Patient Information Leaflet: Information for the User

Arava 10 mg film-coated tablets

leflunomide
Please read all of this leaflet carefully before taking this medicine because it contains
important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor, pharmacist, or nurse.
This medicine has been prescribed for you only. Do not give it to other people, even if they have the same symptoms as you, because it may be harmful.
If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

What Arava is and what it is used for
What you need to know before taking Arava
How to take Arava
Possible side effects
How to store Arava
Contents of the pack and other information

1. What Arava is and what it is used for

Arava belongs to a group of medicines called disease-modifying antirheumatic drugs (DMARDs). It contains the active substance leflunomide.
Arava is used to treat adult patients with active rheumatoid arthritis or active psoriatic arthritis.
Symptoms of rheumatoid arthritis include joint inflammation, swelling, difficulty in movement, and pain. Other symptoms that may affect the whole body include loss of appetite, fever, loss of strength, and anaemia (reduction in the number of red blood cells).
Symptoms of active psoriatic arthritis include joint inflammation, swelling, difficulty in movement, pain, and red, scaly skin patches (skin lesions).

2. What you need to know before taking Arava

Do not take Arava:

if you have previously had an allergic reaction to leflunomide (especially a severe skin reaction, often accompanied by fever, joint pain, red skin spots or blisters, such as Stevens-Johnson syndrome) or to any of the other ingredients of this medicine (listed in section 6), or if you are allergic to teriflunomide (used to treat multiple sclerosis),
if you have any liver problems,
if you have moderate or severe kidney problems,
if you have extremely low protein levels in the blood (hypoproteinemia),
if you suffer from any condition affecting your immune system (e.g. AIDS),
if you have any bone marrow disorder or if your red blood cell or white blood cell count is low, or if your platelet count is reduced,
if you have a serious infection,
if you are pregnant, planning to become pregnant, or breastfeeding.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before taking Arava

if you have ever had lung inflammation (interstitial lung disease).
if you have ever had tuberculosis or have been in close contact with someone who has or has had tuberculosis. Your doctor may perform tests to check whether you have tuberculosis.
if you are male and intend to father a child. Since it cannot be ruled out that Arava passes into semen, you must use a reliable contraceptive method during treatment with Arava. Men who intend to father a child should contact their doctor, who may advise stopping Arava treatment and taking certain medications to rapidly and adequately remove Arava from the body. After this, a blood test must be performed to confirm that Arava has been sufficiently eliminated from the body, and you must then wait at least another 3 months before attempting conception.
if you need to undergo a specific blood test (calcium level). Falsely low calcium levels may be observed.
if you are scheduled for or have recently undergone major surgery, or if you still have an unhealed surgical wound. ARAVA may impair wound healing.

Rarely, Arava can cause problems affecting the blood, liver, lungs, or nerves in the arms or legs. Arava may also cause some serious allergic reactions (including drug reaction with eosinophilia and systemic symptoms [DRESS]) or increase the risk of serious infections. For further information, see section 4 (Possible side effects).
DRESS syndrome initially presents with flu-like symptoms and a rash on the face, followed by widespread rash with fever, elevated liver enzyme levels, increased levels of a type of white blood cell (eosinophilia) in blood tests, and swollen lymph nodes.
Before starting Arava and during treatment, your doctor will prescribe regular blood tests to monitor your blood cells and liver function. Your doctor will also check your blood pressure regularly, as Arava may cause an increase in blood pressure.
Inform your doctor if you develop unexplained chronic diarrhea. Your doctor may perform additional tests for differential diagnosis.
Inform your doctor if you develop a skin ulcer during treatment with Arava (see also section 4).

Children and adolescents
The use of Arava is not recommended in children and adolescents under 18 years of age.

Other medicines and Arava
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. This includes medicines purchased without a prescription.
This information is particularly important if you are taking:

other medicines for the treatment of rheumatoid arthritis such as antimalarials (e.g. chloroquine and hydroxychloroquine), gold salts administered intramuscularly or orally, D-penicillamine, azathioprine, and other immunosuppressive medicines (e.g. methotrexate), as these combinations are not recommended,
warfarin and other oral medicines used to thin the blood, as monitoring is required to reduce the risk of side effects from this medicine,
teriflunomide for multiple sclerosis,
repaglinide, pioglitazone, nateglinide, or rosiglitazone for diabetes,
daunorubicin, doxorubicin, paclitaxel, or topotecan for cancer,
duloxetine for depression, urinary incontinence, or kidney disease in diabetics,
alosetron for managing severe diarrhea,
theophylline for asthma,
tizanidine, to relax muscles,
oral contraceptives (containing ethinylestradiol and levonorgestrel),
cefaclor, benzylpenicillin (penicillin G), ciprofloxacin for infections,
indomethacin, 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,
a medicine called colestyramine (used to lower cholesterol) or activated charcoal, as these medicines may reduce the amount of Arava absorbed by the body.

If you are already taking non-steroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids, you may continue taking them after starting Arava treatment.

Vaccinations
If you need to be vaccinated, consult your doctor. Certain vaccinations should not be given while you are taking Arava, and for a certain period after stopping treatment.

Arava with food, drinks, and alcohol
Arava may be taken with or without food.
It is recommended that you avoid drinking alcohol during treatment with Arava. Drinking alcohol while taking Arava may increase the risk of liver damage.

Pregnancy and breastfeeding
Do not take Arava if you are pregnant or think you might be pregnant. If you become pregnant while being treated with Arava, the risk of having a baby with serious birth defects is increased. Women of childbearing potential must not take Arava without using reliable contraceptive measures.
If you plan to become pregnant after stopping Arava treatment, it is important to inform your doctor in advance, as you must ensure that all traces of Arava have been eliminated from your body before attempting to conceive. Elimination of Arava from the body may take up to two years. This period can be reduced to a few weeks by taking certain medications that accelerate the removal of Arava from the body.
In either case, blood tests must confirm that Arava has been sufficiently eliminated from your body before you become pregnant, and you must then wait at least one additional month.
For further information on laboratory tests, contact your doctor.
If you suspect you are pregnant during treatment with Arava or within two years after stopping treatment, you must inform your doctor immediately, who will arrange for a pregnancy test. If this confirms that you are pregnant, your doctor will advise treatment with certain medications to rapidly and adequately remove Arava from your body, thereby reducing the risk to your baby.

Do not take Arava during breastfeeding, as leflunomide passes into breast milk.

Driving and using machines
Arava may make you feel unsteady, and this sensation may affect your ability to concentrate and react. If this occurs, do not drive and do not operate machinery.

Arava contains lactose
If your doctor has informed you that you have an intolerance to certain sugars, contact your doctor before taking this medicine.

3. How to take Arava

Always take this medicine exactly as instructed by your doctor or pharmacist. If
you have any doubts, consult your doctor or pharmacist.
The usual starting dose of Arava is 100 mg of leflunomide once daily for the first three
days. Afterwards, most patients require:

for rheumatoid arthritis: a daily dose of 10 or 20 mg of Arava, depending on the severity of the disease.
for psoriatic arthritis: a daily dose of 20 mg of Arava.

Swallow the tablet whole with plenty of water.
It may take approximately 4 weeks or longer before you begin to notice an
improvement in your condition. Some patients may continue to experience further improvements even
after 4–6 months of treatment.
Generally, Arava is taken for long periods of time.
If you take more Arava than you should
If you take more Arava than you should, contact your doctor or seek medical advice immediately.
If possible, bring the tablets or the pack with you to show your doctor.
If you forget to take Arava
If you forget to take a dose, take it as soon as you remember, unless it is almost time for your next dose.
Do not take a double dose to make up for the missed dose.
If you have any questions about the use of this medicine, ask your doctor, pharmacist, or
nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Stop treatment with Arava and contact your doctor immediately if:

you experience a feeling of weakness, lightheadedness or dizziness, or if you have difficulty breathing, as these signs may indicate a severe allergic reaction,
you develop skin redness or mouth ulcers, as these signs may indicate serious, sometimes fatal, allergic reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, drug reaction with eosinophilia and systemic symptoms [DRESS]); see section 2.

Contact your doctor immediately if you experience:

pallor, fatigue or bruising, as these may indicate blood disorders caused by an imbalance between the different types of blood cells,
fatigue, abdominal pain or jaundice (yellowing of the eyes or skin), as these may indicate serious liver problems such as liver failure, which can be fatal,
any signs of infection such as fever, sore throat or cough, as this medicine may increase the incidence of serious, potentially life-threatening infections,
cough or breathing problems, as these may indicate lung problems (interstitial lung disease or pulmonary hypertension),
unusual tingling, weakness or pain in the hands or feet, as these may indicate nerve problems (peripheral neuropathy).

Common side effects (may affect up to 1 in 10 people)

mild decrease in white blood cell count (leucopenia),
mild allergic reactions,
loss of appetite, decrease in body weight (usually not significant),
fatigue (asthenia),
headache, dizziness,
abnormal skin sensations such as tingling (paraesthesiae),
moderate increase in blood pressure,
colitis,
diarrhoea,
nausea, vomiting,
mouth inflammation or mouth ulcers,
abdominal pain,
increased values in some liver function tests,
increased hair loss,
eczema, dry skin, redness, itching,
tendinitis (pain due to inflammation of the sheath covering tendons, usually in feet or hands),
increased levels of certain blood enzymes (creatine phosphokinase),
nerve problems in arms or legs (peripheral neuropathy).

Uncommon side effects (may affect up to 1 in 100 people)

decrease in red blood cell count (anaemia) and decrease in platelet count (thrombocytopenia),
decreased potassium levels in the blood,
anxiety,
taste disturbances,
urticaria (red, itchy rash),
tendon rupture,
increased levels of fats in the blood (cholesterol and triglycerides),
decreased phosphate levels in the blood.

Rare side effects (may affect up to 1 in 1,000 people)

increase in blood cells called eosinophils (eosinophilia); mild decrease in white blood cell count (leucopenia); reduction in all blood cells (pancytopenia),
increased blood pressure,
lung inflammation (interstitial lung disease),
increased liver function test values that may lead to serious clinical conditions such as hepatitis and jaundice,
severe infections known as sepsis, which may be fatal,
increased levels of certain enzymes in the blood (lactate dehydrogenase).

Very rare side effects (may affect up to 1 in 10,000 people)

marked decrease in certain white blood cells (agranulocytosis),
severe and potentially serious allergic reactions,
inflammation of blood vessels (vasculitis, including necrotizing cutaneous vasculitis),
inflammation of the pancreas (pancreatitis),
severe liver damage such as liver failure or necrosis, which may be fatal,
serious, sometimes fatal reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme).

Other side effects may also occur with unknown frequency, such as kidney failure,
decreased levels of uric acid in the blood, pulmonary hypertension, male infertility (which is
reversible when treatment with this medicine is stopped), cutaneous lupus (characterized
by rash/erythema in skin areas exposed to light), psoriasis (onset or worsening),
DRESS, and skin ulcer (a round, open sore in the skin through which underlying tissues can be seen).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system referred to in Annex V.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Arava

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the outer packaging.
The expiry date refers to the last day of the month.
Blister packs: store in the original packaging.
Bottles: keep the bottle tightly closed.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What Arava contains

The active substance is leflunomide. Each film-coated tablet contains 10 mg of leflunomide.
The other components are: maize starch, povidone (E1201), crospovidone (E1202), anhydrous colloidal silica, magnesium stearate (E470b) and monohydrate lactose in the tablet core; talc (E553b), hypromellose (E464), titanium dioxide (E171) and macrogol 8000 in the coating.

Description of the appearance of Arava and contents of the pack
Arava 10 mg film-coated tablets are white or almost white and round.
Marked on one side: ZBN.
The tablets are packed in blisters or bottles.
Pack sizes of 30 and 100 tablets are available.
Not all pack sizes may be marketed.

Marketing Authorization Holder
Sanofi-aventis Deutschland GmbH
D-65926 Frankfurt am Main, Germany

Manufacturer
Opella Healthcare International SAS
56, Route de Choisy
60200 Compiègne
France

For further information on this medicinal product, please contact the local representative of the Marketing Authorization Holder.

België/Belgique/Belgien Lietuva
Sanofi Belgium Swixx Biopharma UAB
Tél/Tel: +32 (0)2 710 54 00 Tel: +370 5 236 91 40

България Luxembourg/Luxemburg
Swixx Biopharma EOOD Sanofi Belgium
Тел.: +359 (0)2 4942 480 Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien)

Česká republika Magyarország
Sanofi s.r.o. SANOFI-AVENTIS Zrt.
Tel: +420 233 086 111 Tel.: +36 1 505 0050

Danmark Malta
Sanofi A/S Sanofi S.r.l.
Tlf: +45 45 16 70 00 Tel: +39 02 39394275

Deutschland Nederland
Sanofi-Aventis Deutschland GmbH Sanofi B.V.
Tel.: 0800 52 52 010 Tel: +31 20 245 4000
Tel. aus dem Ausland: +49 69 305 21 131

Eesti Norge
Swixx Biopharma OÜ sanofi-aventis Norge AS
Tel: +372 640 10 30 Tlf: +47 67 10 71 00

Ελλάδα Österreich
Sanofi-Aventis Μονοπρόσωπη AEBE sanofi-aventis GmbH
Τηλ: +30 210 900 16 00 Tel: +43 1 80 185 – 0

España Polska
sanofi-aventis, S.A. Sanofi Sp. z o.o.
Tel.: +48 22 280 00 00
Tel: +34 93 485 94 00

France Portugal
Sanofi Winthrop Industrie Sanofi - Produtos Farmacêuticos, Lda
Tél: 0 800 222 555 Tel: +351 21 35 89 400
Appel depuis l’étranger : +33 1 57 63 23 23

Hrvatska România
Swixx Biopharma d.o.o. Sanofi Romania SRL
Tel: +385 1 2078 500 Tel: +40 (0) 21 317 31 36

Ireland Slovenija
sanofi-aventis Ireland Ltd. T/A SANOFI Swixx Biopharma d.o.o.
Tel: +353 (0) 1 403 56 00 Tel: +386 1 235 51 00

Ísland Slovenská republika
Vistor hf. Swixx Biopharma s.r.o.
Sími: +354 535 7000 Tel: +421 2 208 33 600

Italia Suomi/Finland
Sanofi S.r.l. Sanofi Oy
Tel: 800 536389 Puh/Tel: +358 (0) 201 200 300

Κύπρος Sverige
C.A. Papaellinas Ltd. Sanofi AB
Τηλ: +357 22 741741 Tel: +46 (0)8 634 50 00

Latvija United Kingdom (Northern Ireland)
Swixx Biopharma SIA sanofi-aventis Ireland Ltd. T/A SANOFI
Tel: +371 6 616 47 50 Tel: +44 (0) 800 035 2525

This leaflet was last updated on:

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu/.

Package Leaflet: Information for the User

Arava 20 mg film-coated tablets

leflunomide
Please read this leaflet carefully before taking this medicine because it contains
important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor, pharmacist or nurse.
This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it could be harmful.
If you experience any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet:

What Arava is and what it is used for
What you need to know before taking Arava
How to take Arava
Possible side effects
How to store Arava
Contents of the pack and other information

1. What Arava is and what it is used for

Arava belongs to a group of medicines called disease-modifying antirheumatic drugs (DMARDs).
Arava is used to treat adult patients with active rheumatoid arthritis or active psoriatic arthritis.
Symptoms of rheumatoid arthritis include joint inflammation, swelling, limited mobility, and pain. Other systemic symptoms may include loss of appetite, fever, weakness, and anemia (reduced number of red blood cells).
Symptoms of active psoriatic arthritis include joint inflammation, swelling, limited mobility, pain, and red, scaly skin patches (skin lesions).

2. What you should know before taking Arava

Do not take Arava

if you have previously experienced an allergic reaction to leflunomide (especially a severe skin reaction, often accompanied by fever, joint pain, red skin spots or blisters, for example Stevens-Johnson syndrome) or to any of the other ingredients of this medicine (listed in section 6), or if you are allergic to teriflunomide (used to treat multiple sclerosis),
if you have any liver problems,
if you have moderate or severe kidney problems,
if you have extremely low blood protein levels (hypoproteinemia),
if you suffer from any condition affecting your immune system (e.g. AIDS),
if you have any bone marrow disorder, or if your red blood cell or white blood cell count is low, or if your platelet count is reduced,
if you have a serious infection,
if you are pregnant, planning to become pregnant, or breastfeeding.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before taking Arava

if you have ever had lung inflammation (interstitial lung disease).
if you have ever had tuberculosis or have been in close contact with someone who has or has had tuberculosis. Your doctor may carry out tests to check whether you have tuberculosis.
if you are male and intend to father a child. Since it cannot be ruled out that Arava passes into semen, a reliable contraceptive method must be used during treatment with Arava. Men who intend to father a child should contact their doctor, who may advise stopping treatment with Arava and taking certain medications to rapidly and sufficiently eliminate Arava from the body. Afterwards, a blood test must be performed to ensure that Arava has been sufficiently removed from the body, and then you must wait at least another 3 months before attempting conception.
if you are due to have a specific blood test (calcium level). False low calcium levels may be observed.
if you are scheduled for or have recently undergone major surgery, or if you still have an unhealed wound following surgery. ARAVA may impair wound healing.

Rarely, Arava may cause problems affecting the blood, liver, lungs, or nerves in the arms or legs. Arava may also cause some serious allergic reactions (including drug reaction with eosinophilia and systemic symptoms [DRESS]), or increase the risk of serious infections. For further information, read section 4 (Possible side effects).
DRESS syndrome initially presents with flu-like symptoms and a rash on the face, followed by widespread rash, fever, elevated liver enzyme levels, increased levels of a type of white blood cell (eosinophilia) in blood tests, and swollen lymph nodes.
Before starting Arava and during treatment, your doctor will prescribe regular blood tests to monitor your blood cells and liver function. Your doctor will also regularly check your blood pressure, as Arava may cause an increase in blood pressure.
Inform your doctor if you have unexplained chronic diarrhea. Your doctor may perform additional tests for differential diagnosis.
Inform your doctor if a skin ulcer develops during treatment with Arava (see also section 4).

Children and adolescents
The use of Arava is not recommended in children and adolescents under 18 years of age.

other medicines for the treatment of rheumatoid arthritis, such as antimalarials (e.g. chloroquine and hydroxychloroquine), gold salts administered intramuscularly or orally, D-penicillamine, azathioprine, and other immunosuppressive medicines (e.g. methotrexate), as these combinations are not recommended,
warfarin and other oral anticoagulants used to thin the blood, as monitoring is required to reduce the risk of side effects,
teriflunomide for multiple sclerosis,
repaglinide, pioglitazone, nateglinide, or rosiglitazone for diabetes,
daunorubicin, doxorubicin, paclitaxel, or topotecan for cancer,
duloxetine for depression, urinary incontinence, or kidney disease in diabetics,
alosetron for managing severe diarrhea,
theophylline for asthma,
tizanidine, to relax muscles,
oral contraceptives (containing ethinylestradiol and levonorgestrel),
cefaclor, benzylpenicillin (penicillin G), ciprofloxacin for infections,
indomethacin, 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,
a medicine called colestyramine (used to lower cholesterol) or activated charcoal, as these medicines may reduce the amount of Arava absorbed by the body.

If you are already taking non-steroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids, you may continue taking them after starting Arava treatment.

Vaccinations
If you need to be vaccinated, consult your doctor. Certain vaccinations should not be administered while taking Arava, and for a certain period after stopping treatment.

Arava with food, drinks, and alcohol
Arava may be taken with or without food.
It is recommended not to drink alcohol during treatment with Arava. Drinking alcohol while taking Arava may increase the risk of liver damage.

Pregnancy and breastfeeding
Do not take Arava if you are pregnant or think you might be pregnant. If you become pregnant while taking Arava, the risk of having a baby with serious birth defects is increased. Women of childbearing potential must not take Arava without using reliable contraception.
If you plan to become pregnant after stopping Arava treatment, it is important to inform your doctor in advance, as you must ensure that all traces of Arava have been eliminated from your body before attempting to conceive. Elimination of Arava may take up to two years. This period can be reduced to a few weeks by taking certain medications that accelerate the removal of Arava from the body. In either case, blood tests must confirm that Arava has been sufficiently eliminated from your body before you attempt pregnancy, and after that, you must wait at least another month.
For further information about laboratory tests, contact your doctor.
If you suspect you are pregnant while taking Arava or within two years after stopping treatment, you must inform your doctor immediately, who will arrange for a pregnancy test. If pregnancy is confirmed, your doctor will advise treatment with certain medications to rapidly and sufficiently eliminate Arava from your body, thereby reducing the risk to your baby.

Do not take Arava during breastfeeding, as leflunomide passes into breast milk.

Driving and using machines
Arava may make you feel unsteady, and this sensation may impair your ability to concentrate and react. In this case, do not drive or operate machinery.

Arava contains lactose
If your doctor has informed you that you have an intolerance to certain sugars, contact your doctor before taking this medicine.

3. How to take Arava

Always take this medicine exactly as instructed by your doctor or pharmacist. If
you have any doubts, consult your doctor or pharmacist.
The initial dose of Arava is usually 100 mg of leflunomide once daily for the first three
days. Afterwards, most patients require:

for rheumatoid arthritis: a daily dose of 10 or 20 mg of Arava, depending on the severity of the disease,
for psoriatic arthritis: a daily dose of 20 mg of Arava.

Take the tablet whole with plenty of water.
It may take approximately 4 weeks or longer before you begin to notice an
improvement in your condition. Some patients may experience further improvements even
after 4–6 months of treatment.
Generally, Arava is taken for long periods of time.
If you take more Arava than you should
If you take more Arava than you should, contact your doctor or seek medical advice immediately.
If possible, bring the tablets or the pack with you to show your doctor.
If you forget to take Arava
If you forget to take a dose, take it as soon as you remember, unless it is almost time for your next dose.
Do not take a double dose to make up for a forgotten dose.
If you have any questions about the use of this medicine, ask your doctor, pharmacist, or
nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
Stop treatment with Arava and contact your doctor immediately if:

you feel weak, lightheaded or dizzy, or have difficulty breathing, as these signs may indicate a severe allergic reaction,
you develop skin redness or mouth ulcers, as these signs may indicate serious, sometimes fatal, allergic reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, drug reaction with eosinophilia and systemic symptoms [DRESS]); see section 2.

Contact your doctor immediately if you experience:

pallor, fatigue or bruising, as these may indicate blood disorders caused by an imbalance between the different types of blood cells,
fatigue, abdominal pain or jaundice (yellowing of the eyes or skin), as these may indicate serious conditions such as liver failure, which can be fatal,
any signs of infection such as fever, sore throat or cough, as this medicine may increase the risk of serious, potentially life-threatening infections,
cough or breathing problems, as these may indicate lung problems (interstitial lung disease or pulmonary hypertension),
tingling, unusual weakness or pain in the hands or feet, as these may indicate nerve problems (peripheral neuropathy).

Common side effects (may affect up to 1 in 10 people)

mild decrease in white blood cell count (leucopenia),
mild allergic reactions,
loss of appetite, weight loss (usually not significant),
fatigue (asthenia),
headache, dizziness,
abnormal skin sensations such as tingling (paraesthesia),
moderate increase in blood pressure,
colitis,
diarrhoea,
nausea, vomiting,
mouth inflammation or mouth ulcers,
abdominal pain,
increased values in some liver function tests,
increased hair loss,
eczema, dry skin, redness and itching,
tendinitis (pain due to inflammation of the sheath covering tendons, usually in the feet or hands),
increased levels of certain blood enzymes (creatine phosphokinase),
nerve problems in arms or legs (peripheral neuropathy).

Uncommon side effects (may affect up to 1 in 100 people)

decrease in red blood cell count (anaemia) and decrease in platelet count (thrombocytopenia),
decreased potassium levels in the blood,
anxiety,
taste disturbances,
urticaria (red, itchy rash),
tendon rupture,
increased levels of fats in the blood (cholesterol and triglycerides),
decreased phosphate levels in the blood.

Rare side effects (may affect up to 1 in 1,000 people)

increased number of blood cells called eosinophils (eosinophilia); mild decrease in white blood cell count (leucopenia); reduction in all blood cell types (pancytopenia),
increased blood pressure,
lung inflammation (interstitial lung disease),
increased liver function test values that may lead to serious clinical conditions such as hepatitis and jaundice,
severe infections known as sepsis, which may be fatal,
increased levels of certain blood enzymes (lactate dehydrogenase).

Very rare side effects (may affect up to 1 in 10,000 people)

marked decrease in certain white blood cells (agranulocytosis),
severe and potentially life-threatening allergic reactions,
inflammation of blood vessels (vasculitis, including necrotizing cutaneous vasculitis),
inflammation of the pancreas (pancreatitis),
severe liver damage such as liver failure or necrosis, which may be fatal,
serious, sometimes fatal reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme).

Additionally, the following side effects may occur, with unknown frequency: kidney failure, decreased uric acid levels in the blood, pulmonary hypertension, male infertility (which is reversible when treatment with this medicine is stopped), cutaneous lupus (characterized by rash/erythema on skin areas exposed to light), psoriasis (onset or worsening), DRESS, and skin ulcer (a round, open sore in the skin through which underlying tissues may be visible).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system referred to in Annex V.
By reporting side effects, you help provide more information on the safety of this medicine.

5. How to store Arava

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the outer packaging.
The expiry date refers to the last day of the month.
Blister: store in the original packaging.
Bottle: keep the bottle tightly closed.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What Arava contains

The active substance is leflunomide. Each film-coated tablet contains 20 mg of leflunomide.
The other components are: maize starch, povidone (E1201), crospovidone (E1202), anhydrous colloidal silica, magnesium stearate (E470b) and monohydrate lactose in the tablet core, as well as talc (E553b), hypromellose (E464), titanium dioxide (E171), macrogol 8000 and yellow iron oxide (E172) in the coating.

Description of the appearance of Arava and contents of the pack
The 20 mg film-coated tablets of Arava are yellowish to ochre in colour and triangular in shape.
Marked on one side: ZBO.
The tablets are packed in blisters or bottles.
Pack sizes of 30, 50 and 100 tablets are available.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
Sanofi-Aventis Deutschland GmbH
D-65926 Frankfurt am Main, Germany

Manufacturer
Opella Healthcare International SAS
56, Route de Choisy
60200 Compiègne
France

For further information about this medicine, please contact the local representative of the Marketing Authorisation Holder.

België/Belgique/Belgien Lietuva
Sanofi Belgium Swixx Biopharma UAB
Tél/Tel: +32 (0)2 710 54 00 Tel: +370 5 236 91 40
България Luxembourg/Luxemburg
Swixx Biopharma EOOD Sanofi Belgium
Тел.: +359 (0)2 4942 480 Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien)
Česká republika Magyarország
Sanofi s.r.o. Tel: +420 233 086 111 SANOFI-AVENTIS Zrt.
Tel.: +36 1 505 0050
Danmark Malta
Sanofi A/S Sanofi S.r.l.
Tlf: +45 45 16 70 00 Tel: +39 02 39394275
Deutschland Nederland
Sanofi-Aventis Deutschland GmbH Sanofi B.V.
Tel.: 0800 52 52 010 Tel: +31 20 245 4000
Tel. aus dem Ausland: +49 69 305 21 131
Eesti Norge
Swixx Biopharma OÜ sanofi-aventis Norge AS
Tel: +372 640 10 30 Tlf: +47 67 10 71 00
Ελλάδα Österreich
Sanofi-Aventis Μονοπρόσωπη AEBE sanofi-aventis GmbH
Τηλ: +30 210 900 16 00 Tel: +43 1 80 185 – 0
España Polska
sanofi-aventis, S.A. Sanofi Sp. z o.o. Tel.: +48 22 280 00 00
Tel: +34 93 485 94 00
France Portugal
Sanofi Winthrop Industrie Sanofi - Produtos Farmacêuticos, Lda
Tél: 0 800 222 555 Tel: +351 21 35 89 400
Appel depuis l’étranger : +33 1 57 63 23 23
Hrvatska România
Swixx Biopharma d.o.o. Sanofi Romania SRL
Tel: +385 1 2078 500 Tel: +40 (0) 21 317 31 36
Ireland Slovenija
sanofi-aventis Ireland Ltd. T/A SANOFI Swixx Biopharma d.o.o.
Tel: +353 (0) 1 403 56 00 Tel: +386 1 235 51 00
Ísland Slovenská republika
Vistor hf. Swixx Biopharma s.r.o.
Sími: +354 535 7000 Tel: +421 2 208 33 600
Italia Suomi/Finland
Sanofi S.r.l. Sanofi Oy
Tel: 800 536389 Puh/Tel: +358 (0) 201 200 300
Κύπρος Sverige
C.A. Papaellinas Ltd. Sanofi AB
Τηλ: +357 22 741741 Tel: +46 (0)8 634 50 00
Latvija United Kingdom (Northern Ireland)
Swixx Biopharma SIA sanofi-aventis Ireland Ltd. T/A SANOFI
Tel: +371 6 616 47 50 Tel: +44 (0) 800 035 2525

This leaflet was last updated on:
Other sources of information
More detailed information on this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu/.

Package Leaflet: Information for the User

Arava 100 mg film-coated tablets

leflunomide
Please read this leaflet carefully before taking this medicine because it contains
important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor, pharmacist or nurse.
This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet:

What Arava is and what it is used for
What you need to know before taking Arava
How to take Arava
Possible side effects
How to store Arava
Contents of the pack and other information

1. What Arava is and what it is used for

Arava belongs to a group of medicines called disease-modifying antirheumatic drugs (DMARDs).
Arava is used to treat adult patients with active rheumatoid arthritis or active psoriatic arthritis.
Symptoms of rheumatoid arthritis include joint inflammation, swelling, limited mobility, and pain. Other symptoms that may affect the entire body include loss of appetite, fever, weakness, and anaemia (reduction in the number of red blood cells).
Symptoms of active psoriatic arthritis include joint inflammation, swelling, limited mobility, pain, and red, scaly skin patches (skin lesions).

2. What you need to know before taking Arava

Do not take Arava:

if you have previously had an allergic reaction to leflunomide (especially a severe skin reaction, often accompanied by fever, joint pain, red skin spots or blisters, for example Stevens-Johnson syndrome) or to any of the other ingredients of this medicine (listed in section 6), or if you are allergic to teriflunomide (used to treat multiple sclerosis),
if you have any liver problems,
if you have moderate or severe kidney problems,
if you have extremely low levels of proteins in the blood (hypoproteinemia),
if you suffer from any condition affecting your immune system (e.g. AIDS),
if you have any bone marrow disorder or if your red blood cell or white blood cell count is low, or if your platelet count is reduced,
if you have a severe infection,
if you are pregnant, planning to become pregnant, or breastfeeding.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before taking Arava:

if you have ever had inflammation of the lung (interstitial lung disease).
if you have ever had tuberculosis or have been in close contact with someone who has or has had tuberculosis. Your doctor may perform tests to check whether you have tuberculosis.
if you are male and intend to father a child. Since it cannot be ruled out that Arava passes into semen, you must use a reliable contraceptive method during treatment with Arava. Men who intend to father a child should contact their doctor, who may advise stopping Arava treatment and taking certain medications to rapidly and adequately remove Arava from the body. After this, you will need a blood test to confirm that Arava has been sufficiently eliminated from your body, and then wait at least another 3 months before trying to conceive.
if you are due to have a specific blood test (calcium level). False low calcium levels may be observed.
if you are scheduled for or have recently undergone major surgery, or if you still have an unhealed surgical wound. ARAVA may impair wound healing.

Rarely, Arava may cause problems affecting the blood, liver, lungs, or nerves in the arms or legs. Arava may also cause serious allergic reactions (including drug reaction with eosinophilia and systemic symptoms [DRESS]), or increase the risk of serious infections. For further information, see section 4 (Possible side effects).
The DRESS syndrome initially presents with flu-like symptoms and a rash on the face, followed by widespread rash with fever, elevated liver enzyme levels, increased levels of a type of white blood cell (eosinophilia) in blood tests, and swollen lymph nodes.
Before starting Arava and during treatment, your doctor will prescribe regular blood tests to monitor your blood cells and liver function. Your doctor will also regularly check your blood pressure, as Arava may cause an increase in blood pressure.
Inform your doctor if you develop unexplained chronic diarrhea. Your doctor may perform additional tests for differential diagnosis.
Inform your doctor if a skin ulcer develops during treatment with Arava (see also section 4).

Children and adolescents
The use of Arava is not recommended in children and adolescents under 18 years of age.

Other medicines and Arava
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. This includes medicines purchased without a prescription.
These details are particularly important if you are taking:

other medicines for the treatment of rheumatoid arthritis such as antimalarials (e.g. chloroquine and hydroxychloroquine), gold salts administered intramuscularly or orally, D-penicillamine, azathioprine, and other immunosuppressive medicines (e.g. methotrexate), as these combinations are not recommended,
warfarin and other oral anticoagulants used to thin the blood, as monitoring is required to reduce the risk of side effects,
teriflunomide for multiple sclerosis,
repaglinide, pioglitazone, nateglinide, or rosiglitazone for diabetes,
daunorubicin, doxorubicin, paclitaxel, or topotecan for cancer,
duloxetine for depression, urinary incontinence, or diabetic kidney disease,
alosetron for managing severe diarrhea,
theophylline for asthma,
tizanidine, to relax muscles,
oral contraceptives (containing ethinylestradiol and levonorgestrel),
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,
a medicine called cholestyramine (used to lower cholesterol) or activated charcoal, as these medicines may reduce the amount of Arava absorbed by the body.

If you are already taking non-steroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids, you may continue taking them after starting Arava treatment.

Vaccinations
If you need to be vaccinated, consult your doctor. Certain vaccinations should not be given while you are taking Arava, and for a certain period after stopping treatment.

Arava with food, drinks and alcohol
Arava can be taken with or without food.
It is recommended not to drink alcohol during treatment with Arava. Drinking alcohol while taking Arava may increase the risk of liver damage.

Pregnancy and breastfeeding
Do not take Arava if you are pregnant or think you might be pregnant. If you become pregnant while being treated with Arava, the risk of having a baby with serious birth defects is increased. Women must not take Arava without using reliable contraceptive methods if they are of childbearing age.
If you plan to become pregnant after stopping Arava treatment, it is important to inform your doctor in advance, as you must ensure that all traces of Arava have been eliminated from your body before attempting to conceive. Elimination of Arava may take up to two years. This period can be reduced to a few weeks by taking certain medications that accelerate the removal of Arava from your body. In either case, blood tests must confirm that Arava has been sufficiently eliminated from your body before you become pregnant, and after this, you must wait at least another month.
For further information on laboratory tests, contact your doctor.
If you suspect you are pregnant while taking Arava or within two years after stopping treatment, you must inform your doctor immediately, who will arrange a pregnancy test. If pregnancy is confirmed, your doctor will advise treatment with certain medications to rapidly and adequately remove Arava from your body, thereby reducing the risk to your baby.
Do not take Arava during breastfeeding, as leflunomide passes into breast milk.

Driving and using machines
Arava may make you feel unsteady, and this sensation may affect your ability to concentrate and react. In this case, do not drive or operate machinery.

Arava contains lactose
If your doctor has informed you that you have an intolerance to certain sugars, contact your doctor before taking this medicine.

3. How to take Arava

Always take this medicine exactly as instructed by your doctor or pharmacist. If you
have any doubts, consult your doctor or pharmacist.
The initial dose of Arava is usually 100 mg of leflunomide once daily for the first three
days. Afterwards, most patients require:

for rheumatoid arthritis: a daily dose of 10 or 20 mg of Arava, depending on the severity of the disease.
for psoriatic arthritis: a daily dose of 20 mg of Arava.

Take the tablet whole and with plenty of water.
It may take approximately 4 weeks or longer before you begin to notice an
improvement in your condition. Some patients may experience further improvements even
after 4–6 months of treatment.
Generally, Arava is taken for long periods of time.
If you take more Arava than you should
If you take more Arava than prescribed, contact your doctor or seek medical advice immediately.
If possible, bring the tablets or the pack with you to show your doctor.
If you forget to take Arava
If you forget to take a dose, take it as soon as you remember, unless it is almost time for your next dose.
Do not take a double dose to make up for the missed dose.
If you have any doubts about how to use this medicine, consult your doctor, pharmacist, or
nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.
Stop treatment with Arava and contact your doctor immediately if you:

feel weak, lightheaded or dizzy, or have difficulty breathing, as these symptoms may indicate a severe allergic reaction,
develop skin rash or mouth ulcers, as these may indicate serious, sometimes fatal, allergic reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, drug reaction with eosinophilia and systemic symptoms [DRESS]) – see section 2.

Contact your doctor immediately if you experience:

pallor, fatigue or bruising, as these may indicate blood disorders caused by an imbalance in the different types of blood cells,
fatigue, abdominal pain or jaundice (yellowing of the eyes or skin), as these may indicate serious liver problems such as liver failure, which can be fatal,
any signs of infection such as fever, sore throat or cough, as this medicine may increase the risk of serious, potentially life-threatening infections,
cough or breathing problems, as these may indicate lung disorders (interstitial lung disease or pulmonary hypertension),
tingling, weakness or unusual pain in the hands or feet, as these may indicate nerve problems (peripheral neuropathy).

Common side effects (may affect up to 1 in 10 people)

mild decrease in white blood cell count (leucopenia),
moderate allergic reactions,
loss of appetite, decrease in body weight (usually not significant),
fatigue (asthenia),
headache, dizziness,
abnormal skin sensations such as tingling (paraesthesiae),
moderate increase in blood pressure,
colitis,
diarrhoea,
nausea, vomiting,
inflammation of the mouth or mouth ulcers,
abdominal pain,
increased liver function test values,
increased hair loss,
eczema, dry skin, redness and itching,
tendinitis (pain caused by inflammation of the sheath covering tendons, usually in feet or hands),
increased levels of certain blood enzymes (creatine phosphokinase),
nerve problems in arms or legs (peripheral neuropathy).

Uncommon side effects (may affect up to 1 in 100 people)

decrease in red blood cell count (anaemia) and decrease in platelet count (thrombocytopenia),
low potassium levels in the blood,
anxiety,
taste disturbances,
urticaria (red, itchy rash),
tendon rupture,
increased levels of fats in the blood (cholesterol and triglycerides),
low phosphate levels in the blood.

Rare side effects (may affect up to 1 in 1,000 people)

increase in blood cells called eosinophils (eosinophilia); mild decrease in white blood cell count (leucopenia); reduction in all types of blood cells (pancytopenia),
increased blood pressure,
lung inflammation (interstitial lung disease),
increased liver function test values, which may lead to serious clinical conditions such as hepatitis and jaundice,
severe infections known as sepsis, which may be fatal,
increased levels of certain blood enzymes (lactate dehydrogenase).

Very rare side effects (may affect up to 1 in 10,000 people)

marked decrease in certain white blood cells (agranulocytosis),
severe and potentially life-threatening allergic reactions,
inflammation of blood vessels (vasculitis, including necrotizing cutaneous vasculitis),
inflammation of the pancreas (pancreatitis),
severe liver damage such as liver failure or necrosis, which may be fatal,
serious, sometimes fatal, skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme).

Other side effects with unknown frequency may also occur, such as kidney failure, decreased levels of uric acid in the blood, pulmonary hypertension, male infertility (which is reversible when treatment with this medicine is stopped), cutaneous lupus (characterised by rash/erythema in skin areas exposed to light), psoriasis (onset or worsening), DRESS, and skin ulcer (a round, open sore in the skin through which underlying tissues can be seen).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly through the national reporting system listed in Annex V.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Arava

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the outer packaging.
The expiry date refers to the last day of the month.
Store in the original packaging.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Arava contains

The active substance is leflunomide. Each film-coated tablet contains 100 mg of leflunomide.
The other components are: maize starch, povidone (E1201), crospovidone (E1202), talc (E553b), anhydrous colloidal silica, magnesium stearate (E470b) and monohydrate lactose in the tablet core, and talc (E553b), hypromellose (E464), titanium dioxide (E171) and macrogol 8000 in the coating.

Description of the appearance of Arava and contents of the pack
Arava 100 mg film-coated tablets are white or almost white and round.
Imprinted on one side: ZBP.
The tablets are packed in blisters.
A pack containing 3 tablets is available.

Marketing Authorization Holder
Sanofi-Aventis Deutschland GmbH
D-65926 Frankfurt am Main, Germany

Manufacturer
Opella Healthcare International SAS
56, Route de Choisy
60200 Compiègne
France

For further information about this medicinal product, please contact the local representative of the Marketing Authorization Holder.

België/Belgique/Belgien Lietuva
Sanofi Belgium Swixx Biopharma UAB
Tél/Tel: +32 (0)2 710 54 00 Tel: +370 5 236 91 40

България Luxembourg/Luxemburg
Swixx Biopharma EOOD Sanofi Belgium
Тел.: +359 (0)2 4942 480 Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien)

Česká republika Magyarország
Sanofi s.r.o. SANOFI-AVENTIS Zrt.
Tel: +420 233 086 111 Tel.: +36 1 505 0050

Danmark Malta
Sanofi A/S Sanofi S.r.l.
Tlf: +45 45 16 70 00 Tel: +39 02 39394275

Deutschland Nederland
Sanofi-Aventis Deutschland GmbH Sanofi B.V.
Tel.: 0800 52 52 010 Tel: +31 20 245 4000
Tel. aus dem Ausland: +49 69 305 21 131

Eesti Norge
Swixx Biopharma OÜ sanofi-aventis Norge AS
Tel: +372 640 10 30 Tlf: +47 67 10 71 00

Ελλάδα Österreich
Sanofi-Aventis Μονοπρόσωπη AEBE sanofi-aventis GmbH
Τηλ: +30 210 900 16 00 Tel: +43 1 80 185 – 0

España Polska
sanofi-aventis, S.A. Sanofi Sp. z o.o. Tel.: +48 22 280 00 00
Tel: +34 93 485 94 00

France Portugal
Sanofi Winthrop Industrie Sanofi - Produtos Farmacêuticos, Lda
Tél: 0 800 222 555 Tel: +351 21 35 89 400
Appel depuis l’étranger : +33 1 57 63 23 23

Hrvatska România
Swixx Biopharma d.o.o. Sanofi Romania SRL
Tel: +385 1 2078 500 Tel: +40 (0) 21 317 31 36

Ireland Slovenija
sanofi-aventis Ireland Ltd. T/A SANOFI Swixx Biopharma d.o.o.
Tel: +353 (0) 1 403 56 00 Tel: +386 1 235 51 00

Ísland Slovenská republika
Vistor hf. Swixx Biopharma s.r.o.
Sími: +354 535 7000 Tel: +421 2 208 33 600

Italia Suomi/Finland
Sanofi S.r.l. Sanofi Oy
Tel: 800 536389 Puh/Tel: +358 (0) 201 200 300

Κύπρος Sverige
C.A. Papaellinas Ltd. Sanofi AB
Τηλ: +357 22 741741 Tel: +46 (0)8 634 50 00

Latvija United Kingdom (Northern Ireland)
Swixx Biopharma SIA sanofi-aventis Ireland Ltd. T/A SANOFI
Tel: +371 6 616 47 50 Tel: +44 (0) 800 035 2525

This leaflet was last updated on:

Other sources of information
More detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu/.

ANNEX IV
SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE
MARKETING AUTHORISATIONS

Scientific conclusions
Taking into account the evaluation by the Pharmacovigilance and Risk Assessment Committee (PRAC) of the Periodic Safety Update Report (PSUR) for leflunomide, the PRAC's scientific conclusions are as follows:
In light of available data on impaired wound healing following surgical intervention, derived from an observational study, the literature and spontaneous reports, and considering a plausible mechanism of action, the PRAC considers that a warning on impaired wound healing following surgical intervention is necessary.
The PRAC concluded that product information for medicinal products containing leflunomide should be amended accordingly.

Having reviewed the PRAC's recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the general conclusions and the rationale of the recommendation.

Grounds for the variation to the terms of the marketing authorisations
Based on the scientific conclusions regarding leflunomide, the CHMP considers that the benefit-risk balance of medicinal products containing leflunomide remains favourable, subject to the proposed changes to the product information.
The CHMP recommends variation to the terms of the marketing authorisations.