ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Myclausen 500 mg film-coated tablets
2.
Each tablet contains 500 mg mycophenolate mofetil.
For a full list of excipients, see section 6.1.
3.
White round film-coated tablets.
4.
Myclausen is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of
acute transplant rejection in patients receiving allogeneic renal, cardiac or hepatic transplants.
Treatment with Myclausen should be initiated and maintained by appropriately qualified
transplant specialists.
Posology
Use in renal transplant
:
Adults
: oral Myclausen 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).
administered orally twice daily (up to a maximum of 2 g daily). Myclausen film-coated
tablets should only be prescribed to patients with a body surface area greater than 1.5 m
2
, 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 Myclausen 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.
Use in hepatic transplant
:
2
Film-coated tablet
Children and adolescents (aged 2 to 18 years)
: the recommended dose of mycophenolate mofetil is
600 mg/m
2
Adults
: intravenous mycophenolate mofetil should be administered for the first 4 days following
hepatic transplant, with oral Myclausen 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 Myclausen is not required. There is no basis for Myclausen dose
adjustment following cardiac transplant rejection. No pharmacokinetic data are available during
hepatic transplant rejection.
Method of administration
The tablets should be swallowed whole with a glass of water. The tablets should not be broken or
crushed.
Hypersensitivity reactions to mycophenolate mofetil have been observed (see section 4.8).
Therefore, Myclausen is contraindicated in patients with a hypersensitivity to mycophenolate
mofetil or mycophenolic acid.
Myclausen is contraindicated in women who are breastfeeding (see section 4.6).
For information on use in pregnancy and contraceptive requirements see section 4.6 .
Patients receiving immunosuppressive regimens involving combinations of medicinal products,
including Myclausen, 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 Myclausen 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 Myclausen, are at increased risk for opportunistic
3
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 Myclausen should be monitored for neutropenia, which may be related to
Myclausen itself, concomitant medications, viral infections, or some combination of these causes.
Patients taking Myclausen 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 Myclausen.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate
mofetil in combination with other immunosuppressants. The mechanism for mycophenolate mofetil
induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of Myclausen
therapy. Changes to Myclausen 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 Myclausen, 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 Myclausen has been associated with an increased incidence of digestive system adverse
events, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation,
Myclausen should be administered with caution in patients with active serious digestive system
disease.
Myclausen 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 Myclausen 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 Myclausen with medicinal products that interfere with
enterohepatic recirculation because of the potential to reduce the efficacy of Myclausen.
The risk: benefit of mycophenolate mofetil in combination with tacrolimus or sirolimus has not been
established (see also section 4.5).
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.
4
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 Myclausen.
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 Myclausen.
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 Myclausen (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
Myclausen dose adjustment is not required. In patients with renal impairment in which Myclausen 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 mycophenolate mofetil (see also section 5.2).
Rifampicin
: in patients not also taking ciclosporin, concomitant administration of mycophenolate
mofetil 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 Myclausen doses accordingly to maintain
clinical efficacy when rifampicin is administered concomitantly.
Sirolimus
: in renal transplant patients, concomitant administration of mycophenolate mofetil and
CsA resulted in reduced MPA exposures by 30-50 % compared with patients receiving the
combination of sirolimus and similar doses of mycophenolate mofetil (see also section 4.4).
Sevelamer
: decrease in MPA Cmax and AUC0-12 by 30 % and 25 %, respectively, were observed
when mycophenolate mofetil was concomitantly administered with sevelamer without any clinical
consequences (i.e. graft rejection). It is recommended, however, to administer Myclausen 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 mycophenolate mofetil 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
mycophenolate mofetil 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 Myclausen.
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 Myclausen should not normally be necessary in the absence of clinical evidence
5
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 mycophenolate mofetil and tacrolimus, the
AUC and Cmax of MPA, the active metabolite of mycophenolate mofetil, were not significantly
affected by coadministration with tacrolimus. In contrast, there was an increase of approximately 20
% in tacrolimus AUC when multiple doses of mycophenolate mofetil (1.5 g BID) were administered
to patients taking tacrolimus. However, in renal transplant patients, tacrolimus concentration did not
appear to be altered by mycophenolate mofetil (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 4.4).
It is recommended that Myclausen therapy should not be initiated until a negative pregnancy test has
been obtained. Effective contraception must be used before beginning Myclausen 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 Myclausen is not recommended during pregnancy and should be reserved for cases where
no more suitable alternative treatment is available. Myclausen 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
mycophenolate mofetil 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 Myclausen in combination with other immunosuppressants during pregnancy.
Cases of spontaneous abortions have been reported in patients exposed to mycophenolate mofetil
.
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, Myclausen is contraindicated in nursing
mothers (see section 4.3).
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.
The following undesirable effects cover adverse reactions from clinical trials
:
The principal adverse reactions associated with the administration of mycophenolate mofetil 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 mycophenolate mofetil, 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 mycophenolate mofetil (2 g or 3 g daily) in combination with
6
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 mycophenolate mofetil (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 %.
mycophenolate mofetil orally twice daily, were
generally similar to those observed in adult patients given 1 g Myclausen 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 Myclausen 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 mycophenolate mofetil, reported in ≥ 1/10 and in
≥ 1/100 to < 1/10 of patients treated with mycophenolate mofetil 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 mycophenolate mofetil, Reported in Patients
Treated with mycophenolate mofetil 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
from 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
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
Very common
-
7
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
System organ class
Adverse drug reactions
and unspecified (incl. cysts and
polyps)
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,
hyperuricaemia, gout, anorexia
Very common -
Psychiatric disorders
Common Agitation, confusional state, depression,
anxiety, thinking abnormal, insomnia
Very common -
Nervous system disorders
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
Common Gastrointestinal haemorrhage, peritonitis, ileus,
colitis, gastric ulcer, duodenal ulcer, gastritis,
oesophagitis, stomatitis, constipation,
dyspepsia, flatulence, eructation
Very common -
Hepatobiliary disorders
Common Hepatitis, jaundice, hyperbilirubinaemia
Very common -
Skin and subcutaneous tissue
disorders
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 mycophenolate mofetil daily), 289 (3 g mycophenolate mofetil daily) and 277 (2 g IV /
3 g oral mycophenolate mofetil 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 mycophenolate mofetil 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.
8
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 mycophenolate mofetil. Agranulocytosis (≥ 1/1000 to < 1/100)
and neutropenia have been reported; therefore, regular monitoring of patients taking Myclausen is
advised (see section 4.4). There have been reports of aplastic anaemia and bone marrow depression in
patients treated with mycophenolate mofetil, 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 mycophenolate
mofetil (see section 4.4).
Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have
been observed in patients treated with mycophenolate mofetil. 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 mycophenolate mofetil.
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 mycophenolate mofetil in combination with other immunosuppressants, some of which have been
fatal.
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 Myclausen 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.
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,
9
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 mycophenolate
mofetil is correlated with MPA concentration. The mean bioavailability of oral mycophenolate
mofetil, based on MPA AUC, is 94 % relative to IV mycophenolate mofetil. Food had no effect on the
extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g BID
to renal transplant patients. However, MPA Cmax was decreased by 40 % in the presence of food.
Mycophenolate mofetil is not measurable systemically in plasma following oral administration. 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 Cmax 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 Myclausen does not appear to be
necessary.
10
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 Myclausen 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 posttransplant
period.
Elderly patients (≥ 65 years)
:
Pharmacokinetic behaviour of mycophenolate mofetil in the elderly has not been formally evaluated.
Oral contraceptives
:
The pharmacokinetics of oral contraceptives were unaffected by coadministration of mycophenolate
mofetil (see also section 4.5). A study of the coadministration of mycophenolate mofetil (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 mycophenolate mofetil 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 Cmax) observed in renal transplant patients at the recommended clinical dose of 2 g/day and
1.3-2 times the systemic exposure (AUC or 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
11
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).
6.1 List of excipients
Tablet core:
Microcrystalline cellulose
Povidone (K-30)
Croscarmellose sodium
Magnesium stearate
Tablet coating:
Polyvinyl alcohol (partially hydrolysed)
Titanium dioxide (E171)
Macrogol 3000
Talc
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVC-aluminium blisters
1 carton contains 50 tablets (in blister packs of 10)
1 carton contains 150 tablets (in blister packs of 10)
Not all pack size may be marketed.
6.6 Special precautions for disposal and other handling
12
6.
Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, Myclausen
500 mg film-coated tablets should not be crushed.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Herbert J. Passauer GmbH & Co. KG
Stubenrauchstrasse 33, 14167
Berlin, Germany
Tel.: 0049 (0)30 744 60 12
Fax: 0049 (0)30 744 60 41
8.
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
13
9.
ANNEX II
A.
Manufacturing authorisation holder responsible for batch release
B.
Conditions of the marketing authorisation
14
A.
Manufacturing authorisation holder responsible for batch release
Name and address of the manufacturer responsible for batch release
Lindopharm GmbH
Neustrasse 82
D-40721 Hilden
Germany
B.
Conditions of the marketing authorisation
Conditions or restrictions regarding supply and use imposed on the marketing
authorisation holder
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
Conditions or restrictions with regard to the safe and effective use of the medicinal
product
Not applicable.
Other conditions
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 1.2 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
PSURs
The PSUR submission schedule should follow the PSUR schedule for the reference product.
15
ANNEX III
LABELLING AND PACKAGE LEAFLET
16
A. LABELLING
17
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 500 mg mycophenolate mofetil.
5. METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
Myclausen film-coated tablets should be handled with care.
Do not crush the tablets.
8. EXPIRY DATE
EXP
18
9. SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused product or waste material should be disposed of in accordance with local requirements.
Herbert J. Passauer GmbH & Co. KG
Stubenrauchstrasse 33
14167 Berlin
Germany
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Myclausen 500 mg
19
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 500 mg mycophenolate mofetil.
5. METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
Myclausen film-coated tablets should be handled with care.
Do not crush the tablets.
8. EXPIRY DATE
EXP
20
9. SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused product or waste material should be disposed of in accordance with local requirements.
Herbert J. Passauer GmbH & Co. KG,
Stubenrauchstrasse 33,
14167 Berlin,
Germany
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Myclausen 500 mg
21
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER FOIL
1.
Myclausen 500 mg film-coated tablets
Mycophenolate mofetil
2.
Herbert J. Passauer GmbH & Co. KG
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER<, DONATION AND PRODUCT CODES>
Lot
5.
OTHER
22
B. PACKAGE LEAFLET
23
PACKAGE LEAFLET: INFORMATION FOR THE USER
Myclausen 500 mg film-coated tablets
Mycophenolate mofetil
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them,
even if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this
leaflet, please tell your doctor or pharmacist.
In this leaflet
:
1.
What Myclausen is and what it is used for
3.
How to take Myclausen
4.
Possible side effects
5.
How to store Myclausen
6.
Further information
1.
WHAT MYCLAUSEN IS AND WHAT IT IS USED FOR
Myclausen is a medicine used to suppress immune activity. The active substance of Myclausen is
mycophenolate mofetil.
Myclausen is used to prevent your body from rejecting a transplanted kidney, heart or liver. It is used
together with other medicines with a similar function (i.e. ciclosporin and corticosteroids).
2. BEFORE YOU TAKE MYCLAUSEN
Do not take Myclausen
if you are allergic (hypersensitive) to mycophenolate mofetil, mycophenolic acid or any of the
other ingredients of Myclausen.
if you are breast-feeding.
Take special care with Myclausen
Patients taking Myclausen should be monitored carefully.
You should inform your doctor immediately:
if you experience any evidence of infection (e.g. fever, sore throat), unexpected bruising
and/or bleeding
if you have or ever have had any problems with your digestive system, e.g. stomach ulcers
if you are planning to become pregnant, or if you fall pregnant while taking Myclausen.
Myclausen reduces your body’s defence mechanism. Because of this, there is an increased risk of
skin cancer. Therefore you should limit your exposure to sunlight and UV light by wearing
appropriate protective clothing and using a sunscreen with a high protection factor.
24
2.
Before you take Myclausen
Myclausen should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine
phosphoribosyl-transferase (HGPRT) (an enzyme which acts against conditions such as gout).
Use in children
Children (under 2 years of age)
Myclausen is not recommended for use in children under 2 years of age.
Children and adolescents (aged 2 to 18 years)
No data are available to recommend the use of Myclausen in children and adolescents who have
received a heart transplant or a liver transplant.
Taking other medicines
Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Speak with your doctor if you are taking any of the following:
medicines containing:
azathioprine or other immunosuppressive agents (which are sometimes given to patients
after a transplant operation)
cholestyramine (used to treat patients with high cholesterol)
rifampicin (antibiotic)
antacids
phosphate binders (used in patients with chronic renal failure to reduce the absorption
of phosphate)
vaccines (live vaccines).
Taking Myclausen with food and drink
Taking food and drink has no influence on your treatment with Myclausen.
Pregnancy and breast-feeding
Use of Myclausen during pregnancy may cause miscarriage or damage to your unborn baby (abnormal
development of ears for example).
If you plan to become pregnant, discuss with your doctor alternative medicines to best prevent
rejection of your transplanted organ. In certain situations, you and your doctor may decide that the
benefits of taking Myclausen for your health are more important than the possible risks to your unborn
baby.
If you become pregnant while taking Myclausen, do not stop taking it, but tell your doctor about your
pregnancy as soon as possible.
Do not take Myclausen if you are:
-
Pregnant (unless your doctor clearly tells you)
Tell your doctor straight away if:
-
You think you may be pregnant
-
You plan to start a family in the near future
25
-
Breast-feeding
-
You are breast-feeding
You must always use an effective method of birth control:
-
During your entire treatment with Myclausen
-
For 6 weeks after you stop taking Myclausen
You should talk to your doctor about the most suitable methods for birth control for you based on your
individual situation.
Women who are capable of becoming pregnant must have a negative pregnancy test BEFORE starting
treatment with Myclausen.
You are a woman who is not capable of becoming pregnant if any of the following applies to you:
-
You are post-menopausal, i.e. at least 50 years old and your last period was more than a year
ago (if your periods have stopped because you have had treatment for cancer, then there is still a
chance you could become pregnant).
-
Your fallopian tubes and both ovaries have been removed (bilateral salpingo-oophorectomy).
-
Your uterus has been surgically removed (hysterectomy).
-
You have premature failure of the ovaries, confirmed by a specialist gynaecologist.
-
You have been diagnosed with one of the following rare conditions that some patients are born
with that make pregnancy impossible: the XY genotype, Turner’s syndrome or uterine agenesis.
-
You are a child/teenager who has not started having periods, and cannot become pregnant.
Driving and using machines
Myclausen has not been shown to impair your ability to drive or operate machinery.
3. HOW TO TAKE MYCLAUSEN
Treatment with Myclausen should be initiated and maintained by appropriately qualified
transplant specialists.
Always take Myclausen exactly as your doctor has told you. You should check with your doctor
or pharmacist if you are not sure. The usual way to take Myclausen is as follows:
Kidney Transplant
Adults
The first dose will be given within 72 hours after the transplant operation. The recommended daily
dose is 4 tablets (2 g of the active ingredient) taken as 2 separate doses. This means taking 2 tablets in
the morning then 2 tablets in the evening.
In renal transplant patients with severe chronic renal impairment, outside the immediate post-
transplant period, the recommended daily dose should not be greater than 1 g administered twice a
day.
Children and adolescents (aged 2 to 18 years)
The dose given will vary depending on the size of the child. Your doctor will decide the most
appropriate dose based on body surface area (height and weight). The recommended dose is 600 mg
per m
2
taken twice a day.
26
-
Before you start taking Myclausen
Heart Transplant
Adults
The first dose will be given within 5 days following the transplant operation. The recommended daily
dose is 6 tablets (3 g of the active ingredient) taken as 2 separate doses. This means taking 3 tablets in
the morning then 3 tablets in the evening.
Liver Transplant
Adults
The first dose of oral Myclausen will be given to you at least 4 days after the transplant operation and
when you are able to swallow oral medications. The recommended daily dose is 6 tablets (3 g of the
active ingredient) taken as 2 separate doses. This means taking 3 tablets in the morning and then 3
tablets in the evening.
Method and route of administration
Swallow your tablets whole with a glass of water. Do not break or crush them.
Treatment will continue for as long as you need immunosuppression to prevent you from rejecting
your transplanted organ.
If you take more Myclausen than you should
It is important not to take too many tablets.
If you take more tablets than you have been told to take, or if someone else accidentally takes your
medicine, immediately see a doctor or go to a hospital straight away.
If you forget to take Myclausen
If you forget to take your medicine at any time, take it as soon as you remember, then continue to take
it at the usual times.
Do not take a double dose to make up for a forgotten dose.
If you stop taking Myclausen
Do not stop taking Myclausen because you feel better.
Stopping your treatment with Myclausen may increase the chance of rejection of your
transplanted organ. Do not stop taking your medicine unless your doctor tells you to.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4. POSSIBLE SIDE EFFECTS
Like all medicines, Myclausen can have side effects, although not everybody gets them. Some of the
more usual problems are diarrhoea, fewer white cells and/or red cells in your blood, infection and
vomiting. Your doctor will do regular blood tests to monitor any changes in the number of your blood
cells or changes in the levels of any of the substances carried in your blood, e.g. sugar, fat, cholesterol.
Children may be more likely than adults to have side effects such as diarrhoea, infections, fewer white
cells and fewer red cells in the blood.
Myclausen reduces your body’s own defence mechanisms to stop you rejecting your transplanted
kidney, heart or liver. Consequently your body will not be as good as normal at fighting infections. So
if you are taking Myclausen you may therefore catch more infections than usual, such as infections of
27
the brain, skin, mouth, stomach and intestines, lungs and urinary tract. As can happen in patients
taking this type of medicine, a very small number of Myclausen patients have developed cancer of the
lymphoid tissues and skin.
General unwanted effects affecting your body as a whole could include hypersensitivity (such as
anaphylaxis, angioeodema), fever, lethargy, difficulty in sleeping, pains (such as abdominal, chest,
joint/muscle, pain on passing urine), headache, flu symptoms and swelling.
Very common side effects
likely to affect more than 1 user in 10
Diarrhoea, vomiting, feeling sick
Decrease in normal amounts of different blood cells, which can result in increased risk of
infections, bruising, bleeding, breathlessness and weakness
Bacterial, fungal and viral infections of the digestive and urinary tract, cold sores and shingles.
Common side effects
likely to affect 1 to 10 users in 100
Changes in different laboratory parameters, including increase in liver enzymes, kidney
function changes such as creatinine, potassium, blood sugar, blood lipids, cholesterol,
phosphates, magnesium, calcium and uric acid
Kidney problems with increased levels of urea
Disorders of the digestive system such as constipation, indigestion, flatulence, belching,
inflammation of the mouth, oesophagus, stomach, intestine, liver or pancreas and
gastrointestinal bleeding
Convulsions, increased tension in the muscles, shaking and muscle weakness, joint pain
Sleeplessness, dizziness and headache, tingling or numbness, change of the sence of taste, loss
of appetite, weight loss
Inflammation and infections of the respiratory and gastrointestinal tract, sore throat,
inflammation of the sinuse, runny and itchy nose
Skin cancer or non-cancerous growth of the skin and fungal infections of the skin and vagina
Changes in blood pressure, faster heart beat, dilation of blood vessels
Fluid retention in the body, fever, discomfort, lethargy and weakness
Inflammation of the liver (indicated by dark coloured urine), yellowing of the skin and whites
of the eyes
Unusual bruising or bleeding, including vomiting blood or passing blood in your stools
Uncommon side effects
likely to affect 1 to 10 users in 1,000
Proliferation of the lymphatic tissue, including malignant tumours
Inflammation or infections of the heart and its valves and of the membrane that covers the
brain and spinal cord.
Other side effects that have been reported where frequency has not been established
Hypersensitivity (allergic) reactions
There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients
treated with mycophenolate mofetil in combination with other immunosuppressive agents,
some of which have been fatal.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5. HOW TO STORE MYCLAUSEN
Keep out of the reach and sight of children.
Do not use the tablets after the expiry date stated on the blister and carton after EXP. The expiry date
refers to the last day of that month.
This medicine does not require any special storage conditions.
28
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6. FURTHER INFORMATION
What Myclausen contains
The active substance is mycophenolate mofetil.
Each tablet contains 500 mg mycophenolate mofetil
The other ingredients are:
Tablet core:
Microcrystalline cellulose
Povidone (K-30)
Croscarmellose sodium
Magnesium stearate
Tablet coat:
Polyvinyl alcohol (partially hydrolysed)
Titanium dioxide (E171)
Macrogol 3000
Talc
What Myclausen looks like and contents of the pack
White round film-coated tablets.
Myclausen 500 mg film-coated tablets are available in PVC-aluminium blisters in
pack sizes of 50 or 150 per carton.
Marketing Authorisation Holder
Herbert J. Passauer GmbH & Co. KG
Stubenrauchstrasse 33
14167 Berlin
Germany
Manufacturer
Lindopharm GmbH
Neustrasse 82
40721 Hilden
Germany
This leaflet was last approved in
{MM/YYYY}
Detailed information on this medicinal product is available on the website of the European
Medicines Agency http://www.ema.europa.eu
29
Source: European Medicines Agency
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