CellCept

1.

NAME OF THE MEDICINAL PRODUCT

CellCept 250 mg capsules.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 250 mg mycophenolate mofetil.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Capsules, hard.

CellCept capsules: oblong, blue/brown, branded with black "CellCept 250" on the capsule cap and

"Company logo" on the capsule body.

4.

CLINICAL PARTICULARS

4.1 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 with CellCept should be initiated and maintained by appropriately qualified transplant

specialists.

Use in renal transplant :

Adults : oral CellCept 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).

Children and adolescents (aged 2 to 18 years) : the recommended dose of mycophenolate mofetil is

600 mg/m 2 administered orally twice daily (up to a maximum of 2 g daily). CellCept capsules should

only be prescribed to patients with a body surface area of at least 1.25 m 2 . Patients with a body surface

area of 1.25 to 1.5 m 2 may be prescribed CellCept capsules at a dose of 750 mg twice daily (1.5 g

daily dose). Patients with a body surface area greater than 1.5 m 2 may be prescribed CellCept 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.

Children (< 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 : oral CellCept 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).

Children : no data are available for paediatric cardiac transplant patients.

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Use in hepatic transplant :

Adults : 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).

Children : no data are available for paediatric hepatic transplant patients.

Use in elderly (≥ 65 years) : 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.

Use in renal impairment : in renal transplant patients with severe chronic renal impairment (glomerular

filtration rate < 25 ml•min -1 •1.73 m -2 ), 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.

Use in 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 : MPA (mycophenolic acid) 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.

4.3 Contraindications

Hypersensitivity reactions to CellCept have been observed (see section 4.8). Therefore, CellCept is

contraindicated in patients with a hypersensitivity to mycophenolate mofetil or mycophenolic acid.

CellCept is contraindicated in women who are breastfeeding (see section 4.6).

For information on use in pregnancy and contraceptive requirements see section 4.6.

4.4 Special warnings and precautions for use

Patients receiving immunosuppressive regimens involving combinations of medicinal products,

including CellCept, are at increased risk of developing lymphomas and other malignancies,

particularly of the skin (see section 4.8). The risk appears to be related to the intensity and duration of

immunosuppression rather than to the use of any specific agent. As general advice to minimise the risk

for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing

and using a sunscreen with a high protection factor.

Patients receiving CellCept should be instructed to report immediately any evidence of infection,

unexpected bruising, bleeding or any other manifestation of bone marrow depression.

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). Among

the opportunistic infections are BK virus associated nephropathy and JC virus associated progressive

multifocal leukoencephalopathy (PML). 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.

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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 x 10 3 /µl), it may be appropriate to interrupt or discontinue CellCept.

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

combination with other immunosuppressants. The mechanism for mycophenolate mofetil induced

PRCA is unknown. PRCA may resolve with dose reduction or cessation of CellCept therapy. Changes

to CellCept therapy should only be undertaken under appropriate supervision in transplant recipients

in order to minimise the risk of graft rejection (see section 4.8).

Patients 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.

Because 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. On theoretical grounds,

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.

It is recommended that CellCept should not be administered concomitantly with azathioprine because

such concomitant administration has not been studied.

In view of the significant reduction in the AUC of MPA by cholestyramine, caution should be used in

the concomitant administration of CellCept with medicinal products that interfere with enterohepatic

recirculation because of the potential to reduce the efficacy of CellCept.

The risk: benefit of mycophenolate mofetil in combination with tacrolimus or sirolimus has not been

established (see also section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

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 with magnesium and aluminium hydroxides : absorption of mycophenolate mofetil was

decreased when administered with antacids.

Cholestyramine : following single dose administration of 1.5 g of mycophenolate mofetil to normal

healthy subjects pre-treated with 4 g TID of cholestyramine for 4 days, there was a 40 % reduction in

the AUC of MPA (see section 4.4 and section 5.2). Caution should be used during concomitant

administration because of the potential to reduce efficacy of CellCept.

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Medicinal products that interfere with enterohepatic circulation : caution should be used with

medicinal products that interfere with enterohepatic circulation because of their potential to reduce the

efficacy of CellCept.

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

In contrast, if concomitant ciclosporin treatment is stopped, an increase in MPA AUC of around 30%

should be expected.

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 which 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 pharmacokinetics and pharmacodynamics of oral contraceptives were

unaffected by coadministration 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.

Sirolimus : in renal transplant patients, concomitant administration of CellCept and CsA resulted in

reduced MPA exposures by 30-50% compared with patients receiving the combination of sirolimus

and similar doses of CellCept (see also section 4.4).

Sevelamer : decrease in MPA Cmax and AUC0-12 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 is no data

on CellCept with phosphate binders other than sevelamer.

Trimethoprim/sulfamethoxazole : no effect on the bioavailability of MPA was observed.

Norfloxacin and metronidazole : in healthy volunteers, no significant interaction was observed when

CellCept was concomitantly administered with norfloxacin and metronidazole separately. However,

norfloxacin and metronidazole combined reduced the MPA exposure by approximately 30 %

following a single dose of CellCept.

Ciprofloxacin and 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 their discontinuation. The

change in predose level may not accurately represent changes in overall MPA exposure. Therefore, a

change in the dose of CellCept should not normally be necessary in the absence of clinical evidence of

graft dysfunction. However, close clinical monitoring should be performed during the combination

and shortly after antibiotic treatment.

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 coadministration 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 patients taking tacrolimus. However, in

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renal transplant patients, tacrolimus concentration did not appear to be altered by CellCept (see also

section 4.4).

Other interactions : 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.

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).

4.6 Pregnancy and lactation

It is recommended that CellCept therapy should not be initiated until a negative pregnancy test has

been obtained. Effective contraception must be used before beginning CellCept therapy, during

therapy, and for six weeks following discontinuation of therapy (see section 4.5). Patients should be

instructed to consult their physician immediately should pregnancy occur.

The use of CellCept is not recommended during pregnancy and should be reserved for cases where no

more suitable alternative treatment is available. CellCept should be used in pregnant women only if

the potential benefit outweighs the potential risk to the foetus. There is limited data from the use of

CellCept in pregnant women. However, congenital malformations including ear malformations, i.e.

abnormally formed or absent external/middle ear, have been reported in children of patients exposed

to CellCept in combination with other immunosuppressants during pregnancy. Cases of spontaneous

abortions have been reported in patients exposed to CellCept . Studies in animals have shown

reproductive toxicity (see section 5.3).

Mycophenolate mofetil has been shown to be excreted in the milk of lactating rats. It is not known

whether this substance is excreted in human milk. Because of the potential for serious adverse

reactions to mycophenolate mofetil in breast-fed infants, CellCept is contraindicated in nursing

mothers (see section 4.3).

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. The

pharmacodynamic profile and the reported adverse reactions indicate that an effect is unlikely.

4.8 Undesirable effects

The following undesirable effects cover adverse reactions from clinical trials :

The principal adverse reactions associated with the administration of CellCept in combination with

ciclosporin and corticosteroids include diarrhoea, leucopenia, sepsis and vomiting, and there is

evidence of a higher frequency of certain types of infections (see section 4.4).

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). Lymphoproliferative disease or lymphoma developed in

0.6 % of patients receiving CellCept (2 g or 3 g daily) in combination with other immunosuppressants

in controlled clinical trials of renal (2 g data), cardiac and hepatic transplant patients followed for at

least 1 year. Non-melanoma skin carcinomas occurred in 3.6 % of patients; other types of malignancy

occurred in 1.1 % of patients. 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.

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Opportunistic infections :

All transplant patients are at increased risk of opportunistic infections; the risk increased with total

immunosuppressive load (see section 4.4). The most common opportunistic infections in patients

receiving CellCept (2 g or 3 g daily) with other immunosuppressants in controlled clinical trials of

renal (2 g data), 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 %.

Children and adolescents (aged 2 to 18 years) :

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/m 2 mycophenolate mofetil orally twice daily, were

generally similar to those observed in adult patients given 1 g CellCept twice daily. However, the

following treatment-related adverse events were more frequent in the paediatric population,

particularly in children under 6 years of age, when compared to adults:diarrhoea, sepsis, leucopenia,

anaemia and infection.

Elderly patients (≥ 65 years) :

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.

Other adverse reactions :

Adverse reactions, probably or possibly related to CellCept, reported in ≥1/10 and in ≥1/100 to<1/10

of patients treated with CellCept in the controlled clinical trials of renal (2 g data), cardiac and hepatic

transplant patients are listed in the following table.

Adverse Reactions, Probably or Possibly Related to CellCept, Reported in Patients Treated with

CellCept in Renal, Cardiac and Hepatic Clinical Trials when Used in Combination with

Ciclosporin and Corticosteroids

Within the system organ classes, undesirable effects are listed under headings of frequency, using the

following categories: 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); very rare (<1/10,000), not known (cannot be estimated form the

available data). Within each frequency grouping, undesirable effects are presented in order of

decreasing seriousness.

System organ class Adverse drug reactions

Very common Sepsis, gastrointestinal candidiasis, urinary

tract infection, herpes simplex, herpes zoster

Neoplasms benign, malignant

and unspecified (incl cysts and

polyps)

Common Pneumonia, influenza, respiratory tract

infection, respiratory moniliasis,

gastrointestinal infection, candidiasis,

gastroenteritis, infection, bronchitis,

pharyngitis, sinusitis, fungal skin infection,

skin candida, vaginal candidiasis, rhinitis

Very common -

Common

Skin cancer, benign neoplasm of skin

Blood and lymphatic system

disorders

Very common Leucopenia, thrombocytopenia, anaemia

Common

Pancytopenia, leucocytosis

Metabolism and nutrition

Very common -

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Infections and infestations

System organ class

Adverse drug reactions

disorders

Common Acidosis, hyperkalaemia, hypokalaemia,

hyperglycaemia, hypomagnesaemia,

hypocalcaemia, hypercholesterolaemia,

hyperlipidaemia, hypophosphataemia,

hyperuricaemia, gout, anorexia

Very common -

Psychiatric disorders

Nervous system disorders

Common Agitation, confusional state, depression,

anxiety, thinking abnormal, insomnia

Very common -

Cardiac disorders

Common Convulsion, hypertonia, tremor, somnolence,

myasthenic syndrome, dizziness, headache,

paraesthesia, dysgeusia

Very common -

Vascular disorders

Common Tachycardia

Very common -

Respiratory, thoracic and

mediastinal disorders

Common Hypotension, hypertension, vasodilatation

Very common -

Common Pleural effusion, dyspnoea, cough

Very common Vomiting, abdominal pain, diarrhoea, nausea

Gastrointestinal disorders

Hepatobiliary disorders

Common Gastrointestinal haemorrhage, peritonitis, ileus,

colitis, gastric ulcer, duodenal ulcer, gastritis,

oesophagitis, stomatitis, constipation,

dyspepsia, flatulence, eructation

Very common -

Skin and subcutaneous tissue

disorders

Common Hepatitis, jaundice, hyperbilirubinaemia

Very common -

Common Skin hypertrophy, rash, acne, alopecia,

Very common -

Musculoskeletal and connective

Tissue disorders

Common Arthralgia

Very common -

Renal and urinary disorders

General disorders and

administration site conditions

Common Renal impairment

Very common -

Common Oedema, pyrexia, chills, pain, malaise,

asthenia,

Very common -

Investigations

Common Hepatic enzyme increased, blood creatinine

increased, blood lactate dehydrogenase

increased, blood urea increased, blood alkaline

phosphatase increased, weight decreased

Note: 501 (2 g CellCept daily), 289 (3 g CellCept daily) and 277 (2 g IV / 3 g oral CellCept daily) patients were treated in

Phase III studies for the prevention of rejection in renal, cardiac and hepatic transplantation, respectively.

The following undesirable effects cover adverse reactions from post-marketing experience :

The types of adverse reactions reported during post-marketing with CellCept are similar to those seen

in the controlled renal, cardiac and hepatic transplant studies. Additional adverse reactions reported

during post-marketing are described below with the frequencies reported within brackets if known.

Gastrointestinal : gingival hyperplasia (≥1/100 to <1/10), colitis including cytomegalovirus colitis,

(≥1/100 to <1/10), pancreatitis, (≥1/100 to <1/10) and intestinal villous atrophy.

Disorders related to immunosuppression : serious life-threatening infections including meningitis,

endocarditis, tuberculosis and atypical mycobacterial infection. Cases of BK virus associated

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nephropathy, as well as cases of JC virus associated progressive multifocal leucoencephalopathy

(PML), have been reported in patients treated with immunosuppressants, including CellCept.

Agranulocytosis (≥1/1000 to <1/100) 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 depression in patients treated with CellCept, some of which have been

fatal.

Blood and lymphatic system disorder:

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.

Hypersensitivity : Hypersensitivity reactions, including angioneurotic oedema and anaphylactic

reaction, have been reported.

Congenital disorders : see further details in 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.

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 re-

circulation of the drug (see section 5.2)..

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: immunosuppressive agents ATC code L04AA06

Mycophenolate mofetil is the 2-morpholinoethyl ester of MPA. MPA is a potent, selective,

uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase, 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.

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5.2 Pharmacokinetic properties

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 C max was decreased by 40 % in the presence of food.

Mycophenolate mofetil is not measurable systemically in plasma following oral administration. MPA

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

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 is metabolised principally by glucuronyl transferase to form the phenolic glucuronide of MPA

(MPAG), which is not pharmacologically active.

A negligible amount of substance is excreted as MPA (< 1 % of dose) in the urine. Orally

administered 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 (> 100µg/ml), small amounts of MPAG are removed.

In the early post-transplant period (< 40 days post-transplant), renal, cardiac and hepatic transplant

patients had mean MPA AUCs approximately 30 % lower and C max approximately 40 % lower

compared to the late post-transplant period (3 – 6 months post-transplant).

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 •1.73 m -2 ) were 28 – 75 % higher

relative to the means observed in normal healthy subjects or subjects with lesser degrees of renal

impairment. However, 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 AUC (0–12h) was

comparable to that seen in post-transplant patients without delayed graft function. Mean plasma

MPAG AUC (0-12h) was 2 – 3-fold 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 this process probably depend

on the particular disease. However, hepatic disease with predominantly biliary damage, such as

primary biliary cirrhosis, may show a different effect.

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Children and adolescents (aged 2 to 18 years) :

Pharmacokinetic parameters were evaluated in 49 paediatric renal transplant patients given 600 mg/m 2

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 patients (≥ 65 years) :

Pharmacokinetic behaviour of CellCept in the elderly has not been formally evaluated.

Oral contraceptives :

The pharmacokinetics of oral contraceptives were unaffected by coadministration of CellCept (see

also section 4.5). A study of the coadministration of CellCept (1 g bid) and combined oral

contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to

0.15 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) conducted in 18 non-transplant

women (not taking other immunosupressants) 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.

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

C max ) observed in renal transplant patients at the recommended clinical dose of 2 g/day and 1.3 – 2

times the systemic exposure (AUC or C max ) 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.

Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg•kg -1 •day -1 . 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 -1 •day -1 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.

In teratology studies in rats and rabbits, foetal resorptions and malformations occurred in rats at

6 mg•kg -1 •day -1 (including anophthalmia, agnathia, and hydrocephaly) and in rabbits at

90 mg•kg 1 •day -1 (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.

Refer to 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

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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 PARTICULARS

6.1 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

3 years.

6.4 Special precautions for storage

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

6.5 Nature and contents of container

CellCept 250 mg capsules: 1 carton contains 100 capsules (in blister packs of 10)

1 carton contains 300 capsules (in blister packs of 10)

6.6 Special precautions for disposal

Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, CellCept

capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous

membranes of the powder contained in CellCept capsules. If such contact occurs, wash thoroughly

with soap and water; rinse eyes with plain water.

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

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7.

MARKETING AUTHORISATION HOLDER

Roche Registration Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/96/005/001 CellCept

(100 capsules)

EU/1/96/005/003 CellCept

(300 capsules)

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 14 February 1996

Date of latest renewal: 14 February 2006

10. DATE OF REVISION OF THE TEXT

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

Agency (EMEA) http://www.emea.europa.eu /

13

1.

NAME OF THE MEDICINAL PRODUCT

CellCept 500 mg powder for concentrate for solution for infusion.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains the equivalent of 500 mg mycophenolate mofetil (as hydrochloride salt).

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion.

CellCept 500 mg powder for concentrate for solution for infusion must be reconstituted and further

diluted with glucose intravenous infusion 5 % prior to administration to the patient (see section 6.6).

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

CellCept 500 mg powder for concentrate for solution for infusion is indicated in combination with

ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving

allogeneic renal or hepatic transplants.

4.2 Posology and method of administration

Treatment with CellCept should be initiated and maintained by appropriately qualified transplant

specialists.

CAUTION: CELLCEPT I.V. SOLUTION SHOULD NEVER BE ADMINISTERED BY RAPID

OR BOLUS INTRAVENOUS INJECTION.

CellCept 500 mg powder for concentrate for solution for infusion is an alternative dosage form to

CellCept oral forms (capsules, tablets and powder for oral suspension) that may be administered for up

to 14 days. The initial dose of CellCept 500 mg powder for concentrate for solution for infusion

should be given within 24 hours following transplantation.

Following reconstitution to a concentration of 6 mg/ml, CellCept 500 mg powder for concentrate for

solution for infusion must be administered by slow intravenous infusion over a period of 2 hours by

either a peripheral or a central vein (see section 6.6).

Use in renal transplant : the recommended dose in renal transplant patients is 1 g administered twice

daily (2 g daily dose).

Use in hepatic transplant : the recommended dose of CellCept for infusion in hepatic transplant patients

is 1 g administered twice daily (2 g daily dose). IV CellCept should continue for the first 4 days

following hepatic transplant, with oral CellCept initiated as soon after this as it can be tolerated. The

recommended dose of oral CellCept in hepatic transplant patients is 1.5 g administered twice daily

(3 g daily dose).

Use in children : safety and efficacy of CellCept for infusion in paediatric patients have not been

established. No pharmacokinetic data with CellCept for infusion are available for paediatric renal

14

transplant patients. No pharmacokinetic data are available for paediatric patients following hepatic

transplants.

Use in elderly (≥ 65 years) : the recommended dose of 1 g administered twice a day for renal or hepatic

transplant patients is appropriate for the elderly.

Use in renal impairment : in renal transplant patients with severe chronic renal impairment (glomerular

filtration rate < 25 ml•min -1 •1.73 m -2 ), 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 hepatic transplant patients with severe chronic renal

impairment.

Use in severe hepatic impairment : no dose adjustments are needed for renal transplant patients with

severe hepatic parenchymal disease.

Treatment during rejection episodes : MPA (mycophenolic acid) 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. No pharmacokinetic data are available

during hepatic transplant rejection.

4.3 Contraindications

Hypersensitivity reactions to CellCept have been observed (see section 4.8). Therefore, CellCept is

contraindicated in patients with a hypersensitivity to mycophenolate mofetil or mycophenolic acid.

CellCept 500 mg powder for concentrate for solution for infusion is contraindicated in patients who

are allergic to polysorbate 80.

CellCept is contraindicated in women who are breastfeeding (see section 4.6).

For information on use in pregnancy and contraceptive requirements, see section 4.6.