Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639, Grenzach-Wyhlen, Germany
Patients receiving immunosuppressive regimens involving combinations of medicinal products, including CellCept, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.8). The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.
As general advice to minimise the 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.
Patients treated with immunosuppressants, including CellCept, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis (see section 4.8). Such infections include latent viral reactivation, such as hepatitis B or hepatitis C reactivation and infections caused by polyomaviruses (BK virus associated nephropathy, JC virus associated progressive multifocal leukoencephalopathy PML). Cases of hepatitis due to reactivation of hepatitis B or hepatitis C have been reported in carrier patients treated with immunosuppressants. These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.
There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving CellCept in combination with other immunosuppressants. In some of these cases switching CellCept to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on CellCept 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 CellCept in combination with other immunosuppressants. In some of these cases switching CellCept 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 section 4.8). It is recommended that patients who develop persistent pulmonary symptoms, such as cough and dyspnoea, are investigated.
Patients receiving CellCept should be monitored for neutropenia, which may be related to CellCept itself, concomitant medications, viral infections, or some combination of these causes. Patients taking CellCept should have complete blood counts weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year. If neutropenia develops (absolute neutrophil count <1.3 × 103/μl), it may be appropriate to interrupt or discontinue CellCept.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with CellCept in combination with other immunosuppressants. The mechanism for mycophenolate mofetil induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of CellCept therapy. Changes to CellCept therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimise the risk of graft rejection (see section 4.8).
Patients receiving CellCept should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow failure.
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 section 4.5). Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.
CellCept has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation. CellCept should be administered with caution in patients with active serious 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.
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 also section 4.5). 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 such concomitant administration has not been studied.
The risk/benefit ratio of mycophenolate mofetil in combination with sirolimus has not been established (see also section 4.5).
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 section 4.8).
Mycophenolate is a powerful human teratogen. Spontaneous abortion (rate of 45% to 49%) and congenital malformations (estimated rate of 23% to 27%) have been reported following MMF exposure during pregnancy. Therefore, CellCept is contraindicated in pregnancy unless there are no suitable alternative treatments to prevent transplant rejection. Female patients of childbearing potential should be made aware of the risks and follow the recommendations provided in section 4.6 (e.g. contraceptive methods, pregnancy testing) prior to, during, and after therapy with CellCept. Physicians should ensure that women taking mycophenolate understand the risk of harm to the baby, the need for effective contraception, and the need to immediately consult their physician if there is a possibility of pregnancy.
Because of robust clinical evidence showing a high risk of abortion and congenital malformations when mycophenolate mofetil is used in pregnancy every effort to avoid pregnancy during treatment should be taken. Therefore, women with childbearing potential must use at least one form of reliable contraception (see section 4.3) before starting CellCept therapy, during therapy, and for six weeks after stopping the therapy; unless abstinence is the chosen method of contraception. Two complementary forms of contraception simultaneously are preferred to minimise the potential for contraceptive failure and unintended pregnancy.
For contraception advice for men see section 4.6.
In order to assist patients in avoiding foetal exposure to mycophenolate and to provide additional important safety information, the Marketing Authorisation holder will provide educational materials to healthcare professionals. The educational materials will reinforce the warnings about the teratogenicity of mycophenolate, provide advice on contraception before therapy is started and guidance on the need for pregnancy testing. Full patient information about the teratogenic risk and the pregnancy prevention measures should be given by the physician to women of childbearing potential and, as appropriate, to male patients.
Patients should not donate blood during therapy or for at least 6 weeks following discontinuation of mycophenolate. Men should not donate semen during therapy or for 90 days following discontinuation of mycophenolate.
Higher aciclovir plasma concentrations were observed when mycophenolate mofetil was administered with aciclovir in comparison to the administration of aciclovir alone. The changes in MPAG (the phenolic glucuronide of MPA) pharmacokinetics (MPAG increased by 8%) were minimal and are not considered clinically significant. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are aciclovir concentrations, the potential exists for mycophenolate mofetil and aciclovir, or its prodrugs, e.g. valaciclovir, to compete for tubular secretion and further increases in concentrations of both substances may occur.
Decreased MPA exposure has been observed when antacids, such as magnesium and aluminium hydroxides, and PPIs, including lansoprazole and pantoprazole, were administered with CellCept. When comparing rates of transplant rejection or rates of graft loss between CellCept patients taking PPIs vs. CellCept patients not taking PPIs, no significant differences were seen. This data support extrapolation of this finding to all antacids because the reduction in exposure when CellCept was co- administered with magnesium and aluminium hydroxides is considerably less than when CellCept was co-administered with PPIs.
Caution should be used with medicinal products that interfere with enterohepatic recirculation because of their potential to reduce the efficacy of CellCept.
Following single dose administration of 1.5 g of mycophenolate mofetil to normal healthy subjects pre-treated with 4 g TID of cholestyramine for 4 days, there was a 40% reduction in the AUC of MPA (see section 4.4 and section 5.2). Caution should be used during concomitant administration because of the potential to reduce efficacy of CellCept.
Ciclosporin A (CsA) pharmacokinetics are unaffected by mycophenolate mofetil. In contrast, if concomitant CsA treatment is stopped, an increase in MPA AUC of around 30% should be expected. CsA interferes with MPA enterohepatic recycling, resulting in reduced MPA exposures by 30-50% in renal transplant patients treated with CellCept and CsA compared with patients receiving sirolimus or belatacept and similar doses of CellCept (see also section 4.4). Conversely, changes of MPA exposure should be expected when switching patients from CsA to one of the immunosuppressants which does not interfere with MPA’s enterohepatic cycle.
Antibiotics eliminating β-glucuronidase-producing bacteria in the intestine (e.g. aminoglycoside, cephalosporin, fluoroquinolone, and penicillin classes of antibiotics) may interfere with MPAG/MPA enterohepatic recirculation thus leading to reduced systemic MPA exposure. Information concerning the following antibiotics is available:
Reductions in pre-dose (trough) MPA concentrations of about 50% have been reported in renal transplant recipients in the days immediately following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. This effect tended to diminish with continued antibiotic use and to cease within a few days of antibiotic discontinuation. The change in predose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of CellCept should not normally be necessary in the absence of clinical evidence of graft dysfunction. However, close clinical monitoring should be performed during the combination and shortly after antibiotic treatment.
In healthy volunteers, no significant interaction was observed when CellCept was concomitantly administered with norfloxacin or metronidazole separately. However, norfloxacin and metronidazole combined reduced the MPA exposure by approximately 30% following a single dose of CellCept.
No effect on the bioavailability of MPA was observed.
Concomitant administration of drugs affecting glucuronidation of MPA may change MPA exposure.
Caution is therefore recommended when administering these drugs concomitantly with CellCept.
An increase of MPA AUC0-∞ by 35% was observed with concomitant administration of isavuconazole.
Concomitant administration of telmisartan and CellCept resulted in an approximately 30% decrease of 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. When comparing rates of transplant rejection, rates of graft loss or adverse event profiles between CellCept patients with and without concomitant telmisartan medication, no clinical consequences of the pharmacokinetic drug-drug interaction were seen.
Based on the results of a single dose administration study of recommended doses of oral mycophenolate and IV ganciclovir and the known effects of renal impairment on the pharmacokinetics of CellCept (see section 4.2) and ganciclovir, it is anticipated that co-administration of these agents (which compete for mechanisms of renal tubular secretion) will result in increases in MPAG and ganciclovir concentration. No substantial alteration of MPA pharmacokinetics is anticipated and CellCept dose adjustment is not required. In patients with renal impairment in whom CellCept and ganciclovir or its prodrugs, e.g. valganciclovir, are co-administered, the dose recommendations for ganciclovir should be observed and patients should be monitored carefully.
The pharmacokinetics and pharmacodynamics of oral contraceptives were unaffected by co-administration of CellCept (see also section 5.2).
In patients not also taking ciclosporin, concomitant administration of CellCept and rifampicin resulted in a decrease in MPA exposure (AUC0-12h) of 18% to 70%. It is recommended to monitor MPA exposure levels and to adjust CellCept doses accordingly to maintain clinical efficacy when rifampicin is administered concomitantly.
Decrease in MPA Cmax and AUC0-12h by 30% and 25%, respectively, were observed when CellCept was concomitantly administered with sevelamer without any clinical consequences (i.e. graft rejection). It is recommended, however, to administer CellCept at least one hour before or three hours after sevelamer intake to minimise the impact on the absorption of MPA. There are no data on CellCept with phosphate binders other than sevelamer.
In hepatic transplant patients initiated on CellCept and tacrolimus, the AUC and Cmax of MPA, the active metabolite of CellCept, were not significantly affected by co-administration with tacrolimus. In contrast, there was an increase of approximately 20% in tacrolimus AUC when multiple doses of CellCept (1.5 g BID) were administered to hepatic transplant patients taking tacrolimus. However, in renal transplant patients, tacrolimus concentration did not appear to be altered by CellCept (see also section 4.4).
Live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished (see also section 4.4).
Interaction studies have only been performed in adults.
Co-administration of probenecid with mycophenolate mofetil in monkeys raises plasma AUC of MPAG by 3-fold. Thus, other substances known to undergo renal tubular secretion may compete with MPAG, and thereby raise plasma concentrations of MPAG or the other substance undergoing tubular secretion.
Pregnancy whilst taking mycophenolate must be avoided. Therefore, women of childbearing potential must use at least one form of reliable contraception (see section 4.3) before starting CellCept therapy, during therapy, and for six weeks after stopping the therapy, unless abstinence is the chosen method of contraception. Two complementary forms of contraception simultaneously are preferred.
CellCept is contraindicated during pregnancy unless there is no suitable alternative treatment to prevent transplant rejection. Treatment should not be initiated without providing a negative pregnancy test result to rule out unintended use in pregnancy.
Female patients of reproductive potential must be made aware of the increased risk of pregnancy loss and congenital malformations at the beginning of the treatment and must be counseled regarding pregnancy prevention and planning.
Before starting CellCept treatment, women of childbearing potential should have two negative serum or urine pregnancy tests with a sensitivity of at least 25 mIU/mL in order to exclude unintended exposure of the embryo to mycophenolate. It is recommended that the second test should be performed 8-10 days after the first test. For transplants from deceased donors, if it is not possible to perform two tests 8-10 days apart before treatment starts (because of the timing of transplant organ availability), a pregnancy test must be performed immediately before starting treatment and a further test performed 8-10 days later. Pregnancy tests should be repeated as clinically required (e.g. after any gap in contraception is reported). Results of all pregnancy tests should be discussed with the patient. Patients should be instructed to consult their physician immediately should pregnancy occur.
Mycophenolate is a powerful human teratogen, with an increased risk of spontaneous abortions and congenital malformations in case of exposure during pregnancy;
Congenital malformations, including reports of multiple malformations, have been observed post-marketing in children of patients exposed to CellCept in combination with other immunosuppressants during pregnancy. The following malformations were most frequently reported:
In addition, there have been isolated reports of the following malformations:
Studies in animals have shown reproductive toxicity (see section 5.3).
Mycophenolate mofetil has been shown to be excreted in the milk of lactating rats. It is not known whether this substance is excreted in human milk. Because of the potential for serious adverse reactions to mycophenolate mofetil in breast-fed infants, CellCept is contraindicated in nursing mothers (see section 4.3).
Limited clinical evidence does not indicate an increased risk of malformations or miscarriage following paternal exposure to mycophenolate mofetil.
MPA is a powerful teratogen. It is not known if MPA is present in semen. Calculations based on animal data show that the maximum amount of MPA that could potentially be transferred to woman is so low that it would be unlikely to have an effect. Mycophenolate has been shown to be genotoxic in animal studies at concentrations exceeding the human therapeutic exposures only by small margins, such that the risk of genotoxic effects on sperm cells cannot completely be excluded.
Therefore, the following precautionary measures are recommended: sexually active male patients or their female partners are recommended to use reliable contraception during treatment of the male patient and for at least 90 days after cessation of mycophenolate mofetil. Male patients of reproductive potential should be made aware of and discuss with a qualified health-care professional the potential risks of fathering a child.
CellCept has a moderate influence on the ability to drive and use machines. Cellcept may cause somnolence, confusion, dizziness, tremor or hypotension, and therefore patients are advised to use caution when driving or using machines.
An estimated total of 1557 patients received CellCept during five clinical trials in the prevention of acute organ rejection. Of these, 991 were included in the three renal studies, 277 were included in one hepatic study, and 289 were included in one cardiac study. Azathioprine was the comparator used in the hepatic and cardiac studies and in two of the renal studies whilst the other renal study was placebo- controlled. Patients in all study arms also received cyclosporine and corticosteroids. The types of adverse reactions reported during post-marketing with CellCept are similar to those seen in the controlled renal, cardiac and hepatic transplant studies.
Diarrhoea, leucopenia, sepsis and vomiting were among the most common and/or serious adverse drug reactions associated with the administration of CellCept in combination with ciclosporin and corticosteroids. There is also evidence of a higher frequency of certain types of infections (see section 4.4).
The adverse drug reactions (ADRs) from clinical trials and post marketing experience are listed in Table 1, by MedDRA system organ class (SOC) along with their frequencies. The corresponding frequency category for each adverse drug reaction is based on the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000). Due to the large differences observed in the frequency of certain ADRs across the different transplant indications, the frequency is presented separately for renal, hepatic and cardiac transplant patients.
Table 1. Summary of adverse drug reactions occurring in patients treated with CellCept reported from clinical trials and post marketing experience:
Patients receiving immunosuppressive regimens involving combinations of medicinal products, including CellCept, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.4). Three-year safety data in renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. Hepatic transplant patients were followed for at least 1 year, but less than 3 years.
All patients treated with immunosuppressants are at increased risk of bacterial, viral and fungal infections (some of which may lead to a fatal outcome), including those caused by opportunistic agents and latent viral reactivation. The risk increases with total immunosuppressive load (see section 4.4). The most serious infections were sepsis, peritonitis, meningitis, endocarditis, tuberculosis and atypical mycobacterial infection. The most common opportunistic infections in patients receiving CellCept (2 g or 3 g daily) with other immunosuppressants in controlled clinical trials in renal, cardiac and hepatic transplant patients followed for at least 1 year were candida mucocutaneous, CMV viraemia/syndrome and Herpes simplex. The proportion of patients with CMV viraemia/syndrome was 13.5%. Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including CellCept.
Cytopenias, including leucopenia, anemia, thrombocytopenia and pancytopenia, are known risks associated with mycophenolate mofetil and may lead or contribute to the occurrence of infections and hemorrhages (see section 4.4). Agranulocytosis and neutropenia have been reported; therefore, regular monitoring of patients taking CellCept is advised (see section 4.4). There have been reports of aplastic anaemia and bone marrow failure in patients treated with CellCept, some of which have been fatal. Cases of pure red cell aplasia (PRCA) have been reported in patients treated with CellCept (see section 4.4).
Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with CellCept. These changes are not associated with impaired neutrophil function. These changes may suggest a ‘left shift’ in the maturity of neutrophils in haematological investigations, which may be mistakenly interpreted as a sign of infection in immunosuppressed patients such as those that receive CellCept.
The most serious gastrointestinal disorders were ulceration and hemorrhage which are known risks associated with mycophenolate mofetil. Mouth, esophageal, gastric, duodenal, and intestinal ulcers often complicated by hemorrhage, as well as hematemesis, melena, and hemorrhagic forms of gastritis and colitis were commonly reported during the pivotal clinical trials. The most common gastrointestinal disorders, however, were diarrhea, nausea and vomiting. Endoscopic investigation of patients with CellCept-related diarrhea have revealed isolated cases of intestinal villous atrophy (see section 4.4).
Hypersensitivity reactions, including angioneurotic oedema and anaphylactic reaction, have been reported.
Cases of spontaneous abortions have been reported in patients exposed to mycophenolate mofetil, mainly in the first trimester, see section 4.6.
Congenital malformations have been observed post-marketing in children of patients exposed to CellCept in combination with other immunosuppressants, see section 4.6.
There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients treated with CellCept in combination with other immunosuppressants, some of which have been fatal. There have also been reports of bronchiectasis in children and adults.
Hypogammaglobulinaemia has been reported in patients receiving CellCept in combination with other immunosuppressants.
Edema, including peripheral, face and scrotal edema, was reported very commonly during the pivotal trials. Musculoskeletal pain such as myalgia, and neck and back pain were also very commonly reported.
The type and frequency of adverse reactions in a clinical study, which recruited 92 paediatric patients aged 2 to 18 years who were given 600 mg/m² mycophenolate mofetil orally twice daily, were generally similar to those observed in adult patients given 1 g CellCept twice daily. However, the following treatment-related adverse events were more frequent in the paediatric population, particularly in children under 6 years of age, when compared to adults: diarrhoea, sepsis, leucopenia, anaemia and infection.
Elderly patients (≥65 years) may generally be at increased risk of adverse reactions due to immunosuppression. Elderly patients receiving CellCept as part of a combination immunosuppressive regimen may be at increased risk of certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared to younger individuals.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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