(SEE BOXED WARNING)

Embryofetal Toxicity

Myfortic can cause fetal harm when administered to a pregnant female. Use of Myfortic 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 (see PRECAUTIONS: Pregnancy).

Pregnancy Exposure Prevention and Planning

Females of reproductive potential must be made aware of the increased risk of first trimester pregnancy loss and congenital malformations and must be counseled regarding pregnancy prevention and planning. For recommended pregnancy testing and contraception methods (see PRECAUTIONS: Pregnancy Exposure Prevention and Planning).

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-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).

Polyomavirus Infections

Patients receiving immunosuppressants, including Myfortic are at increased risk for opportunistic infections, including Polyomavirus infections. Polyomavirus infections in transplant patients may have serious, and sometimes, fatal outcomes. These include cases of JC virus associated progressive multifocal leukoencephalopathy (PML) and Polyomavirus associated nephropathy (PVAN) especially due to BK virus infection which have been observed in patients receiving Myfortic.

PVAN, especially due to BK virus infection, is associated with serious outcomes, including deteriorating renal function and renal graft loss (see ADVERSE REACTIONS). Patient monitoring may help detect patients at risk for PVAN.

Cases of PML, have been reported in patients treated with MPA derivatives which include mycophenolate mofetil (MMF) and mycophenolate sodium (see ADVERSE REACTIONS). PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.

Reduction in immunosuppression should be considered for patients who develop evidence of PML or PVAN. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft.

Blood Dyscrasias Including Pure Red Cell Aplasia

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolic acid (MPA) derivatives in combination with other immunosuppressive agents. The mechanism for MPA derivatives induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppressive regimen is also unknown. In some cases PRCA was found to be reversible with dose reduction or cessation of therapy with MPA derivatives. In transplant patients, however, reduced immunosuppression may place the graft at risk. Changes to Myfortic 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).

Patients receiving Myfortic should be monitored for blood dyscrasias (e.g. neutropenia or anemia (see PRECAUTIONS, Laboratory Tests). The development of neutropenia may be related to Myfortic itself, concomitant medications, viral infections, or some combination of these events. If blood dyscrasias occur (e.g. neutropenia (ANC < 1.3x10³/ μL or anemia)), dosing with Myfortic should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately (see DOSAGE AND ADMINISTRATION).

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

Concomitant Use

Myfortic 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 in combination with other immunosuppression agents have not been determined.

Pregnancy Exposure Prevention and Planning

Females of reproductive potential must be made aware of the increased risk of first trimester pregnancy loss and congenital malformations and must be counseled regarding pregnancy prevention and planning.

Females of reproductive potential include girls who have entered puberty and all women who have a uterus and have not passed through menopause. Menopause is the permanent end of 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 amenorrhea (not amenorrhea induced by a medical condition or medical therapy) or 2) postsurgical 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 Myfortic. 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 certain situations.

Contraception

Females of reproductive potential taking Myfortic must receive contraceptive counseling and use acceptable contraception (see Table 4 for Acceptable Contraception Methods). Patients must use acceptable birth control during entire Myfortic therapy, and for 6 weeks after stopping Myfortic, unless the patient chooses abstinence (she chooses to avoid heterosexual intercourse completely).

Patients should be aware that Myfortic reduces blood levels of the hormones in the oral contraceptive pill and could theoretically reduce its effectiveness (see PATIENT INFORMATION and PRECAUTIONS: DRUG INTERACTIONS: Oral Contraceptives).

Table 4 : Acceptable Contraception Methods for Females of Reproductive Potential Pick from the following birth control options:

Pregnancy Planning

For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of Myfortic should be discussed with the patient.

Gastrointestinal Disorders

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).

Patients with Renal Impairment

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).

Concomitant Medications

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).

Patients with HGPRT Deficiency

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.

Immunizations

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 The Patients

See Medication Guide

• Inform females of reproductive potential that use of Myfortic during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations , and advise them as to the appropriate steps to manage these risks including that they must use acceptable contraception (see WARNINGS: Embryofetal Toxicity, PRECAUTIONS: Pregnancy Exposure Prevention and Planning).
• Discuss pregnancy testing, pregnancy prevention and planning with females of reproductive potential. In the event of a positive pregnancy test, the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in certain situations
• Females of reproductive potential must use acceptable birth control during entire Myfortic therapy and for 6 weeks after stopping Myfortic, unless the patient chooses to avoid heterosexual sexual intercourse completely (abstinence)(see PRECAUTIONS: Pregnancy Exposure Prevention and Planning, Table 4).
• For patients who are considering pregnancy, discuss appropriate alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of Myfortic should be discussed with the patient.
• 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.
• Advise patients that they should not breastfeed during Myfortic therapy.

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 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

Pregnancy Category D

(See WARNINGS)

Following oral or IV administration, MMF is metabolized to mycophenolic acid (MPA), the active ingredient in Myfortic 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, especially external ear and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, and kidney. In animal studies, congenital malformations and pregnancy loss occurred when pregnant rats and rabbits received mycophenolic acid at dose multiples similar to and less than clinical doses. 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.

Risks and benefits of Myfortic should be discussed with the patient. When appropriate, consider alternative immunosuppressants with less potential for embryofetal toxicity. In certain situations, the patient and her healthcare practitioner may decide that the maternal benefits outweigh the risks to the fetus. For those females using Myfortic at any time during pregnancy and those becoming pregnant within 6 weeks of discontinuing therapy, the healthcare practitioner should report the pregnancy to the Mycophenolate Pregnancy Registry (1800-617-8191). The healthcare practitioner should strongly encourage the patient to enroll in the pregnancy registry. The information provided to the registry will help the Health Care Community to better understand the effects of mycophenolate in pregnancy.

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. There are no relevant qualitative or quantitative differences in the teratogenic potential of mycophenolate sodium and mycophenolate mofetil.

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. 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).

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.

Last reviewed on RxList: 7/6/2012
This monograph has been modified to include the generic and brand name in many instances.