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Lymphoma and Other Malignancies

Patients receiving immunosuppressive regimens involving combinations of drugs, including Myfortic® (mycophenolic acid), as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see ADVERSE REACTIONS). The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.

The rates for lymphoproliferative disease or lymphoma in Myfortic (mycophenolic acid) -treated patients were comparable to the mycophenolate mofetil group in the de novo and maintenance studies (see ADVERSE REACTIONS). As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Infections

Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections, fatal infections, and sepsis. Fatal infections can occur in patients receiving immunosuppressive therapy (see ADVERSE REACTIONS).

Progressive Multifocal Leukoencephalopathy (PML)

Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with mycophenolate mofetil (MMF). Hemiparesis, apathy, confusion, cognitive deficiencies and ataxia were the most frequent clinical features observed. Mycophenolate mofetil (MMF) is metabolized to mycophenolic acid (MPA), the active ingredient in Myfortic (mycophenolic acid) and the active form of the drug. The reported cases generally had risk factors for PML, including treatment with immunosuppressant therapies and impairment of immune functions. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated. Consideration should be given to reducing the amount of immunosuppression in patients who develop PML. In transplant patients, physicians should also consider the risk that reduced immunosuppression represents to the graft.

Pure Red Cell Aplasia

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil (MMF) in combination with other immunosuppressive agents. MMF is metabolized to mycophenolic acid (MPA), the active ingredient in Myfortic (mycophenolic acid) and the active form of the drug. The mechanism for MMF induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppressive regimen are also unknown. In some cases PRCA was found to be reversible with dose reduction or cessation of MMF therapy. In transplant patients, however, reduced immunosuppression may place the graft at risk. Changes to Myfortic (mycophenolic acid) therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimize the risk of graft rejection (see ADVERSE REACTIONS, Postmarketing Experience).

Concomitant Use

Myfortic (mycophenolic acid) has been administered in combination with the following agents in clinical trials: antithymocyte/lymphocyte immunoglobulin, muromonab-CD3, basiliximab, daclizumab, cyclosporine, and corticosteroids. The efficacy and safety of Myfortic (mycophenolic acid) in combination with other immunosuppression agents have not been determined.

Pregnancy

Teratogenic Effects: Pregnancy Category D

Mycophenolate mofetil (MMF) can cause fetal harm when administered to a pregnant woman. Following oral or IV administration, MMF is metabolized to mycophenolic acid (MPA), the active ingredient in Myfortic (mycophenolic acid) and the active form of the drug. Use of Myfortic (mycophenolic acid) during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations, especially external ear and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, and kidney. In the National Transplantation Pregnancy Registry (NTPR), there were data on 33 MMF-exposed pregnancies in 24 transplant patients; there were 15 spontaneous abortions (45%) and 18 live-born infants. Four of these 18 infants had structural malformations (22%). In postmarketing 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 postmarketing data are reported voluntarily, it is not always possible to reliably estimate the frequency of particular adverse outcomes. These malformations are similar to findings in animal reproductive toxicology studies. For comparison, the background rate for congenital anomalies in the United States is about 3%, and NTPR data show a rate of 4-5% among babies born to organ transplant patients using other immunosuppressive drugs.

In a teratology study performed with mycophenolate sodium in rats, at a dose as low as 1 mg/kg, malformations in the offspring were observed, including anophthalmia, exencephaly and umbilical hernia. The systemic exposure at this dose represents 0.05 times the clinical exposure at the dose of 1.44 g/day Myfortic (mycophenolic acid) . In teratology studies in rabbits, fetal resorptions and malformations occurred from 80 mg/kg/day, in the absence of maternal toxicity (dose levels are equivalent to about 0.8 times the recommended clinical dose, corrected for BSA). There are no relevant qualitative or quantitative differences in the teratogenic potential of mycophenolate sodium and mycophenolate mofetil.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. In certain situations, the patient and her healthcare practitioner may decide that the maternal benefits outweigh the risks to the fetus. Women using Myfortic (mycophenolic acid) at any time during pregnancy should be encouraged to enroll in the National Transplantation Pregnancy Registry.

Pregnancy Exposure Prevention

Women of childbearing potential should have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 1 week prior to beginning therapy. Myfortic (mycophenolic acid) therapy should not be initiated until a negative pregnancy test report is obtained.

Women of childbearing potential (including pubertal girls and perimenopausal women) taking Myfortic (mycophenolic acid) must receive contraceptive counseling and use effective contraception. The patient should begin using her two chosen methods of contraception 4 weeks prior to starting Myfortic (mycophenolic acid) therapy, unless abstinence is the chosen method. She should continue contraceptive use during therapy and for 6 weeks after stopping Myfortic (mycophenolic acid) . Patients should be aware that Myfortic (mycophenolic acid) reduces blood levels of the hormones in the oral contraceptive pill and could theoretically reduce its effectiveness (see PRECAUTIONS, Information for Patients and PRECAUTIONS: DRUG INTERACTIONS, Oral Contraceptives).

Patients receiving Myfortic (mycophenolic acid) should be monitored for neutropenia (see PRECAUTIONS, Laboratory Tests). The development of neutropenia may be related to Myfortic (mycophenolic acid) itself, concomitant medications, viral infections, or some combination of these events. If neutropenia develops (ANC < 1.3 ×10³/µL), dosing with Myfortic (mycophenolic acid) should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately (see DOSAGE AND ADMINISTRATION).

Patients receiving Myfortic (mycophenolic acid) should be instructed to immediately report any evidence of infection, unexpected bruising, bleeding, or any other manifestation of bone marrow suppression.

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 (mycophenolic acid) 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 (mycophenolic acid) . 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 (mycophenolic acid) 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 (mycophenolic acid) 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 (mycophenolic acid) 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 (mycophenolic acid) with drugs that interfere with enterohepatic recirculation because of the potential to reduce the efficacy (see PRECAUTIONS: DRUG INTERACTIONS).

On theoretical grounds, because Myfortic (mycophenolic acid) 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 (mycophenolic acid) , 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 (mycophenolic acid) 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 (mycophenolic acid) 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 (mycophenolic acid) .
• Inform women of childbearing potential that use of Myfortic (mycophenolic acid) 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 (mycophenolic acid) therapy and continue contraception until 6 weeks after stopping Myfortic (mycophenolic acid) treatment, unless abstinence is the chosen method (see WARNINGS, Pregnancy).
• A patient who is planning a pregnancy should not use Myfortic (mycophenolic acid) unless she can not be successfully treated with other immunosuppressant drugs. Risks and benefits of Myfortic (mycophenolic acid) 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 < 1.3 ×10³/µL), dosing with Myfortic (mycophenolic acid) should be interrupted or the dose reduced, appropriate tests performed, and the patient managed accordingly (see WARNINGS).

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 (mycophenolic acid) 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 (mycophenolic acid) have been established in the age group 5-16 years in stable pediatric renal transplant patients. Use of Myfortic (mycophenolic acid) in this age group is supported by evidence from adequate and well-controlled studies of Myfortic (mycophenolic acid) 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 (mycophenolic acid) 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.

Last reviewed on RxList: 10/26/2009
This monograph has been modified to include the generic and brand name in many instances.