Mycophenolate mofetil Teva

1.

NAME OF THE MEDICINAL PRODUCT

Mycophenolate mofetil Teva 250 mg hard capsules

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 250 mg mycophenolate mofetil.

Excipient

For a full list of excipients, see section 6.1

3.

PHARMACEUTICAL FORM

Hard capsule (capsule)

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

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

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Mycophenolate mofetil Teva 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 Mycophenolate mofetil Teva should be initiated and maintained by appropriately

qualified transplant specialists.

Use in renal transplant:

Adults : oral Mycophenolate mofetil Teva 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: the recommended dose of mycophenolate mofetil is 600 mg/m 2

administered orally twice daily (up to a maximum of 2 g daily).Mycophenolate mofetil Teva capsules

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

surface are of 1.25 to 1.5 m 2 may be prescribed Mycophenolate mofetil Teva 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 Mycophenolate mofetil Teva 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 dose recommendations and therefore use in this age group is not

recommended.

2

Use in cardiac transplant :

Adults : oral Mycophenolate mofetil Teva 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 and adolescents : no data are available for paediatric cardiac transplant patients, therefore use

in this patients group is not recommended until further data to support this is available.

Use in hepatic transplant :

Adults : intravenous mycophenolate mofetil should be administered for the first 4 days following

hepatic transplant, with oral Mycophenolate mofetil Teva 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 and adolescents : no data are available for paediatric hepatic transplant patients, therefore use

in this patients group is not recommended until further data to support this is available.

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 x min -1 x 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

Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil. Renal transplant

rejection does not lead to changes in MPA pharmacokinetics; dose reduction or interruption of

Mycophenolate mofetil Teva is not required. There is no basis for Mycophenolate mofetil Teva dose

adjustment following cardiac transplant rejection. No pharmacokinetic data are available during

hepatic transplant rejection.

4.3 Contraindications

Hypersensitivity to the active substance, to mycophenolic acid or any of the excipients.

Mycophenolate mofetil Teva is contraindicated in women who are breast-feeding (see section 4.6).

4.4 Special warnings and precautions for use

Patients receiving immunosuppressive regimens involving combinations of medicinal products,

including Mycophenolate mofetil Teva, 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

3

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 ultra violet (UV) light should be limited by

wearing protective clothing and using a sunscreen with a high protection factor.

Patients receiving Mycophenolate mofetil Teva 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 Mycophenolate mofetil Teva, 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 Mycophenolate mofetil Teva should be monitored for neutropenia, which may be

related to Mycophenolate mofetil Teva itself, concomitant medicinal products, viral infections, or

some combination of these causes. Patients taking Mycophenolate mofetil Teva 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 Mycophenolate mofetil Teva.

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 Mycophenolate

mofetil Teva therapy. Changes to Mycophenolate mofetil Teva 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 Mycophenolate mofetil Teva 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 mycophenolate mofetil has been associated with an increased incidence of digestive system

adverse events, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and

perforation, Mycophenolate mofetil Teva should be administered with caution in patients with active

serious digestive system disease.

Mycophenolate mofetil Teva is an inosine monophosphate dehydrogenase (IMPDH) 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 Mycophenolate mofetil Teva should not be administered concomitantly with

azathioprine because such concomitant administration has not been studied.

In view of the significant reduction in the AUC (area under the curve) of MPA by cholestyramine,

caution should be used in the concomitant administration of Mycophenolate mofetil Teva with

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

efficacy of Mycophenolate mofetil Teva.

The risk-benefit ratio of mycophenolate mofetil in combination with tacrolimus or sirolimus has not

been established (see also section 4.5).

4

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 1.5 g of mycophenolate mofetil to normal

healthy subjects pre-treated with 4 g three times a day (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 mycophenolate mofetil.

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 mycophenolate mofetil.

Ciclosporin A : ciclosporin A (CsA) pharmacokinetics were 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 mofetil and intravenous ganciclovir and the known effects of renal impairment on the

pharmacokinetics of mycophenolate mofetil (see section 4.2) and ganciclovir, it is anticipated that co-

administration of these agents (which compete for mechanisms of renal tubular secretion) will result in

increases in MPAG and ganciclovir concentration No substantial alteration of MPA pharmacokinetics

is anticipated and mycophenolate mofetil dose adjustment is not required. In patients with renal

impairment in which Mycophenolate mofetil Teva and ganciclovir or its prodrugs, e.g.valganciclovir,

are co-administered the dose recommendations for ganciclovir should be observed and patients

monitored carefully.

Oral contraceptives : the pharmacokinetics and pharmacodynamics of oral contraceptives were

unaffected by co-administration 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 (AUC 0-12h ) of 18% to 70%. It is

recommended to monitor MPA exposure levels and to adjust Mycophenolate mofetil Teva 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 C max and AUC 0-12 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 Mycophenolate mofetil

Teva 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.

5

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 mycophenolate mofetil.

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 Mycophenolate mofetil Teva 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 liver transplant recipients initiated on mycophenolate mofetil and tacrolimus, the AUC

and C max of MPA, the active metabolite of mycophenolate mofetil, were not significantly affected by

trough tacrolimus level. In renal transplant patients, the tacrolimus concentration did not appear to be

altered by mycophenolate mofetil. However, in hepatic transplant patients, there was an increase of

approximately 20 % in tacrolimus AUC when multiple doses of mycophenolate mofetil (1.5 g taken

twice a day [BID] ,morning and evening]) were administered to patients taking tacrolimus (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 Mycophenolate mofetil Teva therapy should not be initiated until a negative

pregnancy test has been obtained. Effective contraception must be used before beginning

mycophenolate mofetil 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 Mycophenolate mofetil Teva is not recommended during pregnancy and should be reserved

for cases where no more suitable alternative treatment is available. Mycophenolate mofetil Teva

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 mycophenolate mofetil 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, Mycophenolate mofetil Teva is

contraindicated in breast-feeding mothers (see section 4.3).

6

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

pharmacodynamics 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 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

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, cytomegalovirus (CMV) viraemia/syndrome and Herpes simplex. The

proportion of patients with CMV viraemia/syndrome was 13.5%.

Children and adolescents :

The type and frequency of adverse reactions in a clinical study, which recruited 92 paediatric patients

aged 2 to 18 years who where given 600 mg/m 2 mycophenolate mofetil orally twice daily, were

generally similar to those observed in adult patients given 1 g mycophenolate mofetil twice daily.

However, the following treatment-related adverse events were more frequent in the 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 Mycophenolate mofetil Teva 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.

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

7

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

decreasing seriousness.

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

System organ

class

Frequency

Adverse drug reactions

Investigations

Very common

-

Common

Hepatic enzyme increased, blood creatinine increased,

blood lactate dehydrogenase increased, blood urea

increased, blood alkaline phosphatase increased, weight

decreased

Cardiac

disorders

Very common

-

Common

Tachycardia

Blood and

lymphatic

system

disorders

Very common

Leukopenia, thrombocytopenia, anaemia

Common

Pancytopenia, leukocytosis

Nervous system

disorders

Very common

-

Common

Convulsion, hypertonia, tremor, somnolence, myasthenic

syndrome, dizziness, headache, paraesthesia, dysgeusia

Respiratory,

thoracic and

mediastinal

disorders

Very common

-

Common

Pleural effusion, dyspnoea, cough

Gastrointestinal

disorders

Very common

Vomiting, abdominal pain, diarrhoea, nausea

Common

Gastrointestinal haemorrhage, peritonitis, ileus, colitis,

gastric ulcer, duodenal ulcer, gastritis, oesophagitis,

stomatitis, constipation, dyspepsia, flatulence, eructation

Renal and

urinary

disorders

Very common

-

Common

Renal impairment

Skin and

subcutaneous

tissue disorders

Very common

-

Common

Skin hypertrophy, rash, acne, alopecia

Musculoskeletal Very common

-

8

and connective

tissue disorders

Common

Arthralgia

System organ

class

Frequency

Adverse drug reactions

Metabolism

and nutrition

disorders

Very common

-

Common

Acidosis, hyperkalaemia, hypokalaemia, hyperglycaemia,

hypomagnesaemia, hypocalcaemia, hypercholesterolaemia,

hyperlipidaemia, hypophosphataemia, hyperuricaemia, gout,

anorexia

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 and

unspecified

(incl cysts and

polyps)

Very common

-

Common

Skin cancer, benign neoplasm of skin

Vascular

disorders

Very common

-

Common

Hypotension, hypertension, vasodilatation

General

disorders and

administration

site conditions

Very common

-

Common

Oedema, pyrexia, chills, pain, malaise, asthenia

Hepatobiliary

disorders

Very common

-

Common

Hepatitis, jaundice, hyperbilirubinaemia

Psychiatric

disorders

Very common

-

Common

Agitation, confusional state, depression, anxiety, thinking

abnormal, insomnia

9

Note: 501 (2 g mycophenolate mofetil daily), 289 (3 g mycophenolate mofetil daily) and 277 (2 g

intravenous / 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.

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

(common), pancreatitis, (common) 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 Teva. Agranulocytosis (uncommon) and neutropenia have been reported; therefore regular

monitoring of patients taking Mycophenolate mofetil Teva 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 Teva.

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.

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 Mycophenolate mofetil Teva 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).

10

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: immunosuppressive agents ATC code: LO4A A06

Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid (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 mycophenolate

mofetil is correlated with MPA concentration. The mean bioavailability of oral mycophenolate

mofetil, based on MPA AUC, is 94% relative to intravenous 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 x min -1 x 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

11

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 Mycophenolate mofetil Teva 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 :

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 mycophenolate mofetil 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 mycophenolate mofetil in the elderly has not been formally evaluated.

Oral contraceptives :

The pharmacokinetics of oral contraceptives were unaffected by co-administration of mycophenolate

mofetil (see also section 4.5). A study of the co-administration 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 immunosuppressants) 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 luteinizing hormone (LH), follicle-stimulating hormone (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 as 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 pharmacodynamics 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 x kg -1 x 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,

12

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 x kg -1 x day -1 (including anophthalmia, agnathia, and hydrocephaly) and in rabbits at 90 mg x kg -1 x 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 are 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 doses.

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

Capsule content:

Pregelatinised starch (maize)

Povidone K-30

Croscarmellose sodium

Magnesium stearate

Capsule shell:

Cap:

Indigo carmine (E132)

Titanium dioxide (E171)

Gelatin

Body:

Red iron oxide (E172)

Yellow iron oxide (E172)

Titanium dioxide (E171)

Gelatin

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

Formatted: Portuguese

(Portugal)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

13

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

Transparent PVC/PVdC – aluminium blisters in pack sizes of 100 or 300 or 100 x 1 capsules per

carton.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbit,

Mycophenolate mofetil Teva capsules should not be opened or crushed. Inhalation or direct contact

with skin or mucous membranes of the powder contained in the capsules should be avoided. If such

contact occurs, soap and water should be used to wash thoroughly and the eyes should be rinsed with

plain water.

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

7.

MARKETING AUTHORISATION HOLDER

Teva Pharma B.V.

Computerweg 10

3542 DR Utrecht

The Netherlands

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/07/439/001 (100 capsules)

EU/1/07/439/002 (300 capsules)

EU/1/07/439/006 (100 x 1 capsules)

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 February 2008

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

14

1.

NAME OF THE MEDICINAL PRODUCT

Mycophenolate mofetil Teva 500 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 500 mg mycophenolate mofetil

For a full list of excipients, see section 6.1

3.

PHARMACEUTICAL FORM

Film-coated tablet (tablet)

Pale purple, oval shaped film-coated tablet, debossed with "M500" on one side and plain on the other

side.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Mycophenolate mofetil Teva 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 Mycophenolate mofetil Teva should be initiated and maintained by appropriately

qualified transplant specialists.

Use in renal transplant:

Adults : oral Mycophenolate mofetil Teva 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 : the recommended dose of mycophenolate mofetil is 600 mg/m 2

administered orally twice daily (up to a maximum of 2 g daily). Mycophenolate mofetil Teva 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 48) 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 dose recommendations and therefore use in this age group is not

recommended.

Use in cardiac transplant :

Adults : oral Mycophenolate mofetil Teva 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).

15

Children and adolescents : no data are available for paediatric cardiac transplant patients, therefore use

in this patients group is not recommended until further data to support this is available.

Use in hepatic transplant :

Adults : intravenous mycophenolate mofetil should be administered for the first 4 days following

hepatic transplant, with oral Mycophenolate mofetil Teva 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 and adolescents : no data are available for paediatric hepatic transplant patients, therefore use

in this patient group is not recommended until further data to support this is available.

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 x min -1 x 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

Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil. Renal transplant

rejection does not lead to changes in MPA pharmacokinetics; dose reduction or interruption of

Mycophenolate mofetil Teva is not required. There is no basis for Mycophenolate mofetil Teva dose

adjustment following cardiac transplant rejection. No pharmacokinetic data are available during

hepatic transplant rejection.

4.3 Contraindications

Hypersensitivity reactions to the active substance, to mycophenolic acid or any of the excipients.

Mycophenolate mofetil Teva is contraindicated in women who are breast-feeding (see section 4.6).

4.4 Special warnings and precautions for use

Patients receiving immunosuppressive regimens involving combinations of medicinal products,

including Mycophenolate mofetil Teva, 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 ultra-violet (UV) light should be limited by

wearing protective clothing and using a sunscreen with a high protection factor.

16

Patients receiving Mycophenolate mofetil Teva 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.