CellCept Special Precautions

General: Neoplasms: As in all patients receiving immunosuppressive regimens involving combinations of drugs, patients receiving CellCept 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.
As with all patients at an 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 (see Adverse Reactions). Such infections include latent viral reactivation, such as hepatitis B or hepatitis C reactivation, or infections caused by polyomaviruses. Cases of hepatitis due to reactivation of hepatitis B or hepatitis C have been reported in carrier patients treated with immunosuppressants. Cases of Progressive Multifocal Leukoencephalopathy (PML) associated with the JC virus, sometimes fatal, have been reported in CellCept treated patients. The reported cases generally had risk factors for PML, including 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.
Consideration should be given to reducing the amount of immunosuppressive in patients who develop PML. In transplant patients, physicians should also consider the risk that reduced immunosuppressant represents to the graft.
BK virus-associated nephropathy has been observed during the use of CellCept in patients post renal transplant. This infection can be associated with serious outcomes, sometimes leading to renal graft loss. Patient monitoring may help detect patients at risk for BK virus-associated nephropathy. Reduction in immunosuppression should be considered for patients who develop evidence of BK virus-associated nephropathy.
Blood and immune system: Cases of pure red cell aplasia (PRCA) have been reported in patients treated with CellCept in combination with other immunosuppressive agents. The mechanism for mycophenolate mofetil induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppression regimen are also unknown. In some cases PRCA was found to be reversible with dose reduction or cessation of CellCept therapy. In transplant patients however reduced immunosuppression may place the graft at risk.
Patients receiving CellCept should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Patients on CellCept should have complete blood counts weekly during the first month of treatment, twice monthly for the second and third months, then monthly through the first year. In particular, patients receiving CellCept should be monitored for neutropenia. The development of neutropenia may be related to CellCept, concomitant medications, viral infection or some combination of these causes (see Special Dosage Instructions under Dosage & Administration). If neutropenia develops (absolute neutrophil count <1.3 x 10³/μL), dosing with CellCept should be interrupted or the dose should be reduced and the patient carefully observed (see Special Dosage Instructions under Dosage & Administration).
Blood Donation: Patients should not donate blood during therapy and for at least 6 weeks following discontinuation of CellCept.
Vaccination: Patients should be advised that during treatment with CellCept vaccinations may be less effective and the use of live attenuated vaccines should be avoided (see Interactions). Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.
Gastro-intestinal: CellCept has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, hamorrhage, and perforation. CellCept should be administered with caution in patients with active digestive system disease.
CellCept is an inosine monophosphate dehydrogenase (IMPDH) inhibitor; therefore it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.
Interactions: Caution should be exercised when switching combination therapy from regimens containing immunosuppressants, which interfere with MPA enterohepatic recirculation e.g. ciclosporin to others devoid of this effect e.g. tacrolimus, sirolimus, belatacept, or vice versa, as this might result in changes of MPA exposure. (see Interactions). Therapeutic drug monitoring of MPA may be appropriate when switching combination therapy (e.g. from ciclosporin to tacrolimus or vice versa) or to ensure adequate immunosuppression in patients with high immunological risk (e.g. risk of rejection, treatment with antibiotics, addition or removal of an interacting medication).
Drugs which interfere with MPA's enterohepatic cycle (e.g. cholestyramine, sevelamer, antibiotics) should be used with caution due to their potential to reduce the plasma levels and efficacy of CellCept. (see Interactions). Sevelamer and other calcium free phosphate binders should be taken 2 hours after CellCept intake to minimise the impact on the absorption of MPA. (See Interactions.)
It is recommended that CellCept should not be administered concomitantly with azathioprine because both have the potential to cause bone marrow suppression and such concomitant administration has not been studied.
Ability to Drive and Use Machines: CellCept may have a moderate influence on the ability to drive and use machines. Patients should be advised to use caution when driving or using machines if they experience adverse drug reactions such as somnolence, confusion, dizziness, tremor or hypotension during treatment with CellCept (see Adverse Reactions).
Special Populations: Semen Donation: Men should not donate semen during therapy and for 90 days following discontinuation of CellCept.
Drug abuse and dependence: There is no data available to show that CellCept has the potential for drug abuse or dependence.
Females and Males of Reproductive Potential: Fertility: CellCept is contraindicated in women of childbearing potential not using highly effective contraceptive methods (see Contraindications). Malformations (including anophthalmia, agnathia, and hydrocephaly) occurred in the first generation offspring of female rats treated with oral doses of mycophenolate mofetil in the absence of maternal toxicity (see Pharmacology: Toxicology: Impairment of Fertility under Actions). No effect was seen on the fertility of male rats treated with mycophenolate mofetil.
Pregnancy Testing: Prior to starting therapy with CellCept, female patients of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mlU/mL. A second test should be performed 8-10 days later. Repeat pregnancy tests should be performed during routine follow-up visits. Results of all pregnancy tests should be discussed with the patient. Patients should be instructed to consult their physician immediately should pregnancy occur.
Contraception: Females: Cellcept is contraindicated in women of childbearing potential not using highly effective contraceptive methods (see Contraindications).
Before the start of treatment, female patients of reproductive potential must be made aware of the increased risk of pregnancy loss and congenital malformations and must be counseled regarding pregnancy prevention, and planning. Women of childbearing potential should use two reliable forms of contraception simultaneously, at least one of which must be highly effective, before beginning CellCept therapy, during therapy, and for six weeks following discontinuation of therapy, unless abstinence is the chosen method of contraception.
Males: Limited clinical evidence is currently available on paternal exposure to CellCept. This evidence does not indicate an increased risk of malformations or miscarriage following paternal exposure to mycophenolate.
Non-clinical evidence shows that the dose of mycophenolate that could be transferred via the seminal fluid to a potentially pregnant partner is 30-fold lower than the concentration without teratogenic effects in animals, and 200-fold lower than the lowest teratogenic concentration in animals. Therefore, the risk of harm mediated via seminal fluid is considered negligible. However, 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 completely be excluded.
In absence of sufficient data to exclude a risk of harm to the fetus conceived during or directly after the treatment of the father, the following precautionary measure is recommended: 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.
Renal impairment: See Dosage & Administration and Pharmacology: Pharmacokinetics under Actions.
Hepatic impairment: See Dosage and Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Use in Pregnancy & Lactation: CellCept is contraindicated in pregnancy and during breastfeeding (see Use in Pregnancy & Lactation).
Use in Children: See Dosage & Administration, Adverse Reactions and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Use in the Elderly: Geriatric patients may be at an increased risk of adverse events such as certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal hemorrhage and pulmonary edema, compared with younger individuals (see Adverse Reactions).
See Dosage & Administration, Precautions, Adverse Reactions and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.