, gamma glutamyl transpeptidase increased, hypercalcemia, hyperlipemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hypoproteinemia, lactic dehydrogenase increased, AST increased, ALT increased, weight gain.

Digestive: anorexia, esophagitis, flatulence, gastritis, gastroenteritis, gastrointestinal hemorrhage, gastrointestinal moniliasis, gingivitis, gum hyperplasia, hepatitis, ileus, infection, liver function tests abnormal, mouth ulceration, rectal disorder.

Respiratory: asthma, lung disorder, lung edema, pleural effusion, rhinitis, sinusitis.

Skin and Appendages: alopecia, fungal dermatitis, hirsutism, pruritus, skin benign neoplasm, skin disorder, skin hypertrophy, skin ulcer, sweating.

Nervous: anxiety, depression, hypertonia, paresthesia, somnolence.

Endocrine: diabetes mellitus, parathyroid disorder.

Musculoskeletal: arthralgia, joint disorder, leg cramps, myalgia, myasthenia.

Special Senses: cataract (not specified), conjunctivitis, visual disturbance.

The following adverse events, not mentioned above, were reported in clinical trials and in postmarketing experience in patients treated with mycophenolate mofetil.

Digestive: colitis.

Resistance Mechanism Disorders: There is evidence of a higher frequency of certain types of serious infections such as meningitis, infectious endocarditis, pulmonary and extra-pulmonary tuberculosis and other mycobacterial infections.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There has been no reported experience of overdosage of mycophenolate mofetil in humans. The highest dose administered to renal transplant patients has been 4 g/day. In limited experience with cardiac and hepatic transplant patients, the highest doses used were 4 or 5 g/day. At doses of 4 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 hematologic abnormalities, 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 4 000 mg/kg or in adult monkeys at doses up to 1 000 mg/kg; these were the highest doses of mycophenolate mofetil tested in these species. These doses represent 11 times the recommended clinical dose when corrected for BSA. In adult rats, deaths occurred after single oral doses of 500 mg/kg of mycophenolate mofetil. The dose represents 3 times the recommended clinical dose when corrected for BSA.

At clinically encountered concentrations, MPA and MPAG are not removed by hemodialysis. However, at high MPAG plasma concentrations (>100 µg/mL), small amounts of MPAG are removed. By interfering with enterohepatic recirculation of the drug, bile acid sequestrants, such as cholestyramine reduce the MPA AUC.

Dosage And Administration: The initial dose should be given within 72 hours following transplantation. A dose of 1.0 g administered twice a day (daily dose of 2 g) is recommended for use in combination with corticosteroids and cyclosporine 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. Patients receiving 2 g per day demonstrated an overall better safety profile than did patients receiving 3 g per day. Food had no effect on MPA AUC, but has been shown to decrease MPA Cmax by 40%. It is recommended that mycophenolate mofetil be administered on an empty stomach.

Handling and Disposal: Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, mycophenolate mofetil capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in mycophenolate mofetil capsules. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.

Availability And Storage: Capsules: Each oblong, blue/brown, two-piece hard gelatin capsule, printed in black with “CellCept 250” on the blue cap and “ROCHE” on the brown body, contains: mycophenolate mofetil 250 mg. Nonmedicinal ingredients: croscarmellose sodium, magnesium stearate, povidone (K-90) and pregelatinized starch; capsule: black iron oxide, FD&C blue #2, gelatin, potassium hydroxide, red iron oxide, shellac, sodium lauryl sulfate, titanium dioxide and yellow iron oxide. May also contain silicon dioxide. Blister packs of 10, boxes of 10. Store at 15 to 30°C.

Tablets: Each lavender-colored, caplet-shaped, film-coated tablet, printed in black with “CellCept 500” on one side and “ROCHE” on the other, contains: mycophenolate mofetil 500 mg. Nonmedicinal ingredients: croscarmellose sodium, FD&C blue #2 aluminum lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxide, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, povidone (K-90), talc and titanium dioxide. May also contain propylene glycol and shellac. Blister strips of 10, boxes of 5. Store at 15 to 30°C. Protect from light.

CellCept® Roche Mycophenolate Mofetil Immunosuppressant Agent Manufacturers

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