Mycophenolic Acid Drug Information

Dosage in Adult Kidney Transplant Patients

The recommended dose of mycophenolic acid delayed-release tablets are 720 mg administered twice daily (1,440 mg total daily dose).

Dosage in Pediatric Kidney Transplant Patients

The recommended dose of mycophenolic acid in conversion (at least 6 months post-transplant) pediatric patients age 5 years and older is 400 mg/m 2 body surface area (BSA) administered twice daily (up to a maximum dose of 720 mg administered twice daily).

Administration Mycophenolic acid delayed-release tablets should be taken on an empty stomach

1 hour before or 2 hours after food intake. Mycophenolic acid delayed-release tablets should not be crushed, chewed, or cut prior to ingesting. The tablets should be swallowed whole in order to maintain the integrity of the enteric coating.

Pediatric patients with a BSA of 1.19 m 2 to 1.58 m 2 may be dosed either with three mycophenolic acid 180 mg tablets, or one 180 mg tablet plus one 360 mg tablet twice daily (1,080 mg daily dose). Patients with a BSA of > 1.58 m 2 may be dosed either with four mycophenolic acid 180 mg tablets, or two mycophenolic acid 360 mg tablets twice daily (1,440 mg daily dose). Pediatric doses for patients with BSA < 1.19 m 2 cannot be accurately administered using currently available formulations of mycophenolic acid tablets.

Clinical Studies 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. The data described below derive from two randomized, comparative, active-controlled, double-blind, double-dummy trials in prevention of acute rejection in de novo and converted stable kidney transplant patients. In the de novo trial, patients were administered either mycophenolic acid delayed-release tablets 1.44 grams per day (N = 213) or MMF 2 grams per day (N = 210) within 48 hours post-transplant for 12 months in combination with cyclosporine, USP MODIFIED and corticosteroids.

Forty-one percent of patients also received antibody therapy as induction treatment. In the conversion trial, renal transplant patients who were at least 6 months post-transplant and receiving 2 grams per day MMF in combination with cyclosporine USP MODIFIED, with or without corticosteroids for at least two weeks prior to entry in the trial were randomized to mycophenolic acid delayed-release tablets 1.44 grams per day (N = 159) or MMF 2 grams per day (N = 163) for 12 months. The average age of patients in both studies was 47 years and 48 years ( de novo study and conversion study, respectively), ranging from 22 to 75 years.

Approximately 66% of patients were male; 82% were white, 12% were black, and 6% other races. About 40% of patients were from the United States and 60% from other countries. In the de novo trial, the overall incidence of discontinuation due to adverse reactions was 18% (39/213) and 17% (35/210) in the mycophenolic acid delayed-release tablets and MMF arms, respectively.

The most common adverse reactions leading to discontinuation in the mycophenolic acid arm were graft loss (2%), diarrhea (2%), vomiting (1%), renal impairment (1%), CMV infection (1%), and leukopenia (1%). The overall incidence of patients reporting dose reduction at least once during the 0 to 12-month study period was 59% and 60% in the mycophenolic acid delayed-release tablets and MMF arms, respectively. The most frequent reasons for dose reduction in the mycophenolic acid delayed-release tablets arm were adverse reactions (44%), dose reductions according to protocol guidelines (17%), dosing errors (11%) and missing data (2%). The most common adverse reactions (≥ 20%) associated with the administration of mycophenolic acid delayed-release tablets were anemia, leukopenia, constipation, nausea, diarrhea, vomiting, dyspepsia, urinary tract infection, CMV infection, insomnia, and postoperative pain. The adverse reactions reported in ≥ 10% of patients in the de novo trial are presented in Table 2 below.

Table 2: Adverse Reactions (%) Reported in ≥ 10% of de novo Kidney Transplant Patients in Either Treatment Group de novo Renal Trial The trial was not designed to support comparative claims for mycophenolic acid for the adverse reactions reported in this table. System Organ Class Mycophenolic acid delayed-release tablets mycophenolate mofetil (MMF) Adverse drug reactions 1.44 grams per day 2 grams per day (n = 213) (%) (n = 210) (%) Blood and Lymphatic System Disorders Anemia 22 22 Leukopenia 19 21 Gastrointestinal System Disorders Constipation 38 40 Nausea 29 27 Diarrhea 24 25 Vomiting 23 20 Dyspepsia 23 19 Abdominal pain upper 14 14 Flatulence 10 13 General and Administrative Site Disorders Edema 17 18 Edema lower limb 16 17 Pyrexia 13 19 Investigations Increased blood creatinine 15 10 Infections and Infestations Urinary tract infection 29 33 CMV infection 20 18 Metabolism and Nutrition Disorders Hypocalcemia 11 15 Hyperuricemia 13 13 Hyperlipidemia 12 10 Hypokalemia 13 9 Hypophosphatemia 11 9 Musculoskeletal, Connective Tissue & Bone Disorders Back pain 12 6 Arthralgia 7 11 Nervous System Disorder Insomnia 24 24 Tremor 12 14 Headache 13 11 Vascular Disorders Hypertension 18 18 Table 3 summarizes the incidence of opportunistic infections in de novo transplant patients. Table 3: Viral and Fungal Infections (%) Reported Over 0 to 12 Months de novo Renal Trial Mycophenolic acid delayed-release tablets 1.44 grams per day (n = 213) (%) mycophenolate mofetil (MMF) 2 grams per day (n = 210) (%) Any Cytomegalovirus 22 21 - Cytomegalovirus Disease 5 4 Herpes Simplex 8 6 Herpes Zoster 5 4 Any Fungal Infection 11 12 - Candida NOS 6 6 - Candida albicans 2 4 Lymphoma developed in 2 de novo patients (1%), (1 diagnosed 9 days after treatment initiation) and in 2 conversion patients (1%) receiving mycophenolic acid delayed-release tablets with other immunosuppressive agents in the 12-month controlled clinical trials.

Nonmelanoma skin carcinoma occurred in 1% de novo and 12% conversion patients. Other types of malignancy occurred in 1% de novo and 1% conversion patients. The adverse reactions reported in less than 10% of de novo or conversion patients treated with mycophenolic acid delayed-release tablets in combination with cyclosporine and corticosteroids are listed in Table 4. Table 4: Adverse Reactions Reported in < 10% of Patients Treated with Mycophenolic Acid Delayed-Release Tablets in Combination With Cyclosporine USP MODIFIED and Corticosteroids Blood and Lymphatic Disorders Lymphocele, thrombocytopenia Cardiac Disorder Tachycardia Eye Disorder Vision blurred Gastrointestinal Disorders Abdominal pain, abdominal distension, gastroesophageal reflux disease, gingival hyperplasia General Disorders and Administration-Site Conditions Fatigue, peripheral edema Infections and Infestations Nasopharyngitis, herpes simplex, upper respiratory infection, oral candidiasis, herpes zoster, sinusitis, influenza, wound infection, implant infection, pneumonia, sepsis Investigations Hemoglobin decrease, liver function tests abnormal Metabolism and Nutrition Disorders Hypercholesterolemia, hyperkalemia, hypomagnesemia, diabetes mellitus, hyperglycemia, Musculoskeletal and Connective Tissue Disorders Arthralgia, pain in limb, peripheral swelling, muscle cramps, myalgia Nervous System Disorders Dizziness (excluding vertigo) Psychiatric Disorders Anxiety Renal and Urinary Disorders Renal tubular necrosis, renal impairment, hematuria, urinary retention Respiratory, Thoracic and Mediastinal Disorders Cough, dyspnea, dyspnea exertional Skin and Subcutaneous Tissue Disorders Acne, pruritus, rash Vascular Disorders Hypertension aggravated, hypotension The following additional adverse reactions have been associated with the exposure to MPA when administered as a sodium salt or as mofetil ester: Gastrointestinal: Intestinal perforation, gastrointestinal hemorrhage, gastric ulcers, duodenal ulcers, colitis (including CMV colitis), pancreatitis, esophagitis, and ileus.

Infections: Serious life-threatening infections, such as meningitis and infectious endocarditis, tuberculosis, and atypical mycobacterial infection. Respiratory: Interstitial lung disorders, including fatal pulmonary fibrosis.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of mycophenolic acid or other MPA derivatives. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Congenital malformations, including ear, facial, cardiac and nervous system malformations and an increased incidence of first trimester pregnancy loss have been reported following exposure to MMF during pregnancy. Infections Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal.

Polyomavirus associated nephropathy (PVAN), especially due to BK virus infection, associated with serious outcomes, including deteriorating renal function and renal graft loss. Viral reactivation in patients infected with HBV or HCV. Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives in combination with other immunosuppressive agents. The following additional adverse reactions have been identified during post-approval use of mycophenolic acid: agranulocytosis, asthenia, osteomyelitis, lymphadenopathy, lymphopenia, wheezing, dry mouth, gastritis, peritonitis, anorexia, alopecia, pulmonary edema, Kaposi’s sarcoma, de novo purine synthesis inhibitors-associated acute inflammatory syndrome.

Antacids With Magnesium and Aluminum Hydroxides

Concomitant use of mycophenolic acid delayed-release tablets and antacids decreased plasma concentrations of mycophenolic acid (MPA). It is recommended that mycophenolic acid delayed-release tablets and antacids not be administered simultaneously.

Azathioprine Given that azathioprine and

MMF inhibit purine metabolism, it is recommended that mycophenolic acid delayed-release tablets not be administered concomitantly with azathioprine or MMF.

Cholestyramine, Bile Acid Sequestrates, Oral Activated Charcoal and Other Drugs That Interfere

With Enterohepatic Recirculation Drugs that interrupt enterohepatic recirculation may decrease MPA plasma concentrations when coadministered with MMF. Therefore, do not administer mycophenolic acid delayed-release tablets with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, e.g., bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of mycophenolic acid delayed-release tablets.

Sevelamer

Concomitant administration of sevelamer and MMF may decrease MPA plasma concentrations. Sevelamer and other calcium-free phosphate binders should not be administered simultaneously with mycophenolic acid delayed-release tablets.

Cyclosporine Cyclosporine inhibits the enterohepatic recirculation of

MPA, and therefore, MPA plasma concentrations may be decreased when mycophenolic acid delayed-release tablets are coadministered with cyclosporine. Clinicians should be aware that there is also a potential change of MPA plasma concentrations after switching from cyclosporine to other immunosuppressive drugs or from other immunosuppressive drugs to cyclosporine in patients concomitantly receiving mycophenolic acid delayed-release tablets.

Norfloxacin and Metronidazole

MPA plasma concentrations may be decreased when MMF is administrated with norfloxacin and metronidazole. Therefore, mycophenolic acid delayed-release tablets are not recommended to be given with the combination of norfloxacin and metronidazole. Although there will be no effect on MPA plasma concentrations when mycophenolic acid delayed-release tablets are concomitantly administered with norfloxacin or metronidazole when given separately.

Rifampin

The concomitant administration of MMF and rifampin may decrease MPA plasma concentrations. Therefore, mycophenolic acid delayed-release tablets are not recommended to be given with rifampin concomitantly unless the benefit outweighs the risk.

Hormonal Contraceptives

In a drug interaction study, mean levonorgestrel AUC was decreased by 15% when coadministered with MMF. Although mycophenolic acid delayed-release tablets may not have any influence on the ovulation-suppressing action of oral contraceptives, additional barrier contraceptive methods must be used when mycophenolic acid delayed-release tablets are coadministered with hormonal contraceptives (e.g., birth control pill, transdermal patch, vaginal ring, injection, and implant).

Acyclovir (Valacyclovir), Ganciclovir (Valganciclovir), and Other Drugs That Undergo Renal Tubular Secretion

The coadministration of MMF and acyclovir or ganciclovir may increase plasma concentrations of mycophenolic acid glucuronide (MPAG) and acyclovir/valacyclovir/ganciclovir/valganciclovir as their coexistence competes for tubular secretion. Both acyclovir/valacyclovir/ganciclovir/valganciclovir and MPAG concentrations will be also increased in the presence of renal impairment. Acyclovir/valacyclovir/ganciclovir/valganciclovir may be taken with mycophenolic acid; however, during the period of treatment, physicians should monitor blood cell counts. 7.10 Ciprofloxacin, Amoxicillin Plus Clavulanic Acid and Other Drugs That Alter the Gastrointestinal Flora Drugs that alter the gastrointestinal flora, such as ciprofloxacin or amoxicillin plus clavulanic acid may interact with MMF by disrupting enterohepatic recirculation.

Interference of MPAG hydrolysis may lead to less MPA available for absorption when mycophenolic acid delayed-release tablet is concomitantly administered with ciprofloxacin or amoxicillin plus clavulanic acid. The clinical relevance of this interaction is unclear; however, no dose adjustment of mycophenolic acid delayed-release tablet is needed when coadministered with these drugs. 7.11 Pantoprazole Administration of pantoprazole at a dose of 40 mg twice daily for 4 days to healthy volunteers did not alter the pharmacokinetics of a single dose of mycophenolic acid delayed-release tablets.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to mycophenolate during pregnancy and those becoming pregnant within 6 weeks of discontinuing mycophenolic acid treatment. To report a pregnancy or obtain information about the registry, visit www.mycophenolateREMS.com or call 1-800-617-8191. Risk Summary Following oral or intravenous (IV) administration, MMF is metabolized to mycophenolic acid (MPA), the active ingredient in mycophenolic acid delayed-release tablets and the active form of the drug. Use of MMF during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of multiple congenital malformations in multiple organ systems (see Human Data). Oral administration of mycophenolate to rats and rabbits during the period of organogenesis produced congenital malformations and pregnancy loss at doses less than the recommended clinical dose (0.05 and 1.1 times exposure at the recommended clinical doses in kidney transplant patients for rats and rabbits, respectively) (see Animal Data). Risks and benefits of mycophenolic acid delayed-release tablets should be discussed with the patient.

When appropriate, consider alternative immunosuppressants with less potential for embryo-fetal toxicity. The estimated background risk of pregnancy loss and congenital malformations in organ transplant populations is not clear. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data Human Data A spectrum of congenital malformations (including multiple malformations in individual newborns) has been reported in 23% to 27% of live births in MMF exposed pregnancies, based on published data from pregnancy registries. Malformations that have been documented include external ear, eye, and other facial abnormalities, including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, kidney, and nervous system. Based on published data from pregnancy registries, the risk of first trimester pregnancy loss has been reported at 45% to 49% following MMF exposure.

Animal Data In animal reproductive toxicology studies, congenital malformations and pregnancy loss occurred when pregnant rats and rabbits received mycophenolate at dose multiples equivalent to and less than the recommended human dose. Oral administration of mycophenolate sodium to pregnant rats from Gestational Day 7 to Day 16 at a dose as low as 1 mg per kg resulted in malformations including anophthalmia, exencephaly, and umbilical hernia. The systemic exposure at this dose represents 0.05 times the clinical exposure at the human dose of 1,440 mg per day mycophenolic acid delayed-release tablets.

Oral administration of mycophenolate to pregnant rabbits from Gestational Day 7 to Day 19 resulted in embryo-fetal lethality and malformations, including ectopia cordis, ectopic kidneys, diaphragmatic hernia, and umbilical hernia at doses equal to or greater than 80 mg per kg per day, in the absence of maternal toxicity. This corresponds to about 1.1 times the recommended clinical dose based on BSA.

Pediatric Use The safety and effectiveness of mycophenolic acid delayed-release tablets have been established in pediatric kidney transplant patients 5 to 16 years of age who were initiated on mycophenolic acid delayed-release tablets at least 6 months post-transplant. Use of mycophenolic acid delayed-release tablets in this age group is supported by evidence from adequate and well-controlled studies of mycophenolic acid delayed-release tablets in a similar population of adult kidney transplant patients with additional pharmacokinetic data in pediatric kidney transplant patients . Pediatric doses for patients with BSA < 1.19 m 2 cannot be accurately administered using currently available formulations of mycophenolic acid delayed-release tablets. The safety and effectiveness of mycophenolic acid delayed-release tablets in de novo pediatric kidney transplant patients and in pediatric kidney transplant patients below the age of 5 years have not been established.

Hypersensitivity Reactions Mycophenolic acid delayed-release tablets are contraindicated in patients with a

hypersensitivity to mycophenolate sodium, mycophenolic acid (MPA), mycophenolate mofetil, or to any of its excipients. Reactions like rash, pruritus, hypotension, and chest pain have been observed in clinical trials and post marketing reports.

Signs and Symptoms There have been anecdotal reports of deliberate or accidental overdoses with mycophenolic acid delayed-release tablets, whereas not all patients experienced related adverse reactions. In those overdose cases in which adverse reactions were reported, the reactions fall within the known safety profile of the class. Accordingly, an overdose of mycophenolic acid delayed-release tablets could possibly result in oversuppression of the immune system and may increase the susceptibility to infection, including opportunistic infections, fatal infections and sepsis.

If blood dyscrasias occur (e.g., neutropenia with absolute neutrophil count < 1.5 x 10 3 /mcL or anemia), it may be appropriate to interrupt or discontinue mycophenolic acid delayed-release tablets. Possible signs and symptoms of acute overdose could include the following: hematological abnormalities, such as leukopenia and neutropenia, and gastrointestinal symptoms, such as abdominal pain, diarrhea, nausea and vomiting, and dyspepsia. Treatment and Management General supportive measures and symptomatic treatment should be followed in all cases of overdosage.

Although dialysis may be used to remove the inactive metabolite mycophenolic acid glucuronide (MPAG), it would not be expected to remove clinically significant amounts of the active moiety, mycophenolic acid, due to the 98% plasma protein binding of mycophenolic acid. By interfering with enterohepatic circulation of mycophenolic acid, activated charcoal or bile sequestrates, such as cholestyramine, may reduce the systemic mycophenolic acid exposure.