MYFENAX 250mg capsules medication leaflet

Myfenax 250 mg hard capsules

Each capsule contains 250 mg mycophenolate mofetil.

For the full list of excipients, see section 6.1.

Hard capsule (capsule)

The capsule body is caramel opaque, printed with ‘250’ axially in black ink.

The capsule cap is light blue opaque printed ‘M’ axially in black ink.

Myfenax is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acutetransplant rejection in patients receiving allogeneic renal, cardiac or hepatic transplants.

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

Use in 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).

Paediatric population aged 2 to 18 years

The recommended dose of mycophenolate mofetil is 600 mg/m2 administered orally twice daily (up toa maximum of 2 g daily). Capsules should only be prescribed to patients with a body surface area of atleast 1.25 m2. Patients with a body surface area of 1.25 to 1.5 m2 may be prescribed mycophenolatemofetil capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a body surface areagreater than 1.5 m2 may be prescribed mycophenolate mofetil capsules at a dose of 1 g twice daily (2 gdaily dose). As some adverse reactions occur with greater frequency in this age group (see section 4.8)compared with adults, temporary dose reduction or interruption may be required; these will need totake into account relevant clinical factors including severity of reaction.

Paediatric population < 2 years

There are limited safety and efficacy data in children below the age of 2 years. These are insufficientto make dosage recommendations and therefore use in this age group is not recommended.

Use in 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).

No data are available for paediatric cardiac transplant patients.

Use in hepatic transplant

Intravenous mycophenolate mofetil should be administered for the first 4 days following hepatictransplant, with oral Myfenax initiated as soon after this as it can be tolerated. The recommended oraldose in hepatic transplant patients is 1.5 g administered twice daily (3 g daily dose).

No data are available for paediatric hepatic transplant patients.

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; dosage reduction or interruption of

Myfenax is not required. There is no basis for Myfenax dose adjustment following cardiac transplantrejection. 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, capsulesshould not be opened or crushed to avoid inhalation or direct contact with skin or mucous membranesof the powder contained in the capsules. If such contact occurs, wash thoroughly with soap and water;rinse eyes with plain water.

Myfenax 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 to

Myfenax have been observed (see section 4.8).

Myfenax should not be given to women of childbearing potential who are not using highly effectivecontraception (see section 4.6).

Myfenax treatment should not be initiated in women of child bearing potential without providing apregnancy test result to rule out unintended use in pregnancy (see section 4.6).

Myfenax should not be used during pregnancy unless there is no suitable alternative treatment toprevent transplant rejection (see section 4.6).

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

Neoplasms

Patients receiving immunosuppressive regimens involving combinations of medicinal products,including Myfenax, 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 ultraviolet (UV) light should be limited by wearing protectiveclothing and using a sunscreen with a high protection factor.

Patients treated with immunosuppressants, including Myfenax, are at increased risk for opportunisticinfections (bacterial, fungal, viral and protozoal), fatal infections and sepsis (see section 4.8). Suchinfections include latent viral reactivation, such as hepatitis B or hepatitis C reactivation and infectionscaused by polyomaviruses (BK virus associated nephropathy, JC virus associated progressivemultifocal 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 oftenrelated to a high total immunosuppressive burden and may lead to serious or fatal conditions thatphysicians should consider in the differential diagnosis in immunosuppressed patients withdeteriorating renal function or neurological symptoms. Mycophenolic acid has a cytostatic effect on B-and Tlymphocytes, therefore an increased severity of COVID19 may occur, and appropriate clinicalaction 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 Myfenax should be monitored for neutropenia, which may be related to Myfenaxitself, concomitant medicinal products, viral infections, or some combination of these causes. Patientstaking Myfenax should have complete blood counts weekly during the first month, twice monthly forthe second and third months of treatment then monthly through the first year. If neutropenia develops(absolute neutrophil count < 1.3 x 103/ µl) it may be appropriate to interrupt or discontinue Myfenax.

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 Myfenax therapy.

Changes to Myfenax therapy should only be undertaken under appropriate supervision in transplantrecipients in order to minimise the risk of graft rejection (see section 4.8).

Patients receiving Myfenax 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 Myfenax, vaccinations may be less effective andthe use of live attenuated vaccines should be avoided (see section 4.5). Influenza vaccination may beof value. Prescribers should refer to national guidelines for influenza vaccination.

Gastro-intestinal

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

Myfenax should be administered with caution in patients with active serious digestive system disease.

Myfenax is an inosine monophosphate dehydrogenase (IMPDH) inhibitor. Therefore, it should beavoided 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 plasmalevels and efficacy of mycophenolate mofetil (see also section 4.5). Therapeutic drug monitoring of

MPA may be appropriate when switching combination therapy (e.g. from ciclosporin to tacrolimus orvice 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 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 beenestablished (see also section 4.5).

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 following MMFexposure during pregnancy. Therefore, Myfenax is contraindicated in pregnancy unless there are nosuitable alternative treatments to prevent transplant rejection. Female patients of childbearing potentialshould 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 mycophenolate.

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 apossibility 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 Myfenax therapy, during therapy, and for six weeksafter 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 materials tohealthcare professionals. The educational materials will reinforce the warnings about the teratogenicityof mycophenolate, provide advice on contraception before therapy is started and guidance on the needfor pregnancy testing. Full patient information about the teratogenic risk and the pregnancy preventionmeasures should be given by the physician to women of childbearing potential and, as appropriate, tomale patients.

Additional precautions

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

Excipient

This medicinal product contains less than 1 mmol sodium (23 mg) per hard capsule, that is to sayessentially ‘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. This 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 three times a day (TID) of cholestyramine for 4 days, there was a 40% reductionin the AUC of MPA (see section 4.4 and section 5.2). Caution should be used during concomitantadministration because of the potential to reduce efficacy of mycophenolate mofetil.

Ciclosporin A

Ciclosporin A (CsA) pharmacokinetics are unaffected by mycophenolate mofetil. In contrast, ifconcomitant 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% inrenal transplant patients treated with mycophenolate mofetil and CsA compared with patientsreceiving sirolimus or belatacept and similar doses of mycophenolate mofetil (see also section 4.4).

Conversely, changes of MPA exposure should be expected when switching patients from CsA to oneof 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 predose level may not accuratelyrepresent changes in overall MPA exposure. Therefore, a change in the dose of Myfenax should notnormally be necessary in the absence of clinical evidence of graft dysfunction. However, close clinicalmonitoring should be performed during the combination and shortly after antibiotic treatment.

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 PPARgamma (peroxisome proliferator-activated receptor gamma) expression, which in turn results in anenhanced uridine diphosphate glucuronyltransferase isoform 1A9 (UGT1A9) expression and activity.

When comparing rates of transplant rejection, rates of graft loss or adverse event profiles betweenmycophenolate mofetil patients with and without concomitant telmisartan medication, no clinicalconsequences 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 Myfenax and ganciclovir or its prodrugs, e.g. valganciclovir, are co-administeredthe dose recommendations for ganciclovir should be observed and patients monitored 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 Myfenax doses accordingly to maintain clinical efficacywhen 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 Myfenax at least onehour before or three hours after sevelamer intake to minimise the impact on the absorption of 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 Cmaxof 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 taken twice a day [BID], morning andevening) were administered to hepatic transplant patients taking tacrolimus. However, in renaltransplant patients, tacrolimus concentration did 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 section 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 must be avoided. Therefore, women of childbearing potentialmust use at least one form of reliable contraception (see section 4.3) before starting Myfenax therapy,during therapy, and for six weeks after stopping the therapy, unless abstinence is the chosen method ofcontraception. Two complementary forms of contraception simultaneously are preferred.

Myfenax is contraindicated during pregnancy unless there is no suitable alternative treatment toprevent transplant rejection. Treatment should not be initiated without providing a negative pregnancytest result to rule out unintended use in pregnancy.

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 Myfenax treatment, women of childbearing potential must have two negative serum orurine pregnancy tests with a sensitivity of at least 25 mIU/mL in order to exclude unintended exposureof an embryo to mycophenolate. It is recommended that the second test should be performed8-10 days after the first test. For transplants from deceased donors, if it is not possible to perform twotests 8-10 days apart before treatment starts (because of the timing of transplant organ availability), apregnancy test must be performed immediately before starting treatment and a further test 8-10 dayslater. Pregnancy tests should be repeated as clinically required (e.g. after any gap in contraception isreported). Results of all pregnancy tests should be discussed with the patient. Patients should beinstructed to consult their 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 women exposedto mycophenolate mofetil during pregnancy (compared to 2 to 3% of live births in the overallpopulation and approximately 4 to 5% of live births in solid organ transplant recipients treated withimmunosuppressants other than mycophenolate mofetil).

Congenital malformations, including reports of multiple malformations, have been observed post-marketing in children of patients exposed to mycophenolate in combination with otherimmunosuppressants during pregnancy. 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).

Mycophenolate mofetil has been shown to be excreted in the milk of lactating rats. It is not knownwhether this substance is excreted in human milk. Because of the potential for serious adversereactions to mycophenolate mofetil in breast-fed infants, Myfenax is contraindicated in breast-feedingmothers (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 by small margins, suchthat 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 health-care 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.

Mycophenolate mofetil may cause somnolence, confusion, dizziness, tremor or hypotension, andtherefore patients are advised to use caution when driving or using machines.

Diarrhoea (up to 52.6%), leucopenia (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 isalso evidence 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

Adverse reaction Renal transplant Hepatic transplant Cardiac transplant(MedDRA)

System Organ Class

Frequency Frequency Frequency

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

Anemia 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

Hypercholesterolemia Very common Common Very common

Hyperglycemia Common Very common Very common

Hyperkalemia Common Very common Very common

Hyperlipidemia Common Common Very common

Adverse reaction Renal transplant Hepatic transplant Cardiac transplant(MedDRA)

S ystem Organ Class

Frequency Frequency Frequency

Hypocalcemia Common Very common Common

Hypokalemia Common Very common Very common

Hypomagnesemia Common Very common Very common

Hypophosphatemia 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

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

Dyspnea 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

Adverse reaction Renal transplant Hepatic transplant Cardiac transplant(MedDRA)

S ystem Organ Class

Frequency Frequency Frequency

Decreased appetite Common Very common Very common

Diarrhea 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 hemorrhage 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

Vomiting Very common Very common Very common

Hypersenstivity Uncommon Common Common

Hypogammaglobulinaemia Uncommon Very rare Very rare

Blood alkaline phosphatase Common Common Commonincreased

Blood lactate dehydrogenase Common Uncommon Very commonincreased

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

Hematuria Very common Common Common

Renal impairment Common Very common Very common

Asthenia Very common Very common Very common

Chills Common Very common Very common

Adverse reaction Renal transplant Hepatic transplant Cardiac transplant(MedDRA)

System Organ Class

Frequency Frequency Frequency

Edema 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 synthesis Uncommon Uncommon Uncommoninhibitors-associated acuteinflammatory syndrome

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,cytomegalovirus (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 patientstreated with immunosuppressants, including mycophenolate mofetil.

Blood and lymphatic disorders

Cytopenias, including leucopenia, anemia, thrombocytopenia and pancytopenia, are known risksassociated with mycophenolate mofetil and may lead or contribute to the occurrence of infections andhemorrhages (see section 4.4). Agranulocytosis and neutropenia have been reported; therefore, regularmonitoring of patients taking mycophenolate mofetil is advised (see section 4.4). There have beenreports of aplastic anaemia and bone marrow failure in patients treated with mycophenolate mofetil,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 hemorrhage which are known risksassociated with mycophenolate mofetil. Mouth, esophageal, gastric, duodenal, and intestinal ulcersoften complicated by hemorrhage, as well as hematemesis, melena, and hemorrhagic forms of gastritisand 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 abortions 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 mofetil 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 edema, was reported very commonly during the pivotaltrials. 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 in a clinical study, which recruited 92 paediatric patientsaged 2 to 18 years who were given 600 mg/m2 mycophenolate mofetil orally twice daily, weregenerally similar to those observed in adult patients given 1 g mycophenolate mofetil twice daily.

However, the following treatment-related adverse events were more frequent in the paediatricpopulation, 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 toimmunosuppression. Elderly patients receiving Myfenax as part of a combination immunosuppressiveregimen may be at increased risk of certain infections (including cytomegalovirus tissue invasivedisease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared to youngerindividuals.

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 many of these cases, no adverse events were reported. In those overdosecases in which adverse events were reported, the events fall within the known safety profile of themedicinal product.

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 Myfenax should be interrupted or the dose reduced (seesection 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: LO4A A06

Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid (MPA). MPA is aselective, uncompetitive and reversible inhibitor of IMPDH, and therefore inhibits the de novopathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines whereasother cell types can utilise salvage pathways, MPA has more potent cytostatic effects on lymphocytesthan 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 MMF´s side effects(diarrhoea, leucopenia).

A negligible amount of substance is excreted as MPA (< 1% of dose) in the urine. Oral administrationof radiolabelled mycophenolate mofetil results in complete recovery of the administered dose; with93% of the administered dose recovered in the urine and 6% recovered in the faeces. Most (about87%) 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 areremoved. 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 is seen when mycophenolate mofetil is co-administered with cyclosporine (see section 4.5) and why plasma concentrations tend to increase overtime 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 AUC0-12 h was comparable tothat seen in post-transplant patients without delayed graft function. Mean plasma MPAG AUC0-12 hwas 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 Myfenax 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.

Pharmacokinetic parameters were evaluated in 49 paediatric renal transplant patients (aged 2 to18 years) given 600 mg/m2 mycophenolate mofetil orally twice daily. This dose achieved MPA AUCvalues similar to those seen in adult renal transplant patients receiving mycophenolate mofetil at adose of 1 g BID in the early and late post-transplant period. MPA AUC values across age groups weresimilar in the early and late post-transplant period.

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 luteinizing hormone (LH), follicle-stimulating hormone (FSH) andprogesterone were not significantly affected. The pharmacokinetics of oral contraceptives were notaffected to a clinically relevant degree by co-administration of mycophenolate mofetil (see alsosection 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 and 1.3-2 timesthe systemic exposure (AUC or Cmax) observed in cardiac transplant patients at the recommendedclinical 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 doses.

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). The nonclinicaltoxicity profile of mycophenolate mofetil appears to be consistent with adverse events observed inhuman clinical trials which now provide safety data of more relevance to the patient population (seesection 4.8).

Pregelatinised starch (maize)

Povidone K-30

Croscarmellose sodium

Magnesium stearate

Cap

Indigo carmine (E132)

Titanium dioxide (E171)

Gelatin

Body

Red iron oxide (E172)

Yellow iron oxide (E172)

Titanium dioxide (E171)

Gelatin

Black ink containing: shellac, black iron oxide (E172), propylene glycol and potassium hydroxide.

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Transparent PVC/PVdC-aluminium blisters

Pack sizes of 100, 300 or 100 x 1 and multipacks containing 300 (3 packs of 100) capsules.

Not all pack sizes may be marketed.

Any unused product or waste material should be disposed of in accordance with local requirements.

Teva B.V.

Swensweg 52031GA Haarlem

Netherlands

EU/1/07/438/001 (100 capsules)

EU/1/07/438/002 (300 capsules)

EU/1/07/438/006 (100 x 1 capsules)

EU/1/07/438/009 (300 (3 x 100) capsules)

Date of first authorisation: 21 February 2008

Date of first renewal: 19 November 2012

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

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