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.
Teratogenic Effects: Pregnancy Category D. (See WARNINGS.)
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.
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).
Myfortic® (mycophenolic acid) is contraindicated in patients with a hypersensitivity to mycophenolate sodium, mycophenolic acid, mycophenolate mofetil, or to any of its excipients.
WARNINGS (SEE BOXED WARNING)
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.
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 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.
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: Teratogenic Effects: Pregnancy Category D
Mycophenolate mofetil (MMF) can cause fetal harm when administered to a pregnant women. 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 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. 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. 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 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 therapy should not be initiated until a negative pregnancy test report is obtained.
Women of childbearing potential (including pubertal girls and peri-menopausal women) taking Myfortic 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 therapy, unless abstinence is the chosen method. She should continue contraceptive use during therapy and for 6 weeks after stopping Myfortic. Patients should be aware that Myfortic 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 should be monitored for neutropenia (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 neutropenia develops (ANC <1.3×103 /µL), 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.