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Mycodr-r4mex

HIGHLIGHTS OF PRESCRIBING INFORMATION
ter with caution to patients with active digestive system disease. (5.8) • Immunizations: Avoid live vaccines. (5.9) These highlights do not include all the information needed to use mycophenolic acid
delayed-release tablets safely and effectively. See full prescribing information for

• Patients with Hereditary Deficiency of Hypoxanthine-guanine Phosphoribosyl-transferase mycophenolic acid delayed-release tablets.
(HGPRT): May cause exacerbation of disease symptoms; avoid use. (5.10) MYCOPHENOLIC ACID delayed-release tablets, for oral use
------------------------------------- ADVERSE REACTIONS -------------------------------------
Initial U.S. Approval: 2004
Most common adverse reactions (≥ 20%): anemia, leukopenia, constipation, nausea, diarrhea,vomiting, dyspepsia, urinary tract infection, CMV infection, insomnia, and postoperative pain.
WARNING: EMBRYOFETAL TOXICITY, MALIGNANCIES, AND SERIOUS INFECTIONS
See full prescribing information for complete boxed warning
To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at
• Use during pregnancy is associated with increased risks of pregnancy loss and con-
1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
genital malformations. Females of reproductive potential must be counseled regarding
------------------------------------- DRUG INTERACTIONS -------------------------------------
pregnancy prevention and planning. (5.1, 8.1, 8.6)
• Antacids with Magnesium and Aluminum Hydroxides: Decreases concentrations of mycophe- • Increased risk of development of lymphoma and other malignancies, particularly of the
nolic acid (MPA); concomitant use is not recommended. (7.1) skin, due to immunosuppression. (5.4)
• Azathioprine: Competition for purine metabolism; concomitant administration is not recom- • Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including
opportunistic infections. (5.5, 5.6)
• Cholestyramine, Bile Acid Sequestrates, Oral Activated Charcoal, and Other Drugs that Inter- • Only physicians experienced in immunosuppressive therapy and management of organ
fere with Enterohepatic Recirculation: May decrease MPA concentrations; concomitant use is transplant patients should prescribe mycophenolic acid delayed-release tablets. (5.3)
• Sevelamer: May decrease MPA concentrations; concomitant use is not recommended. (7.4) ----------------------------------- RECENT MAJOR CHANGES -----------------------------------
• Cyclosporine: May decrease MPA concentrations; exercise caution when switching from Warnings and Precautions, New or Reactivated Viral Infections (5.6) cyclosporine to other drugs or from other drugs to cyclosporine. (7.5) ----------------------------------- INDICATIONS AND USAGE -----------------------------------
• Norfloxacin and Metronidazole: May decrease MPA concentrations; concomitant use with both • Mycophenolic acid delayed-release tablets are an antimetabolite immunosuppressant indi- cated for prophylaxis of organ rejection in adult patients receiving kidney transplants and in • Rifampin: May decrease MPA concentrations; concomitant use is not recommended unless pediatric patients at least 5 years of age and older who are at least 6 months post kidney • Hormonal Contraceptives: Additional barrier contraceptive methods must be used. (5.2, 7.8) • Use in combination with cyclosporine and corticosteroids. (1.1) • Acyclovir, Valacyclovir, Ganciclovir, Valganciclovir, and Other Drugs that Undergo Renal Tubu- lar Secretion: May increase concentrations of mycophenolic acid glucuronide (MPAG) and • Mycophenolic acid delayed release tablets and mycophenolate mofetil tablets and capsules coadministered drug; monitor blood cell counts. (7.9) should not be used interchangeably. (1.2) -------------------------------- USE IN SPECIFIC POPULATION --------------------------------
-------------------------------- DOSAGE AND ADMINISTRATION -------------------------------- • Pregnancy: Can cause fetal harm. (5.1, 8.1)
• In adults: 720 mg by mouth, twice daily (1440 mg total daily dose) on an empty stomach, one • Nursing Mothers: Discontinue drug or discontinue nursing while on treatment or within 6 hour before or 2 hours after food intake. (2.1) weeks after stopping therapy, taking into consideration the importance of the drug to the • In children: 5 years of age and older (who are at least 6 months post kidney transplant), 400 mg/m2 by mouth, twice daily (up to a maximum of 720 mg twice daily). (2.2) • Females of reproductive potential must be counseled regarding pregnancy prevention and • Do not crush, chew, or cut tablet prior to ingestion. (2.3) ------------------------------ DOSAGE FORMS AND STRENGTHS --------------------------------
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide
Mycophenolic acid delayed-release tablets are available as 180 mg and 360 mg tablets. (3) ------------------------------------- CONTRAINDICATIONS -------------------------------------
REVISED OCTOBER 2013
Known hypersensitivity to mycophenolate sodium, mycophenolic acid, mycophenolate mofetil, or MYCODR:R4m/MG:MYCODR:R3m
------------------------------- WARNINGS AND PRECAUTIONS ---------------------------------
• New or Reactivated Viral Infections: Consider reducing immunosuppression. (5.6)• Blood Dyscrasias including Pure Red Cell Aplasia (PRCA): Monitor for neutropenia or anemia; consider treatment interruption or dose reduction. (5.7) • Serious GI Tract Complications (gastrointestinal bleeding, perforations and ulcers): Adminis- FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: EMBRYOFETAL TOXICITY, MALIGNANCIES, AND
DRUG INTERACTIONS
13 NONCLINICAL TOXICOLOGY
SERIOUS INFECTIONS
Antacids with Magnesium and Aluminum Hydroxides 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility INDICATIONS AND USAGE
14 CLINICAL STUDIES
Prophylaxis of Organ Rejection in Kidney Transplant Cholestyramine, Bile Acid Sequestrates, Oral Activat- 14.1 Prophylaxis of Organ Rejection in Patients Re ceiv ing ed Charcoal and Other Drugs that Interfere with DOSAGE AND ADMINISTRATION
16 HOW SUPPLIED/STORAGE AND HANDLING
Dosage in Adult Kidney Transplant Patients 17 PATIENT COUNSELING INFORMATION
Dosage in Pediatric Kidney Transplant Patients * Sections or subsections omitted from the full prescribing information are DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
Acyclovir (Valacyclovir), Ganciclovir (Valganciclovir),and Other Drugs that Undergo Renal Tubular Secretion 7.10 Ciprofloxacin, Amoxicillin plus Clavulanic Acid and WARNINGS AND PRECAUTIONS
Other Drugs that Alter the Gastrointestinal Flora Pregnancy Exposure Prevention and Planning USE IN SPECIFIC POPULATIONS
Blood Dyscrasias Including Pure Red Cell Aplasia 10 OVERDOSAGE
11 DESCRIPTION
ADVERSE REACTIONS
12 CLINICAL PHARMACOLOGY
FULL PRESCRIBING INFORMATION
WARNINGS AND PRECAUTIONS
Embryofetal Toxicity
WARNING: EMBRYOFETAL TOXICITY, MALIGNANCIES, AND SERIOUS INFECTIONS
Use of mycophenolic acid delayed-release tablets during pregnancy is associated with an • Use during pregnancy is associated with increased risks of pregnancy loss and con-
increased risk of first trimester pregnancy loss and an increased risk of congenital malfor- genital malformations. Females of reproductive potential must be counseled regard-
mations, especially external ear and other facial abnormalities including cleft lip and palate, ing pregnancy prevention and planning [see Warnings and Precautions (5.1), Use in
and anomalies of the distal limbs, heart, esophagus, and kidney [see Use in Specific Popula- Specific Populations (8.1, 8.6)].
• Increased risk of development of lymphoma and other malignancies, particularly of
Pregnancy Exposure Prevention and Planning
the skin, due to immunosuppression [see Warnings and Precautions (5.4)].
Females of reproductive potential must be aware of the increased risk of first trimester preg- • Increased susceptibility to bacterial, viral, fungal, and protozoal infections, includ-
nancy loss and congenital malformations and must be counseled regarding pregnancy pre- ing opportunistic infections [see Warnings and Precautions (5.5, 5.6].
vention and planning. For recommended pregnancy testing and contraception methods [seeUse in Specific Populations (8.6)]. • Only physicians experienced in immunosuppressive therapy and management of
organ transplant patients should prescribe mycophenolic acid delayed-release
Management of Immunosuppression
tablets. Patients receiving mycophenolic acid delayed-release tablets should be
Only physicians experienced in immunosuppressive therapy and management of organ managed in facilities equipped and staffed with adequate laboratory and supportive
transplant patients should prescribe mycophenolic acid delayed-release tablets. Patients medical resources. The physician responsible for maintenance therapy should have
receiving the drug should be managed in facilities equipped and staffed with adequate lab- complete information requisite for the follow-up of the patient [see Warnings and
oratory and supportive medical resources. The physicians responsible for maintenance ther- Precautions (5.3)].
apy should have complete information requisite for the follow-up of the patient [see BoxedWarning].
INDICATIONS AND USAGE
Lymphoma and Other Malignancies
Prophylaxis of Organ Rejection in Kidney Transplant
Patients receiving immunosuppressants, including mycophenolic acid delayed-releasetablets, are at increased risk of developing lymphomas and other malignancies, particularly Mycophenolic acid delayed-release tablets are indicated for the prophylaxis of organ rejection of the skin [see Adverse Reactions (6)]. The risk appears to be related to the intensity and in adult patients receiving a kidney transplant. duration of immunosuppression rather than to the use of any specific agent. Mycophenolic acid delayed-release tablets are indicated for the prophylaxis of organ rejection As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light in pediatric patients 5 years of age and older who are at least 6 months post kidney trans- should be limited by wearing protective clothing and using a sunscreen with a high protection Mycophenolic acid delayed-release tablets are to be used in combination with cyclosporine Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear related to Epstein Barr Virus Limitations of Use
(EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seroneg- Mycophenolic acid delayed-release tablets and mycophenolate mofetil (MMF) tablets and cap- ative, a population which includes many young children. sules should not be used interchangeably without physician supervision because the rate of Serious Infections
absorption following the administration of these two products is not equivalent. Patients receiving immunosuppressants, including mycophenolic acid delayed-release DOSAGE AND ADMINISTRATION
tablets, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, Dosage in Adult Kidney Transplant Patients
and new or reactivated viral infections including opportunistic infections [see Warnings andPre cautions (5.6)]. These infections may lead to serious, including fatal outcomes. Because of The recommended dose of mycophenolic acid delayed-release tablets is 720 mg administered the danger of oversuppression of the immune system which can increase susceptibility to twice daily (1440 mg total daily dose).
infection, combination im mu no suppressant therapy should be used with caution. Dosage in Pediatric Kidney Transplant Patients
New or Reactivated Viral Infections
The recommended dose of mycophenolic acid delayed-release tablets in conversion (at least Polyomavirus associated nephropathy (PVAN), JC virus associated progressive multifocal 6 months post-transplant) pediatric patients age 5 years and older is 400 mg/m2 body sur- leukoencephalopathy (PML), cytomegalovirus (CMV) infections, reactivation of hepatitis B face area (BSA) administered twice daily (up to a maximum dose of 720 mg administered (HBV) or hepatitis C (HCV) have been reported in patients treated with immunosuppressants, including the mycophenolic acid (MPA) derivatives mycophenolic acid delayed-release tablets Administration
and MMF. Reduction in immunosuppression should be considered for patients who develop Mycophenolic acid delayed-release tablets should be taken on an empty stomach, one hour evidence of new or reactivated viral infections. Physicians should also consider the risk that before or 2 hours after food intake [see Clinical Pharmacology (12.3)]. reduced immunosuppression represents to the functioning allograft. Mycophenolic acid delayed-release tablets should not be crushed, chewed, or cut prior to PVAN, especially due to BK virus infection, is associated with serious outcomes, including ingesting. The tablets should be swallowed whole in order to maintain the integrity of the deteriorating renal function and renal graft loss. Patient monitoring may help detect patients Pediatric patients with a BSA of 1.19 to 1.58 m2 may be dosed either with three mycopheno- PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, lic acid delayed-release 180 mg tablets, or one 180 mg tablet plus one 360 mg tablet twice cognitive deficiencies, and ataxia. Risk factors for PML include treatment with immuno- daily (1080 mg daily dose). Patients with a BSA of > 1.58 m2 may be dosed either with four suppressant therapies and impairment of immune function. In immunosuppressed mycophenolic acid delayed-release 180 mg tablets, or two mycophenolic acid delayed- patients, physicians should consider PML in the differential diagnosis in patients reporting release 360 mg tablets twice daily (1440 mg daily dose). Pediatric doses for patients with neurological symptoms and consultation with a neurologist should be considered as clini- BSA < 1.19 m2 cannot be accurately administered using currently available formulations of mycophenolic acid delayed-release tablets.
The risk of CMV viremia and CMV disease is highest among transplant recipients seroneg-ative for CMV at time of transplant who receive a graft from a CMV seropositive donor.
DOSAGE FORMS AND STRENGTHS
Therapeutic approaches to limiting CMV disease exist and should be routinely provided.
Mycophenolic acid delayed-release tablets are available as 180 mg and 360 mg tablets. Patient monitoring may help detect patients at risk for CMV disease [see Adverse Reac- Table 1. Description of Mycophenolic Acid Delayed-Release Tablets
tions (6.1)].
Viral reactivation has been reported in patients infected with HBV or HCV. Monitoring Dosage Strength
180 mg tablet
360 mg tablet
infected patients for clinical and laboratory signs of active HBV or HCV infection is rec- Blood Dyscrasias Including Pure Red Cell Aplasia
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA deriv- atives in combination with other immunosuppressive agents. The mechanism for MPA deriv-atives induced PRCA is unknown; the relative contribution of other immunosuppressants and M over MC1 on one side of
M MC2 on one side of the
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 tablet therapy should only be undertaken CONTRAINDICATIONS
under appropriate supervision in transplant recipients in order to minimize the risk of graft Hypersensitivity Reactions
Mycophenolic acid delayed-release tablets are contraindicated in patients with a hypersensi- Patients receiving mycophenolic acid delayed-release tablets should be monitored for blood tivity to mycophenolate sodium, mycophenolic acid, mycophenolate mofetil, or to any of its dyscrasias (e.g., neutropenia or anemia). The development of neutropenia may be related excipients. Reactions like rash, pruritus, hypotension, and chest pain have been observed in to mycophenolic acid delayed-release tablets itself, concomitant medications, viral infec- clinical trials and post-marketing reports [see Adverse Reactions (6)]. tions, 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 treat- Table 2. Adverse Reactions (%) in Reported in ≥ 10% of De Novo Kidney Transplant
ment, then monthly through the first year. If blood dyscrasias occur [neutropenia develops Patients in Either Treatment Group
(ANC < 1.3×103/mcL) or anemia], dosing with mycophenolic acid delayed-release tablets System organ class
de novo Renal Trial
should be interrupted or the dose reduced, appropriate tests performed, and the patient Mycophenolic Acid
Mycophenolate Mofetil
Delayed-release Tablets
Serious GI Tract Complications
1.44 grams per day
2 grams per day
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 cau- Blood and Lymphatic System Disorders
tion in patients with active serious digestive system disease.
5.9
Immunizations
The use of live attenuated vaccines should be avoided during treatment with mycophenolic acid delayed-release tablets; examples include (but not limited to) the following: intranasal Gastrointestinal System Disorders
influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid 5.10 Rare Hereditary Deficiencies
Mycophenolic acid delayed-release tablets are an inosine monophosphate dehydrogenase inhibitor (IMPDH Inhibitor). Mycophenolic acid delayed-release tablets should be avoided inpatients 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, nephrolithi- General and Administrative Site Disorders
asis or urolithiasis and renal disease including renal failure. ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the label. • Embryofetal Toxicity [see Boxed Warning, Warnings and Precautions (5.1)] Investigations
• Lymphomas and Other Malignancies [see Boxed Warning, Warnings and Precautions (5.4)] • Serious Infections [see Boxed Warning, Warnings and Precautions (5.5)] Infections and Infestations
• New or Reactivated Viral Infections [see Warnings and Precautions (5.6)] • Blood Dyscrasias Including Pure Red Cell Aplasia [see Warnings and Precautions (5.7)] • Serious GI Tract Complications [see Warnings and Precautions (5.8)] Metabolism and Nutrition Disorders
• Rare Hereditary Deficiencies [see Warnings and Precautions (5.10)] 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 tri- als of another drug and may not reflect the rates observed in practice. The data described below derive from two randomized, comparative, active-controlled, dou-ble-blind, double-dummy trials in prevention of acute rejection in de novo and converted sta- Musculoskeletal, Connective Tissue and Bone Disorders
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- Nervous System Disorders
transplant for 12 months in combination with cyclosporine, USP MODIFIED and corticos- teroids. 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-transplantand receiving 2 grams per day MMF in combination with cyclosporine USP MODIFIED, with or without corticosteroids for at least 2 weeks prior to entry in the trial were randomized to Vascular Disorders
mycophenolic acid delayed-release tablets 1.44 grams per day (n = 159) or MMF 2 grams per ** The trial was not designed to support comparative claims for mycophenolic acid delayed-release tablets The average age of patients in both studies was 47 years and 48 years (de novo study and for the adverse reactions reported in this table.
conversion study, respectively), ranging from 22 to 75 years. Approximately 66% of patients Table 3 summarizes the incidence of opportunistic infections in de novo transplant patients.
were male; 82% were white, 12% were black, and 6% other races. About 40% of patients were Table 3. Viral and Fungal Infections (%) Reported Over 0 to 12 Months
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% de novo Renal Trial
(39/213) and 17% (35/210) in the mycophenolic acid delayed-release tablets and MMF arms, Mycophenolic Acid
Mycophenolate Mofetil
respectively. The most common adverse reactions leading to discontinuation in the mycophe- Delayed-release Tablets
nolic acid delayed-release tablets arm were graft loss (2%), diarrhea (2%), vomiting (1%), 1.44 grams per day
2 grams per day
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 myco - phenolic acid delayed-release tablets were anemia, leukopenia, constipation, nausea, diar-rhea, vomiting, dyspepsia, urinary tract infection, CMV infection, insomnia and postoperative The adverse reactions reported in ≥ 10% of patients in the de novo trial are presented in Table Lymphoma developed in two de novo patients (1%), (one diagnosed 9 days after treatment ini- tiation) and in two conversion patients (1%) receiving mycophenolic acid delayed-releasetablets with other immunosuppressive agents in the 12-month controlled clinical trials. Nonmelanoma skin carcinoma occurred in 1% de novo and 12% conversion patients. Othertypes of malignancy occurred in 1% de novo and 1% conversion patients [see Warnings andPre cau tions (5.4)]. The adverse reactions reported in < 10% of de novo or conversion patients treated withmycophenolic acid delayed-release tablets in combination with cyclosporine and corticos-teroids are listed in Table 4.
Table 4. Adverse Reactions Reported in < 10% of Patients Treated with Mycophenolic Acid
release tablets with cholestyramine or other agents that may interfere with enterohepatic Delayed-release Tablets in Combination with Cyclosporine* and Corticosteroids
recirculation or drugs that may bind bile acids, e.g., bile acid sequestrates or oral activatedcharcoal, because of the potential to reduce the efficacy of mycophenolic acid delayed-release tablets [see Clinical Pharmacology (12.3)]. Sevelamer
Concomitant administration of sevelamer and MMF may decrease MPA plasma concentra- tions. Sevelamer and other calcium free phosphate binders should not be administered simul- taneously with mycophenolic acid delayed-release tablets [see Clinical Pharmacology (12.3)]. Cyclosporine
General Disorders and Administration Site Fatigue, peripheral edema Cyclosporine inhibits the enterohepatic recirculation of MPA, and therefore, MPA plasma con- centrations may be decreased when mycophenolic acid delayed-release tablets are coadmin- istered with cyclosporine. Clinicians should be aware that there is also a potential change of respiratory infection, oral candidiasis, 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)]. Norfloxacin and Metronidazole
Hemoglobin decrease, liver function tests MPA plasma concentrations may be decreased when MMF is administrated with norfloxacin and metronidazole. Therefore, mycophenolic acid delayed-release tablets are not recommend-ed 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 Arthralgia, pain in limb, peripheral swelling, Rifampin
The concomitant administration of MMF and rifampin may decrease MPA plasma concentra- tions. Therefore, mycophenolic acid delayed-release tablets are not recommended to be given with rifampin concomitantly unless the benefit outweighs the risk [see Clinical Pharmacology Renal tubular necrosis, renal impairment, Hormonal Contraceptives
In a drug interaction study, mean levonorgestrel AUC was decreased by 15% when coadmin- istered with MMF. Although mycophenolic acid delayed-release tablets may not have any influ-ence on the ovulation-suppressing action of oral contraceptives, it is recommended to coad- minister mycophenolic acid delayed-release tablets with hormonal contraceptives (e.g., birth control pill, transdermal patch, vaginal ring, injection, and implant) with caution, and addi- tional barrier contraceptive methods must be used [see Warnings and Precautions (5.2), Use The following additional adverse reactions have been associated with the exposure to in Specific Populations (8.6), and Clinical Pharmacology (12.3)]. mycophenolic acid (MPA) when administered as a sodium salt or as mofetil ester: Acyclovir (Valacyclovir), Ganciclovir (Valganciclovir), and Other Drugs that Undergo
Gastrointestinal: Intestinal perforation, gastrointestinal hemorrhage, gastric ulcers, duode-
Renal Tubular Secretion
nal ulcers [see Warnings and Precautions (5.8)], colitis (including CMV colitis), pancreatitis, The coadministration of MMF and acyclovir or ganciclovir may increase plasma concentrations of mycophenolic acid glucuronide (MPAG) and acyclovir/valacyclovir/ganciclovir/valganci- Infections: Serious life threatening infections such as meningitis and infectious endocardi-
clovir as their coexistence competes for tubular secretion. Both acyclovir/valacyclovir/ganci- tis, tuberculosis, and atypical mycobacterial infection [see Warnings and Precautions (5.5)]. clovir/valganciclovir and MPAG concentrations will be also increased in the presence of renal Respiratory: Interstitial lung disorders, including fatal pulmonary fibrosis.
impairment. Acyclovir/valacyclovir/ganciclovir/valganciclovir may be taken with mycopheno-lic acid delayed-release tablets; however, during the period of treatment, physicians should Post-Marketing Experience
monitor blood cell counts [see Clinical Pharmacology (12.3)].
The following adverse reactions have been identified during post-approval use of mycopheno- 7.10 Ciprofloxacin, Amoxicillin plus Clavulanic Acid and Other Drugs that Alter the Gas -
lic acid delayed-release tablets or other MPA derivatives. Because these reactions are report- tro intestinal Flora
ed voluntarily from a population of uncertain size, it is not always possible to reliably estimate Drugs that alter the gastrointestinal flora such as ciprofloxacin or amoxicillin plus clavulan- their frequency or establish a causal relationship to drug exposure. ic acid may interact with MMF by disrupting enterohepatic recirculation. Interference of MPAG • Congenital malformations and an increased incidence of first trimester pregnancy loss hydrolysis may lead to less MPA available for absorption when mycophenolic acid delayed- have been reported following exposure to MMF during pregnancy [see Boxed Warning, release tablets is concomitantly administered with ciprofloxacin or amoxicillin plus clavulan- ic acid. The clinical relevance of this interaction is unclear; however, no dose adjustment of • Infections [see Warning and Precautions (5.5, 5.6)] mycophenolic acid delayed-release tablets is needed when coadministered with these drugs • Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal. • Polyomavirus associated nephropathy (PVAN), especially due to BK virus infection, 7.11 Pantoprazole
associated with serious outcomes, including deteriorating renal function and renal Administration of a pantoprazole at a dose of 40 mg twice daily for 4 days to healthy volun- teers did not alter the pharmacokinetics of a single dose of mycophenolic acid delayed-release • Viral reactivation in patients infected with HBV or HCV. tablets [see Clinical Pharmacology (12.3)]. • 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 Pre- USE IN SPECIFIC POPULATIONS
Pregnancy
The following additional adverse reactions have been identified during post approval use of Teratogenic Effects. Pregnancy Category D: [See Warnings and Precautions (5.1).]
mycophenolic acid delayed-release tablets: agranulocytosis, asthenia, osteomyelitis, lym- For those females using mycophenolic acid delayed-release tablets at any time during preg- phadenopathy, lymphopenia, wheezing, dry mouth, gastritis, peritonitis, anorexia, alopecia, nancy and those becoming pregnant within 6 weeks of discontinuing therapy, the health- pulmonary edema, Kaposi’s sarcoma.
care practitioner should report the pregnancy to the Mycophenolate Pregnancy Registry (1-800-617-8191). The healthcare practitioner should strongly encourage the patient to DRUG INTERACTIONS
enroll in the pregnancy registry. The information provided to the registry will help the Health Antacids with Magnesium and Aluminum Hydroxides
Care Community to better understand the effects of mycophenolate in pregnancy. Concomitant use of mycophenolic acid delayed-release tablets and antacids decreased plas- Risk Summary: Following oral or intravenous (IV) administration, MMF is metabolized to
ma concentrations of mycophenolic acid (MPA). It is recommended that mycophenolic acid mycophenolic acid (MPA), the active ingredient in mycophenolic acid delayed-release tablets delayed-release tablets and antacids not be administered simultaneously [see Clinical Phar- 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 congenital malformations, espe- Azathioprine
cially external ear and other facial abnormalities including cleft lip and palate, and anomalies Given that azathioprine and MMF inhibit purine metabolism, it is recommended that mycophe- of the distal limbs, heart, esophagus, and kidney. In animal studies, congenital malforma- nolic acid delayed-release tablets not be administered concomitantly with azathioprine or MMF. tions and pregnancy loss occurred when pregnant rats and rabbits received mycophenolic Cholestyramine, Bile Acid Sequestrates, Oral Activated Charcoal and Other Drugs
acid at dose multiples similar to and less than clinical doses. that Interfere with Enterohepatic Recirculation
Risks and benefits of mycophenolic acid delayed-release tablets should be discussed with the Drugs that interrupt enterohepatic recirculation may decrease MPA plasma concentrations patient. When appropriate, consider alternative immunosuppressants with less potential for when coadministered with MMF. Therefore, do not administer mycophenolic acid delayed- embryofetal toxicity. In certain situations, the patient and her healthcare practitioner may decide that the maternal benefits outweigh the risks to the fetus. If this drug is used during Patients should be aware that mycophenolic acid delayed-release tablets reduces blood lev- pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be els of the hormones in the oral contraceptive pill and could theoretically reduce its effective- apprised of the potential hazard to the fetus. ness [see Patient Counseling Information (17), Drug Interactions (7.8)].
Data: Human Data: In the National Transplantation Pregnancy Registry (NTPR), there were
Table 5. Acceptable Contraception Methods for Females of Reproductive Potential
data on 33 MMF-exposed pregnancies in 24 transplant patients; there were 15 spontaneous Pick from the following birth control options:
abortions (45%) and 18 live-born infants. Four of these 18 infants had structural malforma-tions (22%). In post-marketing data (collected from 1995 to 2007) on 77 women exposed to systemic MMF during pregnancy, 25 had spontaneous abortions and 14 had a malformed infant or fetus. Six of 14 malformed offspring had ear abnormalities. Because these post-mar- Methods to Use Alone
keting data are reported voluntarily, it is not always possible to reliably estimate the frequen- cy of particular adverse outcomes. These malformations are similar to findings in animal reproductive toxicology studies. For comparison, the background rate for congenital anomalies Hormone Methods
Barrier Methods
in the United States is about 3%, and NTPR data show a rate of 4% to 5% among babies born to organ transplant patients using other immunosuppressive drugs. There are no relevantqualitative or quantitative differences in the teratogenic potential of mycophenolate sodium Estrogen and Progesterone
Choose One
Animal Data: In a teratology study performed with mycophenolate sodium in rats, at a dose Hormone Method Transdermal Patch
as low as 1 mg per kg, malformations in the offspring were observed, including anoph- AND One Barrier
thalmia, exencephaly, and umbilical hernia. The systemic exposure at this dose represents Progesterone-only
0.05 times the clinical exposure at the dose of 1440 mg per day mycophenolic acid delayed- release tablets. In teratology studies in rabbits, fetal resorptions and malformations occurred at doses equal to or greater than 80 mg per kg per day, in the absence of maternaltoxicity (which corresponds to about 1.1 times the recommended clinical dose, based on body Barrier Methods
Barrier Methods
Nursing Mothers
Choose One
It is not known whether MPA is excreted in human milk. Because many drugs are excreted in Barrier Method
human milk and because of the potential for serious adverse reactions in nursing infants from from each column
mycophenolic acid delayed-release tablets, a decision should be made whether to discontin- (must choose two
ue nursing or discontinue the drug, taking into account the importance of the drug to the methods)
Pregnancy Planning: For patients who are considering pregnancy, consider alternative
Pediatric Use
immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of The safety and effectiveness of mycophenolic acid delayed-release tablets have been estab- mycophenolic acid delayed-release tablets should be discussed with the patient. lished in pediatric kidney transplant patients 5 to 16 years of age who were initiated onmycophenolic acid delayed-release tablets at least 6 months post-transplant. Use of OVERDOSAGE
mycophenolic acid delayed-release tablets in this age group is supported by evidence from Signs and Symptoms: There have been anecdotal reports of deliberate or accidental overdos-
adequate and well controlled studies of mycophenolic acid delayed-release tablets in a simi- es with mycophenolic acid delayed-release tablets, whereas not all patients experienced relat- lar population of adult kidney transplant patients with additional pharmacokinetic data in pediatric kidney transplant patients [see Dosage and Administration (2.2, 2.3), Clinical Phar- In those overdose cases in which adverse reactions were reported, the reactions fall with- macology (12.3)]. Pediatric doses for patients with BSA < 1.19 m2 cannot be accurately in the known safety profile of the class. Accordingly an overdose of mycophenolic acid administered using currently available formulations of mycophenolic acid delayed-release delayed-release tablets could possibly result in oversuppression of the immune system and may increase the susceptibility to infection including opportunistic infections, fatal infec- The safety and effectiveness of mycophenolic acid delayed-release tablets in de novo pediatric tions and sepsis. If blood dyscrasias occur (e.g., neutropenia with absolute neutrophil kidney transplant patients and in pediatric kidney transplant patients below the age of 5 years count < 1.5 x 103/mcL or anemia), it may be appropriate to interrupt or discontinue mycophenolic acid delayed-release tablets. Geriatric Use
Possible signs and symptoms of acute overdose could include the following: hematological Clinical studies of mycophenolic acid delayed-release tablets did not include sufficient num- abnormalities such as leukopenia and neutropenia, and gastrointestinal symptoms such as bers of subjects aged 65 and over to determine whether they respond differently from younger abdominal pain, diarrhea, nausea and vomiting, and dyspepsia. subjects. Of the 372 patients treated with mycophenolic acid delayed-release tablets in the Treatment and Management: General supportive measures and symptomatic treatment
clinical trials, 6 % (n = 21) were 65 years of age and older and 0.3 % (n = 1) were 75 years should be followed in all cases of overdosage. Although dialysis may be used to remove the of age and older. Other reported clinical experience has not identified differences in respons- inactive metabolite mycophenolic acid glucuronide (MPAG), it would not be expected to remove es between the elderly and younger patients. In general, dose selection for an elderly patient clinically significant amounts of the active moiety, mycophenolic acid, due to the 98% plas- should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac ma protein binding of mycophenolic acid. By interfering with enterohepatic circulation of function, and of concomitant disease or other drug therapy. mycophenolic acid, activated charcoal or bile sequestrates, such as cholestyramine, may Females of Reproductive Potential
reduce the systemic mycophenolic acid exposure. Pregnancy Exposure Prevention and Planning: Females of reproductive potential must be
DESCRIPTION
made aware of the increased risk of first trimester pregnancy loss and congenital malforma- Mycophenolic acid delayed-release tablets are an enteric formulation of mycophenolate sodi- tions and must be counseled regarding pregnancy prevention and planning. um that delivers the active moiety mycophenolic acid (MPA). Mycophenolic acid is an immuno- Females of reproductive potential include girls who have entered puberty and all women who suppressive agent. As the sodium salt, MPA is chemically designated as Sodium 4(E)-6-(4- have a uterus and have not passed through menopause. Menopause is the permanent end of hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate. menstruation and fertility. Menopause should be clinically confirmed by a patient’s healthcare practitioner. Some commonly used diagnostic criteria include 1) 12 months of spontaneous 17H19O6Na. The molecular weight is 342.32 and the structural for- amenorrhea (not amenorrhea induced by a medical condition or medical therapy), or 2) post-
surgical from a bilateral oophorectomy.
Pregnancy Testing: To prevent unplanned exposure during pregnancy, females of reproductive
potential should have a serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL
immediately before starting mycophenolic acid delayed-release tablets. Another pregnancy
test with the same sensitivity should be done 8 to 10 days later. Repeat pregnancy tests
should be performed during routine follow-up visits. Results of all pregnancy tests should be
discussed with the patient.
In the event of a positive pregnancy test, females should be counseled with regard to whether
the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in cer-
tain situations.
Mycophenolic acid, as the sodium salt, is a white to off-white, crystalline powder and is high- Contraception: Females of reproductive potential taking mycophenolic acid delayed-release
ly soluble in aqueous media at physiological pH and practically insoluble in 0.1 N hydrochlo- tablets must receive contraceptive counseling and use acceptable contraception (see Table 5 for Acceptable Contraception Methods). Patients must use acceptable birth control during Mycophenolic acid is available for oral use as delayed-release tablets containing either 180 mg entire mycophenolic acid delayed-release tablets therapy, and for 6 weeks after stopping mycophenolic acid delayed-release tablets, unless the patient chooses abstinence (she choos- Inactive ingredients include colloidal silicon dioxide, croscarmellose sodium, crospovidone, es to avoid heterosexual intercourse completely). FD&C Blue No. 2 Aluminum Lake, hypromellose, hypromellose acetate succinate, magnesium stearate, maltodextrin, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, prege- Table 6: Mean ± SD Pharmacokinetic Parameters for MPA Following the Oral Administra-
latinized starch (corn), propylene glycol, sodium lauryl sulfate, talc, titanium dioxide and tri- tion of Mycophenolic Acid Delayed-release Tablets to Renal Transplant Patients on
ethyl citrate. In addition, the 180 mg strength contains yellow iron oxide and the 360 mg Cyclosporine, USP MODIFIED Based Immunosuppression
strength contains FD&C Red No. 40 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake.
Mycophenolic Acid
AUC0-12hr
The black imprinting ink contains the following: black iron oxide, hypromellose and propylene (mcg/mL)
(mcg*hr/mL)
CLINICAL PHARMACOLOGY
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 ofpurines, whereas other cell types can utilize salvage pathways. MPA has cytostatic effects Mycophenolate sodium has been shown to prevent the occurrence of acute rejection in rat models of kidney and heart allotransplantation. Mycophenolate sodium also decreases anti- 12.3 Pharmacokinetics
Mycophenolic acid delayed-release tablets exhibit linear and dose proportional pharmacoki- netics over the dose-range (360 mg to 2160 mg) evaluated. The absolute bioavailability ofmycophenolic acid delayed-release tablets in stable renal transplant patients on cyclosporine * median (range), ** AUC0-∞, *** age range of 5 to 16 years was 72%. MPA is highly protein bound (> 98% bound to albumin). The predominant metabo-lite of MPA is the phenolic glucuronide (MPAG) which is pharmacologically inactive. A minor Specific Populations: Renal Insufficiency: No specific pharmacokinetic studies in individuals
metabolite AcMPAG which is an acyl glucuronide of MPAG is also formed and has pharmaco- with renal impairment were conducted with mycophenolic acid delayed-release tablets. How- logical activity comparable to MPA. MPAG undergoes renal elimination. A fraction of MPAG also ever, based on studies of renal impairment with MMF, MPA exposure is not expected to be undergoes biliary excretion, followed by deconjugation by gut flora and subsequent reabsorp- appreciably increased over the range of normal to severely impaired renal function following tion as MPA. The mean elimination half-lives of MPA and MPAG ranged between 8 and 16 mycophenolic acid delayed-release tablet administration. hours, and 13 and 17 hours, respectively. In contrast, MPAG exposure would be increased markedly with decreased renal function; MPAG Absorption: In vitro studies demonstrated that the enteric-coated mycophenolic acid delayed-
exposure being approximately 8-fold higher in the setting of anuria. Although dialysis may be release tablet does not release MPA under acidic conditions (pH < 5) as in the stomach but is used to remove the inactive metabolite MPAG, it would not be expected to remove clinically highly soluble in neutral pH conditions as in the intestine. Following mycophenolic acid significant amounts of the active moiety MPA. This is in large part due to the high plasma pro- delayed-release tablets oral administration without food in several pharmacokinetic studies conducted in renal transplant patients, consistent with its enteric-coated formulation, the Hepatic Insufficiency: No specific pharmacokinetic studies in individuals with hepatic impair- median delay (Tlag) in the rise of MPA concentration ranged between 0.25 and 1.25 hours and ment were conducted with mycophenolic acid delayed-release tablets. In a single dose (MMF the median time to maximum concentration (Tmax) of MPA ranged between 1.5 and 2.75 hours.
1000 mg) trial of 18 volunteers with alcoholic cirrhosis and 6 healthy volunteers, hepatic MPA In comparison, following the administration of MMF, the median Tmax ranged between 0.5 and glucuronidation processes appeared to be relatively unaffected by hepatic parenchymal dis- one hour. In stable renal transplant patients on cyclosporine, USP MODIFIED based immuno- ease when the pharmacokinetic parameters of healthy volunteers and alcoholic cirrhosis suppression, gastrointestinal absorption and absolute bioavailability of MPA following the patients within this trial were compared. However, it should be noted that for unexplained rea- administration of mycophenolic acid delayed-release tablet was 93% and 72%, respectively.
sons, the healthy volunteers in this trial had about a 50% lower AUC compared to healthy vol- Mycophenolic acid delayed-release tablets pharmacokinetics is dose proportional over the unteers in other studies, thus making comparison between volunteers with alcoholic cirrhosis and healthy volunteers difficult. Effects of hepatic disease on this process probably depend Distribution: The mean (± SD) volume of distribution at steady state and elimination phase
on the particular disease. Hepatic disease, such as primary biliary cirrhosis, with other eti- for MPA is 54 (± 25) L and 112 (± 48) L, respectively. MPA is highly protein bound to albumin, > 98%. The protein binding of mycophenolic acid glucuronide (MPAG) is 82%. The free MPA Pediatrics: Limited data are available on the use of mycophenolic acid delayed-release tablets concentration may increase under conditions of decreased protein binding (uremia, hepatic at a dose of 450 mg/m2 body surface area in children. The mean MPA pharmacokinetic param- eters for stable pediatric renal transplant patients, 5 to 16 years, on cyclosporine, USP MOD- Metabolism: MPA is metabolized principally by glucuronyl transferase to glucuronidated
IFIED are shown in Table 6. At the same dose administered based on body surface area, the metabolites. The phenolic glucuronide of MPA, mycophenolic acid glucuronide (MPAG), is the respective mean Cmax and AUC of MPA determined in children were higher by 33% and 18% predominant metabolite of MPA and does not manifest pharmacological activity. The acyl glu- than those determined for adults. The clinical impact of the increase in MPA exposure is not curonide is a minor metabolite and has comparable pharmacological activity to MPA. In sta- known [see Dosage and Administration (2.2, 2.3)]. ble renal transplant patients on cyclosporine, USP MODIFIED based immunosuppression, Gender: There are no significant gender differences in mycophenolic acid delayed-release
approximately 28% of the oral mycophenolic acid delayed-release tablet dose was converted to MPAG by presystemic metabolism. The AUC ratio of MPA:MPAG:acyl glucuronide is approxi- Elderly: Pharmacokinetics in the elderly have not been formally studied.
mately 1:24:0.28 at steady state. The mean clearance of MPA was 140 (± 30) mL/min. Ethnicity: Following a single dose administration of 720 mg of mycophenolic acid delayed-
Elimination: The majority of MPA dose administered is eliminated in the urine primarily as
release tablets to 18 Japanese and 18 Caucasian healthy subjects, the exposure (AUC MPAG (> 60%) and approximately 3% as unchanged MPA following mycophenolic acid MPA and MPAG were 15% and 22% lower in Japanese subjects compared to Caucasians. The delayed-release tablet administration to stable renal transplant patients. The mean renal clearance of MPAG was 15.5 (± 5.9) mL/min. MPAG is also secreted in the bile and available max) for MPAG were similar between the two populations, however, for deconjugation by gut flora. MPA resulting from the deconjugation may then be reabsorbed max for MPA. These results do not suggest any clinically and produce a second peak of MPA approximately 6 to 8 hours after mycophenolic aciddelayed-release tablet dosing. The mean elimination half-life of MPA and MPAG ranged Drug Interactions: Antacids with Magnesium and Aluminum Hydroxides: Absorption of a sin-
between 8 and 16 hours, and 13 and 17 hours, respectively. gle dose of mycophenolic acid delayed-release tablet was decreased when administered to Food Effect: Compared to the fasting state, administration of mycophenolic acid delayed-
12 stable kidney transplant patients also taking magnesium-aluminum-containing antacids release tablets 720 mg with a high fat meal (55 g fat, 1000 calories) had no effect on the sys- (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, temic exposure (AUC) of MPA. However, there was a 33% decrease in the maximal concentra- than when mycophenolic acid delayed-release tablets was administered alone under fasting conditions [see Drug Interactions (7.1)]. max), a 3.5 hour delay in the Tlag (range, -6 to 18 hours), and 5 hour delay in the Tmax (range, -9 to 20 hours) of MPA. To avoid the variability in MPA absorption between doses, Pantoprazole: In a trial conducted in 12 healthy volunteers, the pharmacokinetics of MPA were mycophenolic acid delayed-release tablets should be taken on an empty stomach [see Dosage 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 Pharmacokinetics in Renal Transplant Patients: The mean pharmacokinetic parameters for
acid delayed-release tablets and pantoprazole, which was administered at a dose of 40 mg MPA following the administration of mycophenolic acid delayed-release tablets in renal trans- twice daily for 4 days [see Drug Interactions (7.11)]. plant patients on cyclosporine, USP MODIFIED based immunosuppression are shown in Table The following drug interaction studies were conducted following the administration of
6. Single-dose mycophenolic acid delayed-release tablet pharmacokinetics predicts multiple- MMF: Cholestyramine: Following single-dose oral administration of 1.5 grams MMF to 12
dose pharmacokinetics. However, in the early post-transplant period, mean MPA AUC and C healthy volunteers pretreated with 4 grams 3 times daily of cholestyramine for 4 days, MPA were approximately one-half of those measured 6 months post-transplant. AUC decreased approximately 40%. This decrease is consistent with interruption of entero- After near equimolar dosing of mycophenolic acid delayed-release tablets 720 mg twice daily hepatic recirculation which may be due to binding of recirculating MPAG with cholestyramine and MMF 1000 mg twice daily (739 mg as MPA) in both the single- and multiple-dose cross- in the intestine [see Drug Interactions (7.3)]. over trials, mean systemic MPA exposure (AUC) was similar. Sevelamer: Concomitant administration of sevelamer and MMF in stable adult and pediatric kidney transplant patients decreased the mean MPA Cmax and AUC(0-12h) by 36% and 26% The genotoxic potential of mycophenolate sodium was determined in five assays. Mycopheno- respectively [see Drug Interactions (7.4)]. late sodium was genotoxic in the mouse lymphoma/thymidine kinase assay, the micronucleus Cyclosporine: Cyclosporine (Sandimmune®) pharmacokinetics (at doses of 275 to 415 mg/day) test in V79 Chinese hamster cells, and the in vivo mouse micronucleus assay. Mycophenolate were unaffected by single and multiple doses of 1.5 grams twice daily of MMF in ten stable kid- sodium was not genotoxic in the bacterial mutation assay (Salmonella typhimurium TA 1535, ney transplant patients. The mean (± SD) AUC 97a, 98, 100, and 102) or the chromosomal aberration assay in human lymphocytes. (0-12h) and Cmax of cyclosporine after 14 days of multiple doses of MMF were 3290 (± 822) ng•h/mL and 753 (± 161) ng/mL, respectively, com- Mycophenolate mofetil generated similar genotoxic activity. The genotoxic activity of mycophe- pared to 3245 (± 1088) ng•h/mL and 700 (± 246) ng/mL, respectively, one week before admin- nolic acid (MPA) is probably due to the depletion of the nucleotide pool required for DNA syn- thesis as a result of the pharmacodynamic mode of action of MPA (inhibition of nucleotide A total of 73 de novo kidney allograft recipients on MMF therapy received either low dose cyclosporine withdrawal by 6 months post-transplant (50 to 100 ng/mL for up to 3 months Mycophenolate sodium had no effect on male rat fertility at daily oral doses as high as 18 mg post-transplant followed by complete withdrawal at month 6 post-transplant) or standard per kg and exhibited no testicular or spermatogenic effects at daily oral doses of 20 mg per dose cyclosporine (150 to 300 ng/mL from baseline through to month 4 post-transplant and kg for 13 weeks (approximately 2 times the systemic exposure of MPA at the recommended 100 to 200 ng/mL thereafter). At month 12 post-transplant, the mean MPA (AUC(0-12h)) in the therapeutic dose). No effects on female fertility were seen up to a daily dose of 20 mg per kg cyclosporine withdrawal group was approximately 40% higher, than that of the standard dose (approximately 3 times the systemic exposure of MPA at the recommended therapeutic dose). cyclo sporine group.
Cyclosporine inhibits multidrug-resistance-associated protein 2 (MRP-2) transporter in the CLINICAL STUDIES
biliary tract, thereby preventing the excretion of MPAG into the bile that would lead to entero- 14.1 Prophylaxis of Organ Rejection in Patients Receiving Allogeneic Renal Transplants
hepatic recirculation of MPA [see Drug Interactions (7.5)]. The safety and efficacy of mycophenolic acid delayed-release tablets in combination with Norfloxacin and Metronidazole: Following single-dose administration of MMF (1 g) to 11 healthy cyclosporine, USP MODIFIED and corticosteroids for the prevention of organ rejection was volunteers on day 4 of a 5 day course of a combination of norfloxacin and metronidazole, the mean assessed in two multicenter, randomized, double-blind active-controlled trials in de novo and MPA AUC(0-48h) was reduced by 33% compared to the administration of MMF alone (p < 0.05).
conversion renal transplant patients compared to MMF. There was no significant effect on mean MPA AUC(0-48h) when MMF was concomitantly adminis- The de novo trial was conducted in 423 renal transplant patients (ages 18 to 75 years) in Aus- tered with norfloxacin or metronidazole separately. The mean (±SD) MPA AUC(0-48h) after coad- tria, Canada, Germany, Hungary, Italy, Norway, Spain, UK, and USA. Eighty-four percent of ran- ministration of MMF with norfloxacin or metronidazole separately was 48.3 (± 24) mcg•h/mL and domized patients received kidneys from deceased donors. Patients were excluded if they had 42.7 (± 23) mcg•h/mL, respectively, compared with 56.2 (± 24) mcg•h/mL after administration second or multi-organ (e.g., kidney and pancreas) transplants, or previous transplant with of MMF alone [see Drug Interactions (7.6)]. any other organs; kidneys from non-heart beating donors; panel reactive antibodies (PRA) of Rifampin: In a single heart-lung transplant patient on MMF therapy (1 gram twice daily), a > 50% at last assessment prior to transplantation, and presence of severe diarrhea, active 67% decrease in MPA exposure (AUC(0-12h)) was observed with concomitant administration of peptic ulcer disease, or uncontrolled diabetes mellitus. Patients were administered either mycophenolic acid delayed-release tablets 1.44 grams per day or MMF 2 grams per day with- In eight kidney transplant patients on stable MMF therapy (1 gram twice daily), administra- in 48 hours post-transplant for 12 months in combination with cyclosporine, USP MODIFIED tion of 300 mg rifampin twice daily resulted in a 17.5% decrease in MPA AUC(0-12h) due to and corticosteroids. Forty-one percent of patients received antibody therapy as induction inhibition of enterohepatic recirculation of MPAG by rifampin. Rifampin coadministration also treatment. Treatment failure was defined as the first occurrence of biopsy proven acute rejec- resulted in a 22.4% increase in MPAG AUC(0-12h) [see Drug Interactions (7.7)]. tion, graft loss, death or lost to follow-up at 6 months. Oral Contraceptives: In a drug-drug interaction trial, mean AUCs were similar for ethinyl The incidence of treatment failure was similar in mycophenolic acid delayed-release tablets - estradiol and norethindrone, when coadministered with MMF as compared to administration and MMF-treated patients at 6 and 12 months (Table 7). The cumulative incidence of graft of the oral contraceptives alone [see Drug Interactions (7.8)]. loss, death and lost to follow-up at 12 months is also shown in Table 7.
Acyclovir: Coadministration of MMF (1 gram) and acyclovir (800 mg) to 12 healthy volunteers Table 7: Treatment Failure in de novo Renal Transplant Patients (Percent of Patients) at 6
resulted in no significant change in MPA AUC and Cmax. However, MPAG and acyclovir plasma and 12 Months of Treatment when Administered in Combination with Cyclosporine* and
mean AUC(0-24h) were increased 10% and 18%, respectively. Because MPAG plasma concen- Corticosteroids
trations are increased in the presence of kidney impairment, as are acyclovir concentrations, Mycophenolic Acid
Mycophenolate Mofetil (MMF)
the potential exists for mycophenolate and acyclovir or its prodrug (e.g., valacyclovir) to com- 1.44 grams per day
2 grams per day
pete for tubular secretion, further increasing the concentrations of both drugs [see Drug Inter- actions (7.9)]. Ganciclovir: Following single-dose administration to 12 stable kidney transplant patients, no pharmacokinetic interaction was observed between MMF (1.5 grams) and intravenous ganciclovir (5 mg per kg). Mean (± SD) ganciclovir AUC and Cmax (n = 10) were 54.3 (± 19) mcg•h/mL and 11.5 (± 1.8) mcg/mL, respectively, after coadministration of the two drugs, compared to 51 (±17) mcg•h/mL and 10.6 (± 2) mcg/mL, respectively, after administration of intra- venous ganciclovir alone. The mean (± SD) AUC and Cmax of MPA (n = 12) after coadminis-tration were 80.9 (± 21.6) mcg•h/mL and 27.8 (± 13.9) mcg/mL, respectively, compared to values of 80.3 (± 16.4) mcg•h/mL and 30.9 (± 11.2) mcg/mL, respectively, after adminis- 12 Months
Because MPAG plasma concentrations are increased in the presence of renal impairment, as are ganciclovir concentrations, the two drugs will compete for tubular secretion and thus fur- ther increases in concentrations of both drugs may occur. In patients with renal impairment in which MMF and ganciclovir or its prodrug (e.g., valganciclovir) are coadministered, patientsshould be monitored carefully [see Drug Interactions (7.9)]. Ciprofloxacin and Amoxicillin plus Clavulanic Acid: A total of 64 MMF treated kidney trans- plant recipients received either oral ciprofloxacin 500 mg twice daily or amoxicillin plus clavu- lanic acid 375 mg 3 times daily for 7 or at least 14 days. Approximately 50% reductions in median trough MPA concentrations (predose) from baseline (MMF alone) were observed in 3 ** Lost to follow-up indicates patients who were lost to follow-up without prior biopsy-proven acute rejec- days following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. These reductions in trough MPA concentrations tended to diminish within 14 days of antibiotic ther- *** Lost to follow-up indicates patients who were lost to follow-up without prior graft loss or death (nine apy and ceased within 3 days after discontinuation of antibiotics. The postulated mechanism mycophenolic acid patients and four MMF patients) for this interaction is an antibiotic-induced reduction in glucuronidase-possessing enteric # 95% confidence interval of the difference in treatment failure at 6 months (mycophenolic acid – MMF) is organisms leading to a decrease in enterohepatic recirculation of MPA. The change in trough level may not accurately represent changes in overall MPA exposure; therefore, clinical rele- ## 95% confidence interval of the difference in treatment failure at 12 months (mycophenolic acid – MMF)is (-8%, 9.1%). vance of these observations is unclear [see Drug Interactions (7.10)].
The conversion trial was conducted in 322 renal transplant patients (ages 18 to 75 years), NONCLINICAL TOXICOLOGY
who were at least 6 months post-transplant and had undergone primary or secondary, 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
deceased donor, living related, or unrelated donor kidney transplant, stable graft function In a 104-week oral carcinogenicity study in rats, mycophenolate sodium was not tumorigenic (serum creatinine < 2.3 mg/mL), no change in immunosuppressive regimen due to graft mal- at daily doses up to 9 mg per kg, the highest dose tested. This dose resulted in approximate- function, and no known clinically significant physical and/or laboratory changes for at least ly 0.6 to 1.2 times the systemic exposure (based on plasma AUC) observed in renal transplant 2 months prior to enrollment. Patients were excluded if they had three or more kidney trans- patients at the recommended dose of 1440 mg per day. Similar results were observed in a par- plants, multi-organ transplants (e.g., kidney and pancreas), previous organ transplants, evi- allel study in rats performed with MMF. In a 104-week oral carcinogenicity study in mice, MMF dence of graft rejection or who had been treated for acute rejection within 2 months prior to was not tumorigenic at a daily dose level as high as 180 mg per kg (which corresponds to 0.6 screening, clinically significant infections requiring continued therapy, presence of severe times the recommended mycophenolate sodium therapeutic dose, based on body surface diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus. Patients received 2 grams per day MMF in combination with cyclosporine USP MODIFIED, with or without corticosteroids for at least 2 weeks prior to entry in the trial. Patients were ran- • In the event of a positive pregnancy test, discuss the risks and benefits of mycophenolic domized to mycophenolic acid delayed-release tablets 1.44 grams per day or MMF 2 grams per acid delayed-release tablets with the patient. Encourage her to enroll in the pregnancy reg- day for 12 months. The trial was conducted in Austria, Belgium, Canada, Germany, Italy, istry. (1-800-617-8191) [see Use in Specific Populations (8.1)]. Spain, and USA. Treatment failure was defined as the first occurrence of biopsy-proven acute Pregnancy Exposure Prevention and Planning:
rejection, graft loss, death, or lost to follow-up at 6 and 12 months. • Discuss pregnancy testing, pregnancy prevention and planning with females of reproduc- The incidences of treatment failure at 6 and 12 months were similar between mycophenolic tive potential [see Females of Reproductive Potential (8.6)]. acid delayed-release tablets- and MMF-treated patients (Table 8). The cumulative incidence • Inform females of reproductive potential that they must use acceptable birth control dur- of graft loss, death and lost to follow-up at 12 months is also shown in Table 8.
ing the entire mycophenolic acid delayed-release tablet therapy and for 6 weeks after stop- Table 8: Treatment Failure in Conversion Transplant Patients (Percent of Patients) at 6 and
ping mycophenolic acid delayed-release tablets, unless the patient chooses to avoid het- 12 Months of Treatment when Administered in Combination with Cyclosporine* and with or
erosexual sexual intercourse completely (abstinence) [see Warnings and Precautions (5.2) without Corticosteroids
and Females of Reproductive Potential (8.6)]. • For patients who are considering pregnancy, discuss appropriate alternative immunosup- Mycophenolic Acid
Mycophenolate Mofetil (MMF)
pressants with less potential for embryofetal toxicity. Risks and benefits of mycophenolic 1.44 grams per day
2 grams per day
acid delayed-release tablets should be discussed with the patient [see Females of Repro- Nursing Mothers: Advise patients that they should not breast-feed during mycophenolic acid
delayed-release tablet therapy [see Nursing Mothers (8.3)]. Development of Lymphoma and Other Malignancies:
• Inform patients they are at increased risk of developing lymphomas and other malignan- cies, particularly of the skin, due to immunosuppression. • Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protec- 12 Months
tive clothing and use a sunscreen with a high protection factor. Increased Risk of Infection: Inform patients they are at increased risk of developing a vari-
ety of infections, including opportunistic infections, due to immunosuppression and to con-tact their physician if they develop any symptoms of infection [see Warnings and Precautions Blood Dyscrasias: Inform patients they are at increased risk for developing blood dyscrasias
(e.g., neutropenia or anemia) and to immediately contact their healthcare provider if they experience any evidence of infection, unexpected bruising, bleeding, or any other manifesta- tion of bone marrow suppression [see Warnings and Precautions (5.7)]. Gastrointestinal Tract Complications: Inform patients that mycophenolic acid delayed-
** Lost to follow-up indicates patients who were lost to follow-up without prior biopsy-proven acute rejec- release tablets can cause gastrointestinal tract complications including bleeding, intestinal perforations, and gastric or duodenal ulcers. Advise the patient to contact their healthcare *** Lost to follow-up indicates patients who were lost to follow-up without prior graft loss or death (eight provider if they have symptoms of gastrointestinal bleeding or sudden onset or persistent mycophenolic acid patients and 12 MMF patients) abdominal pain [see Warning and Precautions (5.8)]. # 95% confidence interval of the difference in treatment failure at 6 months (mycophenolic acid – MMF) is Immunizations: Inform patients that mycophenolic acid delayed-release tablets can interfere
(-7.3%, 2.7%). ## 95% confidence interval of the difference in treatment failure at 12 months (mycophenolic acid – MMF) with the usual response to immunizations and that they should avoid live vaccines [see Warn- ing and Precautions (5.9)].
Administration Instructions: Advise patients to swallow mycophenolic acid delayed-release
HOW SUPPLIED/STORAGE AND HANDLING
tablets whole, and not crush, chew, or cut the tablets. Inform patients to take mycophenolic Mycophenolic Acid Delayed-release Tablets are available containing mycophenolate sodium acid delayed-release tablets on an empty stomach, one hour before or 2 hours after food equivalent to 180 mg or 360 mg of mycophenolic acid. The 180 mg tablets are sage green film-coated, round tablets with M over MC1 imprinted in
Drug Interactions: Patients should be advised to report to their doctor the use of any other
black ink on one side of the tablet and blank of the other side. They are available as follows: medications while taking mycophenolic acid delayed-release tablets. The simultaneous administration of any of the following drugs with mycophenolic acid delayed-release tablets may result in clinically significant adverse reactions: • Antacids with magnesium and aluminum hydroxides The 360 mg tablets are reddish-orange, film-coated, modified capsule-shaped tablets with M
• Hormonal Contraceptives (e.g., birth control pill, transdermal patch, vaginal ring, injec- MC2 imprinted in black ink on one side of the tablet and blank on the other side. They are
MEDICATION GUIDE
MYCOPHENOLIC ACID* DELAYED-RELEASE TABLETS
(mye koe fe nole' ik as' id)
180 mg and 360 mg
Storage: Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Pro-
*as mycophenolate sodium
tect from moisture.
Read the Medication Guide that comes with mycophenolic acid delayed-release tablets before Dispense in a tight, light resistant container as defined in the USP using a child-resistant clo- you start taking it and each time you get a refill. There may be new information. This Medica- tion Guide does not take the place of talking with your healthcare provider about your medical Handling: Keep out of reach and sight of children. Mycophenolic acid delayed-release tablets
condition or treatment. If you have any questions about mycophenolic acid delayed-release should not be crushed or cut in order to maintain the integrity of the enteric coating [see What is the most important information I should know about mycophenolic acid delayed-
Teratogenic effects have been observed with mycophenolate sodium [see Warnings and Pre- release tablets? Mycophenolic acid delayed-release tablets can cause serious side
cautions (5.1)]. If for any reason, the mycophenolic acid delayed-release tablets must be effects including:
crushed, avoid inhalation of the powder, or direct contact of the powder, with skin or mucous • Increased risk of loss of pregnancy (miscarriage) and higher risk of birth defects.
Females who take mycophenolic acid delayed-release tablets during pregnancy, have a PHARMACIST: Dispense a Medication Guide with each prescription.
higher risk of miscarriage during the first 3 months (first trimester), and a higher risk thattheir baby will be born with birth defects. PATIENT COUNSELING INFORMATION
If you are a female who can become pregnant: See FDA-approved patient labeling (Medication Guide)
• your doctor must talk with you about acceptable birth control methods (contraceptive Embryofetal Toxicity:
counseling) while taking mycophenolic acid delayed-release tablets. • Inform pregnant women and females of reproductive potential that use of mycophenolic • you should have a pregnancy test immediately before starting mycophenolic acid delayed- acid delayed-release tablets in pregnancy is associated with an increased risk of first release tablets and another pregnancy test 8 to 10 days later. Pregnancy tests should be trimester pregnancy loss and an increased risk of congenital malformations [see Use in repeated during routine follow-up visits with your doctor. Talk to your doctor about the • you must use acceptable birth control during your entire mycophenolic acid delayed- Who should not take mycophenolic acid delayed-release tablets?
release tablet therapy and for 6 weeks after stopping mycophenolic acid delayed-release Do not take mycophenolic acid delayed-release tablets if you are allergic to mycophenolic acid, tablets, unless at anytime you choose to avoid sexual intercourse (abstinence) with a man mycophenolate sodium, mycophenolate mofetil, or any of the ingredients in mycophenolic acid completely. Mycophenolic acid delayed-release tablets decreases blood levels of the hor- delayed-release tablets. See the end of this Medication Guide for a complete list of ingredi- mones in birth control pills that you take by mouth. Birth control pills may not work as well ents in mycophenolic acid delayed-release tablets. while you take mycophenolic acid delayed-release tablets and you could become pregnant.
What should I tell my doctor before I start taking mycophenolic acid delayed-release
If you decide to take birth control pills while using mycophenolic acid delayed-release tablets?
tablets, you must also use another form of birth control. Talk to your doctor about otherbirth control methods that can be used while taking mycophenolic acid delayed-release Tell your healthcare provider about all of your medical conditions, including if you: • have any digestive problems, such as ulcers
• plan to receive any vaccines.
You should not receive live vaccines while you take
If you plan to become pregnant, talk with your doctor. Your doctor will decide if other medi- mycophenolic acid delayed-release tablets. Some vaccines may not work as well during cines to prevent rejection may be right for you. treatment with mycophenolic acid delayed-release tablets. • If you become pregnant while taking mycophenolic acid delayed-release tablets, do not
• have Lesch-Nyhan or Kelley-Seegmiller syndrome or another rare inherited deficiency
stop taking mycophenolic acid delayed-release tablets. Call your doctor right away. In
of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT). You should not take
certain situations, you and your doctor may decide that taking mycophenolic acid delayed- mycophenolic acid delayed-release tablets if you have one of these disorders. release tablets is more important to your health than the possible risks to your unbornbaby.
• are pregnant or planning to become pregnant. See “What is the most important infor-
mation I should know about mycophenolic acid delayed-release tablets”
• You and your doctor should report your pregnancy to • are breast-feeding or plan to breast-feed. It is not known if mycophenolic acid passes
• Mycophenolate Pregnancy Registry (1-800-617-8191) into breast milk. You and your doctor will decide if you will take mycophenolic acid delayed- The purpose of this registry is to gather information about the health of your baby. • Increased risk of getting serious infections. Mycophenolic acid delayed-release tablets
Tell your doctor about all the medicines you take, including prescription and nonprescrip-
weakens the body’s immune system and affects your ability to fight infections. Serious tion medicines, vitamins, and herbal supplements.
infections can happen with mycophenolic acid delayed-release tablets and can lead to Some medicines may affect the way mycophenolic acid delayed-release tablets work and death. These serious infections can include: mycophenolic acid delayed-release tablets may affect how some medicines work. Especially • Viral infections. Certain viruses can live in your body and cause active infections when
your immune system is weak. Viral infections that can happen with mycophenolic acid birth control pills (oral contraceptives). See “What is the most important information I
should know about mycophenolic acid delayed-release tablets?”
Shingles, other herpes infections, and cytomegalovirus (CMV). CMV can cause serious
antacids that contain aluminum or magnesium. Mycophenolic acid delayed-release tablets
and antacids should not be taken at the same time. BK virus. BK virus can affect how your kidney works and cause your transplanted kid-
acyclovir (Zovirax®), Ganciclovir (Cytovene® IV, Valcyte®)
azathioprine (Azasan®, Imuran®)
Hepatitis B and C viruses. Hepatitis viruses can affect how your liver works. Talk to
cholestyramine (Questran® Light, Questran®, Locholest Light, Prevalite®)
your doctor about how hepatitis viruses may affect you.
Know the medicines you take. Keep a list of your medicines with you to show your healthcare • A brain infection called Progressive Multifocal Leukoencephalopathy (PML). In some
provider and pharmacist when you get a new medicine. Do not take any new medicine with- patients mycophenolic acid delayed-release tablets may cause an infection of the brain that may cause death. You are at risk for this brain infection because you have a weak-ened immune system. You should tell your healthcare provider right away if you have any How should I take mycophenolic acid delayed-release tablets?
Take mycophenolic acid delayed-release tablets exactly as prescribed. Your healthcare pro -
Weakness on one side of the body
vider will tell you how much mycophenolic acid to take.
You do not care about things that you usually care about (apathy)
Do not stop taking or change your dose of mycophenolic acid delayed-release tablets with-
You are confused or have problems thinking
out talking to your healthcare provider. You cannot control your muscles
Take mycophenolic acid delayed-release tablets on an empty stomach, either one hour
• Fungal infections. Yeast and other types of fungal infections can happen with mycophe-
nolic acid delayed-release tablets and cause serious tissue and blood infections. See
Swallow mycophenolic acid delayed-release tablets whole. Do not crush, chew, or cut
“What are the possible side effects of mycophenolic acid delayed-release tablets?”
mycophenolic acid delayed-release tablets. The mycophenolic acid delayed-release tabletshave a coating so that the medicine will pass through your stomach and dissolve in your Call your doctor right away if you have any of these signs and symptoms of infection:
Temperature of 100.5°F or greater
• If you forget to take mycophenolic acid delayed-release tablets, take it as soon as
Cold symptoms, such as a runny nose or sore throat
you remember and then take your next dose at its regular time. If it is almost time for Flu symptoms, such as an upset stomach, stomach pain, vomiting, or diarrhea
your next dose, skip the missed dose. Do not take two doses at the same time. Call your Earache or headache
doctor or pharmacist if you are not sure what to do. Pain during urination or you need to urinate often
• If you take more than the prescribed dose of mycophenolic acid delayed-release
White patches in the mouth or throat
tablets, call your doctor right away.
Unexpected bruising or bleeding
• Do not change (substitute) between using mycophenolic acid delayed-release
Cuts, scrapes, or incisions that are red, warm, and oozing pus
tablets and mycophenolate mofetil tablets, capsules, or oral suspension for one
• Increased risk of getting certain cancers. People who take mycophenolic acid delayed-
another unless your healthcare provider tells you to. These medicines are absorbed
release tablets have a higher risk of getting lymphoma, and other cancers, especially skin differently. This may affect the amount of medicine in your blood. Be sure to keep all appointments at your transplant clinic. During these visits, your doc-
unexplained fever, tiredness that does not go away, weight loss, or lymph node swelling
a brown or black skin lesion with uneven borders, or one part of the lesion does not look
What should I avoid while taking mycophenolic acid delayed-release tablets?
Avoid pregnancy. See “What is the most important information I should know about
a change in the size or color of a mole
mycophenolic acid delayed-release tablets?”
a new skin lesion or bump
Limit the amount of time you spend in sunlight. Avoid using tanning beds and sunlamps.
any other changes to your health
People who take mycophenolic acid delayed-release tablets have a higher risk of getting See the section “What are the possible side effects of mycophenolic acid delayed-release
skin cancer. See “What is the most important information I should know about
tablets?” for other serious side effects.
mycophenolic acid delayed-release tablets?” Wear protective clothing when you are in
the sun and use a sunscreen with a high sun protection factor (SPF 30 and above). This is
What are mycophenolic acid delayed-release tablets?
especially important if your skin is fair (light colored) or you have a family history of skin Mycophenolic acid delayed-release tablets are a prescription medicine given to prevent rejec- tion (antirejection medicine) in people who have received a kidney transplant. Rejection is Elderly patients 65 years of age or older may have more side effects with mycophenolic acid
when the body’s immune system senses the new organ as “foreign” and attacks it. delayed-release tablets because of a weaker immune system. Mycophenolic acid delayed-release tablets are used with other medicines containingcyclosporine (Sandimmune®, Gengraf®, and Neoral®) and corticosteroids. What are the possible side effects of mycophenolic acid delayed-release tablets?
Mycophenolic acid delayed-release tablets can be used to prevent rejection in children who are Mycophenolic acid delayed-release tablets can cause serious side effects.
5 years or older and are stable after having a kidney transplant. It is not known if mycophe- See “What is the most important information I should know about mycophenolic acid
nolic acid delayed-release tablets are safe and work in children younger than 5 years. It is not delayed-release tablets?”
known how mycophenolic acid delayed-release tablets work in children who have just received Stomach and intestinal bleeding can happen in people who take mycophenolic acid delayed- release tablets. Bleeding can be severe and you may have to be hospitalized for treatment. The most common side effects of taking mycophenolic acid delayed-release tablets include:
In people with a new transplant:
low blood cell counts
red blood cells
white blood cells
platelets
constipation
nausea
diarrhea
vomiting
urinary tract infections
stomach upset
In people who take mycophenolic acid delayed-release tablets for a long time (long-term) after
transplant:
low blood cell counts
red blood cells
white blood cells
nausea
diarrhea
sore throat
Your healthcare provider will do blood tests before you start taking mycophenolic acid delayed-
release tablets and during treatment with mycophenolic acid delayed-release tablets to check
your blood cell counts. Tell your healthcare provider right away if you have any signs of infec-
tion (see “What is the most important information I should know about mycophenolic acid
delayed-release tablets?”
), or any unexpected bruising or bleeding. Also, tell your healthcare
provider if you have unusual tiredness, dizziness, or fainting.
These are not all the possible side effects of mycophenolic acid delayed-release tablets. Your
healthcare provider may be able to help you manage these side effects.
Call your doctor for medical advice about side effects.
You may report side effects to
FDA MedWatch at 1-800-FDA-1088 or
Mylan Pharmaceutical Inc. at 1-877-446-3679 (1-877-4-INFO-RX)
How should I store mycophenolic acid delayed-release tablets?
Store mycophenolic acid delayed-release tablets at room temperature, 20º to 25ºC (68º to
77ºF). Mycophenolic acid delayed-release tablets do not need to be refrigerated. Keep the container tightly closed. Store mycophenolic acid delayed-release tablets in a dry
• Keep mycophenolic acid delayed-release tablets and all medicines out of the reach of
children.
General information about mycophenolic acid delayed-release tablets
Medicines are sometimes prescribed for purposes other than those listed in a Medication
Guide. Do not use mycophenolic acid delayed-release tablets for a condition for which it was
not prescribed. Do not give mycophenolic acid delayed-release tablets to other people, even if
they have the same symptoms you have. It may harm them.
This Medication Guide summarizes the most important information about mycophenolic acid
delayed-release tablets. If you would like more information, talk with your doctor. You can ask
your doctor or pharmacist for information about mycophenolic acid delayed-release tablets
that is written for healthcare professionals. You can also call Mylan Pharmaceuticals Inc. at
1-877-446-3679 (1-877-4-INFO-RX).
What are the ingredients in mycophenolic acid delayed-release tablets?
Active ingredient:
mycophenolic acid (as mycophenolate sodium)
Inactive ingredients: 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, prege-
latinized starch (corn), propylene glycol, sodium lauryl sulfate, talc, titanium dioxide and tri-
ethyl citrate. In addition, the 180 mg strength contains yellow iron oxide and the 360 mg
strength contains FD&C Red No. 40 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake.
The black imprinting ink contains the following: black iron oxide, hypromellose and propylene
glycol.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
*The brands listed are trademarks of their respective owners.
Mylan Pharmaceuticals Inc.

Source: http://www.mylan.com/assets/mylan-corp/pdf/MycophenolicPrescribingInformation.pdf

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ISU MEMORANDUM/ MEDICAL SYNCHRONIZED SKATING The ISU Medical Commission is appointed to assist local Organizing Committees and to report to the ISU Council on medical and Anti-Doping matters. Rule 140 of the ISU General Regulations requires that Organizing Committees provide emergency medical services for all participants at the competition and practice sites. Details of the personnel a

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