Mycophenolate Mofetil

INDICATIONS AND USAGE Mycophenolate mofetil for oral suspension is indicated for the prophylaxis of organ rejection, in adult and pediatric recipients 3 months of age and older of allogeneic kidney [see Clinical Studies (14.1) ] , heart [see Clinical Studies (14.2) ] or liver transplants [see Clinical Studies (14.3) ] , in combination with other immunosuppressants. Mycophenolate mofetil for oral suspension is an antimetabolite immunosuppressant indicated for the prophylaxis of organ rejection in adult and pediatric recipients 3 months of age and older of allogeneic kidney, heart or liver transplants, in combination with other immunosuppressants. (1)

DOSAGE AND ADMINISTRATION ­ADULTS DOSAGE Kidney Transplant 1 g twice daily, orally ( 2.2 ) Heart Transplant 1.5 g twice daily orally ( 2.3 ) Liver Transplant 1.5 g twice daily orally ( 2.4 ) PEDIATRICS Kidney Transplant 600 mg/m 2 orally twice daily, up to maximum of 2 g daily ( 2.2 ) Heart Transplant 600 mg/m 2 orally twice daily (starting dose) up to a maximum of 900 mg/m 2 twice daily (3 g or 15 mL of oral suspension) ( 2.3 ) Liver Transplant 600 mg/m 2 orally twice daily (starting dose) up to a maximum of 900 mg/m 2 twice daily (3 g or 15 mL of oral suspension) ( 2.4 ) CELLCEPT Intravenous is an alternative when patients cannot tolerate oral medication. Administer within 24 hours following transplantation, until patients can tolerate oral medication, up to 14 days. ( 2.1 ) Reduce or interrupt dosing in the event of neutropenia. ( 2.5 ) See full prescribing information (FPI) for: adjustments for renal impairment and neutropenia ( 2.5 ), preparation of oral suspension. ( 2.6 ) 2.1 Important Administration Instructions Mycophenolate mofetil for oral suspension should not be used without the supervision of a physician with experience in immunosuppressive therapy. Mycophenolate mofetil for Oral Suspension Mycophenolate mofetil oral dosage forms (capsules, tablets or oral suspension) should not be used interchangeably with mycophenolic acid delayed-release tablets without supervision of a physician with experience in immunosuppressive therapy because the rates of absorption following the administration of mycophenolate mofetil oral dosage forms and mycophenolic acid delayed-release tablets are not equivalent. CELLCEPT tablets should not be crushed and CELLCEPT capsules should not be opened or crushed. Patients should avoid inhalation or contact of the skin or mucous membranes with the powder contained in CELLCEPT capsules and oral suspension. If such contact occurs, they must wash the area of contact thoroughly with soap and water. In case of ocular contact, rinse eyes with plain water. The initial oral dose of mycophenolate mofetil for oral suspension should be given as soon as possible following kidney, heart or liver transplant. It is recommended that mycophenolate mofetil for oral suspension be administered on an empty stomach. In stable transplant patients, however, mycophenolate mofetil for oral suspension may be administered with food if necessary [see Clinical Pharmacology (12.3) ]. Once reconstituted, mycophenolate mofetil for oral suspension must not be mixed with any liquids prior to dose administration. If needed, mycophenolate mofetil for oral suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter). Patients should be instructed to take a missed dose as soon as they remember, except if it is closer than 2 hours to the next scheduled dose; in this case, they should continue to take mycophenolate mofetil for oral suspension at the usual times. CELLCEPT Intravenous CELLCEPT Intravenous is recommended for patients unable to take oral mycophenolate mofetil. CELLCEPT Intravenous should be administered within 24 hours following transplant. CELLCEPT Intravenous can be administered for up to 14 days; however, patients should be switched to oral mycophenolate mofetil as soon as they can tolerate oral medication. 2.2 Dosage Recommendations for Kidney Transplant Patients Adults The recommended dosage for adult kidney transplant patients is 1 g orally, twice daily (total daily dose of 2 g). Pediatrics (3 months and older) Pediatric dosing is based on body surface area (BSA). The recommended dosage of mycophenolate mofetil for oral suspension for pediatric kidney transplant patients 3 months and older is 600 mg/m 2 , administered twice daily (maximum total daily dose of 2 g or 10 mL of the oral suspension). Pediatric patients with BSA ≥ 1.25 m 2 may be dosed with capsules or tablets as follows: Table 1 Pediatric Kidney Transplant: Dosage Using Capsules or Tablets Body Surface Area Dosage 1.25 m 2 to ˂1.5 m 2 CELLCEPT capsule 750 mg twice daily (1.5 g total daily dose) ≥ 1.5 m 2 CELLCEPT capsules or tablets 1 g twice daily (2 g total daily dose) 2.3 Dosage Recommendations for Heart Transplant Patients Adults The recommended dosage of mycophenolate mofetil for oral suspension for adult heart transplant patients is 1.5 g orally administered twice daily (total daily dose of 3 g). Pediatrics (3 months and older) The recommended starting dosage of mycophenolate mofetil for oral suspension for pediatric heart transplant patients 3 months and older is 600 mg/m 2 , administered twice daily. If well tolerated, the dose can be increased to a maintenance dosage of 900 mg/m 2 twice daily (maximum total daily dose of 3 g or 15 mL of the oral suspension). The dose may be individualized based on clinical assessment . Pediatric patients with BSA ≥1.25 m 2 may be started on therapy with capsules or tablets as follows: Table 2 Pediatric Heart Transplant: Pediatric Starting Dosage Using Capsules or Tablets * Maximum maintenance dose: 3 g total daily. Body Surface Area Starting Dosage * 1.25 m 2 to ˂1.5 m 2 CELLCEPT capsule 750 mg twice daily (1.5 g total daily dose) ≥ 1.5 m 2 CELLCEPT capsules or tablets 1 g twice daily (2 g total daily dose) 2.4 Dosage Recommendations for Liver Transplant Patients Adults The recommended dosage of mycophenolate mofetil for oral suspension for adult liver transplant patients is 1.5 g administered orally twice daily (total daily dose of 3 g). Pediatrics (3 months and older) The recommended starting dosage of mycophenolate mofetil for oral suspension for pediatric liver transplant patients 3 months of age and older is 600 mg/m 2 , administered twice daily. If well tolerated, the dose can be increased to a maintenance dosage of 900 mg/m 2 twice daily (maximum total daily dose of 3 g or 15 mL of the oral suspension). The dose may be individualized based on clinical assessment . Pediatric patients with BSA ≥1.25 m 2 may be started on therapy with capsules or tablets as follows: Table 3 Pediatric Liver Transplant: Pediatric Starting Dosage Using Capsules or Tablets * Maximum maintenance dose: 3 g total daily. Body Surface Area Starting Dosage * 1.25 m 2 to ˂1.5 m 2 CELLCEPT capsule 750 mg twice daily (1.5 g total daily dose) ≥ 1.5 m 2 CELLCEPT capsules or tablets 1 g twice daily (2 g total daily dose) 2.5 Dosage Modifications: Patients with Renal Impairment, Neutropenia Renal Impairment No dosage modifications are needed in kidney transplant patients with delayed graft function postoperatively [see Clinical Pharmacology (12.3) ] . In kidney transplant patients with severe chronic impairment of the graft (GFR <25 mL/min/1.73 m 2 ), do not administer doses of mycophenolate mofetil for oral suspension greater than 1 g twice a day. These patients should be carefully monitored [see Clinical Pharmacology (12.3) ]. Neutropenia If neutropenia develops (ANC <1.3 x 10 3 /μL), dosing with mycophenolate mofetil for oral suspension should be interrupted or reduced, appropriate diagnostic tests performed, and the patient managed appropriately [see Warnings and Precautions (5.4) and Adverse Reactions (6.1) ]. 2.6 Preparation Instructions of Oral Suspension for Pharmacists General Preparation Instructions Before Handling the Formulations Mycophenolate mofetil (MMF) has demonstrated teratogenic effects in humans. Follow applicable special handling and disposal procedures 1 [see Warnings and Precautions (5.1) , Adverse Reactions (6.2) , Use in Specific Populations (8.1 , 8.3), How Supplied/Storage and Handling (16.1) ]. Care should be taken to avoid inhalation or direct contact with skin or mucous membranes of the dry powder or the constituted suspension because MMF has demonstrated teratogenic effects in humans . Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the bottle/cap and the table surface after reconstitution. If such contact occurs, wash

WARNINGS AND PRECAUTIONS Blood Dyscrasias (Neutropenia, Red Blood Cell Aplasia): Monitor with blood tests; consider treatment interruption or dose reduction. ( 5.4 ) Gastrointestinal Complications: Monitor for complications such as bleeding, ulceration and perforations, particularly in patients with underlying gastrointestinal disorders. ( 5.5 ) Hypoxanthine-Guanine Phosphoribosyl-Transferase Deficiency: Avoid use of mycophenolate mofetil. ( 5.6 ) Acute Inflammatory Syndrome Associated with Mycophenolate Products: Monitor for this paradoxical inflammatory reaction. ( 5.7 ) Immunizations: Avoid live attenuated vaccines. ( 5.8 ) Blood Donation: Avoid during therapy and for 6 weeks thereafter. ( 5.11 ) Semen Donation: Avoid during therapy and for 90 days thereafter. ( 5.12 ) Potential Impairment on Driving and Use of Machinery: Mycophenolate mofetil may affect ability to drive or operate machinery. ( 5.14 ) 5.1 Embryofetal Toxicity Use of MMF during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations, especially external ear and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, kidney and nervous system. Females of reproductive potential must be made aware of these risks and must be counseled regarding pregnancy prevention and planning. Avoid use of MMF during pregnancy if safer treatment options are available [see Use in Specific Populations (8.1 , 8.3) ]. 5.2 Lymphoma and Other Malignancies Patients receiving immunosuppressants, including mycophenolate mofetil, are at increased risk of developing lymphomas and other malignancies, particularly of the skin [see Adverse Reactions (6.1) ] . The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. For patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor. Post-transplant lymphoproliferative disorder (PTLD) developed in 0.4% to 1% of patients receiving mycophenolate mofetil (2 g or 3 g) with other immunosuppressive agents in controlled clinical trials of kidney, heart and liver transplant patients [see Adverse Reactions (6.1) ] . The majority of PTLD cases appear to be related to Epstein Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children. In pediatric patients, no other malignancies besides PTLD were observed in clinical trials [see Adverse Reactions (6.1) ]. 5.3 Serious Infections Patients receiving immunosuppressants, including mycophenolate mofetil, are at increased risk of developing bacterial, fungal, protozoal and new or reactivated viral infections, including opportunistic infections. The risk increases with the total immunosuppressive load. These infections may lead to serious outcomes, including hospitalizations and death [see Adverse Reactions (6.1, 6.2) ]. Serious viral infections reported include: Polyomavirus-associated nephropathy (PVAN), especially due to BK virus infection JC virus-associated progressive multifocal leukoencephalopathy (PML), and Cytomegalovirus (CMV) infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at highest risk of CMV viremia and CMV disease. Viral reactivation in patients infected with Hepatitis B and C COVID-19 Consider dose reduction or discontinuation of mycophenolate mofetil in patients who develop new infections or reactivate viral infections, weighing the risk that reduced immunosuppression represents to the functioning allograft. PVAN, especially due to BK virus infection, is associated with serious outcomes, including deteriorating renal function and renal graft loss [see Adverse Reactions (6.2) ]. Patient monitoring may help detect patients at risk for PVAN. PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies, and ataxia [see Adverse Reactions (6.2) ] . In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms. The risk of CMV viremia and CMV disease is highest among transplant recipients seronegative for CMV at time of transplant who receive a graft from a CMV seropositive donor. Therapeutic approaches to limiting CMV disease exist and should be routinely provided. Patient monitoring may help detect patients at risk for CMV disease. Viral reactivation has been reported in patients infected with HBV or HCV. Monitoring infected patients for clinical and laboratory signs of active HBV or HCV infection is recommended. 5.4 Blood Dyscrasias: Neutropenia and Pure Red Cell Aplasia (PRCA) Severe neutropenia [absolute neutrophil count (ANC) <0.5 × 10 3 /µL] developed in transplant patients receiving mycophenolate mofetil 3 g daily [see Adverse Reactions (6.1) ] . Patients receiving mycophenolate mofetil should be monitored for neutropenia. Neutropenia has been observed most frequently in the period from 31 to 180 days post-transplant in patients treated for prevention of kidney, heart and liver rejection. The development of neutropenia may be related to mycophenolate mofetil itself, concomitant medications, viral infections, or a combination of these causes. If neutropenia develops (ANC <1.3 × 10 3 /µL), dosing with mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately [see Dosage and Administration (2.5) ]. Patients receiving mycophenolate mofetil should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression. Consider monitoring with complete blood counts weekly for the first month, twice monthly for the second and third months, and monthly for the remainder of the first year. Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressive agents. In some cases, PRCA was found to be reversible with dose reduction or cessation of mycophenolate mofetil therapy. In transplant patients, however, reduced immunosuppression may place the graft at risk. 5.5 Gastrointestinal Complications Gastrointestinal bleeding requiring hospitalization, ulceration and perforations were observed in clinical trials. Physicians should be aware of these serious adverse effects particularly when administering mycophenolate mofetil to patients with a gastrointestinal disease. 5.6 Patients with Hypoxanthine-Guanine Phosphoribosyl-Transferase Deficiency (HGPRT) Mycophenolate mofetil is an inosine monophosphate dehydrogenase (IMPDH) inhibitor; therefore it should be avoided in patients with hereditary deficiencies of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndromes because it may cause an exacerbation of disease symptoms characterized by the overproduction and accumulation of uric acid leading to symptoms associated with gout such as acute arthritis, tophi, nephrolithiasis or urolithiasis and renal disease including renal failure. 5.7 Acute Inflammatory Syndrome Associated with Mycophenolate Products Acute inflammatory syndrome (AIS) has been reported with the use of MMF and mycophenolate products, and some cases have resulted in hospitalization. AIS is a paradoxical pro-inflammatory reaction characterized by fever, arthralgias, arthritis, muscle pain and elevated inflammatory markers including, C-reactive protein and erythrocyte sedimentation rate, without evidence of infection or underlying disease recurrence. Symptoms occur within weeks to months of initiation of treatment or a dose increase. After discontinuation, improvement of symptoms and

CONTRAINDICATIONS Mycophenolate mofetil capsules are contraindicated in patients with a history of hypersensitivity, including anaphylaxis, to mycophenolate mofetil (MMF), mycophenolic acid (MPA) or any component of the drug product [see Warnings and Precautions (5.8) ] . CELLCEPT ® Intravenous (mycophenolate mofetil) for injection is contraindicated in patients who are allergic to Polysorbate 80 (TWEEN). History of hypersensitivity, including anaphylaxis, to mycophenolate mofetil, mycophenolic acid or any component of the drug product ( 4 ) Patients allergic to Polysorbate 80 (present in CELLCEPT IV) ( 4 )

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. 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 admi

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Embryofetal Toxicity [see Warnings and Precautions (5.1) ] Lymphomas and Other Malignancies [see Warnings and Precautions 5.2) ] Serious Infections [see Warnings and Precautions (5.3) ] Blood Dyscrasias: Neutropenia, Pure Red Cell Aplasia [see Warnings and Precautions (5.4) ] Gastrointestinal Complications [see Warnings and Precautions (5.5) ] Acute Inflammatory Syndrome Associated with Mycophenolate Products s [see Warnings and Precautions (5.7) ] The most common adverse reactions in clinical trials (20 % or greater) include diarrhea, leukopenia, infection, vomiting, and there is evidence of a higher frequency of certain types of infections e.g., opportunistic infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.com 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. An estimated total of 1557 adult patients received mycophenolate mofetil during pivotal clinical trials in the prevention of acute organ rejection. Of these, 991 were included in the three renal studies, 277 were included in one hepatic study, and 289 were included in one cardiac study. Patients in all study arms also received cyclosporine and corticosteroids. The data described below primarily derive from five randomized, active-controlled double-blind 12-month trials of mycophenolate mofetil in de novo kidney (3) heart (1) and liver (1) transplant patients [see Clinical Studies (14.1 , 14.2, and 14.3) ] . Mycophenolate Mofetil Oral The incidence of adverse reactions for mycophenolate mofetil was determined in five randomized, comparative, double-blind trials in the prevention of rejection in kidney, heart and liver transplant patients (two active- and one placebo-controlled trials, one active-controlled trial, and one active-controlled trial, respectively) [see Clinical Studies (14.1 , 14.2 and 14.3) ] . The three de novo kidney studies with 12-month duration compared two dose levels of oral mycophenolate mofetil (1 g twice daily and 1.5 g twice daily) with azathioprine (2 studies) or placebo (1 study) when administered in combination with cyclosporine (Sandimmune ® ) and corticosteroids to prevent acute rejection episodes. One study also included anti-thymocyte globulin (ATGAM ®) induction therapy. In the de novo heart transplantation study with 12-month duration, patients received mycophenolate mofetil 1.5 g twice daily (n=289) or azathioprine 1.5 to 3 mg/kg/day (n=289), in combination with cyclosporine (Sandimmune ® or Neoral ® ) and corticosteroids as maintenance immunosuppressive therapy. In the de novo liver transplantation study with 12-month duration, patients received mycophenolate mofetil 1 g twice daily intravenously for up to 14 days followed by mycophenolate mofetil 1.5 g twice daily orally or azathioprine 1 to 2 mg/kg/day intravenously followed by azathioprine 1 to 2 mg/kg/day orally, in combination with cyclosporine (Neoral ® ) and corticosteroids as maintenance immunosuppressive therapy. The total number of patients enrolled was 565. Approximately 53% of the kidney transplant patients, 65% of the heart transplant patients, and 48% of the liver transplant patients were treated for more than 1 year. Adverse reactions reported in ≥ 20% of patients in the mycophenolate mofetil treatment groups are presented below. The safety data of three kidney transplantation studies are pooled together. Table 5 Adverse Reactions in Controlled Studies of De Novo Kidney, Heart or Liver Transplantation Reported in ≥20% of Patients in the Mycophenolate Mofetil Group Adverse drug reaction Kidney Studies Heart Study Liver Study Mycophenolate mofetil 2g/day (n=501) or 3g/day (n=490) AZA 1 to 2 mg/kg/day or 100 to 150 mg/day Placebo Mycophenolate mofetil 3g/day AZA 1.5 to 3 mg/kg/day Mycophenolate mofetil 3g/day AZA 1 to 2 mg/kg/day (n=991) (n=326) (n=166) (n=289) (n=289) (n=277) (n=287) System Organ Class % % % % % % % Infections and infestations Bacterial infections 39.9 33.7 37.3 - - 27.4 26.5 Viral infections - a ."-" Indicates that the incidence was below the cutoff value of 20% for inclusion in the table. - - 31.1 24.9 - - Blood and lymphatic system disorders Anemia 20.0 23.6 2.4 45.0 47.1 43.0 53.0 Ecchymosis - - - 20.1 9.7 - - Leukocytosis - - - 42.6 37.4 22.4 21.3 Leukopenia 28.6 24.8 4.2 34.3 43.3 45.8 39.0 Thrombocytopenia - - - 24.2 28.0 38.3 42.2 Metabolism and nutrition disorders Hypercholesterolemia - - - 46.0 43.9 - - Hyperglycemia - - - 48.4 53.3 43.7 48.8 Hyperkalemia - - - - - 22.0 23.7 Hypocalcemia - - - - - 30.0 30.0 Hypokalemia - - - 32.5 26.3 37.2 41.1 Hypomagnesemia - - - 20.1 14.2 39.0 37.6 Psychiatric disorders Depression - - - 20.1 15.2 - - Insomnia - - - 43.3 39.8 52.3 47.0 Nervous system disorders Dizziness - - - 34.3 33.9 - - Headache - - - 58.5 55.4 53.8 49.1 Tremor - - - 26.3 25.6 33.9 35.5 Cardiac disorders Tachycardia - - - 22.8 21.8 22.0 15.7 Vascular disorders Hypertension 27.5 32.2 19.3 78.9 74.0 62.1 59.6 Hypotension - - - 34.3 40.1 - - Respiratory, thoracic and mediastinal disorders Cough - - - 40.5 32.2 - - Dyspnea - - - 44.3 44.3 31.0 30.3 Pleural effusion - - - - - 34.3 35.9 Gastrointestinal disorders Abdominal pain 22.4 23.0 11.4 41.9 39.4 62.5 51.2 Constipation - - - 43.6 38.8 37.9 38.3 Decreased appetite - - - - - 25.3 17.1 Diarrhea 30.4 20.9 13.9 52.6 39.4 51.3 49.8 Dyspepsia - - - 22.1 22.1 22.4 20.9 Nausea - - - 56.1 60.2 54.5 51.2 Vomiting - - - 39.1 34.6 32.9 33.4 Hepatobiliary disorders Blood lactate dehydrogenase increased - - - 23.5 18.3 - - Hepatic enzyme increased - - - - - 24.9 19.2 Skin and subcutaneous tissues disorders Rash - - - 26.0 20.8 - - Renal and urinary disorders Blood creatinine increased - - - 42.2 39.8 - - Blood urea increased - - - 36.7 34.3 - - General disorders and administration site conditions Asthenia - - - 49.1 41.2 35.4 33.8 Edema b."Edema" includes peripheral edema, facial edema, scrotal edema. 21.0 28.2 8.4 67.5 55.7 48.4 47.7 Pain c."Pain" includes musculoskeletal pain (myalgia, neck pain, back pain). 24.8 32.2 9.6 79.2 77.5 74.0 77.5 Pyrexia - - - 56.4 53.6 52.3 56.1 In the three de novo kidney studies, patients receiving 2 g/day of mycophenolate mofetil had an overall better safety profile than did patients receiving 3 g/day of mycophenolate mofetil. Post-transplant lymphoproliferative disease (PTLD, pseudolymphoma) 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 kidney, heart and liver transplant patients followed for at least 1 year [see Warnings and Precautions (5.2) ]. 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 kidney and heart transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. In pediatric patients, PTLD was observed in 1.35% (2/148) by 12 months post-transplant. Cytopenias, including leukopenia, anemia, thrombocytopenia and pancytopenia are a known risk associated with mycophenolate and may lead or contribute to the occurrence of infections and hemorrhages [see Warnings and Precautions (5.3) ] . Severe neutropenia (ANC <0.5 × 10 3 /µL) developed in up to 2% of kidney transplant patients, up to 2.8% of heart transplant patients and up to 3.6% of liver transplant patients receiving mycophenolate mofetil 3 g daily [see Warnings and Precautions (5.4) and Dosage and Administration (2.5) ]. The most common opportunistic infections in patients receiving mycophenolate mofetil with other immu

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.