Mycophenilic Acid

FDA Drug Information • Also known as: Mycophenolic Acid

Brand Names: Mycophenolic Acid
Drug Class: Antimetabolite Immunosuppressant [EPC]
Route: ORAL
Dosage Form: TABLET, DELAYED RELEASE
Product Type: HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: EMBRYO-FETAL TOXICITY, MALIGNANCIES, AND SERIOUS INFECTIONS WARNING: EMBRYO-FETAL TOXICITY, MALIGNANCIES, AND SERIOUS INFECTIONS Use during pregnancy is associated with increased risks of pregnancy loss and congenital malformations. Avoid if safer treatment options are available. Females of reproductive potential must be counseled regarding pregnancy prevention and planning [see Warnings and Precautions (5.1) , Use in Specific Populations (8.1 , 8.3 ] . Increased risk of development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression [see Warnings and Precautions (5.3) ] . Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see Warnings and Precautions (5.4 , 5.5) ] . Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe mycophenolic acid delayed-release tablets. Patients receiving mycophenolic acid delayed-release tablets should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient [see Warnings and Precautions (5.2) ] . WARNING: EMBRYO-FETAL TOXICITY, MALIGNANCIES, AND SERIOUS INFECTIONS See full prescribing information for complete boxed warning Use during pregnancy is associated with increased risks of pregnancy loss and congenital malformations. Avoid if safer treatment options are available. Females of reproductive potential must be counseled regarding pregnancy prevention and planning. ( 5.1 , 8.1 , 8.3 ) Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe mycophenolic acid delayed-release tablets. ( 5.2 ) Increased risk of development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression. ( 5.3 ) Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections. ( 5.4 , 5.5 )

Description

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

What Is Mycophenilic Acid Used For?

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.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION In adults: 720 mg by mouth, twice daily (1440 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 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 > 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.

Side Effects (Adverse Reactions)

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) ] Hypersensitivity Reactions [see Warnings and Precautions (5.9) ] Rare Hereditary Deficiencies [see Warnings and Precautions (5.11) ] 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 RK Pharma Inc at 1-844-757-4276 (1-844-RKPHARM) 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 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 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 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:...

Drug Interactions

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...

Contraindications

4 CONTRAINDICATIONS History of hypersensitivity, including anaphylaxis, to mycophenolate sodium, mycophenolic acid (MPA), mycophenolate mofetil, or to any of its excipients ( 4 ) Mycophenolic acid delayed-release tablets are contraindicated in patients with a history of hypersensitivity, including anaphylaxis, to mycophenolate sodium, mycophenolic acid (MPA), mycophenolate mofetil, or to any of its excipients. [see Warnings and Precautions (5.9) , Adverse Reactions (6.2) ] .

Pregnancy and Breastfeeding

8.1 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 delayed-release tablets 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...

Overdosage

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 < 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Mycophenolic Acid Delayed-Release Tablets, USP are available containing mycophenolate sodium, USP equivalent to 180 mg or 360 mg of mycophenolic acid. The 180 mg tablets are sage green, film-coated, round, unscored tablets with M over MC1 imprinted in black ink on one side of the tablet and blank on the other side. They are available as follows: NDC 72819-155-08 bottle of 120 tablets The 360 mg tablets are reddish-orange, film-coated, modified capsule-shaped, unscored tablets with M over MC2 imprinted in black ink on one side of the tablet and blank on the other side. They are available as follows: NDC 72819-156-08 bottle of 120 tablets Storage: Store at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted between 15°C and 30°C (59°F and 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 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.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.