MYCOPHENOLIC ACID

Mycophenolic acid delayed-release tablets, USP are an enteric formulation of mycophenolate sodium, USP that delivers the active moiety mycophenolic acid (MPA). Mycophenolic acid is an immunosuppressive agent. As the sodium salt, MPA is chemically designated as (E)-6-(4‑hydroxy‑6-methoxy-7-methyl-3- oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid sodium salt. Its molecular formula is C 17 H 19 O 6 Na. The molecular weight is 342.32 g/mol and the structural formula is: Mycophenolic acid, as the sodium salt, is a white to off-white, crystalline powder and is slightly soluble in water and practically insoluble in 0.1N hydrochloric acid. Mycophenolic acid is available for oral use as delayed-release tablets containing either 180 mg or 360 mg of mycophenolic acid. Inactive ingredients include anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, magnesium stearate, povidone (K-30), and pregelatinized starch. The enteric coating of the tablet consists of ferric oxide yellow, hypromellose phthalate, titanium dioxide, and FD&C blue no. 2 (180 mg) or ferric oxide red (360 mg). The imprinting ink consist of ammonium hydroxide, ferrosoferric oxide, propylene glycol, and shellac glaze. image description

Mycophenolic acid is an antimetabolite immunosuppressant indicated for prophylaxis of organ rejection in adult patients receiving kidney transplants and in pediatric patients at least 5 years of age and older who are at least 6 months post kidney transplant. ( 1.1 ) Use in combination with cyclosporine and corticosteroids. ( 1.1 ) Limitations of Use: Mycophenolic acid delayed-release tablets and mycophenolate mofetil tablets and capsules should not be used interchangeably. ( 1.2 ) 1.1 Prophylaxis of Organ Rejection in Kidney Transplant Mycophenolic acid delayed-release tablets are indicated for the prophylaxis of organ rejection in adult patients receiving a kidney transplant. Mycophenolic acid delayed-release tablets are indicated for the prophylaxis of organ rejection in pediatric patients 5 years of age and older who are at least 6 months post kidney transplant. Mycophenolic acid delayed-release tablets are to be used in combination with cyclosporine and corticosteroids. 1.2 Limitations of Use Mycophenolic acid delayed-release tablets and mycophenolate mofetil (MMF) tablets and capsules should not be used interchangeably without physician supervision because the rate of absorption following the administration of these two products is not equivalent.

In adults: 720 mg by mouth, twice daily (1,440 mg total daily dose) on an empty stomach, 1 hour before or 2 hours after food intake. ( 2.1 ) In children: 5 years of age and older (who are at least 6 months post kidney transplant), 400 mg/m 2 by mouth, twice daily (up to a maximum of 720 mg twice daily). ( 2.2 ) Do not crush, chew, or cut tablet prior to ingestion. ( 2.3 ) 2.1 Dosage in Adult Kidney Transplant Patients The recommended dose of mycophenolic acid delayed-release tablets is 720 mg administered twice daily (1,440 mg total daily dose). 2.2 Dosage in Pediatric Kidney Transplant Patients The recommended dose of mycophenolic acid delayed-release tablets in conversion (at least 6 months post‑transplant) pediatric patients aged 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). 2.3 Administration Mycophenolic acid delayed-release tablets should be taken on an empty stomach, 1 hour before or 2 hours after food intake [see Clinical Pharmacology (12.3) ] . 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 delayed‑release 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 delayed‑release 180 mg tablets, or two mycophenolic acid delayed‑release 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 delayed-release tablets.

Known hypersensitivity to mycophenolate sodium, mycophenolic acid (MPA), mycophenolate mofetil, or to any of its excipients. ( 4.1 ) 4.1 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 [see Adverse Reactions (6) ].

The following adverse reactions are discussed in greater detail in other sections of the label. Embryo-Fetal Toxicity [see Boxed Warning , Warnings and Precautions (5.1) ] Lymphomas and Other Malignancies [see Boxed Warning , Warnings and Precautions (5.3) ] Serious Infections [see Boxed Warning , Warnings and Precautions (5.4) ] New or Reactivated Viral Infections [see Warnings and Precautions (5.5) ] Blood Dyscrasias, Including Pure Red Cell Aplasia [see Warnings and Precautions (5.6) ] Serious GI Tract Complications [see Warnings and Precautions (5.7) ] Acute Inflammatory Syndrome Associated with Mycophenolate Products [see Warnings and Precautions (5.8) ] Rare Hereditary Deficiencies [see Warnings and Precautions (5.10) ] Most common adverse reactions (≥ 20%): anemia, leukopenia, constipation, nausea, diarrhea, vomiting, dyspepsia, urinary tract infection, CMV infection, insomnia, and postoperative pain. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Biocon Pharma Inc., at 1-866-924-6266 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.com. 6.1 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 years 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 delayed‑release tablets 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-month 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 delayed-release tablets for the adverse reactions reported in this table. System Organ Class Adverse drug reactions Mycophenolic Acid Delayed-Release Tablets 1.44 grams per day (n = 213) (%) Mycophenolate Mofetil (MMF) 2 grams per day (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 and 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 Month 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 [see Warnings and Precautions (5.3) ]. 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 [see Warnings and Precautions (5.7) ], colitis (including CMV colitis), pancreatitis, esophagitis, and ileus. Infections: Serious life-threatening infections, such as meningitis and infectious endocarditis, tuberculosis, and atypical mycobacterial infection [see Warnings and Precautions (5.4) ]. Respiratory: Interstitial lung disorders, including fatal pulmonary fibrosis. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of mycophenolic acid delayed‑release tablets 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 [see Boxed Warning , Warnings and Precautions (5.1) ] . Infections [see Warnings and Precautions ( 5.4 , 5.5 )] 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 [ see Warnings and Precautions ( 5.6 )] . The following additional adverse reactions have been identified during post-approval use of mycophenolic acid delayed‑release tablets: 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: Decreases concentrations of MPA; concomitant use is not recommended. ( 7.1 ) Azathioprine: Competition for purine metabolism; concomitant administration is not recommended. ( 7.2 ) Cholestyramine, Bile Acid Sequestrates, Oral Activated Charcoal, and Other Drugs that Interfere with Enterohepatic Recirculation: May decrease MPA concentrations; concomitant use is not recommended. ( 7.3 ) Sevelamer: May decrease MPA concentrations; concomitant use is not recommended. ( 7.4 ) Cyclosporine: May decrease MPA concentrations; exercise caution when switching from cyclosporine to other drugs or from other drugs to cyclosporine. ( 7.5 ) Norfloxacin and Metronidazole: May decrease MPA concentrations; concomitant use with both drugs is not recommended. ( 7.6 ) Rifampin: May decrease MPA concentrations; concomitant use is not recommended unless the benefit outweighs the risk. ( 7.7 ) Hormonal Contraceptives: May reduce the effectiveness of oral contraceptives. Additional barrier contraceptive methods must be used. ( 5.2 , 7.8 ) Acyclovir, Valacyclovir, Ganciclovir, Valganciclovir, and Other Drugs that Undergo Renal Tubular Secretion: May increase concentrations of mycophenolic acid glucuronide (MPAG) and co-administered drug; monitor blood cell counts. ( 7.9 ) 7.1 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 [see Clinical Pharmacology (12.3) ]. 7.2 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. 7.3 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 co‑administered 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 [see Clinical Pharmacology (12.3) ]. 7.4 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 [see Clinical Pharmacology (12.3) ]. 7.5 Cyclosporine Cyclosporine inhibits the enterohepatic recirculation of MPA, and therefore, MPA plasma concentrations may be decreased when mycophenolic acid delayed‑release tablets are co‑administered 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 [see Clinical Pharmacology (12.3) ]. 7.6 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 [see Clinical Pharmacology (12.3) ]. 7.7 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 [see Clinical Pharmacology (12.3) ]. 7.8 Hormonal Contraceptives In a drug interaction study, mean levonorgestrel AUC was decreased by 15% when co‑administered 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 co‑administered with hormonal contraceptives (e.g., birth control pill, transdermal patch, vaginal ring, injection, and implant) [see Warnings and Precautions (5.1) , Use in Specific Populations (8.3) , Clinical Pharmacology (12.3) ]. 7.9 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 delayed‑release tablets; however, during the period of treatment, physicians should monitor blood cell counts [see Clinical Pharmacology (12.3) ]. 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 tablets 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 tablets is needed when co-administered with these drugs [see Clinical Pharmacology (12.3) ]. 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 [see Clinical Pharmacology (12.3) ].