PRECAUTIONS
General
Gastrointestinal bleeding (requiring hospitalization) has been reported in de novo renal transplant patients (1.0%) and maintenance patients (1.3%) treated with Myfortic® (mycophenolic acid) (up to 12 months). Intestinal perforations, gastrointestinal hemorrhage, gastric ulcers and duodenal ulcers have rarely been observed. Most patients receiving Myfortic were also receiving other drugs known to be associated with these complications. Patients with active peptic ulcer disease were excluded from enrollment in studies with Myfortic. Because MPA derivatives have been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, hemorrhage, and perforation, Myfortic should be administered with caution in patients with active serious digestive system disease (see ADVERSE REACTIONS).
Subjects with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) may present higher plasma MPA and MPAG AUCs relative to subjects with lesser degrees of renal impairment or normal healthy volunteers. No data are available on the safety of long-term exposure to these levels of MPAG.
In the de novo study, 18.3% of Myfortic patients versus 16.7% in the mycophenolate mofetil group experienced delayed graft function (DGF). Although patients with DGF experienced a higher incidence of certain adverse events (anemia, leukopenia, and hyperkalemia) than patients without DGF, these events in DGF patients were not more frequent in patients receiving Myfortic compared to mycophenolate mofetil. No dose adjustment is recommended for these patients; however, such patients should be carefully observed (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
In view of the significant reduction in the AUC of MPA by cholestyramine when administered with mycophenolate mofetil, caution should be used in the concomitant administration of Myfortic with drugs that interfere with enterohepatic recirculation because of the potential to reduce the efficacy (see PRECAUTIONS, Drug Interactions).
On theoretical grounds, because Myfortic is an IMPDH Inhibitor, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.
During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective (see PRECAUTIONS, Drug Interactions, Live Vaccines).
Information for Patients
- It is recommended that Myfortic be administered on an empty stomach, one hour before or two hours after food intake (see DOSAGE AND ADMINISTRATION).
- In order to maintain the integrity of the enteric coating of the tablet, patients should be instructed not to crush, chew, or cut Myfortic tablets and to swallow the tablets whole.
- Give patients complete dosage instructions and inform them about the increased risk of lymphoproliferative disease and certain other malignancies.
- Inform patients that they need repeated appropriate laboratory tests while they are taking Myfortic.
- Inform women of childbearing potential that use of Myfortic in pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of birth defects, and that they must use effective contraception.
- Discuss pregnancy plans with female patients of childbearing potential.
- Any female of childbearing potential must use highly effective (two methods) contraception 4 weeks prior to starting Myfortic therapy and continue contraception until 6 weeks after stopping Myfortic treatment, unless abstinence is the chosen method (see WARNINGS, Pregnancy).
- A patient who is planning a pregnancy should not use Myfortic unless she can not be successfully treated with other immunosuppressant drugs. Risks and benefits of Myfortic and alternative immunosuppressants should be discussed with the patient.
Laboratory Tests
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 neutropenia develops (ANC <1.3x103 /µL), dosing with Myfortic should be interrupted or the dose reduced, appropriate tests performed, and the patient managed accordingly (see WARNINGS).
Drug Interactions
The following drug interaction studies have been conducted with Myfortic:
Antacids : Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum-containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously.
Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady-state dosing of Myfortic.
The following recommendations are derived from drug interaction studies conducted following the administration of mycophenolate mofetil:
Acyclovir/Ganciclovir: May be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two.
Azathioprine/Mycophenolate Mofetil : Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil.
Cholestyramine and Drugs that Bind Bile Acids : These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic.
Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co-administered with Myfortic with caution and additional birth control methods be considered (see PRECAUTIONS, Pregnancy).
Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination (see PRECAUTIONS, General).
Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104-week oral carcinogenicity study in rats, mycophenolate sodium was not tumorigenic at daily doses up to 9 mg/kg, the highest dose tested. This dose resulted in approximately 0.6-1.2 times the systemic exposure (based upon plasma AUC) observed in renal transplant patients at the recommended dose of 1.44 g/day. Similar results were observed in a parallel study in rats performed with mycophenolate mofetil. In a 104-week oral carcinogenicity study in mice, mycophenolate mofetil was not tumorigenic at a daily dose level as high as 180 mg/kg (which corresponds to 0.6 times the proposed mycophenolate sodium therapeutic dose based upon body surface area).
The genotoxic potential of mycophenolate sodium was determined in five assays. Mycophenolate sodium was genotoxic in the mouse lymphoma/thymidine kinase assay the micronucleus test in V79 Chinese hamster cells and the in vivo mouse micronucleus assay. Mycophenolate sodium was not genotoxic in the bacterial mutation assay (Salmonella typhimurium TA 1535, 97a, 98, 100, & 102) or the chromosomal aberration assay in human lymphocytes. Mycophenolate mofetil generated similar genotoxic activity. The genotoxic activity of MPA is probably due to the depletion of the nucleotide pool required for DNA synthesis as a result of the pharmacodynamic mode of action of MPA (inhibition of nucleotide synthesis).
Mycophenolate sodium had no effect on male rat fertility at daily oral doses as high as 18 mg/kg and exhibited no testicular or spermatogenic effects at daily oral doses of 20 mg/kg for 13 weeks (approximately two-fold the therapeutic systemic exposure of MPA). No effects on female fertility were seen up to a daily dose of 20 mg/kg, which was approximately three-fold higher than the recommended therapeutic dose based upon systemic exposure.
Pregnancy
Teratogenic Effects: Pregnancy Category D. (See WARNINGS.)
Nursing Mothers
It is not known whether MPA is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from MPA, a decision should be made whether to discontinue the drug or to discontinue nursing while on treatment or within 6 weeks after stopping therapy, taking into account the importance of the drug to the mother.
Pediatric Use
De novo Renal Transplant
The safety and effectiveness of Myfortic in de novo pediatric renal transplant patients have not been established.
Stable Renal Transplant
There are no pharmacokinetic data available for pediatric patients <5 years. The safety and effectiveness of Myfortic have been established in the age group 5-16 years in stable pediatric renal transplant patients. Use of Myfortic in this age group is supported by evidence from adequate and well-controlled studies of Myfortic in stable adult renal transplant patients. Limited pharmacokinetic data are available for stable pediatric renal transplant patients in the age group 5-16 years. Pediatric doses for patients with BSA <1.19 m2 cannot be accurately administered using currently available formulations of Myfortic tablets (see CLINICAL PHARMACOLOGY, Special Populations and DOSAGE AND ADMINISTRATION).
Geriatric Use
Patients ≥65 years may generally be at increased risk of adverse drug reactions due to immunosuppression. Clinical studies of Myfortic did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
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