Mycophenolic Acid

Warnings and Precautions, New or Reactivated Viral Infections ( 5.5 ) 3/2022 Warnings and Precautions, Acute Inflammatory Syndrome Associated with Mycophenolate Products ( 5.7 ) 3/2022

1 INDICATIONS AND USAGE • Mycophenolic acid delayed-release tablets are 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.

2 DOSAGE AND ADMINISTRATION • 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 are 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 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). 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 greater than 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 less than 1.19 m 2 cannot be accurately administered using currently available formulations of mycophenolic acid delayed-release tablets.

3 DOSAGE FORMS AND STRENGTHS Mycophenolic acid delayed-release tablets, USP are available as 360 mg and 180 mg tablets. Table 1: Description of Mycophenolic acid delayed-release tablets Dosage Strength 180 mg tablet 360 mg tablet Active ingredient mycophenolic acid as mycophenolate sodium, USP mycophenolic acid as mycophenolate sodium, USP Appearance Lime green colored, round shaped, biconvex, film coated tablets Pale orange-red colored, oval shaped, biconvex, film coated tablets Imprint Imprinted “MA 180” with black ink on one side and plain on other side Imprinted “MA 360” with black ink on one side and plain on other side Mycophenolic acid delayed-release tablets are available as 180 mg and 360 mg tablets. ( 3 )

4 CONTRAINDICATIONS 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 ) ].

6 ADVERSE REACTIONS 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 Ascend Laboratories, LLC at 1-877-ASC-RX01 (877-272-7901 ) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 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 1.44grams 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 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 and MMF arms, respectively. The most frequent reasons for dose reduction in the mycophenolic acid 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 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** System organ class Adverse drug reactions mycophenolic acid 1.44 grams per day (n=213 …

7 DRUG INTERACTIONS 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 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 [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 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 [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 …

8 USE IN SPECIFIC POPULATIONS Male Patients: Sexually active male patients and/or their female partners are recommended to use effective contraception during treatment of the male patient and for at least 90 days after cessation of treatment. ( 8.3 ) 8.1 Pregnancy 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 of mycophenolic acid delayed-release tablets. Oral administration of mycophenolate to pregnant rabbits from Gestational Day 7 to Day 19 resulted in embryofetal 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. 8.2 Lactation Risk Summary There are no data on the presence of mycophenolate in human milk, or the effects on milk production. There are limited data in the National Transplantation Pregnancy Registry on the effects of mycophenolate on a breastfed child ( see Data) . Studies in rats treated with MMF have shown mycophenolic acid to be present in milk. Because available data are limited, it is not possible to exclude potential risks to a breastfeeding infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for mycophenolic acid delayed-release tablets and any potential adverse effects on the breastfed infant from mycophenolic acid or from the underlying maternal condition. Because available data are limited, it is not possible to exclude potential risks to a breastfeeding infant. …

12.1 Mechanism of Action Mycophenolic acid (MPA), an immunosuppressant, is an uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation to DNA. 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 cytostatic effects on lymphocytes. Mycophenolate sodium has been shown to prevent the occurrence of acute rejection in rat models of kidney and heart allotransplantation. Mycophenolate sodium also decreases antibody production in mice.

11 DESCRIPTION Mycophenolic acid delayed-release tablets, USP are an enteric formulation of mycophenolate sodium 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 empirical formula is C 17 H 19 O 6 Na. The molecular weight is 342.32 g/mol and the structural formula is: Mycophenolic acid delayed-release tablets, USP as the sodium salt, is a white to off-white, crystalline powder and is highly soluble in aqueous media at physiological pH and practically insoluble in 0.1 N 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 colloidal silicon dioxide, croscarmellose sodium, crospovidone, FD&C Blue No. 2 Aluminum Lake, hypromellose, hypromellose acetate succinate, magnesium stearate, maltodextrin, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, pregelatinized starch (corn), propylene glycol, sodium lauryl sulfate, talc, titanium dioxide and triethyl citrate. In addition, the 180 mg tablet strength contains yellow iron oxide and the 360 mg tablet strength contains FD&C Red No. 40 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake. In addition, the black imprinting ink contains black iron oxide, hypromellose and propylene glycol. The imprinting ink may also contain ammonium hydroxide and shellac glaze. structure

10 OVERDOSAGE 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 less than 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Mycophenolic acid delayed-release tablets, USP are supplied as: 180 mg tablet: Light green, round, slightly biconvex bevelled edge enteric coated tablet. Engraved “MYC” over “180” on one side, “APO” on the other side, containing 180 mg mycophenolic acid (MPA) as mycophenolate sodium. Bottles of 30............................................................NDC 60505-2965-3 Bottles of 60............................................................NDC 60505-2965-6 Bottles of 90............................................................NDC 60505-2965-9 Bottles of 100.......................................................... NDC 60505-2965-1 Bottles of 120.......................................................... NDC 60505-2965-7 Bottles of 500.......................................................... NDC 60505-2965-5 Bottles of 1,000......................................................... NDC 60505-2965-8 360 mg tablet: Light pink, oval, biconvex enteric coated tablet. Engraved “MYC 360” on one side, “APO” on the other side, containing 360 mg mycophenolic acid (MPA) as mycophenolate sodium. Bottles of 30............................................................NDC 60505-2966-3 Bottles of 60............................................................NDC 60505-2966-6 Bottles of 90............................................................NDC 60505-2966-9 Bottles of 100.......................................................... NDC 60505-2966-1 Bottles of 120.......................................................... NDC 60505-2966-7 Bottles of 500.......................................................... NDC 60505-2966-5 Bottles of 1,000......................................................... NDC 60505-2966-8 Storage Store at 20 °C to 25°C ( 68 °F to 77°F); excursions permitted from 15° C to 30°C (59° F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight container (USP). Handling Keep out of reach and sight of children. Mycophenolic acid delayed-release tablets, USP should not be crushed or cut in order to maintain the integrity of the enteric coating [see Dosage and Administration ( 2.3 )]. Teratogenic effects have been observed with mycophenolate sodium [see Warnings and Precautions ( 5.1 )] . If for any reason the mycophenolic acid delayed-release tablets must be crushed, avoid inhalation of the powder, or direct contact of the powder, with skin or mucous membranes.