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CellCept

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Summary for the public


What is CellCept?

CellCept is a medicine containing the active substance mycophenolate mofetil. It is available as capsules (250 mg), tablets (500 mg), a powder to be made up into an oral suspension (1 g/5 ml) and a powder to be made up into a solution for infusion (drip into a vein; 500 mg).


What is CellCept used for?

CellCept is used to prevent the body from rejecting a transplanted kidney, heart or liver. It is used with ciclosporin and corticosteroids (other medicines used to prevent organ rejection).

The medicine can only be obtained with a prescription.


How is CellCept used?

CellCept treatment should be initiated and maintained by a qualified transplant specialist.

The way that CellCept should be given and the dose depend on the type of organ transplant and the patient’s age and size.

For kidney transplants, the recommended dose in adults is 1.0 g twice a day by mouth (capsules, tablets or oral suspension) starting within 72 hours after the transplant. It can also be given as an infusion lasting two hours starting within 24 hours after the transplant, for up to 14 days. In children aged between two and 18 years, the dose of CellCept is calculated depending on height and weight and should be given by mouth.

For heart transplants, the recommended adult dose is 1.5 g twice a day by mouth, starting within five days following the transplant.

For liver transplants in adults, CellCept should be given as a 1-g infusion twice a day for the first four days after the transplant, before the patient is switched to 1.5 g twice a day by mouth as soon as it can be tolerated. CellCept is not recommended for use in children after heart or liver transplants because of a lack of information on its effects in this group.

The dose may need to be adjusted in patients with liver or kidney disease. For more information, see the Summary of Product Characteristics (also part of the EPAR).


How does CellCept work?

The active substance in CellCept, mycophenolate mofetil, is an immunosuppressive medicine. In the body, it is converted into mycophenolic acid, which blocks an enzyme called ‘inosine monophosphate dehydrogenase’. This enzyme is important for the formation of DNA in cells, particularly in the lymphocytes (a type of white blood cell which is involved in the rejection of organ transplants). By preventing the production of new DNA, CellCept reduces the rate at which the lymphocytes multiply. This makes them less effective at recognising and attacking the transplanted organ, lowering the risk of the organ being rejected.


How has CellCept been studied?

CellCept capsules and tablets have been studied in three studies involving a total of 1,493 adults following kidney transplant, in one study involving 650 adults following heart transplant and in one study involving 565 adults following liver transplant. CellCept was compared with azathioprine (another anti-rejection medicine) in all studies except for one of the kidney transplant studies, in which it was compared with placebo (a dummy treatment). A further study looked at the effect of CellCept oral suspension in 100 children following a kidney transplant. In all of the studies, all of the patients also received ciclosporin and corticosteroids, and the main measure of effectiveness was the proportion of patients whose new organ had been rejected after six months.

Further studies showed that the solution for infusion and the oral suspension produced similar levels of the active substance in the blood as the capsules.


What benefit has CellCept shown during the studies?

CellCept was as effective as azathioprine and more effective than placebo in preventing the rejection of transplanted kidneys after six months. In children undergoing kidney transplants, the rejection rates were similar to those seen in adults taking CellCept and lower than those seen in other studies of children who did not receive CellCept.

In the heart transplant study, around 38% of patients taking CellCept and those taking azathioprine experienced rejection after six months. Following liver transplant, 38% of the patients taking CellCept had rejected their new liver after six months, compared with 48% of those taking azathioprine, but the proportion of patients who had lost their new liver after a year was similar in the two groups, at around 4%.


What is the risk associated with CellCept?

The most serious risk associated with CellCept is the possible development of cancer, particularly lymphoma and skin cancer. The most common side effects with CellCept used in combination with ciclosporin and corticosteroids (seen in more than 1 patient in 10) are sepsis (blood infection), gastrointestinal candidiasis (a fungal infection of the stomach or gut), urinary tract infection (infection of the structures that carry urine), herpes simplex (a viral infection that causes cold sores), herpes zoster (a viral infection that causes chickenpox and shingles), leucopenia (low white blood cell counts), thrombocytopenia (low blood platelet counts), anaemia (low red blood cell counts), vomiting, abdominal (tummy) pain, diarrhoea and nausea (feeling sick). For the full list of side effects reported with CellCept, see the Package Leaflet.

CellCept should not be used in people who may be hypersensitive (allergic) to mycophenolate mofetil or mycophenolic acid. It should not be used in women are breast-feeding. CellCept treatment is not recommended for use in pregnant women, and should only be started in women after a negative pregnancy test and if effective contraception is used before, during and for six weeks after CellCept treatment.


Why has CellCept been approved?

The Committee for Medicinal Products for Human Use (CHMP) decided that CellCept’s benefits are greater than its risks in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogeneic renal, cardiac or hepatic transplants. The Committee recommended that CellCept be given marketing authorisation.


Other information about CellCept

The European Commission granted a marketing authorisation valid throughout the European Union for CellCept to Roche Registration Limited on 14 February 1996. The marketing authorisation was renewed on 14 February 2001 and on 14 February 2006.

Authorisation details
Name: CellCept
EMEA Product number: EMEA/H/C/000082
Active substance: mycophenolate mofetil
INN or common name: mycophenolate mofetil
Therapeutic area: Graft Rejection
ATC Code: L04AA06
Marketing Authorisation Holder: Roche Registration Ltd.
Revision: 19
Date of issue of Market Authorisation valid throughout the European Union: 14/02/1996
Contact address:
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom



Product Characteristics

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS


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.
2
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.
3
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.
4
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
5
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.
6
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 -
7
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
8
 
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.
10
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
11
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.
12
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.
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.
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
15
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
phosphoribosyltransferase (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. Some degree of enterohepatic
recirculation is anticipated following intravenous administration 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.
Cholestyramine : following single dose, oral 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.
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.
16
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
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.
17
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). The adverse reaction
profile associated with the administration of CellCept 500 mg powder for concentrate for solution for
infusion has been shown to be similar to that observed after oral administration.
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.
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 %.
18
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 :
The following data refer to the safety experience of oral CellCept in renal transplant patients. Data in
hepatic transplant patients are based on i.v. dosing of CellCept for up to 14 days followed by oral
dosing. 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) 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 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
Very common -
Metabolism and nutrition
disorders
Common Acidosis, hyperkalaemia, hypokalaemia,
hyperglycaemia, hypomagnesaemia,
hypocalcaemia, hypercholesterolaemia,
hyperlipidaemia, hypophosphataemia, anorexia
Very common -
Psychiatric disorders
Common
Depression, thinking abnormal, insomnia
Nervous system disorders
Very common -
Common
Convulsion, hypertonia, tremor, somnolence,
headache, paraesthesia
Cardiac disorders
Very common -
Vascular disorders
Common Tachycardia
Very common -
Common
Hypotension, hypertension
19
Infections and infestations
 
System organ class
Adverse drug reactions
Respiratory, thoracic and
mediastinal disorders
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
Very common -
Skin and subcutaneous tissue
disorders
Common Hepatitis
Very common -
Common 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 alkaline phosphatase
increased, weight decreased
Note: 501 (2 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 and hepatic transplantation, respectively.
Adverse reactions attributable to peripheral venous infusion were phlebitis and thrombosis, both
observed at 4 % in patients treated with CellCept 500 mg powder for concentrate for solution for
infusion.
The following undesirable effects cover adverse reactions from post-marketing experience :
Adverse reactions reported during post-marketing with CellCept are similar to those seen in the
controlled renal and hepatic transplant studies. Additional adverse reactions reported during post-
marketing experience with CellCept 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
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).
20
 
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.
5.2 Pharmacokinetic properties
Following intravenous administration, mycophenolate mofetil undergoes rapid and complete
metabolism to the active metabolite, MPA. MPA at clinically relevant concentrations is 97 % bound to
plasma albumin. The parent substance mycophenolate mofetil can be measured systemically during
intravenous infusion; however, after oral administration it is below the limit of quantitation
(0.4 μg/ml).
21
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 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). MPA AUC values obtained
following administration of 1 g BID intravenous CellCept to renal transplant patients in the early post-
transplant phase are comparable to those observed following 1 g BID oral CellCept. In hepatic
transplant patients, administration of 1 g BID intravenous CellCept followed by 1.5 g BID oral
CellCept resulted in MPA AUC values similar to those found in renal transplant patients administered
1 g CellCept BID.
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 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.
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
22
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.
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 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. 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.
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
systemic exposure levels that are equivalent to or less than the clinical exposure at the recommended
dose of 2 g/day. 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 500 mg powder for concentrate for solution for infusion:
polysorbate 80
citric acid
hydrochloric acid
sodium chloride.
6.2 Incompatibilities
23
CellCept 500 mg powder for concentrate for solution for infusion solution should not be mixed or
administered concurrently via the same catheter with other intravenous medicinal products or infusion
admixtures.
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf-life
Powder for concentrate for solution for infusion: 3 years.
Reconstituted solution and infusion solution : If the infusion solution is not prepared immediately prior
to administration, the commencement of administration of the infusion solution should be within
3 hours from reconstitution and dilution of the medicinal product.
6.4 Special precautions for storage
Powder for concentrate for solution for infusion: Do not store above 30 °C.
Reconstituted solution and infusion solution: Store at 15 – 30°C.
6.5 Nature and contents of container
20 ml type I clear glass vials with grey butyl rubber stopper and aluminium seals with plastic flip-off
caps. CellCept 500 mg powder for concentrate for solution for infusion is available in packs
containing 4 vials.
6.6 Special precautions for disposal and other handling
Preparation of Infusion Solution (6 mg/ml)
CellCept 500 mg powder for concentrate for solution for infusion does not contain an antibacterial
preservative; therefore, reconstitution and dilution of the product must be performed under aseptic
conditions.
CellCept 500 mg powder for concentrate for solution for infusion must be prepared in two steps: the
first step is a reconstitution step with glucose intravenous infusion 5 % and the second step is a
dilution step with glucose intravenous infusion 5 %. A detailed description of the preparation is given
below:
Step 1
a.
Two vials of CellCept 500 mg powder for concentrate for solution for infusion are used for
preparing each 1 g dose. Reconstitute the content of each vial by injecting 14 ml of glucose
intravenous infusion 5 %.
b.
Gently shake the vial to dissolve the medicinal product yielding a slightly yellow solution.
c.
Inspect the resulting solution for particulate matter and discoloration prior to further dilution.
Discard the vial if particulate matter or discoloration is observed.
Step 2
a.
Further dilute the content of the two reconstituted vials (approx. 2 x 15 ml) into 140 ml of
glucose intravenous infusion 5 %. The final concentration of the solution is 6 mg/ml
mycophenolate mofetil.
24
b.
Inspect the infusion solution for particulate matter or discoloration. Discard the infusion
solution if particulate matter or discoloration is observed.
If the infusion solution is not prepared immediately prior to administration, the commencement of
administration of the infusion solution should be within 3 hours from reconstitution and dilution of the
medicinal product. Keep solutions at 15 – 30° C.
Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, avoid direct
contact of prepared solutions of CellCept 500 mg powder for concentrate for solution for infusion with
skin or mucous membranes. 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.
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/1/96/005/005 CellCept (4 vials)
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 /
25
1.
NAME OF THE MEDICINAL PRODUCT
CellCept 1 g/5 ml powder for oral suspension.
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each bottle contains 35 g mycophenolate mofetil in 110 g powder for oral suspension. 5 ml of the
reconstituted suspension contains 1 g of mycophenolate mofetil.
For a full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM
Powder for oral suspension.
4.
CLINICAL PARTICULARS
4.1 Therapeutic indications
CellCept 1 g/5 ml powder for oral suspension 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 1 g/5 ml powder for oral suspension 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), i.e. 5 ml oral suspension twice daily.
Children and adolescents (aged 2 to 18 years) : the recommended dose of CellCept 1 g/5 ml powder for
oral suspension is 600 mg/m 2 administered twice daily (up to a maximum of 2 g/10 ml oral suspension
daily). 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.
26
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.
Note
If required, CellCept 1 g/5 ml powder for oral suspension can be administered via a nasogastric tube
with a minimum size of 8 French (minimum 1.7 mm interior diameter).
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
27
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.
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.
CellCept 1 g/5 ml powder for oral suspension contains aspartame. Therefore, care should be taken if
CellCept 1 g/5 ml powder for oral suspension is administered to patients with phenylketonuria (see
section 6.1)
The risk: benefit of mycophenolate mofetil in combination with tacrolimus or sirolimus has not been
established (see also section 4.5).
This medicinal product contains sorbitol. Patients with rare hereditary problems of fructose intolerance
should not take this medicine.
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
28
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.
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
29
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
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).
30
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.
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
Infections and infestations
Very
common
Sepsis, gastrointestinal candidiasis, urinary
tract infection, herpes simplex, herpes zoster
31
 
System organ class
Adverse drug reactions
Common Pneumonia, influenza, respiratory tract
infection, respiratory moniliasis,
gastrointestinal infection, candidiasis,
gastroenteritis, infection, bronchitis,
pharyngitis, sinusitis, fungal skin infection,
skin candida, vaginal candidiasis, rhinitis
Neoplasms benign, malignant
and unspecified (incl cysts and
polyps)
Very
common
-
Common Skin cancer, benign neoplasm of skin
Very
common
Blood and lymphatic system
disorders
Leucopenia, thrombocytopenia, anaemia
Common Pancytopenia,leucocytosis
Very
common
Metabolism and nutrition
disorders
-
Common Acidosis,hyperkalaemia, hypokalaemia,
hyperglycaemia, hypomagnesaemia,
hypocalcaemia, hypercholesterolaemia,
hyperlipidaemia, hypophosphataemia,
hyperuricaemia, gout, anorexia
Psychiatric disorders
Very
common
-
Common Agitation, confusional state, depression,
anxiety, thinking abnormal, insomnia
Nervous system disorders
Very
common
-
Common Convulsion, hypertonia, tremor, somnolence,
myasthenic syndrome, dizziness, headache,
paraesthesia, dysgeusia
Cardiac disorders
Very
common
-
Common Tachycardia
Very
common
Vascular disorders
-
Common Hypotension, hypertension, vasodilatation
Very
common
Respiratory, thoracic and
mediastinal disorders
-
Common Pleural effusion, dyspnoea, cough
Very
common
Gastrointestinal disorders
Vomiting, abdominal pain, diarrhoea, nausea
Common Gastrointestinal haemorrhage, peritonitis, ileus,
colitis, gastric ulcer, duodenal ulcer, gastritis,
oesophagitis, stomatitis, constipation,
dyspepsia, flatulence, eructation
Hepatobiliary disorders
Very
common
-
Skin and subcutaneous tissue
disorders
Common Hepatitis, jaundice, hyperbilirubinaemia
Very
common
-
Musculoskeletal and connective
Tissue disorders
Common Skin hypertrophy, rash, acne, alopecia,
Very
common
-
Common Arthralgia
Renal and urinary disorders
Very
common
-
32
 
System organ class
Adverse drug reactions
General disorders and
administration site conditions
Common Renalimpairment
Very
common
-
Common Oedema, pyrexia, chills, pain, malaise,
asthenia,
Investigations
Very
common
-
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 cytomegaloviruscolitis,
(≥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
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
33
 
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.
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.
34
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 < 25ml•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.
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.
35
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
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 1 g/5 ml powder for oral suspension:
sorbitol
silica, colloidal anhydrous
sodium citrate
soybean lecithin
mixed fruit flavour
xanthan gum
aspartame* (E951)
methyl parahydroxybenzoate (E218)
citric acid anhydrous
* contains phenylalanine equivalent to 2.78 mg/5 ml of suspension.
36
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf-life
The shelf-life of the powder for oral suspension is 2 years.
The shelf-life of the reconstituted suspension is 2 months.
6.4 Special precautions for storage
Powder for oral suspension and reconstituted suspension: Do not store above 30 °C.
6.5 Nature and contents of container
Each bottle contains 110 g of powder for oral suspension. When reconstituted, the volume of the
suspension is 175 ml, providing a usable volume of 160 – 165 ml.
A bottle adapter and 2 oral dispensers are also provided.
6.6 Special precautions for disposal and other handling
Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, avoid
inhalation or direct contact with skin or mucous membranes of the dry powder as well as direct contact
of the reconstituted suspension with the skin. If such contact occurs, wash thoroughly with soap and
water; rinse eyes with plain water.
It is recommended that CellCept 1 g/5 ml powder for oral suspension be reconstituted by the
pharmacist prior to dispensing to the patient.
Preparation of suspension
1.
Tap the closed bottle several times to loosen the powder.
2.
Measure 94 ml of purified water in a graduated cylinder.
3.
Add approximately half of the total amount of purified water to the bottle and shake the closed
bottle well for about 1 minute.
4.
Add the remainder of water and shake the closed bottle well for about 1 minute.
5.
Remove child-resistant cap and push bottle adapter into neck of bottle.
6.
Close bottle with child-resistant cap tightly. This will assure the proper seating of the bottle
adapter in the bottle and child-resistant status of the cap.
7.
Write the date of expiration of the reconstituted suspension on the bottle label. (The shelf-life of
the reconstituted suspension is two months.)
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
MARKETING AUTHORISATION HOLDER
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
37
8.
MARKETING AUTHORISATION NUMBER(S)
EU/1/96/005/006 CellCept (1 bottle 110g)
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 /
38
1.
FURTHER INFORMATION
What CellCept contains
-
The active substance is mycophenolate mofetil.
CellCept tablets:
microcrystalline cellulose
polyvidone (K-90)
croscarmellose sodium
magnesium stearate
Tablet coating:
hydroxypropyl methylcellulose
hydroxypropyl cellulose
titanium dioxide (E171)
polyethylene glycol 400
indigo carmine aluminium lake (E132)
red iron oxide (E172)
What CellCept looks like and contents of the pack
CellCept 500 mg tablets:
1 carton contains 50 tablets (in blister packs of 10)
1 carton contains 150 tablets (in blister packs of 10)
Tablets:
CellCept tablets: lavender coloured caplet-shaped tablet, engraved with "CellCept 500" on one side
and "Company logo" on the other.
100
-
The other ingredients are:
Marketing Authorisation Holder
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
Manufacturing Authorisation holder responsible for batch release
Roche Pharma AG, Emil Barell Str. 1, 79639 Grenzach Wyhlen, Germany.
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
N.V. Roche S.A.
Tél/Tel: +32 (0) 2 525 82 11
Luxembourg/Luxemburg
(Voir/siehe Belgique/Belgien)
България
Рош България ЕООД
Тел: +359 2 818 44 44
Magyarország
Roche (Magyarország) Kft.
Tel: +36 - 23 446 800
Česká republika
Roche s. r. o.
Tel: +420 - 2 20382111
Malta
(See United Kingdom)
Danmark
Roche a/s
Tlf: +45 - 36 39 99 99
Nederland
Roche Nederland B.V.
Tel: +31 (0) 348 438050
Deutschland
Roche Pharma AG
Tel: +49 (0) 7624 140
Norge
Roche Norge AS
Tlf: +47 - 22 78 90 00
Eesti
Roche Eesti OÜ
Tel: + 372 - 6 177 380
Österreich
Roche Austria GmbH
Tel: +43 (0) 1 27739
Ελλάδα
Roche (Hellas) A.E.
Τηλ: +30 210 61 66 100
Polska
Roche Polska Sp.z o.o.
Tel: +48 - 22 345 18 88
España
Roche Farma S.A.
Tel: +34 - 91 324 81 00
Portugal
Roche Farmacêutica Química, Lda
Tel: +351 - 21 425 70 00
France
Roche
Tél: +33 (0) 1 46 40 50 00
România
Roche România S.R.L.
Tel: +40 21 206 47 01
Ireland
Roche Products (Ireland) Ltd.
Tel: +353 (0) 1 469 0700
Slovenija
Roche farmacevtska družba d.o.o.
Tel: +386 - 1 360 26 00
101
Ísland
Roche a/s
c/o Icepharma hf
Sími: +354 540 8000
Slovenská republika
Roche Slovensko, s.r.o.
Tel: +421 - 2 52638201
Italia
Roche S.p.A.
Tel: +39 - 039 2471
Suomi/Finland
Roche Oy
Puh/Tel: +358 (0) 10 554 500
Kύπρος
Γ.Α.Σταμάτης & Σια Λτδ.
Τηλ: +357 - 22 76 62 76
Sverige
Roche AB
Tel: +46 (0) 8 726 1200
Latvija
Roche Latvija SIA
Tel: +371 - 6 7039831
United Kingdom
Roche Products Ltd.
Tel: +44 (0) 1707 366000
Lietuva
UAB “Roche Lietuva”
Tel: +370 5 2546799
This leaflet was last approved on {MM/YYYY}
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
102


Source: European Medicines Agency



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