Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)
- *the terms “and nervous system” are added at the end of the subsection
Pure Red Cell Aplasia (PRC)
- *the words “SHOULD NEVER” are replaced with the words “MUST NOT.”
- Cyclosporine A interferes with MPA enterohepatic recirculation…changes in MPA exposure should be expected when switching patients from cyclosporine A to one of the immunosuppressants which do not interfere with MPA’s enterohepatic cycle (e.g. tacrolimus; belatacept)…
- Concommitant administration of telmisartan and CellCept resulted in an approximately 30% decrease in mycophenolic acid (MPA) concentrations. Telmisartan changes MPA’s elimination by enhancing PPAR gamma (peroxisome proliferator-activated receptor gamma) expression, which in turn results in an enhanced UGT1A9 expression and activity.
- Use of MMF during pregnancy… and nervous system.
- Congenital Disorders… including ear, facial, cardiac and nervous system malformations…
- Hematologic and Lymphatic…and hypogammaglobulinemia…
- Patients receiving immunosuppressants, including CellCept, are at increased risk of developing bacterial, fungal, protozoal and new or reactivated viral infections, including opportunistic infections. These infections may lead to serious, including fatal outcomes. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution (see ADVERSE REACTIONS).
Latent Viral Infections
New or Reactivated Viral Infections
- Polyomavirus associated nephropathy (PVAN), JC virus associated progressive multifocal leukoencephalopathy (PML), cytomegalovirus (CMV) infections, reactivation of hepatitis B (HBV) or hepatitis C (HCV) have been reported in patients treated with immunosuppressants, including CellCept. Reduction in immunosuppression should be considered for patients who develop evidence of new or reactivated viral infections. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft.
- PVAN, especially due to BK virus infection, is associated with serious outcomes, including deteriorating renal function and renal graft loss (see ADVERSE REACTIONS: Postmarketing Experience). Patient monitoring may help detect patients at risk for PVAN.
- 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 (see ADVERSE REACTIONS: Postmarketing Experience). 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.
- The risk of CMV viremia and CMV disease is highest among transplant recipients seronegative for CMV at time of transplant who receive a graft from a CMV seropositive donor. Therapeutic approaches to limiting CMV disease exist and should be routinely provided. Patient monitoring may help detect patients at risk for CMV disease.
- Viral reactivation has been reported in patients infected with HBV or HCV. Monitoring infected patients for clinical and laboratory signs of active HBV or HCV infection is recommended.
MEDICATION GUIDE (NEW)
WARNING: EMBRYOFETAL TOXICITY, MALIGNANCIES AND SERIOUS INFECTIONS
- Use during pregnancy is associated with increased risks of first trimester pregnancy loss and congenital malformations. Females of reproductive potential (FRP) must be counseled regarding pregnancy prevention and planning.
- Mycophenolate mofetil (MMF) can cause fetal harm when administered to a pregnant female. 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.
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.
- Proton Pump Inhibitors (PPIs) Coadministration of PPIs (e.g., lansoprazole, pantoprazole) in single doses to healthy volunteers and multiple doses to transplant patients receiving CellCept has been reported to reduce the exposure to mycophenolic acid (MPA). An approximate reduction of 30 to 70% in the Cmax and 25% to 35% in the AUC of MPA has been observed, possibly due to a decrease in MPA solubility at an increased gastric pH. The clinical impact of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and CellCept. Because clinical relevance has not been established, PPIs should be used with caution when coadministered to transplant patients being treated with CellCept.
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.
- 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 CellCept. 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.
- Females of reproductive potential taking CellCept must receive contraceptive counseling and use acceptable contraception (see Table 8 for acceptable contraception methods). Patients must use acceptable birth control during entire CellCept therapy, and for 6 weeks after stopping CellCept, unless the patient chooses abstinence (she chooses to avoid heterosexual intercourse completely).
- Patients should be aware that CellCept reduces blood levels of the hormones in the oral contraceptive pill and could theoretically reduce its effectiveness.
- Acceptable Contraception Methods for Females of Reproductive Potential Pick from the following birth control options...
- For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of CellCept should be discussed with the patient.
Information for Patients
- Inform females of reproductive potential that use of CellCept 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.
- Discuss pregnancy testing, pregnancy prevention and planning with females of reproductive potential. 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.
- Females of reproductive potential must use acceptable birth control during entire CellCept therapy and for 6 weeks after stopping CellCept, unless the patient chooses to avoid heterosexual intercourse completely (abstinence).
- For patients who are considering pregnancy, discuss appropriate alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of CellCept should be discussed with the patient.
- Advise patients that they should not breastfeed during CellCept therapy.
- It is recommended to co-administer CellCept with hormonal contraceptives (eg, birth control pill, transdermal patch, vaginal ring, injection, and implant) with caution, and additional barrier contraceptive.
- Use of MMF during pregnancy is associated with an increased risk of first trimester pregnancy loss and...
- Risks and benefits of CellCept should be discussed with the patient. When appropriate, consider alternative...
- In the National Transplantation Pregnancy Registry (NTPR), there were data on 33 MMFexposed pregnancies in 24 transplant patients; there were 15 spontaneous abortions (45%)...
- In animal reproductive toxicology studies, there were increased rates of fetal resorptions and malformations in the absence of maternal toxicity. Female rats and rabbits received mycophenolate mofetil (MMF) doses equivalent to…
- Congenital Disorders: Embryofetal Toxicity: Congenital malformations and an increased incidence of first trimester pregnancy loss have beenreported following exposure to mycophenolate mofetil during pregnancy.
What is the most important information I should know about CellCept? CellCept can cause serious side effects:
- Increased risk of loss of a pregnancy (miscarriage) and higher risk of birth defects.
- If you become pregnant while taking CellCept, do not stop taking CellCept. Call your doctor right away.
- doctor should report your pregnancy to Mycophenolate Pregnancy Registry (1-800-617-8191).
- The purpose of this registry is to gather information about the health of you and your baby.
What should I tell my healthcare provider before taking CellCept?
- Tell your healthcare provider about all of the medicines you are taking including prescription and nonprescription medicines...proton pump inhibitors (PPIs) (Prevacid, Protonix)