Mykofenolatmofetil Actavis 250 mg Kapsel, hård

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

28-09-2018

Produktens egenskaper Produktens egenskaper (SPC)

27-04-2018

Aktiva substanser:
mykofenolatmofetil
Tillgänglig från:
Ebb Medical AB
ATC-kod:
L04AA06
INN (International namn):
mycophenolate mofetil
Dos:
250 mg
Läkemedelsform:
Kapsel, hård
Sammansättning:
propylenglykol Hjälpämne; natriumlaurilsulfat Hjälpämne; mykofenolatmofetil 250 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 100 kapslar
Bemyndigande status:
Avregistrerad
Godkännandenummer:
54460
Tillstånd datum:
2016-10-19

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

14-09-2020

Produktens egenskaper Produktens egenskaper - engelska

04-05-2021

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

13-02-2013

Läs hela dokumentet

Mycophenolate mofetil, SE/H/0790/001, 20.01.20

Package leaflet: Information for the patient

Mykofenolatmofetil Actavis 250 mg capsules, hard

mycophenolate mofetil

Read all of this leaflet carefully before you start taking this medicine because it contains important

information for you.

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 only. Do not pass it on to others. It may harm them, even if

their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. See section 4.

What is in this leaflet

What Mykofenolatmofetil Actavis is and what it is used for

What you need to know before you take Mykofenolatmofetil Actavis

How to take Mykofenolatmofetil Actavis

Possible side effects

How to store Mykofenolatmofetil Actavis

Contents of the pack and other information

1.

What Mykofenolatmofetil Actavis is and what it is used for

Mykofenolatmofetil Actavis contains mycophenolate mofetil.

This belongs to a group of medicines called “immunosuppressants”.

Mykofenolatmofetil Actavis is used to prevent your body rejecting a transplanted organ.

A kidney, heart or liver.

Mykofenolatmofetil Actavis should be used together with other medicines:

Ciclosporin and corticosteroids.

2.

What you need to know before you take Mykofenolatmofetil Actavis

WARNING

Mycophenolate causes birth defects and miscarriage. If you are a woman who could become pregnant, you

must provide a negative pregnancy test before starting treatment and must follow the contraception advice

given to you by your doctor.

Your doctor will speak to you and give you written information, particularly on the effects of mycophenolate

on unborn babies. Read the information carefully and follow the instructions.

If you do not fully understand these instructions, please ask your doctor to explain them again before you

take mycophenolate. See also further information in this section under “Warnings and precautions” and

“Pregnancy, contraception and breast-feeding”.

Do not take Mykofenolatmofetil Actavis

if you are allergic to mycophenolate mofetil, mycophenolic acid or any of the other ingredients of this

medicine (listed in section 6).

if you are a woman who could be pregnant and you have not provided a negative pregnancy test before

your first prescription, as mycophenolate causes birth defects and miscarriage.

if you are pregnant or planning to become pregnant or think you may be pregnant.

if you are not using effective contraception (see Pregnancy, contraception and breast-feeding).

Mycophenolate mofetil, SE/H/0790/001, 20.01.20

if you are breast-feeding.

Do not take this medicine if any of the above applies to you. If you are not sure, talk to your doctor or

pharmacist before taking Mykofenolatmofetil Actavis.

Warnings and precautions

Talk to your doctor before taking Mykofenolatmofetil Actavis:

if you have a sign of infection such as a fever or sore throat

if you have any unexpected bruising or bleeding.

if you have ever had a problem with your digestive system such as a stomach ulcer.

if you are planning to become pregnant or if you get pregnant while you or your partner are taking

Mykofenolatmofetil Actavis.

if you have a rare hereditary deficiency of the enzyme hypoxanthine-guanine phosphoribosyl-

transferase (HGPRT) such as Lesch-Nyhan or Kelley-Seegmiller syndrome, as Mykofenolatmofetil

Actavis should be avoided.

If any of the above apply to you (or you are not sure), talk to your doctor straight away before taking

Mykofenolatmofetil Actavis.

The effect of sunlight

Mykofenolatmofetil Actavis reduces your body’s defences. As a result, there is an increased risk of skin

cancer. Limit the amount of sunlight and UV light you get. Do this by:

wearing protective clothing which also covers your head, neck, arms and legs

using a sunscreen with a high protection factor.

Other medicines and Mykofenolatmofetil Actavis

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This

is because Mykofenolatmofetil Actavis can affect the way some other medicines work. Also other medicines

can affect the way Mykofenolatmofetil Actavis works.

In particular, tell your doctor or pharmacist if you are taking any of the following medicines before you start

Mykofenolatmofetil Actavis:

azathioprine or other medicines which suppress your immune system – given after a transplant

operation

aciclovir – used for treatment and prevention (in immunosuppressed individuals) of viral infections,

such as cold sores, genital herpes, shingles and chickenpox

cholestyramine – used to treat high cholesterol

rifampicin – an antibiotic used to prevent and treat infections such as tuberculosis (TB)

antacids, or proton pump inhibitors – used for acid problems in your stomach such as indigestion

phosphate binders – used by people with chronic kidney failure to reduce how much phosphate gets

absorbed into their blood

medicines that interfere with liver circulation

ganciclovir (used for treatment and prevention of CMV (cytomegalovirus) infections), especially if you

also have kidney problems

norfloxicin and metronidazole in combination

antibiotics – used to treat bacterial infections

isavuconazole – used to treat fungal infections

telmisartan – used to treat high blood pressure.

Vaccines

If you need to have a vaccine (a live vaccine) while taking Mykofenolatmofetil Actavis, talk to your doctor

or pharmacist first. Your doctor will have to advise you on what vaccines you can have.

You must not donate blood during treatment with Mykofenolatmofetil Actavis and for at least 6 weeks after

stopping treatment. Men must not donate semen during treatment with Mykofenolatmofetil Actavis and for

at least 90 days after stopping treatment.

Mykofenolatmofetil Actavis with food and drink

Mycophenolate mofetil, SE/H/0790/001, 20.01.20

Taking food and drink has no effect on your treatment with Mykofenolatmofetil Actavis.

Pregnancy, contraception and breast-feeding

Contraception in women taking Mykofenolatmofetil Actavis

If you are a woman who could become pregnant you must use an effective method of contraception with

Mykofenolatmofetil Actavis. This includes:

Before you start taking Mykofenolatmofetil Actavis

During your entire treatment with Mykofenolatmofetil Actavis

For 6 weeks after you stop taking Mykofenolatmofetil Actavis.

Talk to your doctor about the most suitable contraception for you. This will depend on your individual

situation. Two forms of contraception are preferable as this will reduce the risk of unintended pregnancy.

Contact your doctor as soon as possible, if you think your contraception may not have been effective

or if you have forgotten to take your contraceptive pill.

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 by surgery (bilateral salpingo-oophorectomy)

Your womb (uterus) has been removed by surgery (hysterectomy)

Your ovaries no longer work (premature ovarian failure, which has been confirmed by a specialist

gynaecologist)

You were born with one of the following rare conditions that make pregnancy impossible: the XY

genotype, Turner’s syndrome or uterine agenesis

You are a child or teenager who has not started having periods.

Contraception in men taking Mykofenolatmofetil Actavis

The available evidence does not indicate an increased risk of malformations or miscarriage if the father takes

mycophenolate. However, a risk cannot be completely excluded. As a precaution you or your female partner

are recommended to use reliable contraception during treatment and for 90 days after you stop taking

Mykofenolatmofetil Actavis.

If you are planning to have a child, talk to your doctor about the potential risks and alternative therapies.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your

doctor or pharmacist for advice before taking this medicine. Your doctor will talk to you about the risks in

case of pregnancy and the alternatives you can take to prevent rejection of your transplant organ if:

You plan to become pregnant.

You miss or think you have missed a period, or you have unusual menstrual bleeding, or suspect you are

pregnant.

You have sex without using an effective method of contraception.

If you do become pregnant during the treatment with mycophenolate, you must inform your doctor

immediately. However, keep taking Mykofenolatmofetil Actavis until you see him or her.

Pregnancy

Mycophenolate causes a very high frequency of miscarriage (50%) and of severe birth defects (23-27%) in

the unborn baby. Birth defects which have been reported include anomalies of ears, of eyes, of face (cleft

lip/palate), of development of fingers, of heart, oesophagus (tube that connects the throat with the stomach),

kidneys and nervous system (for example spina bifida (where the bones of the spine are not properly

developed)).Your baby may be affected by one or more of these.

Mycophenolate mofetil, SE/H/0790/001, 20.01.20

If you are a woman who could become pregnant, you must provide a negative pregnancy test before starting

treatment and must follow the contraception advice given to you by your doctor. Your doctor may request

more than one test to ensure you are not pregnant before starting treatment.

Breast-feeding

Do not take Mykofenolatmofetil Actavis if you are breast-feeding. This is because small amounts of the

medicine can pass into the mother’s milk.

Driving and using machines

Mykofenolatmofetil Actavis has a moderate influence on your ability to drive or use any tools or machines.

If you feel drowsy, numb or confused, talk to your doctor or nurse and do not drive or use any tools or

machines until you feel better.

Mykofenolatmofetil Actavis contains sodium

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

3.

How to take Mykofenolatmofetil Actavis

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you

are not sure.

How much to take

The amount you take depends on the type of transplant you have had. The recommended doses are shown

below. Treatment will continue for as long as you need to prevent you from rejecting your transplant organ.

Kidney transplant

Adults

The first dose is given within 3 days of the transplant operation.

The daily dose is 8 capsules (2 g of the medicine) taken as 2 separate doses.

Take 4 capsules in the morning and then 4 capsules in the evening.

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 your child´s height and weight (body

surface area – measured as square metres or “m

2”

). The recommended dose is 600 mg/m

taken twice a

day.

Mykofenolatmofetil Actavis is not recommended for kidney transplant patients under 2 years of age.

Heart transplant

Adults

The first dose is given within 5 days of the transplant operation.

The daily dose is 12 capsules (3 g of the medicine) taken as 2 separate doses.

Take 6 capsules in the morning and then 6 capsules in the evening.

Children and adolescents

There is no information for the use of Mykofenolatmofetil Actavis in children with a heart transplant.

Liver transplant

Adults

The first dose of oral Mykofenolatmofetil Actavis will be given to you at least 4 days after the

transplant operation and when you are able to swallow oral medicines.

Mycophenolate mofetil, SE/H/0790/001, 20.01.20

The daily dose is 12 capsules (3 g of the medicine) taken as 2 separate doses.

Take 6 capsules in the morning and then 6 capsules in the evening.

Children and adolescents

There is no information for the use of Mykofenolatmofetil Actavis in children with a liver transplant.

Taking the medicine

Swallow your capsules whole with a glass of water.

Do not break or crush them.

Do not take any capsules that have broken open or split.

Take care not to let any powder from inside a broken capsule get into your eyes or mouth.

If this happens, rinse with plenty of plain water.

Take care not to let any powder from inside a broken capsule get onto your skin.

If this happens, wash the area thoroughly with soap and water.

If you take more Mykofenolatmofetil Actavis than you should

If you take more Mykofenolatmofetil Actavis than you should, talk to a doctor or go to a hospital straight

away. Also do this if someone else accidentally takes your medicine. Take the medicine pack with you.

If you forget to take Mykofenolatmofetil Actavis

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 Mykofenolatmofetil Actavis

Do not stop taking Mykofenolatmofetil Actavis unless your doctor tells you to. If you stop your treatment

you may increase the chance of rejection of your transplanted organ.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Talk to a doctor straight away if you notice any of the following serious side effects – you may need

urgent medical treatment:

you have a sign of infection such as a fever or sore throat

you have any unexpected bruising or bleeding

you have a rash, swelling of your face, lips, tongue or throat, with difficulty breathing - you may be

having a serious allergic reaction to the medicine (such as anaphylaxis, angioeodema).

Usual problems

Some of the more usual problems are diarrhoea, fewer white cells or red cells in your blood, infection and

vomiting. Your doctor will do regular blood tests to check for any changes in:

the number of your blood cells or signs of infections

Children and adolescents

Children may be more likely than adults to have some side effects. These include diarrhoea, infections, fewer

white cells and fewer red cells in the blood.

Elderly patients

Elderly patients (≥65 years) may generally be at an increased risk of side effects. Elderly patients receiving

Mykofenolatmofetil Actavis in combination with other immunosuppressive medicines, may also be at a

Mycophenolate mofetil, SE/H/0790/001, 20.01.20

greater risk for certain infections, as well as gut bleeding and fluid on the lungs compared to younger

patients.

Fighting infections

Mykofenolatmofetil Actavis reduces your body’s defences. This is to stop you rejecting your transplant. As a

result, your body will not be as good as normal at fighting infections. This means you may catch more

infections than usual. This includes infections of the brain, skin, mouth, stomach and gut, lungs and urinary

system.

Lymph and skin cancer

As can happen in patients taking this type of medicine (immunosuppressants), a very small number of

Mykofenolatmofetil Actavis patients have developed cancer of the lymphoid tissues and skin.

General unwanted effects

You may get general side effects affecting your body as a whole. These include serious allergic reactions

(such as anaphylaxis, angioeodema), fever, feeling very tired, difficulty sleeping, pains (such as stomach,

chest, joint or muscle), headache, flu symptoms and swelling.

Other unwanted effects may include:

Skin problems

such as:

acne, cold sores, shingles, skin growth, hair loss, rash, itching.

Urinary problems

such as:

blood in the urine.

Digestive system and mouth problems

such as:

swelling of the gums, taste disturbance and mouth ulcers

inflammation of the food pipe, pancreas, colon or stomach

gastrointestinal disorders including bleeding and ulcers, liver problems

diarrhea, constipation, feeling sick (nausea), indigestion, loss of appetite, flatulence and

burping/belching.

Nervous system problems

such as:

feeling dizzy, drowsy or numb

tremor, muscle spasms, convulsions

feeling anxious or depressed, changes in your mood or thoughts.

Heart and blood vessel problems

such as:

change in blood pressure, accelerated heart beat, widening of blood vessels.

Lung problems

such as:

pneumonia, bronchitis

shortness of breath, cough, which can be due to bronchiectasis (a condition in which the lung airways

are abnormally dilated) or pulmonary fibrosis (scarring of the lung). Talk to your doctor if you develop

a persistent cough or breathlessness

fluid on the lungs or inside the chest

sinus problems.

Other problems

such as:

weight loss, gout, high blood sugar, bleeding, bruising.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not

listed in this leaflet. You can also report side effects directly via the national reporting system listed in

Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Mycophenolate mofetil, SE/H/0790/001, 20.01.20

5.

How to store Mykofenolatmofetil Actavis

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry

date refers to the last day of that month.

Do not store above 30°C.

Store in the original package in order to protect from moisture

Do not throw away any medicines via wastewater <or household waste>. Ask your pharmacist how to throw

away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Mykofenolatmofetil Actavis contains

The active substance is mycophenolate mofetil.

Each capsule contains 250 mg mycophenolate mofetil.

The other ingredients are:

Capsule: microcrystalline cellulose, povidone (K-90), hydroxypropyl cellulose, croscarmellose sodium,

talc, magnesium stearate.

Capsule shell: gelatine, sodium laurylsulfate, titanium dioxide (E171), iron oxide red (E172), iron oxide

yellow (E172), indigo carmine aluminium lake (E132).

Ink: shellac, iron oxide black (E172).

What Mykofenolatmofetil Actavis looks like and contents of the pack

Light blue/peach, size 1 hard capsule, 18.9 mm ± 0.5 mm in length, imprinted with MMF on cap and 250 on

body, containing white to off-white powder.

PVC/PVdC-Aluminium blister pack

Pack sizes: 100 and 300 capsules

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

[To be completed nationally]

This leaflet was last revised in <{MM/YYYY}>

2020-09-03

Läs hela dokumentet

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Mykofenolatmofetil Actavis 250 mg capsules, hard

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 250 mg mycophenolate mofetil.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Capsules, hard

Light blue/peach, size 1 hard capsule, 18.9 mm ± 0.5 mm in length, imprinted with MMF on cap and 250 on

body, containing white to off-white powder.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Mykofenolatmofetil Actavis 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 Mykofenolatmofetil Actavis should be initiated and maintained by appropriately qualified

transplant specialists.

Posology

Use in renal transplant

Adults

Oral mycophenolate mofetil should be initiated within 72 hours following transplantation. The recommended

dose in renal transplant patients is 1 g administered twice daily (2 g daily dose).

Paediatric population aged 2 to 18 years

The recommended dose of mycophenolate mofetil is 600 mg/m

administered orally twice daily (up to a

maximum of 2 g daily). Mykofenolatmofetil Actavis capsules should only be prescribed to patients with a

body surface area of at least 1.25 m

. Patients with a body surface area of 1.25 to 1.5 m

may be prescribed

Mykofenolatmofetil Actavis 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

may be prescribed Mykofenolatmofetil Actavis capsules at a dose of 1 g

twice daily (2 g daily dose). As some adverse reactions occur with greater frequency in this age group (see

section 4.8) compared with adults, temporary dose reduction or interruption may be required; these will need

to take into account relevant clinical factors including severity of reaction.

Paediatric population < 2 years

There are limited safety and efficacy data in children below the age of 2 years. These are insufficient to make

dosage recommendations and therefore use in this age group is not recommended.

Use in cardiac transplant

Adults

Oral mycophenolate mofetil should be initiated within 5 days following transplantation. The recommended

dose in cardiac transplant patients is 1.5 g administered twice daily (3 g daily dose).

Paediatric population

No data are available for paediatric cardiac transplant patients.

Use in hepatic transplant

Adults

IV mycophenolate mofetil should be administered for the first 4 days following hepatic transplant, with oral

mycophenolate mofetil initiated as soon after this as it can be tolerated. The recommended oral dose in

hepatic transplant patients is 1.5 g administered twice daily (3 g daily dose).

Paediatric population

No data are available for paediatric hepatic transplant patients.

Use in special populations

Elderly

The recommended dose of 1 g administered twice a day for renal transplant patients and 1.5 g twice a day for

cardiac or hepatic transplant patients is appropriate for the elderly.

Renal impairment

In renal transplant patients with severe chronic renal impairment (glomerular filtration rate < 25

mL/min/1.73 m

), outside the immediate post-transplant period, doses greater than 1 g administered twice a

day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in

patients experiencing delayed renal graft function post-operatively (see section 5.2). No data are available for

cardiac or hepatic transplant patients with severe chronic renal impairment.

Severe hepatic impairment

No dose adjustments are needed for renal transplant patients with severe hepatic parenchymal disease. No

data are available for cardiac transplant patients with severe hepatic parenchymal disease.

Treatment during rejection episodes

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

not lead to changes in MPA pharmacokinetics; dosage reduction or interruption of Mykofenolatmofetil

Actavis is not required. There is no basis for Mykofenolatmofetil Actavis dose adjustment following cardiac

transplant rejection. No pharmacokinetic data are available during hepatic transplant rejection.

Paediatric population

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

Method of administration

Oral administration

Precautions to be taken before handling or administering the medicinal product

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

Actavis capsules should not be opened or crushed to avoid inhalation or direct contact with skin or mucous

membranes of the powder contained in mycophenolate mofetil capsules. If such contact occurs, wash

thoroughly with soap and water; rinse eyes with plain water.

4.3

Contraindications

Mykofenolatmofetil Actavis should not be given to patients with hypersensitivity to mycophenolate mofetil,

mycophenolic acid or to any of the excipients listed in section 6.1. Hypersensitivity reactions to

mycophenolate mofetil have been observed (see section 4.8).

Mykofenolatmofetil Actavis should not be given to women of childbearing potential who are not using

highly effective contraception (see section 4.6).

Mykofenolatmofetil Actavis treatment should not be initiated in women of child bearing potential without

providing a pregnancy test result to rule out unintended use in pregnancy (see section 4.6).

Mykofenolatmofetil Actavis should not be used in pregnancy unless there is no suitable alternative treatment

to prevent transplant rejection (see section 4.6).

Mykofenolatmofetil Actavis should not be given to women who are breastfeeding (see section 4.6).

4.4

Special warnings and precautions for use

Neoplasms

Patients receiving immunosuppressive regimens involving combinations of medicinal products, including

mycophenolate mofetil, are at increased risk of developing lymphomas and other malignancies, particularly

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

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

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

sunscreen with a high protection factor.

Infections

Patients treated with immunosuppressants, including mycophenolate mofetil, are at increased risk for

opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis (see section 4.8).

Such infections include latent viral reactivation, such as hepatitis B or hepatitis C reactivation and infections

caused by polyomaviruses (BK virus associated nephropathy, JC virus associated progressive multifocal

leukoencephalopathy PML). Cases of hepatitis due to reactivation of hepatitis B or hepatitis C have been

reported in carrier patients treated with immunosuppressants. These infections are often related to a high

total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider

in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological

symptoms.

There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients

receiving mycophenolate mofetil in combination with other immunosuppressants. In some of these cases

switching mycophenolate mofetil to an alternative immunosuppressant resulted in serum IgG levels returning

to normal. Patients on mycophenolate mofetil who develop recurrent infections should have their serum

immunoglobulins measured. In cases of sustained, clinically relevant hypogammaglobulinaemia, appropriate

clinical action should be considered taking into account the potent cytostatic effects that mycophenolic acid

has on T- and B-lymphocytes.

There have been published reports of bronchiectasis in adults and children who received mycophenolate

mofetil in combination with other immunosuppressants. In some of these cases switching mycophenolate

mofetil to another immunosuppressant resulted in improvement in respiratory symptoms. The risk of

bronchiectasis may be linked to hypogammaglobulinaemia or to a direct effect on the lung. There have also

been isolated reports of interstitial lung disease and pulmonary fibrosis, some of which were fatal (see

section 4.8). It is recommended that patients who develop persistent pulmonary symptoms, such as cough

and dyspnoea, are investigated.

Blood and immune system

Patients receiving Mykofenolatmofetil Actavis should be monitored for neutropenia, which may be related to

mycophenolate mofetil itself, concomitant medications, viral infections, or some combination of these

causes. Patients taking Mykofenolatmofetil Actavis 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

/μl), it may be appropriate to interrupt or

discontinue Mykofenolatmofetil Actavis.

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 therapy. Changes

to mycophenolate mofetil therapy should only be undertaken under appropriate supervision in transplant

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

Patients receiving Mykofenolatmofetil Actavis should be instructed to report immediately any evidence of

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

Patients should be advised that during treatment with Mykofenolatmofetil Actavis, vaccinations may be less

effective, and the use of live attenuated vaccines should be avoided (see section 4.5). Influenza vaccination

may be of value. Prescribers should refer to national guidelines for influenza vaccination.

Gastro-intestinal

Mycophenolate mofetil has been associated with an increased incidence of digestive system adverse events,

including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation.

Mykofenolatmofetil Actavis should be administered with caution in patients with active serious digestive

system disease.

Mycophenolate mofetil is an IMPDH (inosine monophosphate dehydrogenase) inhibitor. Therefore, it should

be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase

(HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.

Interactions

Caution should be exercised when switching combination therapy from regimens containing

immunosuppressants, which interfere with MPA enterohepatic recirculation, e.g. ciclosporin, to others

devoid of this effect, e.g. tacrolimus, sirolimus, belatacept, or vice versa, as this might result in changes of

MPA exposure. Drugs which interfere with MPA’s enterohepatic cycle (e.g. cholestyramine, antibiotics)

should be used with caution due to their potential to reduce the plasma level and efficacy of mycophenolate

mofetil (see also section 4.5). Therapeutic drug monitoring of MPA may be appropriate when switching

combination therapy (e.g. from ciclosporin to tacrolimus or vice versa) or to ensure adequate

immunosuppression in patients with high immunological risk (e.g. risk of rejection, treatment with

antibiotics, addition or removal of an interacting medication).

It is recommended that Mykofenolatmofetil Actavis should not be administered concomitantly with

azathioprine because such concomitant administration has not been studied.

The risk/benefit ratio of mycophenolate mofetil in combination with sirolimus has not been established (see

also section 4.5).

Special populations

Elderly patients may be at an increased risk of adverse events such as certain infections (including

cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema,

compared with younger individuals (see section 4.8).

Teratogenic effects

Mycophenolate is a powerful human teratogen. Spontaneous abortion (rate of 45% to 49%) and congenital

malformations (estimated rate of 23% to 27%) have been reported following MMF exposure during

pregnancy. Therefore, mycophenolate mofetil is contraindicated in pregnancy unless there are no suitable

alternative treatments to prevent transplant rejection. Female patients of childbearing potential should be

made aware of the risks and follow the recommendations provided in section 4.6 (e.g. contraceptive

methods, pregnancy testing) prior to, during, and after therapy with mycophenolate mofetil. Physicians

should ensure that women taking mycophenolate understand the risk of harm to the baby, the need for

effective contraception, and the need to immediately consult their physician if there is a possibility of

pregnancy.

Contraception (see section 4.6)

Because of robust clinical evidence showing a high risk of abortion and congenital malformations when

mycophenolate mofetil is used in pregnancy every effort to avoid pregnancy during treatment should be

taken. Therefore, women with childbearing potential must use at least one form of reliable contraception (see

section 4.3) before starting mycophenolate mofetil therapy, during therapy, and for six weeks after stopping

the therapy, unless abstinence is the chosen method of contraception. Two complementary forms of

contraception simultaneously are preferred to minimise the potential for contraceptive failure and unintended

pregnancy.

For contraception advice for men see section 4.6.

Educational materials

In order to assist patients in avoiding foetal exposure to mycophenolate and to provide additional important

safety information, the Marketing Authorisation holder will provide educational materials to healthcare

professionals. The educational materials will reinforce the warnings about the teratogenicity of

mycophenolate, provide advice on contraception before therapy is started and guidance on the need for

pregnancy testing. Full patient information about the teratogenic risk and the pregnancy prevention measures

should be given by the physician to women of childbearing potential and, as appropriate, to male patients.

Additional precautions

Patients should not donate blood during therapy or for at least 6 weeks following discontinuation of

mycophenolate. Men should not donate semen during therapy or for 90 days following discontinuation of

mycophenolate.

Excipient

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

‘sodium-free’.

4.5

Interaction with other medicinal products and other forms of interaction

Aciclovir

Higher aciclovir plasma concentrations were observed when mycophenolate mofetil was administered with

aciclovir in comparison to the administration of aciclovir alone. The changes in MPAG (the phenolic

glucuronide of MPA) pharmacokinetics (MPAG increased by 8%) were minimal and are not considered

clinically significant. Because MPAG plasma concentrations are increased in the presence of renal

impairment, as are aciclovir concentrations, the potential exists for mycophenolate mofetil and aciclovir, or

its prodrugs, e.g. valaciclovir, to compete for tubular secretion and further increases in concentrations of both

substances may occur.

Antacids and proton pump inhibitors (PPIs)

Decreased MPA exposure has been observed when antacids, such as magnesium and aluminium hydroxides,

and PPIs, including lansoprazole and pantoprazole, were administered with mycophenolate mofetil. When

comparing rates of transplant rejection or rates of graft loss between mycophenolate mofetil patients taking

PPIs vs. mycophenolate mofetil patients not taking PPIs, no significant differences were seen. This data

support extrapolation of this finding to all antacids because the reduction in exposure when mycophenolate

mofetil was co-administered with magnesium and aluminium hydroxides is considerably less than when

mycophenolate mofetil was co-administered with PPIs.

Medicinal products that interfere with enterohepatic recirculation (e.g. cholestyramine, ciclosporin A,

antibiotics)

Caution should be used with medicinal products that interfere with enterohepatic recirculation because of

their potential to reduce the efficacy of mycophenolate mofetil.

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 mycophenolate mofetil.

Ciclosporin A

Ciclosporin A (CsA) pharmacokinetics are unaffected by mycophenolate mofetil. In contrast, if concomitant

CsA treatment is stopped, an increase in MPA AUC of around 30% should be expected. CsA interferes with

MPA enterohepatic recycling, resulting in reduced MPA exposures by 30-50% in renal transplant patients

treated with mycophenolate mofetil and CsA compared with patients receiving sirolimus or belatacept and

similar doses of mycophenolate mofetil (see also section 4.4). Conversely, changes of MPA exposure should

be expected when switching patients from CsA to one of the immunosuppressants which does not interfere

with MPA´s enterohepatic cycle.

Antibiotics eliminating β-glucuronidase-producing bacteria in the intestine (e.g. aminoglycoside,

cephalosporin, fluoroquinolone, and penicillin classes of antibiotics) may interfere with MPAG/MPA

enterohepatic recirculation thus leading to reduced systemic MPA exposure. Information concerning the

following antibiotics is available:

Ciprofloxacin or amoxicillin plus clavulanic acid

Reductions in pre-dose (trough) MPA concentrations of about 50% have been reported in renal transplant

recipients in the days immediately following commencement of oral ciprofloxacin or amoxicillin plus

clavulanic acid. This effect tended to diminish with continued antibiotic use and to cease within a few days

of antibiotic discontinuation. The change in predose level may not accurately represent changes in overall

MPA exposure. Therefore, a change in the dose of mycophenolate mofetil should not normally be necessary

in the absence of clinical evidence of graft dysfunction. However, close clinical monitoring should be

performed during the combination and shortly after antibiotic treatment.

Norfloxacin and metronidazole

In healthy volunteers, no significant interaction was observed when mycophenolate mofetil was

concomitantly administered with norfloxacin or metronidazole separately. However, norfloxacin and

metronidazole combined reduced the MPA exposure by approximately 30% following a single dose of

mycophenolate mofetil.

Trimethoprim/sulfamethoxazole

No effect on the bioavailability of MPA was observed.

Medicinal products that affect glucuronidation (e.g. isavuconazole, telmisartan)

Concomitant administration of drugs affecting glucuronidation of MPA may change MPA exposure. Caution

is therefore recommended when administering these drugs concomitantly with mycophenolate mofetil.

Isavuconazole

An increase of MPA AUC

0-∞

by 35% was observed with concomitant administration of isavuconazole.

Telmisartan

Concomitant administration of telmisartan and mycophenolate mofetil resulted in an approximately 30%

decrease of MPA concentrations. Telmisartan changes MPA’s elimination by enhancing PPAR gamma

(peroxisome proliferator-activated receptor gamma) expression, which in turn results in an enhanced

UGT1A9 expression and activity. When comparing rates of transplant rejection, rates of graft loss or adverse

event profiles between mycophenolate mofetil patients with and without concomitant telmisartan medication,

no clinical consequences of the pharmacokinetic drug-drug interaction were seen.

Ganciclovir

Based on the results of a single dose administration study of recommended doses of oral mycophenolate and

IV ganciclovir and the known effects of renal impairment on the pharmacokinetics of 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 whom mycophenolate mofetil 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 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 doses accordingly to maintain clinical efficacy when

rifampicin is administered concomitantly.

Sevelamer

Decrease in MPA C

and AUC

0-12h

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 at least one hour before or

three hours after sevelamer intake to minimise the impact on the absorption of MPA. There are no data on

mycophenolate mofetil with phosphate binders other than sevelamer.

Tacrolimus

In hepatic transplant patients initiated on mycophenolate mofetil and tacrolimus, the AUC and C

of MPA,

the active metabolite of mycophenolate mofetil, were not significantly affected by co-administration with

tacrolimus. In contrast, there was an increase of approximately 20% in tacrolimus AUC when multiple doses

of mycophenolate mofetil (1.5 g BID) were administered to hepatic transplant patients taking tacrolimus.

However, in renal transplant patients, tacrolimus concentration did not appear to be altered by

mycophenolate mofetil (see also section 4.4).

Live vaccines

Live vaccines should not be given to patients with an impaired immune response. The antibody response to

other vaccines may be diminished (see also section 4.4).

Paediatric population

Interaction studies have only been performed in adults.

Potential interaction

Co-administration of probenecid with mycophenolate mofetil in monkeys raises plasma AUC of MPAG by

3-fold. Thus, other substances known to undergo renal tubular secretion may compete with MPAG, and

thereby raise plasma concentrations of MPAG or the other substance undergoing tubular secretion.

4.6

Fertility, pregnancy and lactation

Women of childbearing potential

Pregnancy whilst taking mycophenolate must be avoided. Therefore, women of childbearing potential must

use at least one form of reliable contraception (see section 4.3) before starting Mykofenolatmofetil Actavis

therapy, during therapy, and for six weeks after stopping the therapy, unless abstinence is the chosen method

of contraception. Two complementary forms of contraception simultaneously are preferred.

Pregnancy

Mycophenolate mofetil is contraindicated during pregnancy unless there is no suitable alternative treatment

to prevent transplant rejection. Treatment should not be initiated without providing a negative pregnancy test

result to rule out unintended use in pregnancy (see section 4.3).

Female patients of reproductive potential must be made aware of the increased risk of pregnancy loss and

congenital malformations at the beginning of the treatment and must be counseled regarding pregnancy

prevention and planning.

Before starting Mykofenolatmofetil Actavis treatment, women of childbearing potential must have two

negative serum or urine pregnancy tests with a sensitivity of at least 25 mIU/mL in order to exclude

unintended exposure of the embryo to mycophenolate. It is recommended that the second test should be

performed 8 – 10 days after the first test. For transplants from deceased donors, if it is not possible to

perform two tests 8-10 days apart before treatment starts (because of the timing of transplant organ

availability), a pregnancy test must be performed immediately before starting treatment and a further test

performed 8-10 days later. Pregnancy tests should be repeated as clinically required (e.g. after any gap in

contraception is reported). Results of all pregnancy tests should be discussed with the patient. Patients should

be instructed to consult their physician immediately should pregnancy occur.

Mycophenolate is a powerful human teratogen, with an increased risk of spontaneous abortions and

congenital malformations in case of exposure during pregnancy;

Spontaneous abortions have been reported in 45 to 49% of pregnant women exposed to mycophenolate

mofetil, compared to a reported rate of between 12 and 33% in solid organ transplant patients treated

with immunosuppressants other than mycophenolate mofetil.

Based on literature reports, malformations occurred in 23 to 27% of live births in women exposed to

mycophenolate mofetil during pregnancy (compared to 2 to 3% of live births in the overall population

and approximately 4 to 5% of live births in solid organ transplant recipients treated with

immunosuppressants other than mycophenolate mofetil).

Congenital malformations, including reports of multiple malformations, have been observed post-marketing

in children of patients exposed to mycophenolate mofetil in combination with other immunosuppressants

during pregnancy. The following malformations were most frequently reported:

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

(middle ear);

Facial malformations such as cleft lip, cleft palate, micrognathia and hypertelorism of the orbits;

Abnormalities of the eye (e.g. coloboma);

Congenital heart disease such as atrial and ventricular septal defects;

Malformations of the fingers (e.g. polydactyly, syndactyly);

Tracheo-Oesophageal malformations (e.g. oesophageal atresia);

Nervous system malformations such as spina bifida;

Renal abnormalities.

In addition there have been isolated reports of the following malformations:

Microphthalmia;

Congenital choroid plexus cyst;

Septum pellucidum agenesis;

Olfactory nerve agenesis.

Studies in animals have shown reproductive toxicity (see section 5.3).

Breast-feeding

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

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

mycophenolate mofetil in breast-fed infants, mycophenolate mofetil is contraindicated in nursing mothers

(see section 4.3).

Limited clinical evidence does not indicate an increased risk of malformations or miscarriage following

paternal exposure to mycophenolate mofetil.

MPA is a powerful teratogen. It is not known if MPA is present in semen. Calculations based on animal data

show that the maximum amount of MPA that could potentially be transferred to woman is so low that it

would be unlikely to have an effect. Mycophenolate has been shown to be genotoxic in animal studies at

concentrations exceeding the human therapeutic exposures only by small margins, such that the risk of

genotoxic effects on sperm cells cannot completely be excluded.

Therefore, the following precautionary measures are recommended: sexually active male patients or their

female partners are recommended to use reliable contraception during treatment of the male patient and for

at least 90 days after cessation of mycophenolate mofetil. Male patients of reproductive potential should be

made aware of and discuss with a qualified health-care professional the potential risks of fathering a child.

4.7

Effects on ability to drive and use machines

Mycophenolate mofetil has a moderate influence on the ability to drive and use machines.

Mycophenolate mofetil may cause somnolence, confusion, dizziness, tremor or hypotension, and therefore

patients are advised to use caution when driving or using machines.

4.8

Undesirable effects

Summary of safety profile

An estimated total of 1557 patients received mycophenolate mofetil during five clinical trials in the

prevention of acute organ rejection. Of these, 991 were included in the three renal studies, 277 were included

in one hepatic study, and 289 were included in one cardiac study. Azathioprine was the comparator used in

the hepatic and cardiac studies and in two of the renal studies whilst the other renal study was placebo-

controlled. Patients in all study arms also received ciclosporine and corticosteroids. 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.

Diarrhoea, leucopenia, sepsis and vomiting were among the most common and/or serious adverse drug

reactions associated with the administration of mycophenolate mofetil in combination with ciclosporin and

corticosteroids. There is also evidence of a higher frequency of certain types of infections (see section 4.4).

Tabulated list of adverse reactions

The adverse drug reactions (ADRs) from clinical trials and post marketing experience are listed in Table 1,

by MedDRA system organ class (SOC) along with their frequencies. The corresponding frequency category

for each adverse drug reaction is based on the following convention: very common (≥1/10), common

(≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000).

Due to the large differences observed in the frequency of certain ADRs across the different transplant

indications, the frequency is presented separately for renal, hepatic and cardiac transplant patients.

Table 1 Summary of adverse drug reactions occurring in patients treated with mycophenolate mofetil

reported from clinical trials and post marketing experience

Adverse drug reaction

(MedDRA)

System Organ Class

Renal transplant

n = 991

Hepatic transplant

n = 277

Cardiac transplant

n = 289

Frequency

Frequency

Frequency

Infections and infestations

Bacterial infections

Very common

Very common

Very common

Fungal infections

Common

Very common

Very common

Protozoal infections

Uncommon

Uncommon

Uncommon

Viral infections

Very common

Very common

Very common

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Benign neoplasm of skin

Common

Common

Common

Lymphoma

Uncommon

Uncommon

Uncommon

Lymphoproliferative disorder

Uncommon

Uncommon

Uncommon

Neoplasm

Common

Common

Common

Skin cancer

Common

Uncommon

Common

Blood and lymphatic system disorders

Anemia

Very common

Very common

Very common

Aplasia pure red cell

Uncommon

Uncommon

Uncommon

Bone marrow failure

Uncommon

Uncommon

Uncommon

Ecchymosis

Common

Common

Very common

Leukocytosis

Common

Very common

Very common

Leukopenia

Very common

Very common

Very common

Pancytopenia

Common

Common

Uncommon

Pseudolymphoma

Uncommon

Uncommon

Common

Thrombocytopenia

Common

Very common

Very common

Metabolism and nutrition disorders

Acidosis

Common

Common

Very common

Hypercholesterolemia

Very common

Common

Very common

Hyperglycemia

Common

Very common

Very common

Hyperkalemia

Common

Very common

Very common

Hyperlipidemia

Common

Common

Very common

Hypocalcemia

Common

Very common

Common

Hypokalemia

Common

Very common

Very common

Hypomagnesemia

Common

Very common

Very common

Hypophosphatemia

Very common

Very common

Common

Hyperuricaemia

Common

Common

Very common

Gout

Common

Common

Very common

Weight decreased

Common

Common

Common

Adverse drug reaction

(MedDRA)

System Organ Class

Renal transplant

n = 991

Hepatic transplant

n = 277

Cardiac transplant

n = 289

Frequency

Frequency

Frequency

Psychiatric disorders

Confusional state

Common

Very common

Very common

Depression

Common

Very common

Very common

Insomnia

Common

Very common

Very common

Agitation

Uncommon

Common

Very common

Anxiety

Common

Very common

Very common

Thinking abnormal

Uncommon

Common

Common

Nervous system disorders

Dizziness

Common

Very common

Very common

Headache

Very common

Very common

Very common

Hypertonia

Common

Common

Very common

Paresthesia

Common

Very Common

Very common

Somnolence

Common

Common

Very common

Tremor

Common

Very common

Very common

Convulsion

Common

Common

Common

Dysgeusia

Uncommon

Uncommon

Common

Cardiac disorders

Tachycardia

Common

Very common

Very common

Vascular disorders

Hypertension

Very common

Very common

Very common

Hypotension

Common

Very common

Very common

Lymphocele

Uncommon

Uncommon

Uncommon

Venous thrombosis

Common

Common

Common

Vasodilatation

Common

Common

Very common

Respiratory, thoracic and mediastinal disorders

Bronchiectasis

Uncommon

Uncommon

Uncommon

Cough

Very common

Very common

Very common

Dyspnea

Very common

Very common

Very common

Interstitial lung disease

Uncommon

Very Rare

Very Rare

Pleural effusion

Common

Very common

Very common

Pulmonary fibrosis

Very Rare

Uncommon

Uncommon

Gastrointestinal disorders

Abdominal distension

Common

Very common

Common

Abdominal pain

Very common

Very common

Very common

Colitis

Common

Common

Common

Constipation

Very common

Very common

Very common

Decreased appetite

Common

Very common

Very common

Diarrhea

Very common

Very common

Very common

Dyspepsia

Very common

Very common

Very common

Esophagitis

Common

Common

Common

Eructation

Uncommon

Uncommon

Common

Flatulence

Common

Very common

Very common

Adverse drug reaction

(MedDRA)

System Organ Class

Renal transplant

n = 991

Hepatic transplant

n = 277

Cardiac transplant

n = 289

Frequency

Frequency

Frequency

Gastritis

Common

Common

Common

Gastrointestinal hemorrhage

Common

Common

Common

Gastrointestinal ulcer

Common

Common

Common

Gingival hyperplasia

Common

Common

Common

Ileus

Common

Common

Common

Mouth ulceration

Common

Common

Common

Nausea

Very common

Very common

Very common

Pancreatitis

Uncommon

Common

Uncommon

Stomatitis

Common

Common

Common

Vomiting

Very common

Very common

Very common

Immune system disorders

Hypersenstivity

Uncommon

Common

Common

Hypogammaglobulinaemia

Uncommon

Very rare

Very rare

Hepatobiliary disorders

Blood alkaline phosphatase

increased

Common

Common

Common

Blood lactate dehydrogenase

increased

Common

Uncommon

Very common

Hepatic enzyme increased

Common

Very common

Very common

Hepatitis

Common

Very common

Uncommon

Hyperbilirubinaemia

Common

Very common

Very common

Jaundice

Uncommon

Common

Common

Skin and subcutaneous tissues disorders

Acne

Common

Common

Very common

Alopecia

Common

Common

Common

Rash

Common

Very common

Very common

Skin hypertrophy

Common

Common

Very common

Musculoskeletal and connective tissue disorders

Arthralgia

Common

Common

Very common

Muscular weakness

Common

Common

Very common

Renal and urinary disorders

Blood creatinine increased

Common

Very common

Very common

Blood urea increased

Uncommon

Very common

Very common

Hematuria

Very common

Common

Common

Renal impairment

Common

Very common

Very common

General disorders and administration site conditions

Asthenia

Very common

Very common

Very common

Chills

Common

Very common

Very common

Edema

Very common

Very common

Very common

Hernia

Common

Very common

Very common

Malaise

Common

Common

Common

Pain

Common

Very common

Very common

Pyrexia

Very common

Very common

Very common

Adverse drug reaction

(MedDRA)

System Organ Class

Renal transplant

n = 991

Hepatic transplant

n = 277

Cardiac transplant

n = 289

Frequency

Frequency

Frequency

De novo purine synthesis

inhibitors-associated acute

inflammatory syndrome

Uncommon

Uncommon

Uncommon

Note: 991 (2 g/3 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.

Description of selected adverse reactions

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). Three-year safety data in renal and cardiac transplant patients did not reveal any

unexpected changes in incidence of malignancy compared to the 1-year data. Hepatic transplant patients

were followed for at least 1 year, but less than 3 years.

Infections

All patients treated with immunosuppressants are at increased risk of bacterial, viral and fungal infections

(some of which may lead to a fatal outcome), including those caused by opportunistic agents and latent viral

reactivation. The risk increases with total immunosuppressive load (see section 4.4). The most serious

infections were sepsis, peritonitis, meningitis, endocarditis, tuberculosis and atypical mycobacterial

infection. The most common opportunistic infections in patients receiving mycophenolate mofetil (2 g or 3 g

daily) with other immunosuppressants in controlled clinical trials in renal, cardiac and hepatic transplant

patients followed for at least 1 year were candida mucocutaneous, cytomegalovirus (CMV)

viraemia/syndrome and Herpes simplex. The proportion of patients with CMV viraemia/syndrome was

13.5%. Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive

multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants,

including mycophenolate mofetil.

Blood and lymphatic disorders

Cytopenias, including leucopenia, anemia, thrombocytopenia and pancytopenia, are known risks associated

with mycophenolate mofetil and may lead or contribute to the occurrence of infections and hemorrhages (see

section 4.4). Agranulocytosis and neutropenia have been reported; therefore, regular monitoring of patients

taking mycophenolate mofetil is advised (see section 4.4). There have been reports of aplastic anaemia and

bone marrow failure in patients treated with mycophenolate mofetil, some of which have been fatal.

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.

Gastrointestinal disorders

The most serious gastrointestinal disorders were ulceration and hemorrhage which are known risks

associated with mycophenolate mofetil. Mouth, esophageal, gastric, duodenal, and intestinal ulcers often

complicated by hemorrhage, as well as hematemesis, melena, and hemorrhagic forms of gastritis and colitis

were commonly reported during the pivotal clinical trials. The most common gastrointestinal disorders,

however, were diarrhea, nausea and vomiting. Endoscopic investigation of patients with mycophenolate

mofetil-related diarrhea have revealed isolated cases of intestinal villous atrophy (see section 4.4).

Hypersensitivity

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

Pregnancy, puerperium and perinatal conditions

Cases of spontaneous abortions have been reported in patients exposed to mycophenolate mofetil, mainly in

the first trimester, see section 4.6.

Congenital disorders

Congenital malformations have been observed post-marketing in children of patients exposed to

mycophenolate mofetil in combination with other immunosuppressants, see section 4.6.

Respiratory, thoracic and mediastinal disorders

There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients treated with

mycophenolate mofetil in combination with other immunosuppressants, some of which have been fatal.

There have also been reports of bronchiectasis in children and adults.

Immune system disorders

Hypogammaglobulinaemia has been reported in patients receiving mycophenolate mofetil in combination

with other immunosuppressants.

General disorders and administration site conditions

Edema, including peripheral, face and scrotal edema, was reported very commonly during the pivotal trials.

Musculoskeletal pain such as myalgia, and neck and back pain were also very commonly reported.

De novo purine synthesis inhibitors-associated acute inflammatory syndrome has been described from post-

marketing experience as a paradoxical proinflammatory reaction associated with mycophenolate mofetil and

mycophenolic acid, characterised by fever, arthralgia, arthritis, muscle pain and elevated inflammatory

markers. Literature case reports showed rapid improvement following discontinuation of the medicinal

product.

Special populations

Paediatric population

The type and frequency of adverse reactions in a clinical study, which recruited 92 paediatric patients aged 2

to 18 years who were given 600 mg/m

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

Elderly patients (

65 years) may generally be at increased risk of adverse reactions due to

immunosuppression. Elderly patients receiving mycophenolate mofetil as part of a combination

immunosuppressive regimen may be at increased risk of certain infections (including cytomegalovirus tissue

invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared to younger

individuals.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked

to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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 Mykofenolatmofetil Actavis should be interrupted or the dose reduced

(see section 4.4).

Haemodialysis would not be expected to remove clinically significant amounts of MPA or MPAG. Bile acid

sequestrants, such as cholestyramine, can remove MPA by decreasing the enterohepatic recirculation of the

drug (see section 5.2).

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: immunosuppressive agents, ATC code L04A A06

Mechanism of action

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

and reversible inhibitor of inosine monophosphate dehydrogenase, and therefore inhibits the

de novo

pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes

are critically dependent for their proliferation on

de novo

synthesis of purines whereas other cell types can

utilise salvage pathways, MPA has more potent cytostatic effects on lymphocytes than on other cells.

5.2

Pharmacokinetic properties

Absorption

Following oral administration, mycophenolate mofetil undergoes rapid and extensive absorption and

complete presystemic metabolism to the active metabolite, MPA. As evidenced by suppression of acute

rejection following renal transplantation, the immunosuppressant activity of 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 C

was decreased by 40% in the presence of food.

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

Distribution

As a result of enterohepatic recirculation, secondary increases in plasma MPA concentration are usually

observed at approximately 6 – 12 hours post-dose. A reduction in the AUC of MPA of approximately 40% is

associated with the co-administration of cholestyramine (4 g TID), indicating that there is a significant

amount of enterohepatic recirculation.

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

Biotransformation

MPA is metabolised principally by glucuronyl transferase (isoform UGT1A9) to form the inactive phenolic

glucuronide of MPA (MPAG).

In vivo

, MPAG is converted back to free MPA via enterohepatic

recirculation. A minor acylglucuronide (AcMPAG) is also formed. AcMPAG is pharmacologically active

and is suspected to be responsible for some of MMF´s side effects (diarrhoea, leucopenia).

Elimination

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

radiolabelled mycophenolate mofetil results in complete recovery of the administered dose with 93% of the

administered dose recovered in the urine and 6% recovered in the faeces. Most (about 87%) of the

administered dose is excreted in the urine as MPAG.

At clinically encountered concentrations, MPA and MPAG are not removed by haemodialysis. However, at

high MPAG plasma concentrations (> 100 μg/mL), small amounts of MPAG are removed. By interfering

with enterohepatic recirculation of the drug, bile acid sequestrants such as cholestyramine, reduce MPA

AUC (see section 4.9).

MPA’s disposition depends on several transporters. Organic anion-transporting polypeptides (OATPs) and

multidrug resistance-associated protein 2 (MRP2) are involved in MPA’s disposition; OATP isoforms,

MRP2 and breast cancer resistance protein (BCRP) are transporters associated with the glucuronides’ biliary

excretion. Multidrug resistance protein 1 (MDR1) is also able to transport MPA, but its contribution seems to

be confined to the absorption process. In the kidney MPA and its metabolites potently interact with renal

organic anion transporters.

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

approximately 40% lower compared to the late

post-transplant period (3 – 6 months post-transplant).

Special populations

Renal impairment

In a single dose study (6 subjects/group), mean plasma MPA AUC observed in subjects with severe chronic

renal impairment (glomerular filtration rate < 25 mL/min/1.73 m

) were 28 - 75% higher relative to the

means observed in normal healthy subjects or subjects with lesser degrees of renal impairment. The mean

single dose MPAG AUC was 3 - 6-fold higher in subjects with severe renal impairment than in subjects with

mild renal impairment or normal healthy subjects, consistent with the known renal elimination of MPAG.

Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been

studied. No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.

Delayed renal graft function

In patients with delayed renal graft function post-transplant, mean MPA 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 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.

Paediatric population

Pharmacokinetic parameters were evaluated in 49 paediatric renal transplant patients (aged 2 to 18 years)

given 600 mg/m

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

The pharmacokinetics of mycophenolate mofetil and its metabolites have not been found to be altered in the

elderly patients (≥ 65 years) when compared to younger transplant patients.

Patients taking oral contraceptives

A study of the co-administration of 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 LH,

FSH and progesterone were not significantly affected. The pharmacokinetics of oral contraceptives were

unaffected by co-administration of mycophenolate mofetil (see also section 4.5).

5.3

Preclinical safety data

In experimental models, mycophenolate mofetil was not tumourigenic. The highest dose tested in the animal

carcinogenicity studies resulted in approximately 2 - 3 times the systemic exposure (AUC or C

) 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

) 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/day. The systemic

exposure at this dose represents 2 - 3 times the clinical exposure at the recommended clinical dose of 2 g/day

in renal transplant patients and 1.3 - 2 times the clinical exposure at the recommended clinical dose of 3

g/day in cardiac transplant patients. In a female fertility and reproduction study conducted in rats, oral doses

of 4.5 mg/kg/day caused malformations (including anophthalmia, agnathia, and hydrocephaly) in the first

generation offspring in the absence of maternal toxicity. The systemic exposure at this dose was

approximately 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day for renal

transplant patients and approximately 0.3 times the clinical exposure at the recommended clinical dose of 3

g/day for cardiac transplant patients. No effects on fertility or reproductive parameters were evident in the

dams or in the subsequent generation.

In teratology studies in rats and rabbits, foetal resorptions and malformations occurred in rats at 6 mg/kg/day

(including anophthalmia, agnathia, and hydrocephaly) and in rabbits at 90 mg/kg/day (including

cardiovascular and renal anomalies, such as ectopia cordis and ectopic kidneys, and diaphragmatic and

umbilical hernia), in the absence of maternal toxicity. The systemic exposure at these levels is approximately

equivalent to or less than 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day for

renal transplant patients and approximately 0.3 times the clinical exposure at the recommended clinical dose

of 3 g/day for cardiac transplant patients (see section 4.6).

The haematopoietic and lymphoid systems were the primary organs affected in toxicology studies conducted

with mycophenolate mofetil in the rat, mouse, dog and monkey. These effects occurred at systemic exposure

levels that are equivalent to or less than the clinical exposure at the recommended dose of 2 g/day for renal

transplant recipients. Gastrointestinal effects were observed in the dog at systemic exposure levels equivalent

to or less than the clinical exposure at the recommended dose. Gastrointestinal and renal effects consistent

with dehydration were also observed in the monkey at the highest dose (systemic exposure levels equivalent

to or greater than clinical exposure). The nonclinical toxicity profile of mycophenolate mofetil appears to be

consistent with adverse events observed in human clinical trials which now provide safety data of more

relevance to the patient population (see section 4.8).

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Capsule

Microcrystalline cellulose

Povidone (K-90)

Hydroxypropyl cellulose

Croscarmellose sodium

Talc

Magnesium stearate

Capsule shell

Gelatine

Sodium laurilsulfate

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide yellow (E172)

Indigo carmine aluminium lake (E132)

Shellac

Iron oxide black (E172)

6.2

Incompatibilities

Not applicable

6.3

Shelf life

3 years

6.4

Special precautions for storage

Do not store above 30°C.

Store in the original package in order to protect from moisture.

6.5

Nature and contents of container

PVC/PVdC-Aluminium blister pack

100 capsules, hard

300 capsules, hard

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

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

7.

MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8.

MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10.

DATE OF REVISION OF THE TEXT

2021-04-30[To be completed nationally]

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