Leflunomide 10mg tablets

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

Buy It Now

Active ingredient:
Leflunomide
Available from:
Mylan
ATC code:
L04AA13
INN (International Name):
Leflunomide
Dosage:
10mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 10010300; GTIN: 5016695004150
Authorization number:
PL 04569/1122

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PACKAGE LEAFLET

Package leaflet: Information for the patient

Leflunomide 10 mg Film-coated Tablets

Leflunomide 20 mg Film-coated Tablets

(leflunomide)

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 Leflunomide is and what it is used for

What you need to know before you take Leflunomide

How to take Leflunomide

Possible side effects

How to store Leflunomide

Contents of the pack and other information

1. What Leflunomide is and what it is used for

Leflunomide belongs to a group of medicines called anti-rheumatic medicines. Leflunomide is used

to treat adult patients with active rheumatoid arthritis.

Symptoms of rheumatoid arthritis include inflammation of joints, swelling, difficulty moving

and pain. Other symptoms that affect the entire body include loss of appetite, fever, loss of

energy and anaemia (reduction of red blood cells).

2.

W hat you need to know before you take Leflunomide

Do not take Leflunomide

if you are allergic to leflunomide (especially a serious skin reaction, often accompanied by

fever, joint pain, red skin stains, or blisters e.g. Stevens-Johnson syndrome), to a medicine

called teriflunomide (which is related to leflunomide) or to any of the other ingredients of

this medicine (listed in section 6)

if you have any

liver problems

if you have moderate to severe

kidney problems

if you have severely low levels of

proteins in your blood

(hypoproteinaemia),

if you suffer from any problem which affects your

immune system

(e.g. AIDS),

if you have any problem with your

bone marrow,

or if you have low numbers of red or

white cells in your blood or a reduced number of blood platelets due to causes other than

rheumatoid arthritis,

if you are suffering from a

serious infection

if you are

pregnant,

think you may be pregnant

or are breast-feeding

if you are woman of child bearing age and not using effective contraception.

Warnings and precautions

Talk to your doctor or pharmacist before taking leflunomide:

if you have ever suffered interstitial lung disease

if you have ever had tuberculosis or if you have been in close contact with someone who has

or has had tuberculosis. Your doctor may perform tests to see if you have tuberculosis.

if you are

male

and wish to father a child. As it cannot be excluded that leflunomide passes

into semen, reliable contraception should be used during treatment with leflunomide. Men

wishing to father a child should contact their doctor who may advise you to stop taking

Leflunomide and take certain medicines to remove leflunomide rapidly and sufficiently

from your body. You will then need a blood test to make sure that leflunomide has been

sufficiently removed from your body, and you should then wait for at least another 3 months

before attempting to father a child.

if you are due to have a specific blood test (calcium level). Falsely low levels of calcium

can be detected.

Leflunomide can occasionally cause some problems with your blood, liver, lungs

or nerves in

your arms or legs. It may also cause some serious allergic reactions (including Drug Reaction

and Eosinophilia and Systemic Symptoms [DRESS]), or increase the chance of a severe

infection. For more information on these, please read section 4 ‘Possible side effects’.

DRESS appears initially as flu-like symptoms and a rash on the face then an extended rash with a high

temperature, increased levels of liver enzymes seen in blood tests and an increase in a type of white

blood cell (eosinophilia) and enlarged lymph nodes.

Your doctor will carry out

blood tests

at regular intervals, before and during treatment with

Leflunomide, to monitor your blood cells and liver. Your doctor will also check your blood

pressure regularly as Leflunomide can cause an increase in blood pressure.

Tell your doctor if you have unexplained, persistent diarrhoea. Your doctor may perform

additional tests to establish its cause.

Children and adolescents

Leflunomide is not recommended for use in children and adolescents below 18 years of age.

Other medicines and Leflunomide

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

medicines.

This is especially important if you are taking:

other medicines for

rheumatoid arthritis

such as antimalarials (e.g. chloroquine and

hydroxychloroquine), intramuscular or oral gold, D-penicillamine, azathioprine, Tumour

Necrosis Factor alpha-Inhibitors (e.g. adalimumab, infliximab) and other immunosuppressive

drugs (e.g. methotrexate) as these combinations are not advisable,

a medicine called colestyramine (used to reduce high cholesterol) or activated charcoal

these medicines can reduce the amount of Leflunomide which is absorbed by the body

a medicine called teriflunomide (used for the treatment of multiple sclerosis)

warfarin and other oral medicines used to thin the blood, as monitoring is necessary to reduce

the risk of side effects of this medicine

repaglinide, pioglitazone, nateglinide, or rosiglitazone for diabetes

daunorubicin, doxorubicin, paclitaxel, or topotecan for cancer

duloxetine for depression, urinary incontinence or in kidney disease in diabetics

alosetron for the management of severe diarrhoea

theophylline for asthma

tizanidine, a muscle relaxant

oral contraceptives (e.g. ethinylestradiol and levonorgestrel)

rifampicin (used in the treatment of tuberculosis)

cefaclor, benzylpenicillin (penicillin G), ciprofloxacin for infections

indometacin, ketoprofen for pain or inflammation

furosemide for heart disease (diuretic, water pill)

zidovudine for HIV infection

rosuvastatin, simvastatin, atorvastatin, pravastatin for hypercholesterolemia (high cholesterol)

sulfasalazine for inflammatory bowel disease or rheumatoid arthritis

cimetidine (for excess stomach acid).

If you are already taking a non-steroidal

anti-inflammatory

drug (NSAID) and/or

corticosteroids

, you may continue to take them after starting Leflunomide.

Vaccinations

If you have to be vaccinated, ask your doctor for advice. Certain vaccinations should not be given

while taking leflunomide, and for a certain amount of time after stopping treatment.

Taking Leflunomide with food, drink and alcohol

Leflunomide may be taken with or without food.

It is not recommended to drink alcohol during treatment with Leflunomide. Drinking alcohol

while taking Leflunomide may increase the chance of liver damage.

Pregnancy and breast-feeding

Do not

take Leflunomide if you are, or think you may be

pregnant

. If you are pregnant or

become pregnant while taking leflunomide, the risk of having a baby with serious birth defects is

increased. Women of childbearing potential must not take Leflunomide without using reliable

contraceptives measures.

Tell your doctor if you plan to become pregnant after stopping treatment with Leflunomide, as you

need to ensure that all traces of leflunomide have left your body before trying to become pregnant.

This may take up to 2 years. This may be reduced to a few weeks by taking certain medicines which

speed up removal of leflunomide from your body.

In either case it should be confirmed by a blood test that leflunomide has been sufficiently removed

from your body and you should then wait for at least another month before you become pregnant.

For further information on the laboratory testing please contact your doctor.

If you suspect that you are pregnant while taking leflunomide or in the two years after you have

stopped treatment, you must contact your doctor

immediately

for a pregnancy test. If the test

confirms that you are pregnant, your doctor may suggest treatment with certain medicines to

remove Leflunomide

rapidly and sufficiently from your body, as this may decrease the risk to your

baby.

Breast-feeding

Do not

take Leflunomide when you are

breast-feeding

, as leflunomide passes into the breast

milk.

Driving and using machines

Leflunomide can make you feel dizzy which may impair your ability to concentrate and react. If

you are affected, do not drive, or use machines.

Leflunomide contains

lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your

doctor before taking this medicine.

3.

How to take Leflunomide

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

doctor or pharmacist if you are not sure.

The recommended starting dose of Leflunomide is 100 mg once daily for the first three days.

After this, most patients need a dose of:

For rheumatoid arthritis: 10 or 20 mg Leflunomide once daily, depending on the severity of the

disease.

Swallow

the tablet

whole

and with plenty of

water

. Leflunomide can be taken with or without food.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

It may take about 4 weeks or longer until you start to feel an improvement in your condition. Some

patients may even still feel further improvements after 4 to 6 months of therapy.

You will normally take Leflunomide over long periods of time.

If you take more Leflunomide than you should

If you take more Leflunomide than you should, contact your doctor or get other medical advice.

If possible, take your tablets or the box with you to show the doctor.

You may have any of these symptoms: stomach pain, diarrhoea, itching and rash.

If you forget to take Leflunomide

If you forget to take a dose, take it as soon as you remember, unless it is nearly time for your next

dose. Do not take a double dose to make up for a forgotten dose.

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.

Tell your doctor

immediately

and stop taking Leflunomide:

if you experience

weakness

, feel light-headed or dizzy or have

difficulty

breathing,

(with or without skin rash including red itchy skin, swelling of the

hands, feet ankles, face, lips, mouth or throat with difficultly in swallowing), as

these may be signs of a serious allergic reaction,

if you develop a

skin rash

inflammation and

ulcers in your mouth

, as these may

indicate severe, sometimes life-threatening allergic reactions (e.g. Stevens-Johnson

syndrome, toxic epidermal necrolysis, erythema multiforme, DRESS) see section 2.

Tell your doctor

immediately

if you experience:

pale skin

tiredness,

bruising,

as these may indicate blood disorders caused by an

imbalance in the different types of blood cells which make up blood,

tiredness

abdominal pain

, or

jaundice

(yellow discolouration of the eyes or skin), as these

may indicate serious conditions such as liver

inflammation (hepatitis) or failure, which may

be fatal,

any symptoms of an

infection

such as

fever,

ulcers in your mouth (signs of

agranulocytosis-marked decrease of some white blood cells-very rare), sore throat

cough,

as this medicine may increase the chance of a severe infection, including

sepsis(rare), which may be life- threatening,

inflammation of the small vessels (vasculitis, including cutaneous necrotising vasculitis),

cough

breathing problems

as these may indicate problems of the lung

(interstitial lung disease or pulmonary hypertension),

unusual tingling, weakness or pain in your hands or feet as these may indicate problems with

your nerves (peripheral neuropathy)

loss of appetite; tummy pain; tenderness over your abdomen when it's touched; feeling sick

and generally unwell, vomiting, fever, these may be signs of inflammation of the pancreas

(pancreatitis),

severe pain or ache on one or both sides of your back, sudden spasms of excruciating pain –

this usually starts in the back below your ribs, radiating around your abdomen, and sometimes

to your groin and genitals; blood in your urine; feeling sick or vomiting; needing to urinate

often, or feeling a burning sensation during urination; fever; nausea, vomiting; rash; weight

gain; these may be signs of kidney failure,

cutaneous lupus (characterised by rash/erythema on skin areas that are exposed to light).

colitis (causing unexplained, persistent diarrhoea)

Other side effects:

Common (may affect up to 1 in 10 people):

mild allergic reactions,

loss of appetite, weight loss (usually insignificant),

tiredness (asthenia),

headache, dizziness,

abnormal skin sensations like tingling (paraesthesia),

mild increase in blood pressure,

diarrhoea,

nausea, vomiting,

abdominal pain,

an increase in some liver test results,

increased hair loss,

eczema, dry skin, rash, itching,

tendonitis (pain caused by inflammation in the membrane surrounding the tendons usually in

the feet or hands),

an increase of certain enzymes in the blood (creatine phosphokinase).

Uncommon (may affect up to 1 in 100 people):

a decrease in the levels of potassium in the blood,

anxiety,

taste disturbances,

urticaria (nettle rash),

tendon rupture,

an increase in the levels of fat in the blood (cholesterol and triglycerides),

a decrease in the levels of phosphate in the blood.

Rare (may affect up to 1 in 1000 people):

an increase in the numbers of blood cells called eosinophiles (eosinophilia);

severe increase in blood pressure,

an increase of certain enzymes in the blood (lactate dehydrogenase).

Not known (frequency cannot be estimated from the available data)

Other side effects such as, a decrease in the levels of uric acid in your blood, pulmonary

hypertension male infertility (which is reversible once treatment with this medicine is stopped) and

psoriasis (new or worsening) may also occur.

Medicines like leflunomide have been associated with an increased risk of developing cancers.

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

www.mhra.gov.uk/yellowcard. By reporting side effects you can help provide more information

on the safety of this medicine.

5.

How to store Leflunomide

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 blister / bottle and carton. The

expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

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 Leflunomide contains

The active substance is leflunomide. One film-coated tablet contains 10 or 20 mg of

leflunomide.

The tablet core: contains microcrystalline cellulose, pregelatinised maize starch, povidine K 30

(E1201), crospovidone (E1202), silica colloidal anhydrous, magnesium stearate (E470b) and lactose

monohydrate.

The film coating additionally contains titanium dioxide (E171), hypromellose (E464) and macrogol.

The 20 mg tablet also contains talcum and yellow iron oxide (E172).

What Leflunomide looks like and contents of the pack

Leflunomide 10mg film-coated tablets are white, round biconvex tablets with a diameter of

about 6.1mm. The product is packaged in a cardboard box containing blisters or bottle

with

an integrated desiccant (white silica gel) or desiccant sachet. Do not eat the desiccant.

Pack sizes of 30, 100 film-coated tablets.

Leflunomide 20mg film-coated tablets are yellow, round biconvex, with a score line on one

side with a diameter of about 8.1mm. The product is packaged in a cardboard box containing

blisters or a bottle

with an integrated desiccant (white silica gel) or desiccant sachet. Do not

eat the desiccant.

Pack sizes of 30, 100 and 500 (only in HDPE bottle) film-coated tablets are available.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Mylan, Potters Bar, Hertfordshire EN6 1TL United Kingdom

Manufacturer

Gerard Laboratories, 35/36 Baldoyle Industrial Estate, Grange Road, Dublin 13 Ireland

Pharmathen S.A., Dervenakion 6, 15351 Pallini Attiki, Greece

Pharmathen International S.A. Industrial Park Sapes, Rodopi Prefecture, Block No 5, Rodopi 69300,

Greece

This leaflet was last revised in 06/2017

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Object 1

Leflunomide Mylan 10 mg film-coated tablets

Summary of Product Characteristics Updated 23-Oct-2017 | Generics UK T/A Mylan

1. Name of the medicinal product

Leflunomide Mylan 10 mg film-coated tablets

2. Qualitative and quantitative composition

Leflunomide Mylan 10 mg film-coated tablets: Each tablet contains 10 mg of leflunomide.

Excipient with known effect: Each film-coated tablet contains 18.81 mg of lactose.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

Leflunomide 10 mg film-coated tablets are white, round biconvex tablets with a diameter of about 6.1

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4. Clinical particulars

4.1 Therapeutic indications

Leflunomide is indicated for the treatment of adult patients with:

active rheumatoid arthritis as a "disease-modifying antirheumatic drug" (DMARD),

Recent or concurrent treatment with hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) may

result in an increased risk of serious adverse reactions; therefore, the initiation of leflunomide treatment

has to be carefully considered regarding these benefit/risk aspects.

Moreover, switching from leflunomide to another DMARD without following the washout procedure (see

section 4.4) may also increase the risk of serious adverse reactions even for a long time after the

switching.

4.2 Posology and method of administration

The treatment should be initiated and supervised by specialists experienced in the treatment of

rheumatoid arthritis.

Alanine aminotransferase (ALT) or serum glutamopyruvate transferase (SGPT) and a complete blood cell

count, including a differential white blood cell count and a platelet count, must be checked

simultaneously and with the same frequency:

before initiation of leflunomide,

every two weeks during the first six months of treatment, and

every 8 weeks thereafter (see section 4.4).

Posology

In rheumatoid arthritis: leflunomide therapy is usually started with a loading dose of 100 mg once daily

for 3 days. Omission of the loading dose may decrease the risk of adverse events (see section 5.1).

The recommended maintenance dose for is leflunomide 10 mg to 20 mg once dailydepending on the

severity (activity) of the disease.

The therapeutic effect usually starts after 4 to 6 weeks and may further improve up to 4 to 6 months.

Special population

Patients with renal impairment

There is no dose adjustment recommended in patients with mild renal impairment.

Elderly

No dosage adjustment is required in patients above 65 years of age.

Paediatric population

Leflunomide Mylan is not recommended for use in patients below 18 years since efficacy and safety in

juvenile rheumatoid arthritis (JRA) have not been established (see sections 5.1 and 5.2).

Method of Administration

Leflunomide Mylan should be swallowed whole orally with sufficient amounts of liquid. The extent of

leflunomide absorption is not affected if it is taken with food.

4.3 Contraindications

Hypersensitivity (especially previous Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema

multiforme) to the active substance, to the principal active metabolite teriflunomide or to any of the

excipients listed in section 6.1.

Patients with impairment of liver function.

Patients with severe immunodeficiency states, e.g. AIDS.

Patients with significantly impaired bone marrow function or significant anaemia, leucopenia,

neutropenia or thrombocytopenia due to causes other than rheumatoid arthritis.

Patients with serious infections (see section 4.4).

Patients with moderate to severe renal insufficiency, because insufficient clinical experience is available

in this patient group.

Patients with severe hypoproteinaemia, e.g. in nephrotic syndrome.

Pregnant women, or women of childbearing potential who are not using reliable contraception during

treatment with leflunomide and thereafter as long as the plasma levels of the active metabolite are above

0.02 mg/l (see section 4.6). Pregnancy must be excluded before start of treatment with leflunomide.

Breast-feeding women (see section 4.6).

4.4 Special warnings and precautions for use

Concomitant administration of hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) is not

advisable.

The active metabolite of leflunomide, A771726, has a long half-life, usually 1 to 4 weeks. Serious

undesirable effects might occur (e.g. hepatotoxicity, haematotoxicity or allergic reactions, see below),

even if the treatment with leflunomide has been stopped. Therefore, when such toxicities occur or if for

any other reason A771726 needs to be cleared rapidly from the body, the washout procedure has to be

followed. The procedure may be repeated as clinically necessary.

For washout procedures and other recommended actions in case of desired or unintended pregnancy, see

section 4.6.

Liver reactions

Rare cases of severe liver injury, including cases with fatal outcome, have been reported during treatment

with leflunomide. Most of the cases occurred within the first 6 months of treatment. Co-treatment with

other hepatotoxic medicinal products was frequently present. It is considered essential that monitoring

recommendations are strictly adhered to.

ALT (SGPT) must be checked before initiation of leflunomide and at the same frequency as the complete

blood cell count (every two weeks) during the first six months of treatment and every 8 weeks thereafter.

For ALT (SGPT) elevations between 2- and 3-fold the upper limit of normal, dose reduction from 20 mg

to 10 mg may be considered and monitoring must be performed weekly. If ALT (SGPT) elevations of

more than 2-fold the upper limit of normal persist or if ALT elevations of more than 3-fold the upper limit

of normal are present, leflunomide must be discontinued and wash-out procedures initiated. It is

recommended that monitoring of liver enzymes be maintained after discontinuation of leflunomide

treatment, until liver enzyme levels have normalised.

Due to a potential for additive hepatotoxic effects, it is recommended that alcohol consumption be

avoided during treatment with leflunomide.

Since the active metabolite of leflunomide, A771726, is highly protein bound and cleared via hepatic

metabolism and biliary secretion, plasma levels of A771726 are expected to be increased in patients with

hypoproteinaemia. Leflunomide Mylan is contraindicated in patients with severe hypoproteinaemia or

impairment of liver function (see section 4.3).

Haematological reactions

Together with ALT, a complete blood cell count, including differential white blood cell count and

platelets, must be performed before start of leflunomide treatment as well as every 2 weeks for the first 6

months of treatment and every 8 weeks thereafter.

In patients with pre-existing anaemia, leucopenia, and/or thrombocytopenia as well as in patients with

impaired bone marrow function or those at risk of bone marrow suppression, the risk of haematological

disorders is increased. If such effects occur, a washout (see below) to reduce plasma levels of A771726

should be considered.

In case of severe haematological reactions, including pancytopenia, Leflunomide Mylan and any

concomitant myelosuppressive treatment must be discontinued and a leflunomide washout procedure

initiated.

Combinations with other treatments

The use of leflunomide with antimalarials used in rheumatic diseases (e.g. chloroquine and

hydroxychloroquine), intramuscular or oral gold, D-penicillamine, azathioprine and other

immunosuppressive agents including Tumour Necrosis Factor alpha-Inhibitors has not been adequately

studied up to now in randomised trials (with the exception of methotrexate, see section 4.5). The risk

associated with combination therapy, in particular in long-term treatment, is unknown. Since such therapy

can lead to additive or even synergistic toxicity (e.g. hepato- or haematotoxicity), combination with

another DMARD (e.g. methotrexate) is not advisable.

Co-administration of teriflunomide with leflunomide is not recommended, as leflunomide is the parent

compound of teriflunomide.

Switching to other treatments

As leflunomide has a long persistence in the body, a switching to another DMARD (e.g. methotrexate)

without performing the washout procedure (see below) may raise the possibility of additive risks even for

a long time after the switching (i.e. kinetic interaction, organ toxicity).

Similarly, recent treatment with hepatotoxic or haematotoxic medicinal products (e.g. methotrexate) may

result in increased side effects; therefore, the initiation of leflunomide treatment has to carefully be

considered regarding these benefit/risk aspects and closer monitoring is recommended in the initial phase

after switching.

Skin reactions

In case of ulcerative stomatitis, leflunomide administration should be discontinued.

Very rare cases of Stevens Johnson syndrome or toxic epidermal necrolysis and Drug Reaction with

Eosinophilia and Systemic Symptoms (DRESS) have been reported in patients treated with leflunomide.

As soon as skin and/or mucosal reactions are observed which raise the suspicion of such severe reactions,

Leflunomide Mylan and any other possibly associated treatment must be discontinued, and a leflunomide

washout procedure initiated immediately. A complete washout is essential in such cases. In such cases re-

exposure to leflunomide is contra-indicated (see section 4.3).

Pustular psoriasis and worsening of psoriasis have been reported after the use of leflunomide. Treatment

withdrawal may be considered taking into account patient's disease and past history.

Infections

It is known that medicinal products with immunosuppressive properties - like leflunomide - may cause

patients to be more susceptible to infections, including opportunistic infections. Infections may be more

severe in nature and may, therefore, require early and vigorous treatment. In the event that severe,

uncontrolled infections occur, it may be necessary to interrupt leflunomide treatment and administer a

washout procedure as described below.

Rare cases of Progressive Multifocal Leukoencephalopathy (PML) have been reported in patients

receiving leflunomide among other immunosuppressants.

Before starting treatment, all patients should be evaluated for active and inactive (“latent”) tuberculosis,

as per local recommendations. This can include medical history, possible previous contact with

tuberculosis, and/or appropriate screening such as lung x-ray, tuberculin test and/or interferon-gamma

release assay, as applicable. Prescribers are reminded of the risk of false negative tuberculin skin test

results, especially in patients who are severely ill or immunocompromised. Patients with a history of

tuberculosis should be carefully monitored because of the possibility of reactivation of the infection.

Colitis, including microscopic colitis has been reported in patients treated with leflunomide. In patients on

leflunomide treatment presenting unexplained chronic diarrhoea appropriate diagnostic procedures should

be performed

Respiratory reactions

Interstitial lung disease, as well as rare cases of pulmonary hypertension, have been reported during

treatment with leflunomide (see section 4.8). The risk their occurrence can be increased in patients with a

history of interstitial lung disease.

Interstitial lung disease is a potentially fatal disorder, which may occur acutely during therapy.

Pulmonary symptoms, such as cough and dyspnoea, may be a reason for discontinuation of the therapy

and for further investigation, as appropriate.

Peripheral Neuropathy

Cases of peripheral neuropathy have been reported in patients receiving leflunomide. Most patients

improved after discontinuation of leflunomide. However there was a wide variability in final outcome, i.e.

in some patients the neuropathy resolved and some patients had persistent symptoms. Age older than 60

years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy.

If a patient taking leflunomide develops a peripheral neuropathy, consider discontinuing therapy and

performing the drug elimination procedure (see section 4.4).

Blood pressure

Blood pressure must be checked before the start of leflunomide treatment and periodically thereafter.

Procreation (recommendations for men)

Male patients should be aware of the possible male-mediated foetal toxicity. Reliable contraception

during treatment with leflunomide should also be guaranteed.

There are no specific data on the risk of male-mediated foetal toxicity. However, animal studies to

evaluate this specific risk have not been conducted. To minimise any possible risk, men wishing to father

a child should consider discontinuing use of leflunomide and taking colestyramine 8 g 3 times daily for

11 days or 50 g of activated powdered charcoal 4 times daily for 11 days.

In either case the A771726 plasma concentration is then measured for the first time. Thereafter, the

A771726 plasma concentration must be determined again after an interval of at least 14 days. If both

plasma concentrations are below 0.02 mg/l, and after a waiting period of at least 3 months, the risk of

foetal toxicity is very low.

Interference with determination of ionised calcium levels

The measurement of ionised calcium levels might show falsely decreased values under treatment with

leflunomide and/or teriflunomide (the active metabolite of leflunomide) depending on the type of ionised

calcium analyser used (e.g. blood gas analyser). Therefore, the plausibility of observed decreased ionised

calcium levels needs to be questioned in patients under treatment with leflunomide or teriflunomide. In

case of doubtful measurements, it is recommended to determine the total albumin adjusted serum calcium

concentration.

Washout procedure

Colestyramine 8 g is administered 3 times daily. Alternatively, 50 g of activated powdered charcoal is

administered 4 times daily. Duration of a complete washout is usually 11 days. The duration may be

modified depending on clinical or laboratory variables.

Lactose

Leflunomide Mylan contains lactose. Patients with rare hereditary problems of galactose intolerance, the

Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

Interactions studies have only been performed in adults.

Increased side effects may occur in case of recent or concomitant use of hepatotoxic or haematotoxic

drugs or when leflunomide treatment is followed by such drugs without a washout period (see also

guidance concerning combination with other treatments, section 4.4). Therefore, closer monitoring of

liver enzymes and haematological parameters is recommended in the initial phase after switching.

Methotrexate

In a small (n=30) study with co-administration of leflunomide (10 to 20 mg per day) with methotrexate

(10 to 25 mg per week) a 2- to 3-fold elevation in liver enzymes was seen on 5 of 30 patients. All

elevations resolved 2 with continuation of both drugs and 3 after discontinuation of leflunomide. A more

than 3-fold increase was seen in another 5 patients. All of these also resolved 2 with continuation of both

drugs and 3 after discontinuation of leflunomide.

In patients with rheumatoid arthritis, no pharmacokinetic interaction between the leflunomide (10 to 20

mg per day) and methotrexate (10 to 25 mg per week) was demonstrated.

Vaccinations

No clinical data are available on the efficacy and safety of vaccinations under leflunomide treatment.

Vaccination with live attenuated vaccines is, however, not recommended. The long half-life of

leflunomide should be considered when contemplating administration of a live attenuated vaccine after

stopping Leflunomide Mylan.

Warfarin and other coumarin anticoagulants

There have been case reports of increased prothrombin time, when leflunomide and warfarin were co-

administered. A pharmacodynamics interaction with warfarin was observed with A771726 in a clinical

pharmacology study (see below). Therefore, when warfarin or another coumarin anticoagulant is co-

administered, close international normalised ratio (INR) follow-up and monitoring is recommended.

NSAIDS/Corticosteroids

If the patient is already receiving nonsteroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids,

these may be continued after starting leflunomide.

Effect of other medicinal products on leflunomide:

Cholestyramine or activated charcoal

It is recommended that patients receiving leflunomide are not treated with colestyramine or activated

powdered charcoal because this leads to a rapid and significant decrease in plasma A771726 (the active

metabolite of leflunomide; see also section 5) concentration. The mechanism is thought to be by

interruption of enterohepatic recycling and/or gastrointestinal dialysis of A771726.

CYP450 inhibitors and inducers

In vitro inhibition studies in human liver microsomes suggest that cytochrome P450 (CYP) 1A2, 2C19

and 3A4 are involved in leflunomide metabolism. An in vivo interaction study with leflunomide and

cimetidine (non-specific weak cytochrome P450 (CYP) inhibitor) has demonstrated a lack of a significant

impact on A771726 exposure. Following concomitant administration of a single dose of leflunomide to

subjects receiving multiple doses of rifampicin (non-specific cytochrome P450 inducer) A771726 peak

levels were increased by approximately 40%, whereas the AUC was not significantly changed. The

mechanism of this effect is unclear.

Effect of leflunomide on other medicinal products:

Oral contraceptives

In a study in which leflunomide was given concomitantly with a triphasic oral contraceptive pill

containing 30 μg ethinyloestradiol to healthy female volunteers, there was no reduction in contraceptive

activity of the pill, and A771726 pharmacokinetics were within predicted ranges. A pharmacokinetic

interaction with oral contraceptives was observed with A771726 (see below).

The following pharmacokinetic and pharmacodynamic interaction studies were conducted with A771726

(principal active metabolite of leflunomide). As similar drug-drug interactions cannot be excluded for

leflunomide at recommended doses, the following study results and recommendations should be

considered in patients treated with leflunomide:

Effect on repaglinide (CYP2C8 substrate)

There was an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, respectively), following

repeated doses of A771726, suggesting that A771726 is an inhibitor of CYP2C8 in vivo. Therefore,

monitoring patients with concomitant use of medicinal products metabolised by CYP2C8, such as

repaglinide, paclitaxel, pioglitazone or rosiglitazone, is recommended as they may have higher exposure.

Effect on caffeine (CYP1A2 substrate)

Repeated doses of A771726 decreased mean Cmax and AUC of caffeine (CYP1A2 substrate) by 18% and

55%, respectively, suggesting that A771726 may be a weak inducer of CYP1A2 in vivo. Therefore,

medicinal products metabolised by CYP1A2 (such as duloxetine, alosetron, theophylline and tizanidine)

should be used with caution during treatment, as it could lead to the reduction of the efficacy of these

products.

Effect on organic anion transporter 3 (OAT3) substrates

There was an increase in mean cefaclor Cmax and AUC (1.43- and 1.54-fold, respectively), following

repeated doses of A771726, suggesting that A771726 is an inhibitor of OAT3 in vivo. Therefore, when

co-administered with substrates of OAT3, such as cefaclor, benzylpenicillin, ciprofloxacin, indometacin,

ketoprofen, furosemide, cimetidine, methotrexate, zidovudine, caution is recommended.

Effect on BCRP (Breast Cancer Resistance Protein) and /or organic anion transporting polypeptide B1

and B3 (OATP1B1/B3) substrates

There was an increase in mean rosuvastatin Cmax and AUC (2.65- and 2.51-fold, respectively), following

repeated doses of A771726. However, there was no apparent impact of this increase in plasma

rosuvastatin exposure on the HMG-CoA reductase activity. If used together, the dose of rosuvastatin

should not exceed 10 mg once daily. For other substrates of BCRP (e.g. methotrexate, topotecan,

sulfasalazine, daunorubicin, doxorubicin) and the OATP family especially HMG-CoA reductase

inhibitors (e.g. simvastatin, atorvastatin, pravastatin, methotrexate, nateglinide, repaglinide, rifampicin)

concomitant administration should also be undertaken with caution. Patients should be closely monitored

for signs and symptoms of excessive exposure to the medicinal products and reduction of the dose of

these medicinal products should be considered.

Effect on oral contraceptive (0.03 mg ethinylestradiol and 0.15 mg levonorgestrel)

There was an increase in mean ethinylestradiol Cmax and AUC0-24 (1.58- and 1.54-fold, respectively)

and levonorgestrel Cmax and AUC0-24 (1.33- and 1.41-fold, respectively) following repeated doses of

A771726. While this interaction is not expected to adversely impact the efficacy of oral contraceptives,

consideration should be given to the type of oral contraceptive treatment.

Effect on warfarin (CYP2C9 substrate)

Repeated doses of A771726 had no effect on the pharmacokinetics of S-warfarin, indicating that

A771726 is not an inhibitor or an inducer of CYP2C9. However, a 25% decrease in peak international

normalised ratio (INR) was observed when A771726 was co-administered with warfarin as compared

with warfarin alone. Therefore, when warfarin is co-administered, close INR follow-up and monitoring is

recommended.

4.6 Fertility, pregnancy and lactation

Pregnancy

The active metabolite of leflunomide, A771726 is suspected to cause serious birth defects when

administered during pregnancy. Leflunomide Mylan is contraindicated in pregnancy (see section 4.3).

Women of childbearing potential have to use effective contraception during and up to 2 years after

treatment (see “waiting period” below) or up to 11 days after treatment (see abbreviated “washout period”

below).

The patient must be advised that if there is any delay in onset of menses or any other reason to suspect

pregnancy, they must notify the physician immediately for pregnancy testing, and if positive, the

physician and patient must discuss the risk to the pregnancy. It is possible that rapidly lowering the blood

level of the active metabolite, by instituting the drug elimination procedure described below, at the first

delay of menses may decrease the risk to the foetus from leflunomide.

In a small prospective study in women (n=64) who became inadvertently pregnant while taking

leflunomide for no more than three weeks after conception and followed by a drug elimination procedure,

no significant differences (p=0.13) were observed in the overall rate of major structural defects (5.4%)

compared to either of the comparison groups (4.2% in the disease matched group [n=108] and 4.2% in

healthy pregnant women [n=78]).

For women receiving leflunomide treatment and who wish to become pregnant, one of the following

procedures is recommended in order to ascertain that the foetus is not exposed to toxic concentrations of

A771726 (target concentration below 0.02 mg/l):

Waiting period

A771726 plasma levels can be expected to be above 0.02 mg/l for a prolonged period. The concentration

may be expected to decrease below 0.02 mg/l about 2 years after stopping the treatment with leflunomide.

After a 2-year waiting period, the A771726 plasma concentration is measured for the first time.

Thereafter, the A771726 plasma concentration must be determined again after an interval of at least 14

days. If both plasma concentrations are below 0.02 mg/l no teratogenic risk is to be expected.

For further information on the sample testing please contact the Marketing Authorisation Holder or its

local representative (see section 7).

Washout procedure

After stopping treatment with leflunomide:

colestyramine 8 g is administered 3 times daily for a period of 11 days,

alternatively, 50 g of activated powdered charcoal is administered 4 times daily for a period of 11 days.

However, also following either of the washout procedures, verification by 2 separate tests at an interval of

at least 14 days and a waiting period of one-and-a-half months between the first occurrence of a plasma

concentration below 0.02 mg/l and fertilisation is required.

Women of childbearing potential should be told that a waiting period of 2 years after treatment

discontinuation is required before they may become pregnant. If a waiting period of up to approximately

2 years under reliable contraception is considered unpractical, prophylactic institution of a washout

procedure may be advisable.

Both colestyramine and activated powdered charcoal may influence the absorption of oestrogens and

progestogens such that reliable contraception with oral contraceptives may not be guaranteed during the

washout procedure with colestyramine or activated powdered charcoal. Use of alternative contraceptive

methods is recommended.

Breast-feeding

Animal studies indicate that leflunomide or its metabolites pass into breast milk. Breast- feeding women

must, therefore, not receive leflunomide.

Fertility

Results of animal fertility studies have shown no effect on male and female fertility, but adverse effects

on male reproductive organs were observed in repeated dose toxicity studies.

4.7 Effects on ability to drive and use machines

In the case of side effects such as dizziness the patient's ability to concentrate and to react properly may

be impaired.

In such cases patients should refrain from driving cars and using machines.

4.8 Undesirable effects

Summary of the safety profile

The most frequently reported adverse effects with leflunomide are: mild increase in blood pressure,

leucopenia, paraesthesia, headache, dizziness, diarrhoea, nausea, vomiting, oral mucosal disorders (e.g.

aphthous stomatitis, mouth ulceration), abdominal pain, increased hair loss, eczema, rash (including

maculo-papular rash), pruritus, dry skin, tenosynovitis, CPK increased, anorexia, weight loss (usually

insignificant), asthenia, mild allergic reactions and elevation of liver parameters (transaminases

(especially ALT), less often gamma-GT, alkaline phosphatise, bilirubin)).

Classification of expected frequencies:

Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to

<1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations

Rare:

severe infections, including sepsis which may be fatal

Like other agents with immunosuppressive potential, leflunomide may increase susceptibility to infections,

including opportunistic infections (see also section 4.4). Thus, the overall incidence of infections can

increase (in particular of rhinitis, bronchitis and pneumonia).

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

The risk of malignancy, particularly lymphoproliferative disorders, is increased with use of some

immunosuppressive agents.

Blood and lymphatic system disorders

Common:

leucopenia (leucocytes >2 G/l)

Uncommon:

anaemia, mild thrombocytopenia (platelets <100 G/l)

Rare:

pancytopenia (probably by antiproliferative mechanism), leucopenia (leucocytes <2 G/l),

eosinophilia

Very rare:

agranulocytosis

Recent, concomitant or consecutive use of potentially myelotoxic agents may be associated with a higher

risk of haematological effects.

Immune system disorders

Common:

mild allergic reactions

Very rare:

severe anaphylactic/anaphylactoid reactions, vasculitis, including cutaneous necrotizing

vasculitis

Metabolism and nutrition disorders

Common:

CPK increased

Uncommon:

hypokalaemia, hyperlipidemia, hypophosphataemia

Rare:

LDH increased

Not known:

hypouricemia

Psychiatric disorders

Uncommon:

anxiety

Nervous system disorders

Common:

paraesthesia, headache, dizziness

peripheral neuropathy

Cardiac disorders

Common:

mild increase in blood pressure

Rare:

severe increase in blood pressure

Respiratory, thoracic and mediastinal disorders

Rare:

interstitial lung disease (including interstitial pneumonitis), which may be fatal

Not known:

pulmonary hypertension

Gastrointestinal disorders

Common:

diarrhoea, nausea, vomiting, oral mucosal disorders (e.g., aphthous stomatitis, mouth

ulceration), abdominal pain, colitis (including microscopic colitis such as lymphocytic

colitis, collagenous colitis)

Uncommon:

taste disturbances

Very rare:

pancreatitis

Hepatobiliary disorders

Common:

elevation of liver parameters (transaminases [especially ALT], less often gamma-GT,

alkaline phosphatase, bilirubin)

Rare:

hepatitis, jaundice/cholestasis

Very rare:

severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal

Skin and subcutaneous tissue disorders

Common:

increased hair loss, eczema, rash (including maculopapular rash), pruritus, dry skin

Uncommon:

urticaria

Very rare:

toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme

Not known:

cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis, Drug Reaction

with Eosinophilia and Systemic Symptoms (DRESS)

Musculoskeletal and connective tissue disorders

Common:

tenosynovitis

Uncommon:

tendon rupture

Renal and urinary disorders

Not known:

renal failure

Reproductive system and breast disorders

Not known:

marginal (reversible) decreases in sperm concentration, total sperm count and rapid

progressive motility

General disorders and administration site conditions

Common:

anorexia, weight loss (usually insignificant), asthenia

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 www.mhra.gov.uk/yellowcard

4.9 Overdose

Symptoms

There have been reports of chronic overdose in patients taking leflunomide tablets at daily doses up to

five times the recommended daily dose, and reports of acute overdose in adults and children. There were

no adverse events reported in the majority of case reports of overdose. Adverse events consistent with the

safety profile for leflunomide were: abdominal pain, nausea, diarrhoea, elevated liver enzymes, anaemia,

leucopenia, pruritus and rash.

Management

In the event of an overdose or toxicity, colestyramine or charcoal is recommended to accelerate

elimination. Colestyramine given orally at a dose of 8 g three times a day for 24 hours to three healthy

volunteers decreased plasma levels of A771726 by approximately 40% in 24 hours and by 49% to 65% in

48 hours.

Administration of activated charcoal (powder made into a suspension) orally or via nasogastric tube (50 g

every 6 hours for 24 hours) has been shown to reduce plasma concentrations of the active metabolite

A771726 by 37% in 24 hours and by 48% in 48 hours.

These washout procedures may be repeated if clinically necessary.

Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that

A771726, the primary metabolite of leflunomide, is not dialysable.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: selective immunosuppressants, ATC code: L04AA13.

Human pharmacology

Leflunomide is a disease-modifying anti-rheumatic agent with antiproliferative properties.

Animal pharmacology

Leflunomide is effective in animal models of arthritis and of other autoimmune diseases and

transplantation, mainly if administered during the sensitisation phase. It has immunomodulating/

immunosuppressive characteristics, acts as an antiproliferative agent, and displays anti-inflammatory

properties. Leflunomide exhibits the best protective effects on animal models of autoimmune diseases

when administered in the early phase of the disease progression. In vivo, it is rapidly and almost

completely metabolised to A771726 which is active in vitro, and is presumed to be responsible for the

therapeutic effect.

Mechanism of action

A771726, the active metabolite of leflunomide, inhibits the human enzyme dihydroorotate dehydrogenase

(DHODH) and exhibits antiproliferative activity.

Clinical efficacy and safety

The efficacy of leflunomide in the treatment of rheumatoid arthritis was demonstrated in 4 controlled

trials (1 in phase II and 3 in phase III). The phase II trial, study YU203, randomised 402 subjects with

active rheumatoid arthritis to placebo (n=102), leflunomide 5 mg (n=95), 10 mg (n=101) or 25 mg/day

(n=104). The treatment duration was 6 months.

All leflunomide patients in the phase III trials used an initial dose of 100 mg for 3 days. Study MN301

randomised 358 subjects with active rheumatoid arthritis to leflunomide 20 mg/day (n=133), sulfasalazine

2 g/day (n=133), or placebo (n=92). Treatment duration was 6 months.

Study MN303 was an optional 6-month blinded continuation of MN301 without the placebo arm,

resulting in a 12-month comparison of leflunomide and sulfasalazine. Study MN302 randomised 999

subjects with active rheumatoid arthritis to leflunomide 20 mg/day (n=501) or methotrexate at 7.5

mg/week increasing to 15 mg/week (n=498). Folate supplementation was optional and only used in 10%

of patients. Treatment duration was 12-months.

Study US301 randomised 482 subjects with active rheumatoid arthritis to leflunomide 20 mg/day

(n=182), methotrexate 7.5 mg/week increasing to 15 mg/week (n=182), or placebo (n=118). All patients

received folate 1 mg bid. Treatment duration was 12 months.

Leflunomide at a daily dose of at least 10 mg (10 to 25 mg in study YU203, 20 mg in studies MN301 and

US301) was statistically significantly superior to placebo in reducing the signs and symptoms of

rheumatoid arthritis in all 3 placebo-controlled trials. The ACR (American College of Rheumatology)

response rates in study YU203 were 27.7% for placebo, 31.9% for 5 mg, 50.5% for 10 mg and 54.5% for

25 mg/day. In the phase III trials, the ACR response rates for leflunomide 20 mg/day vs. placebo were

54.6% vs. 28.6% (study MN301), and 49.4% vs. 26.3% (study US301).After 12 months with active

treatment, the ACR response rates in leflunomide patients were 52.3% (studies MN301/303), 50.5%

(study MN302) and 49.4% (study US301), compared to 53.8% (studies MN301/303) in sulfasalazine

patients, 64.8% (study MN302), and 43.9% (study US301) in methotrexate patients. In study MN302

leflunomide was significantly less effective than methotrexate. However, in study US301 no significant

differences were observed between leflunomide and methotrexate in the primary efficacy parameters. No

difference was observed between leflunomide and sulfasalazine (study MN301). The leflunomide

treatment effect was evident by 1 month, stabilised by 3 to 6 months and continued throughout the course

of treatment.

A randomised, double-blind, parallel-group non-inferiority study compared the relative efficacy of two

different daily maintenance doses of leflunomide, 10 mg and 20 mg. From the results it can be concluded

that efficacy results of the 20 mg maintenance dose were more favourable, on the other hand, the safety

results favoured the 10 mg daily maintenance dose.

Paediatric population

Leflunomide was studied in a single multicenter, randomized, double-blind, active- controlled trial in 94

patients (47 per arm) with polyarticular course juvenile rheumatoid arthritis. Patients were 3–17 years of

age with active polyarticular course JRA regardless of onset type and naive to methotrexate or

leflunomide. In this trial, the loading dose and maintenance dose of leflunomide was based on three

weight categories: <20 kg, 20-40 kg and >40 kg. After 16 weeks treatment, the difference in response

rates was statistically significant in favour of methotrexate for the JRA Definition of Improvement (DOI)

≥30% (p=0.02). In responders, this response was maintained during 48 weeks (see section 4.2). The

pattern of adverse events of leflunomide and methotrexate seems to be similar, but the dose used in

lighter subjects resulted in a relatively low exposure (see section 5.2).

These data do not allow an effective and safe dose recommendation.

Postmarketing Studies

A randomised study assessed the clinical efficacy response rate in DMARD-naïve patients (n=121)with

early RA, who received either 20 mg or 100 mg of leflunomide in two parallel groups during the initial

three day double blind period. The initial period was followed by an open label maintenanceperiod of

three months, during which both groups received leflunomide 20 mg daily. No incremental overall benefit

was observed in the studied population with the use of a loading dose regimen. Thesafety data obtained

from both treatment groups were consistent with the known safety profile of leflunomide, however, the

incidence of gastrointestinal adverse events and of elevated liver enzymestended to be higher in the

patients receiving the loading dose of 100 mg leflunomide.

5.2 Pharmacokinetic properties

Leflunomide is rapidly converted to the active metabolite, A771726, by first-pass metabolism (ring

opening) in gut wall and liver. In a study with radiolabelled 14C- leflunomide in three healthy volunteers,

no unchanged leflunomide was detected in plasma, urine or faeces. In other studies, unchanged

leflunomide levels in plasma have rarely been detected, however, at ng/ml plasma levels. The only

plasma-radiolabelled metabolite detected was A771726. This metabolite is responsible for essentially all

the in vivo activity of leflunomide.

Absorption

Excretion data from the

C study indicated that at least about 82 to 95% of the dose is absorbed. The

time to peak plasma concentrations of A771726 is very variable; peak plasma levels can occur between 1

hour and 24 hours after single administration. Leflunomide can be administered with food, since the

extent of absorption is comparable in the fed and fasting state. Due to the very long half-life of A771726

(approximately 2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the

rapid attainment of steady-state levels of A771726. Without a loading dose, it is estimated that attainment

of steady-state plasma concentrations would require nearly two months of dosing. In multiple dose studies

in patients with rheumatoid arthritis, the pharmacokinetic parameters of A771726 were linear over the

dose range of 5 to 25 mg. In these studies, the clinical effect was closely related to the plasma

concentration of A771726 and to the daily dose of leflunomide.

At a dose level of 20 mg/day, average plasma concentration of A771726 at steady state is approximately

35 μg/ml.

At steady state plasma levels accumulate about 33- to 35-fold compared with single dose.

Distribution

In human plasma, A771726 is extensively bound to protein (albumin). The unbound fraction of A771726

is about 0.62%. Binding of A771726 is linear in the therapeutic concentration range. Binding of A771726

appeared slightly reduced and more variable in plasma from patients with rheumatoid arthritis or chronic

renal insufficiency.

The extensive protein binding of A771726 could lead to displacement of other highly-bound drugs. In

vitro plasma protein binding interaction studies with warfarin at clinically relevant concentrations,

however, showed no interaction. Similar studies showed that ibuprofen and diclofenac did not displace

A771726, whereas the unbound fraction of A771726 is increased 2- to 3-fold in the presence of

tolbutamide. A771726 displaced ibuprofen, diclofenac and tolbutamide but the unbound fraction of these

drugs is only increased by 10% to 50%. There is no indication that these effects are of clinical relevance.

Consistent with extensive protein binding A771726 has a low apparent volume of distribution

(approximately 11 litres). There is no preferential uptake in erythrocytes.

Biotransformation

Leflunomide is metabolised to one primary (A771726) and many minor metabolites including TFMA (4-

trifluoromethylaniline). The metabolic biotransformation of leflunomide to A771726 and subsequent

metabolism of A771726 is not controlled by a single enzyme and has been shown to occur in microsomal

and cytosolic cellular fractions. Interaction studies with cimetidine (non-specific cytochrome P450

inhibitor) and rifampicin (non-specific cytochrome P450 inducer), indicate that in vivo CYP enzymes are

involved in the metabolism of leflunomide only to a small extent.

Elimination

Elimination of A771726 is slow and characterised by an apparent clearance of about 31 ml/hr. The

elimination half-life in patients is approximately 2 weeks. After administration of a radiolabelled dose of

leflunomide, radioactivity was equally excreted in faeces, probably by biliary elimination, and in urine.

A771726 was still detectable in urine and faeces 36 days after a single administration. The principal

urinary metabolites were glucuronide products derived from leflunomide (mainly in 0 to 24 hour samples)

and an oxanilic acid derivative of A771726. The principal faecal component was A771726.

It has been shown in man that administration of an oral suspension of activated powdered charcoal or

colestyramine leads to a rapid and significant increase in A771726 elimination rate and decline in plasma

concentrations (see section 4.9). This is thought to be achieved by a gastrointestinal dialysis mechanism

and/or by interrupting enterohepatic recycling.

Renal impairment

Leflunomide was administered as a single oral 100 mg dose to 3 haemodialysis patients and 3 patients on

continuous peritoneal dialysis (CAPD). The pharmacokinetics of A771726 in CAPD subjects appeared to

be similar to healthy volunteers. A more rapid elimination of A771726 was observed in haemodialysis

subjects which was not due to extraction of drug in the dialysate.

Hepatic impairment

No data are available regarding treatment of patients with hepatic impairment. The active metabolite

A771726 is extensively protein bound and cleared via hepatic metabolism and biliary secretion. These

processes may be affected by hepatic dysfunction.

Paediatric population

The pharmacokinetics of A771726 following oral administration of leflunomide have been investigated in

73 pediatric patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA) who ranged in age

from 3 to 17 years. The results of a population pharmacokinetic analysis of these trials have demonstrated

that pediatric patients with body weights ≤40 kg have a reduced systemic exposure (measured by Css) of

A771726 relative to adult rheumatoid arthritis patients (see section 4.2).

Elderly

Pharmacokinetic data in elderly (>65 years) are limited but consistent with pharmacokinetics in younger

adults.

5.3 Preclinical safety data

Leflunomide, administered orally and intraperitoneally, has been studied in acute toxicity studies in mice

and rats. Repeated oral administration of leflunomide to mice for up to 3 months, to rats and dogs for up

to 6 months and to monkeys for up to 1 month's duration revealed that the major target organs for toxicity

were bone marrow, blood, gastrointestinal tract, skin, spleen, thymus and lymph nodes. The main effects

were anaemia, leucopenia, decreased platelet counts and panmyelopathy and reflect the basic mode of

action of the compound (inhibition of DNA synthesis). In rats and dogs, Heinz bodies and/or Howell-

Jolly bodies were found. Other effects found on heart, liver, cornea and respiratory tract could be

explained as infections due to immunosuppression. Toxicity in animals was found at doses equivalent to

human therapeutic doses.

Leflunomide was not mutagenic. However, the minor metabolite TFMA (4- trifluoromethylaniline)

caused clastogenicity and point mutations in vitro, whilst insufficient information was available on its

potential to exert this effect in vivo.

In a carcinogenicity study in rats, leflunomide did not show carcinogenic potential. In a carcinogenicity

study in mice an increased incidence of malignant lymphoma occurred in males of the highest dose group,

considered to be due to the immunosuppressive activity of leflunomide. In female mice an increased

incidence, dose-dependent, of bronchiolo- alveolar adenomas and carcinomas of the lung was noted. The

relevance of the findings in mice relative to the clinical use of leflunomide is uncertain.

Leflunomide was not antigenic in animal models.

Leflunomide was embryotoxic and teratogenic in rats and rabbits at doses in the human therapeutic range

and exerted adverse effects on male reproductive organs in repeated dose toxicity studies. Fertility was

not reduced.

6. Pharmaceutical particulars

6.1 List of excipients

Tablet core:

Cellulose microcrystalline

Pregelatinised starch maize

Povidone K 30 (E1201)

Crospovidone (E1202)

Silica colloidal anhydrous

Magnesium stearate (E470b)

Lactose monohydrate

Film-coating:

Titanium dioxide (E171)

Lactose monohydrate

Hypromellose (E464)

Macrogol 4000

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Leflunomide Mylan 10 mg film-coated tablets is packaged in a cardboard box containing PA/ALU/PVC –

Aluminum (Alu/Alu) foil blisters or a white opaque HDPE bottle with tamper- evident closure with an

integrated desiccant (white silica gel) or desiccant sachet.

Pack sizes: 30, 100 film-coated tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Generics UK Ltd. t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

U.K.

8. Marketing authorisation number(s)

PL 04569/1122

9. Date of first authorisation/renewal of the authorisation

02/06/2011

10. Date of revision of the text

06/2017

Company Contact Details

Generics UK T/A Mylan

Address

Building 4, Trident Place, Mosquito Way, Hatfield, Hertfordshire, AL10 9UL

Telephone

+44 (0)1707 853 000

Medical Information Direct Line

+44 (0)1707 853 000

Customer Care direct line

+44 (0)1707 853 000 select option 2

Stock Availability

+44 (0)1707 853 000 select option 2

http://www.mylan.com

+44 (0)1707 261 803

Medical Information e-mail

[email

protected]

Medical Information Fax

+44 (0)1707 261 803

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