CELLCEPT 500mg tablets medication leaflet

CellCept 500 mg film-coated tablets

Each tablet contains 500 mg mycophenolate mofetil.

For the full list of excipients, see section 6.1.

Film-coated tablets (tablets)

Lavender-coloured caplet-shaped tablet, engraved with 'CellCept 500' on one side and 'Roche' on theother.

CellCept is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acutetransplant rejection in adult and paediatric (1 to 18 years of age) patients receiving allogeneic renal,cardiac or hepatic transplants.

Treatment should be initiated and maintained by appropriately qualified transplant specialists.

Renal transplant

Treatment should be initiated within 72 hours following transplantation. The recommended dose inrenal transplant patients is 1 g administered twice daily (2 g daily dose).

Cardiac transplant

Treatment should be initiated within 5 days following transplantation. The recommended dose incardiac transplant patients is 1.5 g administered twice daily (3 g daily dose).

Hepatic transplant

Treatment of intravenous mycophenolate mofetil should be administered for the first 4 days followinghepatic transplant, with oral mycophenolate mofetil initiated as soon after this as it can be tolerated.

The recommended oral dose in hepatic transplant patients is 1.5 g administered twice daily (3 g dailydose).

Paediatric population (1 to 18 years)

The paediatric dosing information in this section applies to all oral formulations within the range ofmycophenolate mofetil products, as appropriate. Different oral formulations should not be substitutedwithout clinical supervision.

The recommended mycophenolate mofetil initial dose for paediatric renal, cardiac and hepatictransplant patients is 600 mg/m2 (of body surface area (BSA)), administered orally, twice daily (initialtotal daily dose not to exceed 2 g, or 10 ml of the oral suspension).

The dose and product form should be individualised based on clinical assessment. If the recommendedinitial dose is well tolerated but does not achieve clinically adequate immunosuppression in paediatriccardiac and hepatic transplant patients, the dose can be increased to 900 mg/m2 BSA twice daily(maximum total daily dose of 3 g, or 15 ml of the oral suspension). The recommended maintenancedose for paediatric renal transplant patients remains at 600 mg/m2 twice daily (maximum total dailydose of 2 g or 10 ml of the oral suspension).

The mycophenolate mofetil powder for oral suspension should be used in those patients unable toswallow capsules and tablets and/or with BSA lower than 1.25 m2 due to the increased risk of choking.

Patients with a BSA of 1.25 to 1.5 m2 may be prescribed mycophenolate mofetil capsules at a dose of750 mg twice daily (1.5 g daily dose). Patients with a BSA greater than 1.5 m2 may be prescribedmycophenolate mofetil capsules or tablets at a dose of 1 g twice daily (2 g daily dose). As someadverse reactions occur with greater frequency in this age group (see section 4.8) compared withadults, temporary dose reduction or interruption may be required; these will need to take into accountrelevant clinical factors including severity of reaction.

Use in special populations

The recommended dose of 1 g administered twice a day for renal transplant patients and 1.5 g twice aday for cardiac or hepatic transplant patients is appropriate for the elderly.

In renal transplant patients with severe chronic renal impairment (glomerular filtration rate< 25 ml/min/1.73 m2), outside the immediate post-transplant period, doses greater than 1 gadministered twice a day should be avoided. These patients should also be carefully observed. No doseadjustments are needed in patients experiencing delayed renal graft function post-operatively (seesection 5.2). No data are available for cardiac or hepatic transplant patients with severe chronic renalimpairment.

No dose adjustments are needed for renal transplant patients with severe hepatic parenchymal disease.

No data are available for cardiac transplant patients with severe hepatic parenchymal disease.

Treatment during rejection episodes

Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil. Renal transplantrejection does not lead to changes in MPA pharmacokinetics; dose reduction or interruption oftreatment is not required. There is no basis for dose adjustment following cardiac transplant rejection.

No pharmacokinetic data are available during hepatic transplant rejection.

No data are available for treatment of first or refractory rejection in paediatric transplant patients.

For oral use.

Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, tablets shouldnot be crushed to avoid inhalation or direct contact with skin or mucous membranes with powder. Ifsuch contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.

* CellCept should not be given to patients with hypersensitivity to mycophenolate mofetil,mycophenolic acid or to any of the excipients listed in section 6.1. Hypersensitivity reactions tothis medicinal product have been observed (see section 4.8).

* Treatment should not be given to women of childbearing potential who are not using highlyeffective contraception (see section 4.6).

* Treatment should not be initiated in women of childbearing potential without providing apregnancy test result to rule out unintended use in pregnancy (see section 4.6).

* Treatment should not be used during pregnancy unless there is no suitable alternative treatmentto prevent transplant rejection (see section 4.6).

* Treatment should not be given to women who are breastfeeding (see section 4.6).

Neoplasms

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 ofimmunosuppression rather than to the use of any specific agent. As general advice to minimise the riskfor skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothingand using a sunscreen with a high protection factor.

Patients treated with immunosuppressants, including mycophenolate mofetil, are at increased risk foropportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis (see section4.8). Such infections include latent viral reactivation, such as hepatitis B or hepatitis C reactivationand infections caused by polyomaviruses (BK virus-associated nephropathy, JC virus-associatedprogressive multifocal leukoencephalopathy PML). Cases of hepatitis due to reactivation of hepatitis Bor hepatitis C have been reported in carrier patients treated with immunosuppressants. These infectionsare often related to a high total immunosuppressive burden and may lead to serious or fatal conditionsthat physicians should consider in the differential diagnosis in immunosuppressed patients withdeteriorating renal function or neurological symptoms. Mycophenolic acid has a cytostatic effect on

B- and T-lymphocytes, therefore an increased severity of COVID-19 may occur, and appropriateclinical action should be considered.

There have been reports of hypogammaglobulinaemia in association with recurrent infections inpatients receiving mycophenolate mofetil in combination with other immunosuppressants. In some ofthese cases switching mycophenolate mofetil to an alternative immunosuppressant resulted in serum

IgG levels returning to normal. Patients on mycophenolate mofetil who develop recurrent infectionsshould have their serum immunoglobulins measured. In cases of sustained, clinically relevanthypogammaglobulinaemia, appropriate clinical action should be considered taking into account thepotent cytostatic effects that mycophenolic acid has on T- and B-lymphocytes.

There have been published reports of bronchiectasis in adults and children who receivedmycophenolate mofetil in combination with other immunosuppressants. In some of these casesswitching mycophenolate mofetil to another immunosuppressant resulted in improvement inrespiratory symptoms. The risk of bronchiectasis may be linked to hypogammaglobulinaemia or to adirect effect on the lung. There have also been isolated reports of interstitial lung disease andpulmonary fibrosis, some of which were fatal (see section 4.8). It is recommended that patients whodevelop persistent pulmonary symptoms, such as cough and dyspnoea, are investigated.

Blood and immune system

Patients receiving mycophenolate mofetil should be monitored for neutropenia, which may be relatedto the treatment itself, concomitant medications, viral infections, or some combination of these causes.

Patients taking mycophenolate mofetil should have complete blood counts weekly during the firstmonth, twice monthly for the second and third months of treatment, then monthly through the firstyear. If neutropenia develops (absolute neutrophil count < 1.3 x 103/µl), it may be appropriate tointerrupt or discontinue mycophenolate mofetil.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolatemofetil in combination with other immunosuppressants. The mechanism for mycophenolate mofetilinduced PRCA is unknown. PRCA may resolve with dose reduction or cessation of mycophenolatemofetil therapy. Changes to mycophenolate mofetil therapy should only be undertaken underappropriate supervision in transplant recipients in order to minimise the risk of graft rejection (seesection 4.8).

Patients receiving mycophenolate mofetil should be instructed to report immediately any evidence ofinfection, unexpected bruising, bleeding or any other manifestation of bone marrow failure.

Patients should be advised that, during treatment with mycophenolate mofetil, vaccinations may beless effective, and the use of live attenuated vaccines should be avoided (see section 4.5). Influenzavaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.

Gastrointestinal

Mycophenolate mofetil has been associated with an increased incidence of digestive system adverseevents, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation.

Treatment should be administered with caution in patients with active serious digestive systemdisease.

Mycophenolate is an IMPDH (inosine monophosphate dehydrogenase) inhibitor. Therefore, it shouldbe 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 containingimmunosuppressants, which interfere with MPA enterohepatic recirculation, e.g. ciclosporin, to othersdevoid of this effect, e.g. tacrolimus, sirolimus, belatacept, or vice versa, as this might result inchanges 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 plasmalevel of mycophenolate and its efficacy (see also section 4.5).

It is recommended that mycophenolate mofetil should not be administered concomitantly withazathioprine 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).

Therapeutic drug monitoring

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 patientswith high immunological risk (e.g. risk of rejection, treatment with antibiotics, addition or removal ofan interacting medication).

Very limited post-marketing information indicates a higher frequency of the following adverse eventsin patients under 6 years of age compared to older patients:

* lymphomas and other malignancies, particularly of post-transplant lymphoproliferative disorder incardiac transplant patients.

* blood and lymphatic system disorders including anaemia and neutropenia in cardiac transplantpatients. This applies for children under 6 years of age compared to older patients, and comparedto paediatric hepatic/renal transplant recipients.

Patients taking mycophenolate mofetil should have complete blood counts weekly during the firstmonth, twice monthly for the second and third months of treatment, then monthly through the firstyear. If neutropenia develops, it may be appropriate to interrupt or discontinue mycophenolatemofetil.

* gastrointestinal disorders including diarrhoea and vomiting.

Treatment should be administered with caution in patients with active serious digestive systemdisease.

Elderly patients may be at an increased risk of adverse events such as certain infections (includingcytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonaryoedema, compared with younger individuals (see section 4.8).

Teratogenic effects

Mycophenolate is a powerful human teratogen. Spontaneous abortion (rate of 45% to 49%) andcongenital malformations (estimated rate of 23% to 27%) have been reported followingmycophenolate mofetil exposure during pregnancy. Therefore, treatment is contraindicated inpregnancy unless there are no suitable alternative treatments to prevent transplant rejection. Femalepatients of childbearing potential should be made aware of the risks and follow the recommendationsprovided in section 4.6 (e.g. contraceptive methods, pregnancy testing) prior to, during, and aftertherapy with mycophenolate mofetil. Physicians should ensure that women taking mycophenolatemofetil understand the risk of harm to the baby, the need for effective contraception, and the need toimmediately consult their physician if there is a possibility of pregnancy.

Contraception (see section 4.6)

Because of robust clinical evidence showing a high risk of abortion and congenital malformationswhen mycophenolate mofetil is used in pregnancy, every effort to avoid pregnancy during treatmentshould be taken. Therefore, women with childbearing potential must use at least one form of reliablecontraception (see section 4.3) before starting mycophenolate mofetil therapy, during therapy, and forsix weeks after stopping the therapy, unless abstinence is the chosen method of contraception. Twocomplementary forms of contraception simultaneously are preferred to minimise the potential forcontraceptive 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 additionalimportant safety information, the Marketing Authorisation Holder will provide educational materialsto healthcare professionals. The educational materials will reinforce the warnings about theteratogenicity of mycophenolate, provide advice on contraception before therapy is started andguidance on the need for pregnancy testing. Full patient information about the teratogenic risk and thepregnancy prevention measures should be given by the physician to women of childbearing potentialand, as appropriate, to male patients.

Additional precautions

Patients should not donate blood during therapy or for at least 6 weeks following discontinuation ofmycophenolate mofetil. Men should not donate semen during therapy or for 90 days followingdiscontinuation of mycophenolate mofetil.

Sodium contents

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Higher aciclovir plasma concentrations were observed when mycophenolate mofetil was administeredwith aciclovir in comparison to the administration of aciclovir alone. The changes in MPAG (thephenolic glucuronide of MPA) pharmacokinetics (MPAG increased by 8%) were minimal and are notconsidered clinically significant. Because MPAG plasma concentrations are increased in the presenceof renal impairment, as are aciclovir concentrations, the potential exists for mycophenolate mofetil andaciclovir, or its prodrugs, e.g. valaciclovir, to compete for tubular secretion and further increases inconcentrations of both substances may occur.

Antacids and proton pump inhibitors (PPIs)

Decreased MPA exposure has been observed when antacids, such as magnesium and aluminiumhydroxides, and PPIs, including lansoprazole and pantoprazole, were administered withmycophenolate mofetil. When comparing rates of transplant rejection or rates of graft loss betweenmycophenolate mofetil patients taking PPIs vs. mycophenolate mofetil patients not taking PPIs, nosignificant differences were seen. These data support extrapolation of this finding to all antacidsbecause the reduction in exposure when mycophenolate mofetil was co-administered with magnesiumand aluminium hydroxides is considerably less than when mycophenolate mofetil was co-administeredwith PPIs.

Medicinal products that interfere with enterohepatic recirculation (e.g. cholestyramine, ciclosporin A,antibiotics)

Caution should be used with medicinal products that interfere with enterohepatic recirculation becauseof their potential to reduce the efficacy of mycophenolate mofetil.

Cholestyramine

Following single dose administration of 1.5 g of mycophenolate mofetil to normal healthy subjectspre-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 ofthe potential to reduce efficacy of mycophenolate mofetil.

Ciclosporin A

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% shouldbe expected. CsA interferes with MPA enterohepatic recycling, resulting in reduced MPA exposuresby 30 - 50% in renal transplant patients treated with mycophenolate mofetil and CsA compared withpatients receiving sirolimus or belatacept and similar doses of mycophenolate mofetil (see also section4.4). Conversely, changes of MPA exposure should be expected when switching patients from CsA toone 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/MPAenterohepatic recirculation, thus leading to reduced systemic MPA exposure. Information concerningthe following antibiotics is available:

Ciprofloxacin or amoxicillin plus clavulanic acid

Reductions in pre-dose (trough) MPA concentrations of about 50% have been reported in renaltransplant recipients in the days immediately following commencement of oral ciprofloxacin oramoxicillin plus clavulanic acid. This effect tended to diminish with continued antibiotic use and tocease within a few days of antibiotic discontinuation. The change in pre-dose level may not accuratelyrepresent changes in overall MPA exposure. Therefore, a change in the dose of mycophenolate mofetilshould 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 antibiotictreatment.

Norfloxacin and metronidazole

In healthy volunteers, no significant interaction was observed when mycophenolate mofetil wasconcomitantly administered with norfloxacin or metronidazole separately. However, norfloxacin andmetronidazole combined reduced the MPA exposure by approximately 30% following a single dose ofmycophenolate mofetil.

Trimethoprim/sulfamethoxazole

No effect on the bioavailability of MPA was observed.

Medicinal products that affect glucuronidation (e.g. isavuconazole, telmisartan)

Concomitant administration of drugs affecting glucuronidation of MPA may change MPA exposure.

Caution is therefore recommended when administering these drugs concomitantly with mycophenolatemofetil.

Isavuconazole

An increase of MPA exposure (AUC0-∞) by 35% was observed with concomitant administration ofisavuconazole.

Concomitant administration of telmisartan and mycophenolate mofetil resulted in an approximately30% decrease of MPA concentrations. Telmisartan changes MPA’s elimination by enhancing

PPAR gamma (peroxisome proliferator-activated receptor gamma) expression, which in turn results inan enhanced uridine diphosphate glucuronyltransferase isoform 1A9 (UGT1A9) expression andactivity. When comparing rates of transplant rejection, rates of graft loss or adverse event profilesbetween patients on mycophenolate mofetil with and without concomitant telmisartan medication, noclinical consequences of the pharmacokinetic drug-drug interaction were seen.

Based on the results of a single dose administration study of recommended doses of oralmycophenolate mofetil and intravenous ganciclovir and the known effects of renal impairment on thepharmacokinetics of mycophenolate mofetil (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 inincreases in MPAG and ganciclovir concentration. No substantial alteration of MPA pharmacokineticsis anticipated and mycophenolate mofetil dose adjustment is not required. In patients with renalimpairment in whom mycophenolate mofetil and ganciclovir or its prodrugs, e.g. valganciclovir, areco-administered, the dose recommendations for ganciclovir should be observed and patients should bemonitored carefully.

The pharmacodynamics and pharmacokinetics of oral contraceptives were not affected to a clinicallyrelevant degree by co-administration of mycophenolate mofetil (see also section 5.2).

In patients not also taking ciclosporin, concomitant administration of mycophenolate mofetil andrifampicin resulted in a decrease in MPA exposure (AUC0-12h) of 18% to 70%. It is recommended tomonitor MPA exposure levels and to adjust mycophenolate mofetil doses accordingly to maintainclinical efficacy when rifampicin is administered concomitantly.

Decrease in MPA Cmax and AUC0-12h by 30% and 25%, respectively, were observed whenmycophenolate mofetil was concomitantly administered with sevelamer without any clinicalconsequences (i.e. graft rejection). It is recommended, however, to administer mycophenolate mofetilat least one hour before or three hours after sevelamer intake to minimise the impact on the absorptionof MPA. There are no data on mycophenolate mofetil with phosphate binders other than sevelamer.

In hepatic transplant patients initiated on mycophenolate mofetil and tacrolimus, the AUC and Cmax of

MPA, the active metabolite of mycophenolate mofetil, 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 mycophenolate mofetil (1.5 g BID) were administered to hepatictransplant patients taking tacrolimus. However, in renal transplant patients, tacrolimus concentrationdid not appear to be altered by mycophenolate mofetil (see also section 4.4).

Live vaccines

Live vaccines should not be given to patients with an impaired immune response. The antibodyresponse to other vaccines may be diminished (see also 4.4).

Interaction studies have only been performed in adults.

Potential interaction

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 tubularsecretion.

Pregnancy whilst taking mycophenolate mofetil must be avoided. Therefore, women of childbearingpotential must use at least one form of reliable contraception (see section 4.3) before starting thetherapy, during therapy, and for six weeks after stopping the therapy, unless abstinence is the chosenmethod of contraception. Two complementary forms of contraception simultaneously are preferred.

Mycophenolate mofetil is contraindicated during pregnancy unless there is no suitable alternativetreatment to prevent transplant rejection. Treatment should not be initiated without providing anegative pregnancy test result to rule out unintended use in pregnancy (see section 4.3).

Female patients of reproductive potential must be made aware of the increased risk of pregnancy lossand congenital malformations at the beginning of the treatment and must be counselled regardingpregnancy prevention and planning.

Before starting treatment, women of childbearing potential should have two negative serum or urinepregnancy tests with a sensitivity of at least 25 mIU/ml in order to exclude unintended exposure of anembryo to mycophenolate. It is recommended that the second test should be performed 8-10 days afterthe first test. For transplants from deceased donors, if it is not possible to perform two tests 8-10 daysapart before treatment starts (because of the timing of transplant organ availability), a pregnancy testmust be performed immediately before starting treatment and a further test 8-10 days later. Pregnancytests should be repeated as clinically required (e.g. after any gap in contraception is reported. Resultsof all pregnancy tests should be discussed with the patient. Patients should be instructed to consulttheir physician immediately should pregnancy occur.

Mycophenolate is a powerful human teratogen, with an increased risk of spontaneous abortions andcongenital malformations in case of exposure during pregnancy;

* Spontaneous abortions have been reported in 45 to 49% of pregnant women exposed tomycophenolate mofetil, compared to a reported rate of between 12 and 33% in solid organtransplant patients treated with immunosuppressants other than mycophenolate mofetil.

* Based on literature reports, malformations occurred in 23 to 27% of live births in womenexposed to mycophenolate mofetil during pregnancy (compared to 2 to 3% of live births in theoverall population and approximately 4 to 5% of live births in solid organ transplant recipientstreated with immunosuppressants other than mycophenolate mofetil).

Congenital malformations, including reports of multiple malformations, have been observed post-marketing in children of patients exposed to mycophenolate during pregnancy in combination withother immunosuppressants. The following malformations were most frequently reported:

* Abnormalities of the ear (e.g. abnormally formed or absent external ear), external auditory canalatresia (middle ear);

* Facial malformations such as cleft lip, cleft palate, micrognathia and hypertelorism of the orbits;

* Abnormalities of the eye (e.g. coloboma);

* Congenital heart disease such as atrial and ventricular septal defects;

* Malformations of the fingers (e.g. polydactyly, syndactyly);

* Tracheo-oesophageal malformations (e.g. oesophageal atresia);

* Nervous system malformations such as spina bifida;

* Renal abnormalities.

In addition, there have been isolated reports of the following malformations:

* Microphthalmia;

* Congenital choroid plexus cyst;

* Septum pellucidum agenesis;

* Olfactory nerve agenesis.

Studies in animals have shown reproductive toxicity (see section 5.3).

Limited data shows that mycophenolic acid is excreted in human milk. Because of the potential forserious adverse reactions to mycophenolic acid in breast-fed infants, treatment is contraindicated innursing mothers (see section 4.3).

The limited clinical evidence available does not indicate an increased risk of malformations ormiscarriage following paternal exposure to mycophenolate mofetil.

MPA is a powerful teratogen. It is not known if MPA is present in semen. Calculations based onanimal data show that the maximum amount of MPA that could potentially be transferred to woman isso low that it would be unlikely to have an effect. Mycophenolate has been shown to be genotoxic inanimal studies at concentrations exceeding the human therapeutic exposures only by small marginssuch that the risk of genotoxic effects on sperm cells cannot completely be excluded.

Therefore, the following precautionary measures are recommended: sexually active male patients ortheir female partners are recommended to use reliable contraception during treatment of the malepatient and for at least 90 days after cessation of mycophenolate mofetil. Male patients of reproductivepotential should be made aware of and discuss with a qualified healthcare professional the potentialrisks of fathering a child.

Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. Thesystemic exposure at this dose represents 2 - 3 times the clinical exposure at the recommended clinicaldose of 2 g/day in renal transplant patients and 1.3 - 2 times the clinical exposure at the recommendedclinical dose of 3 g/day in cardiac transplant patients. In a female fertility and reproduction studyconducted in rats, oral doses of 4.5 mg/kg/day caused malformations (including anophthalmia,agnathia, and hydrocephaly) in the first generation offspring in the absence of maternal toxicity. Thesystemic exposure at this dose was approximately 0.5 times the clinical exposure at the recommendedclinical dose of 2 g/day for renal transplant patients and approximately 0.3 times the clinical exposureat the recommended clinical dose of 3 g/day for cardiac transplant patients. No effects on fertility orreproductive parameters were evident in the dams or in the subsequent generation.

Mycophenolate mofetil has a moderate influence on the ability to drive and use machines.

Treatment may cause somnolence, confusion, dizziness, tremor or hypotension, and therefore patientsare advised to use caution when driving or using machines.

Diarrhoea (up to 52.6%), leukopenia (up to 45.8%), bacterial infections (up to 39.9%) and vomiting(up to 39.1%) were among the most common and/or serious adverse reactions associated with theadministration of mycophenolate mofetil in combination with ciclosporin and corticosteroids. There isevidence of a higher frequency of certain types of infections (see section 4.4).

The adverse reactions from clinical trials and post-marketing experience are listed in Table 1, by

MedDRA system organ class (SOC) along with their frequencies. The corresponding frequencycategory for each adverse 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 veryrare (<1/10 000). Due to the large differences observed in the frequency of certain adverse reactionsacross the different transplant indications, the frequency is presented separately for renal, hepatic andcardiac transplant patients.

Table 1 Adverse reactions in studies investigating mycophenolate mofetil treatment in adultsand adolescents, or through post-marketing surveillance

Adverse reaction(MedDRA) Cardiac

Renal transplant Hepatic transplant transplant

System Organ Class

Frequency Frequency Frequency

Adverse reaction(MedDRA) Cardiac

Renal transplant Hepatic transplant transplant

System Organ Class

Bacterial infections Very Common Very Common Very Common

Fungal infections Common Very Common Very Common

Protozoal infections Uncommon Uncommon Uncommon

Viral infections Very Common Very Common Very Common

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Benign neoplasm of skin Common Common Common

Lymphoma Uncommon Uncommon Uncommon

Lymphoproliferative disorder Uncommon Uncommon Uncommon

Neoplasm Common Common Common

Skin cancer Common Uncommon Common

Anaemia Very Common Very Common Very Common

Aplasia pure red cell Uncommon Uncommon Uncommon

Bone marrow failure Uncommon Uncommon Uncommon

Ecchymosis Common Common Very Common

Leukocytosis Common Very Common Very Common

Leukopenia Very Common Very Common Very Common

Pancytopenia Common Common Uncommon

Pseudolymphoma Uncommon Uncommon Common

Thrombocytopenia Common Very Common Very Common

Acidosis Common Common Very Common

Hypercholesterolaemia Very Common Common Very Common

Hyperglycaemia Common Very Common Very Common

Hyperkalaemia Common Very Common Very Common

Hyperlipidaemia Common Common Very Common

Hypocalcaemia Common Very Common Common

Hypokalaemia Common Very Common Very Common

Hypomagnesaemia Common Very Common Very Common

Hypophosphataemia Very Common Very Common Common

Hyperuricaemia Common Common Very Common

Gout Common Common Very Common

Weight decreased Common Common Common

Confusional state Common Very Common Very Common

Depression Common Very Common Very Common

Insomnia Common Very Common Very Common

Agitation Uncommon Common Very Common

Anxiety Common Very Common Very Common

Thinking abnormal Uncommon Common Common

Dizziness Common Very Common Very Common

Adverse reaction(MedDRA) Cardiac

Renal transplant Hepatic transplant transplant

System Organ Class

Headache Very Common Very Common Very Common

Hypertonia Common Common Very Common

Paresthesia Common Very Common Very Common

Somnolence Common Common Very Common

Tremor Common Very Common Very Common

Convulsion Common Common Common

Dysgeusia Uncommon Uncommon Common

Tachycardia Common Very Common Very Common

Hypertension Very Common Very Common Very Common

Hypotension Common Very Common Very Common

Lymphocele Uncommon Uncommon Uncommon

Venous thrombosis Common Common Common

Vasodilatation Common Common Very Common

Bronchiectasis Uncommon Uncommon Uncommon

Cough Very Common Very Common Very Common

Dyspnoea Very Common Very Common Very Common

Interstitial lung disease Uncommon Very Rare Very Rare

Pleural effusion Common Very Common Very Common

Pulmonary fibrosis Very Rare Uncommon Uncommon

Abdominal distension Common Very Common Common

Abdominal pain Very Common Very Common Very Common

Colitis Common Common Common

Constipation Very Common Very Common Very Common

Decreased appetite Common Very Common Very Common

Diarrhoea Very Common Very Common Very Common

Dyspepsia Very Common Very Common Very Common

Esophagitis Common Common Common

Eructation Uncommon Uncommon Common

Flatulence Common Very Common Very Common

Gastritis Common Common Common

Gastrointestinal haemorrhage Common Common Common

Gastrointestinal ulcer Common Common Common

Gingival hyperplasia Common Common Common

Ileus Common Common Common

Mouth ulceration Common Common Common

Nausea Very Common Very Common Very Common

Pancreatitis Uncommon Common Uncommon

Stomatitis Common Common Common

Adverse reaction(MedDRA) Cardiac

Renal transplant Hepatic transplant transplant

System Organ Class

Vomiting Very Common Very Common Very Common

Hypersenstivity Uncommon Common Common

Hypogammaglobulinaemia Uncommon Very Rare Very Rare

Blood alkaline phosphataseincreased Common Common Common

Blood lactate dehydrogenaseincreased Common Uncommon Very Common

Hepatic enzyme increased Common Very Common Very Common

Hepatitis Common Very Common Uncommon

Hyperbilirubinaemia Common Very Common Very Common

Jaundice Uncommon Common Common

Acne Common Common Very Common

Alopecia Common Common Common

Rash Common Very Common Very Common

Skin hypertrophy Common Common Very Common

Arthralgia Common Common Very Common

Muscular weakness Common Common Very Common

Blood creatinine increased Common Very Common Very Common

Blood urea increased Uncommon Very Common Very Common

Haematuria Very Common Common Common

Renal impairment Common Very Common Very Common

Asthenia Very Common Very Common Very Common

Chills Common Very Common Very Common

Oedema Very Common Very Common Very Common

Hernia Common Very Common Very Common

Malaise Common Common Common

Pain Common Very Common Very Common

Pyrexia Very Common Very Common Very Common

De novo purine synthesisinhibitors associated acuteinflammatory syndrome Uncommon Uncommon Uncommon

Patients receiving immunosuppressive regimens involving combinations of medicinal products,including mycophenolate mofetil, are at increased risk of developing lymphomas and othermalignancies, particularly of the skin (see section 4.4). Three-year safety data in renal and cardiactransplant patients did not reveal any unexpected changes in incidence of malignancy compared to the1-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 fungalinfections (some of which may lead to a fatal outcome), including those caused by opportunisticagents and latent viral reactivation. The risk increases with total immunosuppressive load (see section4.4). The most serious infections were sepsis, peritonitis, meningitis, endocarditis, tuberculosis andatypical mycobacterial infection. The most common opportunistic infections in patients receivingmycophenolate mofetil (2 g or 3 g daily) with other immunosuppressants in controlled clinical trials inrenal, 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 CMVviraemia/syndrome was 13.5%. Cases of BK virus associated nephropathy, as well as cases of JC virusassociated progressive multifocal leukoencephalopathy (PML), have been reported in patients treatedwith immunosuppressants, including mycophenolate mofetil.

Blood and lymphatic disorders

Cytopenias, including leukopenia, anaemia, thrombocytopenia and pancytopenia, are known risksassociated with mycophenolate mofetil and may lead or contribute to the occurrence of infections andhaemorrhages (see section 4.4). Agranulocytosis and neutropenia have been reported; therefore,regular monitoring of patients taking mycophenolate mofetil is advised (see section 4.4). There havebeen reports of aplastic anaemia and bone marrow failure in patients treated with mycophenolatemofetil, some of which have been fatal.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolatemofetil (see section 4.4).

Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, havebeen observed in patients treated with mycophenolate mofetil. These changes are not associated withimpaired neutrophil function. These changes may suggest a ‘left shift’ in the maturity of neutrophils inhaematological investigations, which may be mistakenly interpreted as a sign of infection inimmunosuppressed patients such as those that receive mycophenolate mofetil.

The most serious gastrointestinal disorders were ulceration and haemorrhage which are known risksassociated with mycophenolate mofetil. Mouth, oesophageal, gastric, duodenal, and intestinal ulcersoften complicated by haemorrhage, as well as haematemesis, melena, and haemorrhagic forms ofgastritis and colitis were commonly reported during the pivotal clinical trials. The most commongastrointestinal disorders, however, were diarrhoea, nausea and vomiting. Endoscopic investigation ofpatients with mycophenolate mofetil-related diarrhoea have revealed isolated cases of intestinal villousatrophy (see section 4.4).

Hypersensitivity reactions, including angioneurotic oedema and anaphylactic reaction have beenreported.

Pregnancy, puerperium and perinatal conditions

Cases of spontaneous abortion have been reported in patients exposed to mycophenolate mofetil,mainly in the first trimester, see section 4.6.

Congenital disorders

Congenital malformations have been observed post-marketing in children of patients exposed tomycophenolate in combination with other immunosuppressants, see section 4.6.

There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients treatedwith mycophenolate mofetil in combination with other immunosuppressants, some of which have beenfatal. There have also been reports of bronchiectasis in children and adults.

Hypogammaglobulinaemia has been reported in patients receiving mycophenolate mofetil incombination with other immunosuppressants.

Oedema, including peripheral, face and scrotal oedema, was reported very commonly during thepivotal trials. Musculoskeletal pain such as myalgia, and neck and back pain were also very commonlyreported.

De novo purine synthesis inhibitors associated acute inflammatory syndrome has been described frompost-marketing experience as a paradoxical proinflammatory reaction associated with mycophenolatemofetil and mycophenolic acid, characterised by fever, arthralgia, arthritis, muscle pain and elevatedinflammatory markers. Literature case reports showed rapid improvement following discontinuation ofthe medicinal product.

The type and frequency of adverse reactions were assessed in a long-term clinical trial, whichrecruited 33 paediatric renal transplant patients, aged 3 years to 18 years, who were given 23 mg/kg ofmycophenolate mofetil orally, twice daily. Overall, the safety profile in these 33 children andadolescents was similar to that observed in adult recipients of solid organ allografts.

Similar observations were made in another clinical trial, which recruited 100 paediatric renaltransplant patients aged 1 to 18 years. The type and frequency of adverse reactions in patients whowere given 600 mg/m2, up to 1 g/m2 of mycophenolate mofetil orally, twice daily, were comparable tothose observed in adult patients given 1 g mycophenolate mofetil twice daily. A summary of the morefrequently occurring adverse reactions is shown in table 2 below:

Table 2 Summary of adverse reactions observed more frequently in a trial investigatingmycophenolate mofetil in 100 paediatric renal transplant patients (age/surfacearea-based dosing [600 mg/m2, up to 1 g/m2 BID.])

Adverse reaction <6 years 6-11 years 12-18 years(n=33) (n=34) (n=33)(MedDRA)

System Organ Class

Infections and infestations Very common Very common Very common(48.5%) (44.1%) (51.5%)

Leukopenia Very common Very common Very common(30.3%) (29.4%) (12.1%)

Anaemia Very common Very common Very common(51.5%) (32.4%) (27.3%)

Diarrhoea Very common Very common Very common(87.9%) (67.6%) (30.3%)

Vomitting Very common Very common Very common(69.7%) (44.1%) (36.4%)

Based on limited sub-set data (i.e. 33 of the 100 patients) there was a higher frequency of severediarrhoea (common, 9.1%), and candida mucocutaneous (very common, 21.2%) in children under6 years of age, compared to the older paediatric cohort in which no cases of severe diarrhoea werereported (0.0%) and candida mucocutaneous was common (7.5%).

Review of the available medical literature on paediatric hepatic and cardiac transplant patients showsthe type and frequency of the reported adverse reactions are consistent with those observed inpaediatric and adult patients following renal transplant.

Very limited post-marketing data indicates a higher frequency of the following adverse reactions inpatients under 6 years of age compared to older patients (see section 4.4):

- lymphomas and other malignancies particularly of post-transplant lymphoproliferative disorder incardiac transplant patients

- blood and lymphatic system disorders including anaemia and neutropenia in cardiac transplantpatients under 6 years of age compared to older patients, and compared to paediatric hepatic/renaltransplant recipients

- gastrointestinal disorders including diarrhoea and vomiting.

Renal transplant patients under 2 years of age might be at a higher risk of infections and respiratoryevents compared to older patients. However, these data should be interpreted with caution due to avery limited number of post-marketing reports concerning the same patients suffering from multipleinfections.

In case of undesirable effects, temporary dose reduction or interruption may be considered as deemedclinically necessary.

Elderly patients (≥ 65 years) may generally be at increased risk of adverse reactions due toimmunosuppression. Elderly patients receiving mycophenolate mofetil as part of a combinationimmunosuppressive regimen, may be at increased risk of certain infections (including cytomegalovirustissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, comparedto younger individuals.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Reports of overdoses with mycophenolate mofetil have been received from clinical trials and duringpost-marketing experience. In the vast majority of these cases, either no adverse events were reportedor they were in line with the known safety profile of the medicinal product and had a favourableoutcome. However, isolated serious adverse events including a fatal case were observed during post-marketing experience.

It is expected that an overdose of mycophenolate mofetil could possibly result in oversuppression ofthe immune system and increase susceptibility to infections and bone marrow suppression (see section4.4). If neutropenia develops, dosing with mycophenolate mofetil should be interrupted or the dosereduced (see section 4.4).

Haemodialysis would not be expected to remove clinically significant amounts of MPA or MPAG.

Bile acid sequestrants, such as cholestyramine, can remove MPA by decreasing the enterohepaticrecirculation of the drug (see section 5.2).

Pharmacotherapeutic group: immunosuppressive agents ATC code: L04AA06

Mycophenolate mofetil is the 2-morpholinoethyl ester of MPA. MPA is a selective, uncompetitive andreversible inhibitor of IMPDH, and therefore inhibits the de novo pathway of guanosine nucleotidesynthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent fortheir proliferation on de novo synthesis of purines whereas other cell types can utilise salvagepathways, MPA has more potent cytostatic effects on lymphocytes than on other cells.

In addition to its inhibition of IMPDH and the resulting deprivation of lymphocytes, MPA alsoinfluences cellular checkpoints responsible for metabolic programming of lymphocytes. It has beenshown, using human CD4+ T-cells, that MPA shifts transcriptional activities in lymphocytes from aproliferative state to catabolic processes relevant to metabolism and survival leading to an anergicstate of T-cells, whereby the cells become unresponsive to their specific antigen.

Following oral administration, mycophenolate mofetil undergoes rapid and extensive absorption andcomplete presystemic metabolism to the active metabolite, MPA. As evidenced by suppression ofacute rejection following renal transplantation, the immunosuppressant activity of mycophenolatemofetil is correlated with MPA concentration. The mean bioavailability of oral mycophenolatemofetil, based on MPA AUC, is 94% relative to intravenous mycophenolate mofetil. Food had noeffect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at dosesof 1.5 g BID to renal transplant patients. However, MPA Cmax was decreased by 40% in the presenceof food. Mycophenolate mofetil is not measurable systemically in plasma following oraladministration.

As a result of enterohepatic recirculation, secondary increases in plasma MPA concentration areusually observed at approximately 6 - 12 hours post-dose. A reduction in the AUC of MPA ofapproximately 40% is associated with the co-administration of cholestyramine (4 g TID), indicatingthat there is a significant amount of enterohepatic recirculation.

MPA at clinically relevant concentrations is 97% bound to plasma albumin.

In the early post-transplant period (< 40 days post-transplant), renal, cardiac and hepatic transplantpatients had mean MPA AUCs approximately 30% lower and Cmax approximately 40% lowercompared to the late post-transplant period (3 - 6 months post-transplant).

MPA is metabolised principally by glucuronyl transferase (isoform UGT1A9) to form the inactivephenolic glucuronide of MPA (MPAG). In vivo, MPAG is converted back to free MPA viaenterohepatic recirculation. A minor acylglucuronide (AcMPAG) is also formed. AcMPAG ispharmacologically active and is suspected to be responsible for some of mycophenolate mofetil’s sideeffects (diarrhoea, leukopenia).

A negligible amount of substance is excreted as MPA (< 1% of the dose) in the urine. Oraladministration of radiolabelled mycophenolate mofetil results in complete recovery of theadministered dose with 93% of the administered dose recovered in the urine and 6% recovered in thefaeces. Most (about 87%) of the administered dose is excreted in the urine as MPAG.

At clinically encountered concentrations, MPA and MPAG are not removed by haemodialysis.

However, at high MPAG plasma concentrations (> 100 µg/ml), small amounts of MPAG are removed.

By interfering with enterohepatic recirculation of the drug, bile acid sequestrants such ascholestyramine, reduce MPA AUC (see section 4.9).

MPA’s disposition depends on several transporters. Organic anion-transporting polypeptides (OATPs)and multidrug resistance-associated protein 2 (MRP2) are involved in MPA’s disposition; OATPisoforms, MRP2 and breast cancer resistance protein (BCRP) are transporters associated with theglucuronides’ biliary excretion. Multidrug resistance protein 1 (MDR1) is also able to transport MPA,but its contribution seems to be confined to the absorption process. In the kidney, MPA and itsmetabolites potently interact with renal organic anion transporters.

Enterohepatic recirculation interferes with accurate determination of MPA’s disposition parameters;only apparent values can be indicated. In healthy volunteers and patients with autoimmune diseaseapproximate clearance values of 10.6 L/h and 8.27 L/h respectively and half-life values of 17 h wereobserved. In transplant patients mean clearance values were higher (range 11.9-34.9 L/h) and meanhalf-life values shorter (5-11 h) with little difference between renal, hepatic or cardiac transplantpatients. In the individual patients, these elimination parameters vary based on type of co-treatmentwith other immunosuppressants, time post-transplantation, plasma albumin concentration and renalfunction. These factors explain why reduced exposure to mycophenolate is seen when mycophenolatemofetil is co-administered with ciclosporin (see section 4.5) and why plasma concentrations tend toincrease over time compared to what is observed immediately after transplantation.

In a single dose study (6 subjects/group), mean plasma MPA AUC observed in subjects with severechronic renal impairment (glomerular filtration rate < 25 ml/min/1.73 m2) were 28 - 75% higherrelative to the means observed in normal healthy subjects or subjects with lesser degrees of renalimpairment. The mean single dose MPAG AUC was 3 - 6-fold higher in subjects with severe renalimpairment than in subjects with mild renal impairment or normal healthy subjects, consistent with theknown renal elimination of MPAG. Multiple dosing of mycophenolate mofetil in patients with severechronic renal impairment has not been studied. No data are available for cardiac or hepatic transplantpatients with severe chronic renal impairment.

Delayed renal graft function

In patients with delayed renal graft function post-transplant, mean MPA AUC0-12h was comparable tothat seen in post-transplant patients without delayed graft function. Mean plasma MPAG AUC 0-12hwas 2 - 3-fold higher than in post-transplant patients without delayed graft function. There may be atransient increase in the free fraction and concentration of plasma MPA in patients with delayed renalgraft function. Dose adjustment of mycophenolate mofetil does not appear to be necessary.

In volunteers with alcoholic cirrhosis, hepatic MPA glucuronidation processes were relativelyunaffected by hepatic parenchymal disease. Effects of hepatic disease on these processes probablydepend on the particular disease. Hepatic disease with predominantly biliary damage, such as primarybiliary cirrhosis, may show a different effect.

In 33 paediatric renal allograft recipients it was established that the dose predicted to provide an MPA

AUC0-12h closest to the target exposure of 27.2 h⋅ mg/l was 600 mg/m2, and that doses calculated basedon estimated BSA reduced interindividual variability (coefficient of variation, (CV)) by about 10%.

Therefore, dosing based on BSA is preferred rather than dosing based on body weight.

Pharmacokinetic parameters were evaluated in up to 55 paediatric renal transplant patients (aged 1 to18 years) given 600 mg/m2, up to 1 g/m2 of mycophenolate mofetil orally twice daily. This doseachieved MPA AUC values similar to those seen in adult renal transplant patients receivingmycophenolate mofetil at a dose of 1 g BID in the early and late post-transplant period as per Table 3below. MPA AUC values across paediatric age groups were similar in the early and late post-transplant period.

For paediatric hepatic transplant recipients an open-label study of the safety, tolerability andpharmacokinetics of oral mycophenolate mofetil included 7 evaluable patients on concomitantciclosporin and corticosteroid treatment. The dose predicted to achieve an exposure of 58 h⋅mg/l in thestable post-transplant period was estimated. The mean ± SD AUC0-12 (adjusted to a dose of600 mg/m2) was 47.0±21.8 h⋅mg/l, adjusted Cmax was 14.5±4.21 mg/l, with a median time to maximumconcentration of 0.75 h. To achieve the target AUC0-12 of 58 h⋅mg/l in the late post-transplant period, adose in the range of 740-806 mg/m2 BID would therefore have been required in the study population.

A comparison of dose-normalised (to 600 mg/m2) MPA AUC values in 12 paediatric renal transplantpatients less than 6 years of age at 9 months post-transplant with those values in 7 paediatric hepatictransplant patients [median age 17 months (range: 10-60 months at enrolment)] at 6 months andbeyond post-transplant revealed that, at the same dose, the AUC values were on average 23% lower inthe paediatric hepatic patients compared to paediatric renal patients. This is consistent with the needfor higher dosing in adult hepatic transplant patients compared to adult renal transplant patients toachieve the same exposure.

In adult transplant patients administered the same dosage of mycophenolate mofetil, there is similar

MPA exposure among renal transplant and cardiac transplant patients. In line with the establishedsimilarity in MPA exposure between paediatric renal transplant and adult renal transplant patients attheir respective approved doses, existing data allows to conclude that MPA exposure at therecommended dosage will be similar in paediatric cardiac transplant and adult cardiac transplantpatients.

Table 3 Mean computed MPA PK parameters by age and time post-transplant (renal)

Age group (n) Adjusted C Amax mg/l Adjusted AUC0-12 h⋅mg/lmean ± SD mean ± SD (CI)A

Day 7<6 y (17) 13.2±7.16 27.4±9.54 (22.8-31.9)6 - <12 y (16) 13.1±6.30 33.2±12.1 (27.3-39.2)12-18 y (21) 11.7±10.7 26.3±9.14 (22.3-30.3)Dp-valueB - -<2 yC (6) 10.3±5.80 22.5±6.68 (17.2-27.8)>18 y (141) 27.2±11.6

Month 3<6 y (15) 22.7±10.1 49.7±18.26 - <12 y (14)E 27.8±14.3 61.9±19.612-18 y (17) 17.9±9.57 53.6±20.2Fp-valueB - -<2 yC (4) 23.8±13.4 47.4±14.7>18 y (104) 50.3±23.1

Month 9<6 y (12) 30.4±9.16 60.9±10.76 - <12 y (11) 29.2±12.6 66.8±21.2

Age group (n) Adjusted C Amax mg/l Adjusted AUC0-12 h⋅mg/lmean ± SD mean ± SD (CI)A12-18 y (14) 18.1±7.29 56.7±14.0p-valueB 0.004 -<2 yC (4) 25.6±4.25 55.8±11.6>18 y (70) 53.5±18.3

AUC0-12h=area under the plasma concentration-time curve from time 0 h to time 12 h; CI=confidence interval;

Cmax=maximum concentration; MPA=mycophenolic acid; SD=standard deviation; n=number of patients; y=year.

A In the paediatric age groups Cmax and AUC0-12h are adjusted to a dose of 600 mg/m2 (95% confidence intervals (Cls) for

AUC0-12h Day 7 only); in the adult group AUC0-12h is adjusted to a dose of 1 g.

B p-value represents the combined p-value for the three major paediatric age groups, and is noted only if significant(p <0.05).

C The <2-year group is a subset of the <6-year group: no statistical comparisons were made.

D n=20.

E Data for one patient was unavailable due to sampling error.

F n=16.

The pharmacokinetics of mycophenolate mofetil and its metabolites have not been found to be alteredin the elderly patients (≥ 65 years) when compared to younger transplant patients.

Patients taking oral contraceptives

A study of the co-administration of mycophenolate mofetil (1 g BID) and combined oralcontraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to0.20 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) conducted in 18 non-transplantwomen (not taking other immunosuppressants) over 3 consecutive menstrual cycles showed noclinically relevant influence of mycophenolate mofetil on the ovulation-suppressing action of the oralcontraceptives. Serum levels of LH, FSH and progesterone were not significantly affected. Thepharmacokinetics of oral contraceptives were not affected to a clinically relevant degree by co-administration of mycophenolate mofetil (see also section 4.5).

In experimental models, mycophenolate mofetil was not tumourigenic. The highest dose tested in theanimal carcinogenicity studies resulted in approximately 2 - 3 times the systemic exposure (AUC or

Cmax) observed in renal transplant patients at the recommended clinical dose of 2 g/day and1.3 - 2 times the systemic exposure (AUC or Cmax) observed in cardiac transplant patients at therecommended clinical dose of 3 g/day.

Two genotoxicity assays (in vitro mouse lymphoma assay and in vivo mouse bone marrowmicronucleus test) showed a potential of mycophenolate mofetil to cause chromosomal aberrations.

These effects can be related to the pharmacodynamic mode of action, i.e. inhibition of nucleotidesynthesis in sensitive cells. Other in vitro tests for detection of gene mutation did not demonstrategenotoxic activity.

In teratology studies in rats and rabbits, foetal resorptions and malformations occurred in rats at6 mg/kg/day (including anophthalmia, agnathia, and hydrocephaly) and in rabbits at 90 mg/kg/day(including cardiovascular and renal anomalies, such as ectopia cordis and ectopic kidneys, anddiaphragmatic and umbilical hernia), in the absence of maternal toxicity. The systemic exposure atthese levels is approximately equivalent to or less than 0.5 times the clinical exposure at therecommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3 times theclinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients (seesection 4.6).

The haematopoietic and lymphoid systems were the primary organs affected in toxicology studiesconducted with mycophenolate mofetil in the rat, mouse, dog and monkey. These effects occurred atsystemic exposure levels that are equivalent to or less than the clinical exposure at the recommendeddose of 2 g/day for renal transplant recipients. Gastrointestinal effects were observed in the dog atsystemic exposure levels equivalent to or less than the clinical exposure at the recommended dose.

Gastrointestinal and renal effects consistent with dehydration were also observed in the monkey at thehighest dose (systemic exposure levels equivalent to or greater than clinical exposure). Thenon-clinical toxicity profile of mycophenolate mofetil appears to be consistent with adverse eventsobserved in human clinical trials, which now provide safety data of more relevance to the patientpopulation (see section 4.8).

Environmental Risk Assessment (ERA)

Environmental risk assessment studies have shown that the active substance, MPA may pose a risk forgroundwater via bank filtration.

CellCept tabletsmicrocrystalline cellulosepolyvidone (K-90)croscarmellose sodiummagnesium stearate

Tablet coatinghydroxypropyl methylcellulosehydroxypropyl cellulosetitanium dioxide (E171)polyethylene glycol 400indigo carmine aluminium lake (E132)red iron oxide (E172)

Not applicable.

3 years.

Do not store above 30 °C. Store in the original package in order to protect from moisture.

PVC/aluminium foil blister strips

CellCept 500 mg film-coated tablets: 1 carton contains 50 tablets (in blister packs of 10)multipacks containing 150 (3 packs of 50) tablets

Not all pack sizes may be marketed.

This medicinal product may pose a risk to the environment (see section 5.3). Any unused medicinalproduct or waste material should be disposed of in accordance with local requirements.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/96/005/002 CellCept (50 tablets)

EU/1/96/005/004 CellCept (150 (3x50) tablets multipack)

Date of first authorisation: 14 February 1996

Date of latest renewal: 13 March 2006

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.