MYCOPHENOLIC ACID: 16,915 Adverse Event Reports & Safety Profile

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

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.

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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 &gt; 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 &lt; 1.19 m 2 cannot be accurately administered using currently available formulations of mycophenolic acid delayed-release tablets.

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) ] .

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: Adverse Reactions (%) Reported in ≥ 10% of de novo Kidney Transplant Patients in Either Treatment Group ** 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 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) (%) 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 bbone 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 [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 <span class="opacity-50 text-xs">[see Boxed Warning , Warnings and Precautions (5.1) ]</span> . Infections <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4 , 5.5) ]</span> 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6) ]</span> . Hypersensitivity reactions, including anaphylaxis and angioedema [ see Warnings and Precautions (5.9) ] 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.

AND PRECAUTIONS New or Reactivated Viral Infections: Consider reducing immunosuppression. ( 5.5 )

Blood

Dyscrasias, including Pure Red Cell Aplasia (PRCA): Monitor for neutropenia or anemia; consider treatment interruption or dose reduction. ( 5.6 ) Serious GI Tract Complications (gastrointestinal bleeding, perforations and ulcers): Administer with caution to patients with active digestive system disease. ( 5.7 )

Hypersensitivity

Reactions: Discontinue mycophenolic acid delayed-release tablets, treat and monitor until signs and symptoms resolve. ( 5.9 ) Immunizations: Avoid live attenuated vaccines. ( 5.10 ) Patients with Hereditary Deficiency of Hypoxanthine-guanine Phosphoribosyl-transferase (HGPRT): May cause exacerbation of disease symptoms; avoid use. ( 5.11 )

Blood

Donation: Avoid during therapy and for 6 weeks thereafter. ( 5.12 )

Semen

Donation: Avoid during therapy and for 90 days thereafter. ( 5.13 )

5.1 Embryo-Fetal Toxicity Use of mycophenolic acid delayed-release tablets 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 aware of these risks and must be counseled regarding pregnancy prevention and planning. Avoid use of mycophenolic acid delayed-release tablets during pregnancy if safer treatment options are available <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3 )]</span>

5.2 Management of Immunosuppression Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe mycophenolic acid delayed-release tablets. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physicians responsible for maintenance therapy should have complete information requisite for the follow-up of the patient <span class="opacity-50 text-xs">[see Boxed Warning ]</span> .

5.3 Lymphoma and Other Malignancies Patients receiving immunosuppressants, including mycophenolic acid delayed-release tablets, are at increased risk of developing lymphomas and other malignancies, particularly of the skin <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> . The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. As usual 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) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear 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.

5.4 Serious Infections Patients receiving immunosuppressants, including mycophenolic acid delayed-release tablets, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, and new or reactivated viral infections, including opportunistic infections <span class="opacity-50 text-xs">[see Warnings and Precautions (5.5) ]</span> . These infections may lead to serious, including fatal outcomes. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution.

5.5 New or Reactivated Viral Infections Polyomavirus associated nephropathy (PVAN), JC virus-associated progressive multifocal leukoencephalopathy (PML), cytomegalovirus (CMV) infections, reactivation of hepatitis B (HBV) or hepatitis C (HCV), SARS-CoV-2 infection, have been reported in patients treated with immunosuppressants, including the MPA derivatives mycophenolic acid delayed-release tablets and MMF. Reduction in immunosuppression should be considered for patients who develop evidence of new or reactivated viral infections. Physicians should also consider 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. 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. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated. 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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.

5.6 Blood Dyscrasias, Including Pure Red Cell Aplasia Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives in combination with other immunosuppressive agents. The mechanism for MPA derivatives induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppressive regimen is also unknown. In some cases, PRCA was found to be reversible with dose reduction or cessation of therapy with MPA derivatives. In transplant patients, however, reduced immunosuppression may place the graft at risk. Changes to mycophenolic acid delayed-release tablets therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimize the risk of graft rejection. Patients receiving mycophenolic acid delayed-release tablets should be monitored for blood dyscrasias (e.g., neutropenia or anemia). The development of neutropenia may be related to mycophenolic acid delayed-release tablets itself, concomitant medications, viral infections, or some combination of these reactions. Complete blood count should be performed weekly during the first month, twice monthly for the second and the third month of treatment, then monthly through the first year. If blood dyscrasias occur [neutropenia develops (ANC &lt; 1.3×10 3 /mcL) or anemia], dosing with mycophenolic acid delayed-release tablets should be interrupted or the dose reduced, appropriate tests performed, and the patient managed accordingly.

5.7 Serious GI Tract Complications Gastrointestinal bleeding (requiring hospitalization), intestinal perforations, gastric ulcers, and duodenal ulcers have been reported in patients treated with mycophenolic acid delayed-release tablets. Mycophenolic acid delayed-release tablets should be administered with caution in patients with active serious digestive system disease.

5.8 Acute Inflammatory Syndrome Associated With Mycophenolate Products Acute inflammatory syndrome (AIS) has been reported with the use of mycophenolate products, and some cases have been 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 inflammatory markers are usually observed within 24 to 48 hours. Monitor patients for symptoms and laboratory parameters of AIS when starting treatment with mycophenolate products or when increasing the dosage. Discontinue treatment and consider other treatment alternatives based on the risk and benefit for the patient.

5.9 Hypersensitivity Reactions Postmarketing cases of hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with mycophenolic acid delayed-release tablets. These reactions generally occurred within hours to the next day after initiating mycophenolic acid delayed-release tablets. If signs or symptoms of a hypersensitivity reaction occur, discontinue mycophenolic acid delayed release tablets; treat and monitor until signs and symptoms resolve <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.10 Immunizations During treatment with mycophenolic acid delayed-release tablets, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Advise patients to discuss with the physician before seeking any immunizations.

5.11 Rare Hereditary Deficiencies Mycophenolic acid delayed-release tablets are an inosine monophosphate dehydrogenase inhibitor (IMPDH Inhibitor). Mycophenolic acid delayed-release tablets should be avoided in patients with rare hereditary deficiency 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.

5.12 Blood Donation Patients should not donate blood during therapy and for at least 6 weeks following discontinuation of mycophenolic acid delayed-release tablets because their blood or blood products might be administered to a female of reproductive potential or a pregnant woman.

5.13 Semen Donation Based on animal data, men should not donate semen during therapy and for 90 days following discontinuation of mycophenolic acid delayed-release tablets [ see Use in Specific Populations (8.3) ].

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

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) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) , Use in Specific Populations ( 8.3 ), Clinical Pharmacology (12.3) ]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

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 are needed when co-administered with these drugs <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

7.11 Pantoprazole Administration of a 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

Drug Interactions

Antacids with Magnesium and Aluminum Hydroxides: Absorption of a single dose of mycophenolic acid delayed-release tablets was decreased when administered to 12 stable kidney transplant patients also taking magnesium-aluminum-containing antacids (30 mL): the mean C max and AUC (0-t) values for MPA were 25% and 37% lower, respectively, than when mycophenolic acid delayed-release tablets were administered alone under fasting conditions [see Drug Interactions (7.1) ] . Pantoprazole: In a trial conducted in 12 healthy volunteers, the pharmacokinetics of MPA were observed to be similar when a single dose of 720 mg of mycophenolic acid delayed-release tablets was administered alone and following concomitant administration of mycophenolic acid delayed-release tablets and pantoprazole, which was administered at a dose of 40 mg twice daily for 4 days [see Drug Interactions (7.11) ] .