The following adverse reactions have been identified during post-approval use of mycophenolic acid delayed-release tablets or other MPA derivatives. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
- Congenital malformations, including ear, facial, cardiac and nervous system malformations and an increased incidence of first trimester pregnancy loss have been reported following exposure to MMF during pregnancy [see Boxed Warning, Warnings and Precautions ( 5.1) ].
- Infections [see Warnings and Precautions ( 5.4, 5.5 )]
o Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal.
o Polyomavirus associated nephropathy (PVAN), especially due to BK virus infection associated with serious outcomes, including deteriorating renal function and renal graft loss.
o Viral reactivation in patients infected with HBV or HCV.
- 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 Precautions ( 5.6) ].
The following additional adverse reactions have been identified during post-approval use of mycophenolic acid delayed-release tablets: agranulocytosis, asthenia, osteomyelitis, lymphadenopathy, lymphopenia, wheezing, dry mouth, gastritis, peritonitis, anorexia, alopecia, pulmonary edema, Kaposi’s sarcoma, de novo purine synthesis inhibitors-associated acute inflammatory syndrome.
Concomitant use of mycophenolic acid delayed-release tablets and antacids decreased plasma concentrations of mycophenolic acid (MPA). It is recommended that mycophenolic acid delayed-release tablets and antacids not be administered simultaneously [see Clinical Pharmacology ( 12.3) ].
Given that azathioprine and MMF inhibit purine metabolism, it is recommended that mycophenolic acid delayed-release tablets not be administered concomitantly with azathioprine or MMF.
7.3 Cholestyramine, Bile Acid Sequestrates, Oral Activated Charcoal and Other Drugs That Interfere With Enterohepatic Recirculation
Drugs that interrupt enterohepatic recirculation may decrease MPA plasma concentrations when coadministered with MMF. Therefore, do not administer mycophenolic acid delayed-release tablets with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, e.g., bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of mycophenolic acid delayed-release tablets [see Clinical Pharmacology ( 12.3) ].
Concomitant administration of sevelamer and MMF may decrease MPA plasma concentrations. Sevelamer and other calcium-free phosphate binders should not be administered simultaneously with mycophenolic acid delayed-release tablets [see Clinical Pharmacology ( 12.3) ].
Cyclosporine inhibits the enterohepatic recirculation of MPA, and therefore, MPA plasma concentrations may be decreased when mycophenolic acid delayed-release tablets are coadministered with cyclosporine. Clinicians should be aware that there is also a potential change of 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) ].
MPA plasma concentrations may be decreased when MMF is administrated with norfloxacin and metronidazole. Therefore, mycophenolic acid delayed-release tablets are not recommended 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 Clinical Pharmacology ( 12.3) ].
The concomitant administration of MMF and rifampin may decrease MPA plasma concentrations. Therefore, mycophenolic acid delayed-release tablets are not recommended to be given with rifampin concomitantly unless the benefit outweighs the risk [see Clinical Pharmacology ( 12.3) ].
In a drug interaction study, mean levonorgestrel AUC was decreased by 15% when coadministered with MMF. Although mycophenolic acid delayed-release tablets may not have any influence on the ovulation-suppressing action of oral contraceptives,additional barrier contraceptive methods must be used when mycophenolic acid delayed-release tablets is coadministered with hormonal contraceptives (e.g., birth control pill, transdermal patch, vaginal ring, injection, and implant) [see Warnings and Precautions (5.1), Use in Specific Populations (8.3), Clinical Pharmacology (12.3)].
7.9 Acyclovir (Valacyclovir), Ganciclovir (Valganciclovir), and Other Drugs That Undergo Renal Tubular Secretion
The coadministration of MMF and acyclovir or ganciclovir may increase plasma concentrations of mycophenolic acid glucuronide (MPAG) and acyclovir/valacyclovir/ganciclovir/valganciclovir as their coexistence competes for tubular secretion. Both acyclovir/valacyclovir/ganciclovir/valganciclovir and MPAG concentrations will be also increased in the presence of renal impairment. Acyclovir/valacyclovir/ganciclovir/valganciclovir may be taken with mycophenolic acid delayed-release tablets; however, during the period of treatment, physicians should monitor blood cell counts [see Clinical Pharmacology ( 12.3) ].
7.10 Ciprofloxacin, Amoxicillin Plus Clavulanic Acid and Other Drugs That Alter the Gastrointestinal Flora
Drugs that alter the gastrointestinal flora, such as ciprofloxacin or amoxicillin plus clavulanic acid may interact with MMF by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption when mycophenolic acid delayed-release tablets are concomitantly administered with ciprofloxacin or amoxicillin plus clavulanic acid. The clinical relevance of this interaction is unclear; however, no dose adjustment of mycophenolic acid delayed-release tablets is needed when coadministered with these drugs [see Clinical Pharmacology ( 12.3) ].
Administration of a pantoprazole at a dose of 40 mg twice daily for 4 days to healthy volunteers did not alter the pharmacokinetics of a single dose of mycophenolic acid delayed-release tablets [see Clinical Pharmacology ( 12.3) ].
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to mycophenolate during pregnancy and those becoming pregnant within 6 weeks of discontinuing mycophenolic acid delayed-release tablets treatment. To report a pregnancy or obtain information about the registry, visit www.mycophenolateREMS.com or call 1-800-617-8191.
Following oral or intravenous (IV) administration, MMF is metabolized to mycophenolic acid (MPA), the active ingredient in mycophenolic acid delayed-release tablets 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 multiple congenital malformations in multiple organ systems (see Human Data). Oral administration of mycophenolate to rats and rabbits during the period of organogenesis produced congenital malformations and pregnancy loss at doses less than the recommended clinical dose (0.05 and 1.1 times exposure at the recommended clinical doses in kidney transplant patients for rats and rabbits, respectively) (see Animal Data).
Risks and benefits of mycophenolic acid delayed-release tablets should be discussed with the patient. When appropriate, consider alternative immunosuppressants with less potential for embryo-fetal toxicity. The estimated background risk of pregnancy loss and congenital malformations in organ transplant populations is not clear. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
A spectrum of congenital malformations (including multiple malformations in individual newborns) has been reported in 23% to 27% of live births in MMF exposed pregnancies, based on published data from pregnancy registries. Malformations that have been documented include external ear, eye, and other facial abnormalities, including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, kidney, and nervous system. Based on published data from pregnancy registries, the risk of first trimester pregnancy loss has been reported at 45% to 49% following MMF exposure.
In animal reproductive toxicology studies, congenital malformations and pregnancy loss occurred when pregnant rats and rabbits received mycophenolate at dose multiples equivalent to and less than the recommended human dose. Oral administration of mycophenolate sodium to pregnant rats from Gestational Day 7 to Day 16 at a dose as low as 1 mg per kg resulted in 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 human dose of 1,440 mg per day mycophenolic acid delayed-release tablets. Oral administration of mycophenolate to pregnant rabbits from Gestational Day 7 to Day 19 resulted inembryofetal lethality and malformations including ectopia cordis, ectopic kidneys, diaphragmatic hernia, and umbilical hernia at doses equal to or greater than 80 mg per kg per day, in the absence of maternal toxicity. This corresponds to about 1.1 times the recommended clinical dose, based on BSA.
There are no data on the presence of mycophenolate in human milk, or the effects on milk production. There are limited data in the National Transplantation Pregnancy Registry on the effects of mycophenolate on a breastfed child (see Data). Studies in rats treated with MMF have shown mycophenolic acid to be present in milk. Because available data are limited, it is not possible to exclude potential risks to a breastfeeding infant.The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for mycophenolic acid delayed-release tablets and any potential adverse effects on the breastfed infant from mycophenolic acid delayed-release tablets or from the underlying maternal condition. Because available data are limited, it is not possible to exclude potential risks to a breastfeeding infant.
Limited information is available from the National Transplantation Pregnancy Registry. Of seven infants reported by the National Transplantation Pregnancy Registry to have been breastfed while the mother was taking mycophenolate, all were born at 34 to 40 weeks gestation and breastfed for up to 14 months. No adverse events were reported.
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 female patients taking mycophenolic acid delayed-release tablets who are considering pregnancy, consider alternative immunosuppressants with less potential for embryo-fetal toxicity. Risks and benefits of mycophenolic acid delayed-release tablets should be discussed with the patient.
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 followup visits. Results of all pregnancy tests should be discussed with the patient. In the event of a positive pregnancy test, consider alternative immunosuppressants with less potential for embryo-fetal toxicity whenever possible.
Females of reproductive potential taking mycophenolic acid delayed-release tablets must receive contraceptive counseling and use acceptable contraception (see Table 5 for Acceptable Contraception Methods). Patients must use acceptable birth control during entire mycophenolic acid delayed-release tablets therapy, and for 6 weeks after stopping mycophenolic acid delayed-release tablets, unless the patient chooses abstinence (she chooses to avoid heterosexual intercourse completely). Patients should be aware that mycophenolic acid delayed-release tablets reduce blood levels of the hormones in the oral contraceptive pill and could theoretically reduce its effectiveness [see Patient Counseling Information (17), Drug Interactions (7.8)].
Table 5: Acceptable Contraception Methods for Females of Reproductive Potential
Pick from the following birth control options:
|Methods to Use Alone||Intrauterine devices (IUDs) Tubal sterilization Patient’s partner had a vasectomy|
|Option 2||Hormone Methods choose 1||Barrier Methods choose 1|
|Choose One Hormone Method AND One Barrier Method||Estrogen and Progesterone Oral Contraceptive Pill Transdermal patch Vaginal ring Progesterone-only Injection||AND||Diaphragm with spermicide Cervical cap with spermicide Contraceptive sponge Male condom Female condom|
|Option 3||Barrier Methods choose 1||Barrier Methods choose 1|
|Choose One Barrier Method from each column (must choose two methods)||Diaphragm with spermicide Cervical cap with spermicide Contraceptive sponge||AND||Male condom Female condom|
Genotoxic effects have been observed in animal studies at exposures exceeding the human therapeutic exposures by approximately 2.5 times. Thus, the risk of genotoxic effects on sperm cells cannot be excluded. Based on this potential risk, sexually active male patients and/or their female partners are recommended to use effective contraception during treatment of the male patient and for at least 90 days after cessation of treatment. Also, based on the potential risk of genotoxic effects, male patients should not donate sperm during treatment with Mycophenolic acid delayed-release tablets and for at least 90 days after cessation of treatment [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.1), Patient Counseling Information (17)].
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