CellCept - summary of medicine characteristics

NAME OF THE MEDICINAL PRODUCT

CellCept 250 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 250 mg mycophenolate mofetil.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Capsules, hard (capsules)

Oblong, blue/brown, branded with black „CellCept 250“ on the capsule cap and „Roche“ on the capsule body.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

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

4.2 Posology and method of administration

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

Posology

Use in renal transplant

Adults

Treatment should be initiated within 72 hours following transplantation. The recommended dose in renal 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 to a maximum of 2 g daily). Capsules should only be prescribed to patients with a body surface area of at least 1.25 m2. Patients with a body surface area of 1.25 to 1.5 m2 may be prescribed mycophenolate mofetil capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a body surface area greater than 1.5 m2 may be prescribed mycophenolate mofetil capsules at a dose of 1 g twice daily (2 g daily 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 to take 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 insufficient to make dosage recommendations and therefore use in this age group is not recommended.

Use in cardiac transplant

Adults

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

Paediatric population

No data are available for paediatric cardiac transplant patients.

Use in hepatic transplant

Adults

Intravenous (IV) CellCept should be administered for the first 4 days following hepatic transplant, with oral CellCept 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 daily dose).

Paediatric population

No data are available for paediatric hepatic transplant patients.

Use in special populations

Elderly

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

Renal impairment

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 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in patients experiencing delayed renal graft function post-operatively (see section 5.2). No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.

Severe hepatic impairment

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 transplant rejection does not lead to changes in MPA pharmacokinetics; dosage reduction or interruption of CellCept is not required. There is no basis for CellCept dose adjustment following cardiac transplant rejection. No pharmacokinetic data are available during hepatic transplant rejection.

Paediatric population

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

Method of administration

For oral use.

Precautions to be taken before handling or administering the medicinal product.

Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, capsules should not be opened or crushed to avoid inhalation or direct contact with skin or mucous membranes of the powder contained in the capsules. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.

Contraindications

• • CellCept should not be given to women of childbearing potential who are not using highly effective contraception (see section 4.6).
• • CellCept treatment should not be initiated in women of childbearing potential without providing a pregnancy test result to rule out unintended use in pregnancy (see section 4.6).
• • CellCept should not be used in pregnancy unless there is no suitable alternative treatment to prevent transplant rejection (see section 4.6).
• • CellCept should not be given to women who are breastfeeding (see section 4.6).

4.4 Special warnings and precautions for use

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 of immunosuppression rather than to the use of any specific agent.

As general advice to minimise the risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Infections

Patients treated with immunosuppressants, including CellCept, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis (see section 4.8). Such infections include latent viral reactivation, such as hepatitis B or hepatitis C reactivation and infections caused by polyomaviruses (BK virus associated nephropathy, JC virus associated progressive multifocal leukoencephalopathy PML). Cases of hepatitis due to reactivation of hepatitis B or hepatitis C have been reported in carrier patients treated with immunosuppressants. These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms. Mycophenolic acid has a cytostatic effect on B- and T-lymphocytes, therefore an increased severity of COVID-19 may occur, and appropriate clinical action should be considered.

There have been reports of hypogammaglobu­linaemia in association with recurrent infections in patients receiving CellCept in combination with other immunosuppressants. In some of these cases, switching CellCept to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on CellCept who develop recurrent infections should have their serum immunoglobulins measured. In cases of sustained, clinically relevant hypogammaglobu­linaemia, appropriate clinical action should be considered taking into account the potent cytostatic effects that mycophenolic acid has on T- and B-lymphocytes.

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

Blood and immune system

Patients receiving CellCept should be monitored for neutropenia, which may be related to CellCept itself, concomitant medications, viral infections, or some combination of these causes. Patients taking CellCept should have complete blood counts weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year. If neutropenia develops (absolute neutrophil count < 1.3 × 103/^l), it may be appropriate to interrupt or discontinue CellCept.

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

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

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

Gastro-intestinal

CellCept has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation. CellCept should be administered with caution in patients with active serious digestive system disease.

CellCept is an IMPDH (inosine monophosphate dehydrogenase) inhibitor. Therefore, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.

Interactions

Caution should be exercised when switching combination therapy from regimens containing immunosuppressants, which interfere with MPA enterohepatic recirculation, e.g. ciclosporin, to others devoid of this effect, e.g. tacrolimus, sirolimus, belatacept, or vice versa, as this might result in changes of MPA exposure. Drugs which interfere with MPA’s enterohepatic cycle (e.g. cholestyramine, antibiotics) should be used with caution due to their potential to reduce the plasma levels and efficacy of CellCept (see also section 4.5). Therapeutic drug monitoring of MPA may be appropriate when switching combination therapy (e.g. from ciclosporin to tacrolimus or vice versa) or to ensure adequate immunosuppression in patients with high immunological risk (e.g. risk of rejection, treatment with antibiotics, addition or removal of an interacting medication).

It is recommended that CellCept should not be administered concomitantly with azathioprine because such concomitant administration has not been studied.

The risk/benefit ratio of mycophenolate mofetil in combination with sirolimus has not been established (see also section 4.5).

Special populations

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

Teratogenic effects

Mycophenolate is a powerful human teratogen. Spontaneous abortion (rate of 45% to 49%) and congenital malformations (estimated rate of 23% to 27%) have been reported following MMF exposure during pregnancy. Therefore, CellCept is contraindicated in pregnancy unless there are no suitable alternative treatments to prevent transplant rejection. Female patients of childbearing potential should be made aware of the risks and follow the recommendations provided in section 4.6 (e.g. contraceptive methods, pregnancy testing) prior to, during, and after therapy with CellCept. Physicians should ensure that women taking mycophenolate understand the risk of harm to the baby, the need for effective contraception, and the need to immediately consult their physician if there is a possibility of pregnancy.

Contraception (see section 4.6)

Because of robust clinical evidence showing a high risk of abortion and congenital malformations when mycophenolate mofetil is used in pregnancy, every effort to avoid pregnancy during treatment should be taken. Therefore, women with childbearing potential must use at least one form of reliable contraception (see section 4.3) before starting CellCept therapy, during therapy, and for six weeks after stopping the therapy; unless abstinence is the chosen method of contraception. Two complementary forms of contraception simultaneously are preferred to minimise the potential for contraceptive failure and unintended pregnancy.

For contraception advice for men see section 4.6.

Educational materials

In order to assist patients in avoiding foetal exposure to mycophenolate and to provide additional important safety information, the Marketing Authorisation Holder will provide educational materials to healthcare professionals. The educational materials will reinforce the warnings about the teratogenicity of mycophenolate, provide advice on contraception before therapy is started and guidance on the need for pregnancy testing. Full patient information about the teratogenic risk and the pregnancy prevention measures should be given by the physician to women of childbearing potential and, as appropriate, to male patients.

Additional precautions

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

Sodium contents

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

4.5 Interaction with other medicinal products and other forms of interaction

Aciclovir

Higher aciclovir plasma concentrations were observed when mycophenolate mofetil was administered with aciclovir in comparison to the administration of aciclovir alone. The changes in MPAG (the phenolic glucuronide of MPA) pharmacokinetics (MPAG increased by 8%) were minimal and are not considered clinically significant. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are aciclovir concentrations, the potential exists for mycophenolate mofetil and aciclovir, or its prodrugs, e.g. valaciclovir, to compete for tubular secretion and further increases in concentrations of both substances may occur.

Antacids and proton pump inhibitors (PPIs)

Decreased MPA exposure has been observed when antacids, such as magnesium and aluminium hydroxides, and PPIs, including lansoprazole and pantoprazole, were administered with CellCept. When comparing rates of transplant rejection or rates of graft loss between CellCept patients taking PPIs vs. CellCept patients not taking PPIs, no significant differences were seen. Theses data support extrapolation of this finding to all antacids because the reduction in exposure when CellCept was co-administered with magnesium and aluminium hydroxides is considerably less than when CellCept was co-administered with PPIs.

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 because of their potential to reduce the efficacy of CellCept.

Cholestyramine

Following single dose administration of 1.5 g of mycophenolate mofetil to normal healthy subjects pretreated with 4 g TID of cholestyramine for 4 days, there was a 40% reduction in the AUC of MPA (see section 4.4 and section 5.2). Caution should be used during concomitant administration because of the potential to reduce efficacy of CellCept.

Ciclosporin A

Ciclosporin A (CsA) pharmacokinetics are unaffected by mycophenolate mofetil.

In contrast, if concomitant CsA treatment is stopped, an increase in MPA AUC of around 30% should be expected. CsA interferes with MPA enterohepatic recycling, resulting in reduced MPA exposures by 3050% in renal transplant patients treated with CellCept and CsA compared with patients receiving sirolimus or belatacept and similar doses of CellCept (see also section 4.4). Conversely, changes of MPA exposure should be expected when switching patients from CsA to one of the immunosuppressants which does not interfere with MPA’s enterohe­patic cycle.

Antibiotics eliminating P-glucuronidase-producing bacteria in the intestine (e.g. aminoglycoside, cephalosporin, fluoroquinolone, and penicillin classes of antibiotics) may interfere with MPAG/MPA enterohepatic recirculation, thus leading to reduced systemic MPA exposure. Information concerning the following antibiotics is available:

Ciprofloxacin or amoxicillin plus clavulanic acid

Reductions in pre-dose (trough) MPA concentrations of about 50% have been reported in renal transplant recipients in the days immediately following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. This effect tended to diminish with continued antibiotic use and to cease within a few days of antibiotic discontinuation. The change in pre-dose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of CellCept should not normally be necessary in the absence of clinical evidence of graft dysfunction. However, close clinical monitoring should be performed during the combination and shortly after antibiotic treatment.

Norfloxacin and metronidazole

In healthy volunteers, no significant interaction was observed when CellCept was concomitantly administered with norfloxacin or metronidazole separately. However, norfloxacin and metronidazole combined reduced the MPA exposure by approximately 30% following a single dose of CellCept.

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 CellCept.

Isavuconazole

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

Telmisartan

Concomitant administration of telmisartan and CellCept resulted in an approximately 30% decrease of MPA concentrations. Telmisartan changes MPA’s elimination by enhancing PPAR gamma (peroxisome proliferator-activated receptor gamma) expression, which in turn results in an enhanced uridine diphosphate glucuronyltran­sferase isoform 1A9 (UGT1A9) expression and activity. When comparing rates of transplant rejection, rates of graft loss or adverse event profiles between CellCept patients with and without concomitant telmisartan medication, no clinical consequences of the pharmacokinetic drugdrug interaction were seen.

Ganciclovir

Based on the results of a single dose administration study of recommended doses of oral mycophenolate and IV ganciclovir and the known effects of renal impairment on the pharmacokinetics of CellCept (see section 4.2) and ganciclovir, it is anticipated that co-administration of these agents (which compete for mechanisms of renal tubular secretion) will result in increases in MPAG and ganciclovir concentration. No substantial alteration of MPA pharmacokinetics is anticipated and CellCept dose adjustment is not required. In patients with renal impairment in whom CellCept and ganciclovir or its prodrugs, e.g. valganciclovir, are co-administered, the dose recommendations for ganciclovir should be observed and patients should be monitored carefully.

Oral contraceptives

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

Rifampicin

In patients not also taking ciclosporin, concomitant administration of CellCept and rifampicin resulted in a decrease in MPA exposure (AUC0–12h) of 18% to 70%. It is recommended to monitor MPA exposure levels and to adjust CellCept doses accordingly to maintain clinical efficacy when rifampicin is administered concomitantly.

Sevelamer

Decrease in MPA Cmax and AUC0–12h by 30% and 25%, respectively, were observed when CellCept was concomitantly administered with sevelamer without any clinical consequences (i.e. graft rejection). It is recommended, however, to administer CellCept at least one hour before or three hours after sevelamer intake to minimise the impact on the absorption of MPA. There are no data on CellCept with phosphate binders other than sevelamer.

Tacrolimus

In hepatic transplant patients initiated on CellCept and tacrolimus, the AUC and Cmax of MPA, the active metabolite of CellCept, were not significantly affected by co-administration with tacrolimus. In contrast, there was an increase of approximately 20% in tacrolimus AUC when multiple doses of CellCept (1.5 g BID) were administered to hepatic transplant patients taking tacrolimus. However, in renal transplant patients, tacrolimus concentration did not appear to be altered by CellCept (see also section 4.4).

Live vaccines

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

Paediatric population

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 tubular secretion.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

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

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

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

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

• • Spontaneous abortions have been reported in 45 to 49% of pregnant women exposed to mycophenolate mofetil, compared to a reported rate of between 12 and 33% in solid organ transplant patients treated with immunosuppressants other than mycophenolate mofetil.
• • Based on literature reports, malformations occurred in 23 to 27% of live births in women exposed to mycophenolate mofetil during pregnancy (compared to 2 to 3% of live births in the overall population and approximately 4 to 5% of live births in solid organ transplant recipients treated with immunosuppressants other than mycophenolate mofetil).

Congenital malformations, including reports of multiple malformations, have been observed postmarketing in children of patients exposed to CellCept in combination with other immunosuppressants during pregnancy. The following malformations were most frequently reported:

• • Abnormalities of the ear (e.g. abnormally formed or absent external ear), external auditory canal atresia (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).

Breast-feeding

Mycophenolate mofetil has been shown to be excreted in the milk of lactating rats. It is not known whether this substance is excreted in human milk. Because of the potential for serious adverse reactions to mycophenolate mofetil in breast-fed infants, CellCept is contraindicated in nursing mothers (see section 4.3).

Men

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

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

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

Fertility

Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. The systemic exposure at this dose represents 2 – 3 times the clinical exposure at the recommended clinical dose of 2 g/day in renal transplant patients and 1.3 – 2 times the clinical exposure at the recommended clinical dose of 3 g/day in cardiac transplant patients. In a female fertility and reproduction study conducted 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. The systemic exposure at this dose was approximately 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3 times the clinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation.

4.7 Effects on ability to drive and use machines

CellCept has moderate influence on the ability to drive and use machines.

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

4.8 Undesirable effects

Summary of the safety profile

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 the administration of CellCept in combination with ciclosporin and corticosteroids. There is also evidence of a higher frequency of certain types of infections (see section 4.4).

Tabulated list of adverse reactions

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 frequency category 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 very rare (<1/10,000). Due to the large differences observed in the frequency of certain adverse reactions across the different transplant indications, the frequency is presented separately for renal, hepatic and cardiac transplant patients.

Table 1 Adverse reactions

Adverse reaction (MedDRA) System Organ Class	Renal transplant	Hepatic transplant	Cardiac transplant
	Frequency	Frequency	Frequency
Infections and infestations
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 po		yps)
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
Blood and lymphatic system disorders
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

Adverse reaction (MedDRA) System Organ Class	Renal transplant	Hepatic transplant	Cardiac transplant
Leukopenia	Very Common	Very Common	Very Common
Pancytopenia	Common	Common	Uncommon
Pseudolymphoma	Uncommon	Uncommon	Common
Thrombocytopenia	Common	Very Common	Very Common
Metabolism and nutrition disorders
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
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
Psychiatric disorders
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
Nervous system disorders
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
Cardiac disorders
Tachycardia	Common	Very Common	Very Common
Vascular disorders
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

Adverse reaction (MedDRA) System Organ Class	Renal transplant	Hepatic transplant	Cardiac transplant
Respiratory, thoracic and mediastinal disorders
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
Gastrointestinal disorders
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
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
Immune system disorders
Hypersenstivity	Uncommon	Common	Common
Hypogammaglobu­linaemia	Uncommon	Very Rare	Very Rare
Hepatobiliary disorders
Blood alkaline phosphatase increased	Common	Common	Common
Blood lactate dehydrogenase increased	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
Skin and subcutaneous tissue disorders
Acne	Common	Common	Very Common
Alopecia	Common	Common	Common

Adverse reaction (MedDRA) System Organ Class	Renal transplant	Hepatic transplant	Cardiac transplant
Rash	Common	Very Common	Very Common
Skin hypertrophy	Common	Common	Very Common
Musculoskeletal and connective tissue disorders
Arthralgia	Common	Common	Very Common
Muscular weakness	Common	Common	Very Common
Renal and urinary disorders
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
General disorders and administration site conditions
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 synthesis inhibitors associated acute inflammatory syndrome	Uncommon	Uncommon	Uncommon

Description of selected adverse reactions

Malignancies

Patients receiving immunosuppressive regimens involving combinations of medicinal products, including CellCept, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.4). Three-year safety data in renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. Hepatic transplant patients were followed for at least 1 year, but less than 3 years.

Infections

All patients treated with immunosuppressants are at increased risk of bacterial, viral and fungal infections (some of which may lead to a fatal outcome), including those caused by opportunistic agents and latent viral reactivation. The risk increases with total immunosuppressive load (see section 4.4). The most serious infections were sepsis, peritonitis, meningitis, endocarditis, tuberculosis and atypical mycobacterial infection. The most common opportunistic infections in patients receiving CellCept (2 g or 3 g daily) with other immunosuppressants in controlled clinical trials in renal, cardiac and hepatic transplant patients followed for at least 1 year were candida mucocutaneous, CMV viraemia/syndrome and Herpes simplex. The proportion of patients with CMV viraemia/syndrome was 13.5%. Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including CellCept.

Blood and lymphatic disorders

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

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

Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with CellCept. These changes are not associated with impaired neutrophil function. These changes may suggest a ‘left shift’ in the maturity of neutrophils in haematological investigations, which may be mistakenly interpreted as a sign of infection in immunosuppressed patients such as those that receive CellCept.

Gastrointestinal disorders

The most serious gastrointestinal disorders were ulceration and hemorrhage which are known risks associated with mycophenolate mofetil. Mouth, esophageal, gastric, duodenal, and intestinal ulcers often complicated by hemorrhage, as well as hematemesis, melena, and hemorrhagic forms of gastritis and colitis were commonly reported during the pivotal clinical trials. The most common gastrointestinal disorders, however, were diarrhoea, nausea and vomiting. Endoscopic investigation of patients with CellCept-related diarrhoea have revealed isolated cases of intestinal villous atrophy (see section 4.4).

Hypersensitivity

Hypersensitivity reactions, including angioneurotic oedema and anaphylactic reaction, have been reported.

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 to CellCept in combination with other immunosuppressants, see section 4.6.

Respiratory, thoracic and mediastinal disorders

There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients treated with CellCept in combination with other immunosuppressants, some of which have been fatal. There have also been reports of bronchiectasis in children and adults.

Immune system disorders

Hypogammaglobu­linaemia has been reported in patients receiving CellCept in combination with other immunosuppressants.

General disorders and administration site conditions

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

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

Special populations

Paediatric population

The type and frequency of adverse reactions in a clinical study, which recruited 92 paediatric patients aged 2 to 18 years who were given 600 mg/m2 mycophenolate mofetil orally twice daily, were generally similar to those observed in adult patients given 1 g CellCept twice daily. However, the following treatment-related adverse events were more frequent in the paediatric population, particularly in children under 6 years of age, when compared to adults: diarrhoea, sepsis, leucopenia, anaemia and infection.

Elderly

Elderly patients (> 65 years) may generally be at increased risk of adverse reactions due to immunosuppression. Elderly patients receiving CellCept as part of a combination immunosuppressive regimen may be at increased risk of certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared to younger individuals.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

Reports of overdoses with mycophenolate mofetil have been received from clinical trials and during post-marketing experience. In many of these cases, no adverse events were reported. In those overdose cases in which adverse events were reported, the events fall within the known safety profile of the medicinal product.

It is expected that an overdose of mycophenolate mofetil could possibly result in oversuppression of the immune system and increase susceptibility to infections and bone marrow suppression (see section 4.4). If neutropenia develops, dosing with CellCept should be interrupted or the dose reduced (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 enterohepatic recirculation of the drug (see section 5.2).

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: immunosuppressive agents ATC code L04AA06

Mechanism of action

Mycophenolate mofetil is the 2-morpholinoethyl ester of MPA. MPA is a selective, uncompetitive and reversible inhibitor of IMPDH, and therefore inhibits the de novo pathway 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 whereas other cell types can utilise salvage pathways, 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 also influences cellular checkpoints responsible for metabolic programming of lymphocytes. It has been shown, using human CD4+ T-cells, that MPA shifts transcriptional activities in lymphocytes from a proliferative state to catabolic processes relevant to metabolism and survival leading to an anergic state of T-cells, whereby the cells become unresponsive to their specific antigen.

5.2 Pharmacokinetic properties

Absorption

Following oral administration, mycophenolate mofetil undergoes rapid and extensive absorption and complete presystemic metabolism to the active metabolite, MPA. As evidenced by suppression of acute rejection following renal transplantation, the immunosuppressant activity of CellCept is correlated with MPA concentration. The mean bioavailability of oral mycophenolate mofetil, based on MPA AUC, is 94% relative to IV mycophenolate mofetil. Food had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g BID to renal transplant patients. However, MPA Cmax was decreased by 40% in the presence of food. Mycophenolate mofetil is not measurable systemically in plasma following oral administration.

Distribution

As a result of enterohepatic recirculation, secondary increases in plasma MPA concentration are usually observed at approximately 6 – 12 hours post-dose. A reduction in the AUC of MPA of approximately 40% is associated with the co-administration of cholestyramine (4 g TID), indicating that 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 transplant patients had mean MPA AUCs approximately 30% lower and Cmax approximately 40% lower compared to the late post-transplant period (3 – 6 months post-transplant).

Biotransformation

MPA is metabolised principally by glucuronyl transferase (isoform UGT1A9) to form the inactive phenolic glucuronide of MPA (MPAG). In vivo , MPAG is converted back to free MPA via enterohepatic recirculation. A minor acylglucuronide (AcMPAG) is also formed. AcMPAG is pharmacologically active and is suspected to be responsible for some of MMF’s side effects (diarrhoea, leukopenia).

Elimination

A negligible amount of substance is excreted as MPA (< 1% of the dose) in the urine. Oral administration of radiolabelled mycophenolate mofetil results in complete recovery of the administered dose with 93% of the administered dose recovered in the urine and 6% recovered in the faeces. 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 |ag/mi), small amounts of MPAG are removed. By interfering with enterohepatic recirculation of the drug, bile acid sequestrants such as cholestyramine 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; OATP isoforms, MRP2 and breast cancer resistance protein (BCRP) are transporters associated with the glucuronides’ 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 its metabolites 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 disease approximate clearance values of 10.6 L/h and 8.27 L/h respectively and half-life values of 17 h were observed. In transplant patients mean clearance values were higher (range 11.9–34.9 L/h) and mean halflife values shorter (5–11 h) with little difference between renal, hepatic or cardiac transplant patients. In the individual patients, these elimination parameters vary based on type of co-treatment with other immunosuppressants, time post-transplantation, plasma albumin concentration and renal function. These factors explain why reduced exposure is seen when CellCept is co-administered with cyclosporine (see section 4.5) and why plasma concentrations tend to increase over time compared to what is observed immediately after transplantation.

Special populations

Renal impairment

In a single dose study (6 subjects/group), mean plasma MPA AUC observed in subjects with severe chronic renal impairment (glomerular filtration rate < 25 ml/min/1.73 m2) were 28 – 75% higher relative to the means observed in normal healthy subjects or subjects with lesser degrees of renal impairment.

The mean single dose MPAG AUC was 3 – 6-fold higher in subjects with severe renal impairment than in subjects with mild renal impairment or normal healthy subjects, consistent with the known renal elimination of MPAG. Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied. No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.

Delayed renal graft function

In patients with delayed renal graft function post-transplant, mean MPA AUC0–12h was comparable to that seen in post-transplant patients without delayed graft function. Mean plasma MPAG AUC0–12h was 2 – 3fold higher than in post-transplant patients without delayed graft function. There may be a transient increase in the free fraction and concentration of plasma MPA in patients with delayed renal graft function. Dose adjustment of CellCept does not appear to be necessary.

Hepatic impairment

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

Paediatric population

Pharmacokinetic parameters were evaluated in 49 paediatric renal transplant patients (aged 2 to 18 years) given 600 mg/m2 mycophenolate mofetil orally twice daily. This dose achieved MPA AUC values similar to those seen in adult renal transplant patients receiving CellCept at a dose of 1 g BID in the early and late post-transplant period. MPA AUC values across age groups were similar in the early and late post-transplant period.

Elderly

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

Patients taking oral contraceptives

A study of the co-administration of CellCept (1 g BID) and combined oral contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.20 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) conducted in 18 non-transplant women (not taking other immunosuppressants) over 3 consecutive menstrual cycles showed no clinically relevant influence of CellCept on the ovulation-suppressing action of the oral contraceptives. Serum levels of LH, FSH and progesterone were not significantly affected. The pharmacokinetics of oral contraceptives were not affected to a clinically relevant degree by co-administration of CellCept (see also section 4.5).

5.3 Preclinical safety data

In experimental models, mycophenolate mofetil was not tumourigenic. The highest dose tested in the animal 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 times the systemic exposure (AUC or Cmax) observed in cardiac transplant patients at the recommended clinical dose of 3 g/day.

Two genotoxicity assays (in vitro mouse lymphoma assay and in vivo mouse bone marrow micronucleus 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 nucleotide synthesis in sensitive cells. Other in vitro tests for detection of gene mutation did not demonstrate genotoxic activity.

In teratology studies in rats and rabbits, foetal resorptions and malformations occurred in rats at 6 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, and diaphragmatic and umbilical hernia), in the absence of maternal toxicity. The systemic exposure at these levels is approximately equivalent to or less than 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3 times the clinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients (see section 4.6).

The haematopoietic and lymphoid systems were the primary organs affected in toxicology studies conducted with mycophenolate mofetil in the rat, mouse, dog and monkey. These effects occurred at systemic exposure levels that are equivalent to or less than the clinical exposure at the recommended dose of 2 g/day for renal transplant recipients. Gastrointestinal effects were observed in the dog at systemic 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 the highest dose (systemic exposure levels equivalent to or greater than clinical exposure). The nonclinical toxicity profile of mycophenolate mofetil appears to be consistent with adverse events observed in human clinical trials, which now provide safety data of more relevance to the patient population (see section 4.8).

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

CellCept capsules

pregelatinised maize starch

croscarmellose sodium

polyvidone (K-90)

magnesium stearate

Capsule shells

gelatin

indigo carmine (E132)

yellow iron oxide (E172)

red iron oxide (E172)

titanium dioxide (E171)

black iron oxide (E172)

potassium hydroxide

shellac.

6.2 Incompatibilities

Not applicable.

• 6.3 Shelf-life

6.4 Special precautions for storage

Do not store above 25 °C. Store in the original package in order to protect from moisture.

6.5 Nature and contents of containerPVC/aluminium foil blister strips CellCept 250 mg capsules:

1 carton contains 100 capsules (in blister packs of 10)

1 carton contains 300 capsules (in blister packs of 10) multipacks containing 300 (3 packs of 100) capsules

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Roche Registration GmbH Emil-Barell-Strasse 1 79639 Grenzach-Wyhlen Germany

8. MARKETING AUTHORISATION NUMBER(S)EU/1/96/005/001 CellCeptEU/1/96/005/003 CellCeptEU/1/96/005/007 CellCept

(100 capsules)

(300 capsules)

(300 (3×100) capsules multipack)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 14 February 1996

Date of latest renewal: 13 March 2006