General: Neoplasms: As in all patients receiving immunosuppressive regimens involving combinations of drugs, patients receiving CellCept as part of an immunosuppressive regimen are at an 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 by heptatitis 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.
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.
There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving mycophenolate mofetil in combination with other immunosuppressants. In some of these cases switching mycophenolate mofetil to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on mycophenolate mofetil who develop recurrent infections should have their serum immunoglobulins measured. In cases of sustained, clinically relevant hypogammaglobulinaemia, appropriate clinical action should be considered taking into account the potent cytostatic effects that mycophenolic acid has on T- and B-lymphocytes.
There have been published reports of bronchiectasis in adults and children who received mycophenolate mofetil in combination with other immunosuppressants. In some of these cases switching mycophenolate mofetil to another immunosuppressant resulted in improvement in respiratory symptoms. The risk of bronchiectasis may be linked to hypogammaglobulinaemia or to a direct effect on the lung. There have also been isolated reports of interstitial lung disease and pulmonary fibrosis, some of which were fatal (see Adverse Reactions). It is recommended that patients who develop persistent pulmonary symptoms, such as cough and dyspnoea, are investigated.
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).
Patients should not donate blood during therapy and for at least 6 weeks following discontinuation of CellCept.
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, hemorrhage, and perforation. CellCept should be administered with caution in patients with active digestive system disease.
CellCept is an IMPDH (inosine monophosphate dehydrogenase) 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. Drugs which interfere with MPA's enterohepatic cycle (e.g. cholestyramine, antibiotics) should be used with caution due to their potential to reduce the plasma levels and efficacy of CellCept (see Interactions). Some degree of enterohepatic recirculation is anticipated following i.v. administration of CellCept. 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). 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.
Special Populations: Elderly patients may be at an increased risk of adverse events such as certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared with younger individuals (see Adverse Reactions).
CellCept is contraindicated in pregnancy and during breastfeeding (see Use in Pregnancy & Lactation).
Men should not donate semen during therapy and for 90 days following discontinuation of CellCept.
Administration of doses greater than 1 g twice daily. to renal transplant patients with severe chronic renal impairment should be avoided (see Pharmacology: Pharmacokinetics under Actions and Special Dosage Instructions under Dosage & Administration).
No dose adjustment is recommended for post-transplant patients with delayed renal graft function, but patients should be carefully monitored (see Pharmacology: Pharmacokinetics under Actions and Special Dosage Instructions under Dosage & Administration). No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.
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).
Renal Impairment: Patients with severe renal impairment: In renal transplant patients with severe chronic renal impairment (glomerular filtration rate <25 mL/min/1.73m2), outside of the immediate post-transplant period or after treatment of acute of refractory rejection, doses greater than 1 g administered twice a day should be avoided. (see Precautions).
No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.
Patients with delayed renal graft function post-transplant: No dose adjustments are needed in patients experiencing delayed renal graft function post-operatively. (See Pharmacology: Pharmacokinetics under Actions.)
Hepatic Impairment: No dose adjustments are needed for renal transplant patients with severe hepatic parenchymal disease. (see Pharmacology: Pharmacokinetics under Actions). No data are available for cardiac transplant patients with severe hepatic parenchymal disease.
Use in the Elderly: The recommended oral doses of 1 g twice daily for renal transplant patients, 1.5 g twice daily. For cardiac or hepatic transplant patients is appropriate for elderly patients (see Precautions, Adverse Reactions, and Pharmacology: Pharmacokinetics: Pharmacokinetics in special populations under Actions).