Active ingredients: Leflunomide
Arava 10 mg film-coated tablets
Arava package inserts are available for pack sizes:- Arava 10 mg film-coated tablets
- Arava 20 mg film-coated tablets
- Arava 100 mg film-coated tablets
Why is Arava used? What is it for?
Arava belongs to a group of medicines called antirheumatic medicines. 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 moving and pain. Other symptoms that can affect the whole body include lack of appetite, fever, loss of strength and anemia (reduced number of red blood cells).
Symptoms of active psoriatic arthritis include joint inflammation, swelling, difficulty moving, pain, and patches of red, scaly skin (skin lesions).
Contraindications When Arava should not be used
Do not take Arava:
- if you have ever had an allergic reaction to leflunomide (especially a severe skin reaction, often accompanied by fever, joint pain, red patches of skin or blisters such as Stevens-Johnson syndrome) or to any of the other ingredients of this medicinal
- if you have any liver problems,
- if you have severe or moderate kidney problems,
- if you have an extremely low blood protein count (hypoproteinaemia),
- if you suffer from any problem that affects your immune system (for example AIDS),
- if you have any bone marrow problem or if the number of red or white blood cells is low or if the number of platelets in the blood is low,
- if you have a severe infection,
- if you are pregnant, want to become pregnant or are breast-feeding.
Precautions for use What you need to know before you take Arava
Talk to your doctor, pharmacist or nurse before taking Arava
- if you have ever suffered from 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 can do tests to see if you have tuberculosis.
- if you are male and intend to father a child. As it cannot be excluded that Arava p passes into semen, a reliable method of contraception should be used during treatment with Arava. ,
Men wishing to father a child should contact their doctor, who may advise them to stop taking Arava and take certain medications to remove Arava quickly and sufficiently from the body. Then they will have a blood test to make sure that Arava has been sufficiently removed from the body, and will eventually have to wait at least another 3 months before procreating.
Arava can rarely cause problems with the blood, liver, lungs, or nerves in the arms or legs. Arava can also cause some serious allergic reactions (including drug reaction with eosinophilia and systemic symptoms [DRESS]), or increase the incidence of serious infections. For more information, please read section 4 (Possible side effects).
DRESS syndrome begins with flu-like symptoms and a rash on the face, then an extensive rash with fever, increased levels of liver enzymes and a type of white blood cell (eosinophilia) in blood tests and enlarged lymph nodes.
Before you start taking Arava and during treatment, your doctor will order blood tests at regular intervals to monitor your blood cells and liver. Your doctor will also check your blood pressure regularly as Arava can cause your blood pressure to rise.
Children and adolescents
Arava is not recommended for use in children and adolescents below 18 years of age.
Interactions Which medications or foods may change the effect of Arava
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines bought without a prescription.
This information is especially important if you are taking:
- other medicines for the treatment of rheumatoid arthritis such as antimalarials (eg chloroquine and hydroxychloroquine), gold salts administered intramuscularly or orally, Dpenicillamine, azathioprine and other immunosuppressive drugs (eg methotrexate) as these combinations are not recommended,
- warfarin and other oral medicines used to thin the blood, as monitoring is needed to reduce the risk of side effects of 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 the management of severe diarrhea
- theophylline for asthma
- tizanidine, to relax the muscles
- oral contraceptives (containing ethinyl estradiol and levonorgestrel)
- cefaclor, benzylpenicillin (penicillin G), ciprofloxacin for infections
- indomethacin, ketoprofen for pain or inflammation
- furosemide for heart disease (diuretic, urinating pill)
- zidovudine for HIV infection
- rosuvastatin, simvastatin, atorvastatin, pravastatin for hypercholesterolemia (high cholesterol)
- sulfasalazine for inflammatory bowel disease or rheumatoid arthritis
- a drug called cholestyramine (which is used to lower cholesterol) or activated charcoal as these medicines can decrease the amount of Arava absorbed by the body,
If you are already taking non-steroidal anti-inflammatory drugs (NSAIDs) and / or corticosteroids you can continue to take them after starting Arava therapy.
Vaccinations
If you have to be vaccinated, ask your doctor for advice. Certain vaccinations should not be given while you are taking Arava, and for a certain period of time after stopping treatment.
Arava with food, drink and alcohol
Arava can be taken with or without food.
It is recommended not to drink alcohol while taking Arava. Drinking alcohol while taking Arava could increase the likelihood of liver damage.
Warnings It is important to know that:
Pregnancy and breastfeeding
Do not take Arava if you are pregnant or think you are pregnant. If you are pregnant or become pregnant while being treated with Arava, the risk of having a baby with severe birth defects is increased. Women should not take Arava without using reliable contraceptive measures when they are of childbearing age.
If you are planning to become pregnant after stopping treatment with Arava, it is important to inform your doctor in advance, as he must be sure that all traces of Arava have been cleared from your body before attempting to become pregnant. Elimination of Arava. can last for two years, which can be shortened to a few weeks by taking certain medicines that speed up the removal of Arava from your body.
In both cases, before you become pregnant, blood tests must confirm that Arava has been sufficiently cleared from your body and after that you must wait at least another month.
For more information on laboratory tests, contact your doctor.
If you suspect that you are pregnant during treatment with Arava or in the two years after stopping treatment, you must immediately inform your doctor who will arrange for a pregnancy test to be carried out. If this confirms that you are pregnant , your doctor will recommend treatment with certain medicines to remove Arava quickly and sufficiently from your body, thus reducing the risk to your baby.
Do not take Arava while breastfeeding as leflunomide passes into breast milk.
Driving and using machines
Arava can make you feel unstable and this sensation can impair your ability to concentrate and react. In this case, do not drive or use machinery.
Arava 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.
Dose, Method and Time of Administration How to use Arava: Posology
Always take this medicine exactly as your doctor or pharmacist has told you.
If in doubt, consult your doctor or pharmacist. The starting dosage of Arava is usually one 100 mg tablet once a day for the first three days. Subsequently, most patients need:
- 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 about 4 weeks or more before you start to feel an improvement in your condition. Some patients may experience further improvement even after 4-6 months of treatment.
Generally, Arava is taken for long periods of time.
Overdose What to do if you have taken too much Arava
If you use more Arava than you should
If you take more Arava than you should contact your doctor or try to get some other medical advice. If possible, take your tablets or the pack with you to show the 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 further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Side Effects What are the side effects of Arava
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Stop taking Arava and contact your doctor immediately:
- if you have felt faint, light-headed or dizzy or have had difficulty breathing as these signs may indicate a severe allergic reaction,
- if you have experienced red skin or mouth ulceration as these signs may indicate severe allergic reactions, sometimes even fatal (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, drug reaction with eosinophilia and systemic symptoms [DRESS]) , see paragraph 2.
Contact your doctor immediately if you experience:
- paleness, tiredness or bruising as these may indicate blood disorders caused by an imbalance between the different types of cells that make up the blood,
- tiredness, abdominal pain or jaundice (yellowing of the eyes or skin) as these manifestations may indicate serious conditions such as liver failure which can be fatal,
- any symptoms of infection such as fever, sore throat or cough as this medicine may increase the incidence of serious infections which can be life threatening,
- cough or breathing problems as these may indicate inflammation of the lung (interstitial lung disease),
- 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)
- a slight decrease in the number of white blood cells (leukopenia),
- moderate allergic reactions,
- loss of appetite, decrease in body weight (usually not significant),
- tiredness (asthenia),
- headache, dizziness,
- abnormal skin sensations such as tingling (paraesthesia),
- moderate increase in blood pressure,
- diarrhea,
- nausea, vomiting,
- inflammation of the mouth or mouth ulcerations,
- abdominal pain,
- an increase in values in some liver function tests,
- increased hair loss,
- eczema, dry skin, redness, itching, tendonitis (pain caused by inflammation of the sheath that covers the tendons usually in the feet or hands),
- an increase in some blood enzymes (creatine phosphokinase),
- nerve problems in the arms or legs (peripheral neuropathy).
Uncommon side effects (may affect up to 1 in 100 people)
- a decrease in the number of red blood cells (anemia) and a decrease in the number of platelets (thrombocytopenia),
- a decrease in blood potassium levels,
- anxiety,
- taste disturbances,
- hives (itchy redness),
- tendon rupture,
- an increase in blood fat levels (cholesterol and triglycerides),
- a decrease in blood phosphate levels.
Rare side effects (may affect up to 1 in 1,000 people)
- an increase in the number of blood cells called eosinophils (eosinophilia); a slight decrease in the number of white blood cells (leukopenia); a reduction in the number of all blood cells (pancytopenia),
- increased blood pressure,
- inflammation of the lung (interstitial lung disease)
- an increase in some liver function values which can lead to serious clinical conditions such as hepatitis and jaundice,
- severe infections called sepsis which can be fatal,
- an increase in some enzymes in the blood (lactate dehydrogenase).
Very rare side effects (may affect up to 1 in 10,000 people)
- a marked decrease in some white blood cells (agranulocytosis),
- severe and potentially severe allergic reactions,
- inflammation of small vessels (vasculitis, including necrotizing cutaneous vasculitis),
- inflammation of the pancreas (pancreatitis),
- severe liver damage such as liver failure or necrosis which can be fatal,
- severe, sometimes fatal reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme).
Other side effects such as kidney failure, decreased blood uric acid levels, male infertility (which is reversible when treatment with this medicine is stopped), cutaneous lupus (characterized by rash / erythema of light-exposed skin areas), psoriasis (onset or worsening) and DRESS may occur with an unknown frequency.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V.
By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
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 outer carton. The expiry date refers to the last day of the month.
Blisters: Store in the original package.
Bottle: keep the container tightly closed
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Arava contains
- The active substance is leflunomide. Each film-coated tablet contains 10 mg of leflunomide.
- The other ingredients are: maize starch, povidone (E1201), crospovidone (E1202), anhydrous colloidal silica, magnesium stearate (E470b) and lactose monohydrate in the tablet core, as well as talc (E553b), hypromellose (E464), titanium dioxide (E171) and macrogol 8000 in the coating.
Description of what Arava looks like and contents of the pack
Arava 10 mg film-coated tablets are white to almost white and round. Imprint on one side: ZBN.
The tablets are packed in blisters or bottles.
Packs of 30 and 100 tablets are available.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
ARAVA 10 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 10 mg of leflunomide.
Excipients with known effects:
Each tablet contains 78 mg of lactose monohydrate.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
Round, white to off-white film-coated tablet with ZBN debossed on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Leflunomide is indicated for the treatment of adult patients with:
• active rheumatoid arthritis, as an antirheumatic drug capable of modifying the course of the disease (DMARD - Disease-Modifying Antirheumatic Drug),
• active psoriatic arthritis.
Recent or concomitant treatment with hepatotoxic or haematotoxic DMARDs (eg methotrexate) may lead to an increased risk of serious adverse reactions; therefore, a careful risk / benefit assessment should be made before initiating therapy with leflunomide.
Furthermore, switching from leflunomide to other DMARDs without following the washout procedure (see section 4.4) may also increase the risk of serious adverse reactions even for a long time after this switch.
04.2 Posology and method of administration
Treatment should be initiated and supervised by specialists experienced in the treatment of rheumatoid arthritis and psoriatic arthritis.
Alanine aminotransferase (ALT) or serum glutamic pyruvic transaminase (SGPT) and a complete blood test, including a differentiated leukocyte formula and platelet count, should be checked simultaneously and with the same frequency:
• before starting leflunomide therapy,
• every 2 weeks during the first 6 months of therapy, e
• every 8 weeks thereafter (see section 4.4).
Dosage
• Rheumatoid arthritis: leflunomide therapy is usually started with a loading dose of 100 mg once daily for 3 days. Avoiding the loading dose may decrease the risk of adverse reactions (see section 5.1).
The recommended maintenance dose is 10 to 20 mg of leflunomide once daily depending on the severity (activity) of the disease.
• Psoriatic artitis: leflunomide therapy begins with a loading dose of 100 mg once daily for 3 days.
The recommended maintenance dose is 20 mg leflunomide once daily (see section 5.1).
Normally the therapeutic effect occurs after 4-6 weeks of treatment and can further increase within 4-6 months.
No dosage adjustment is anticipated in patients with mild renal impairment.
No dosage adjustment is necessary in patients over 65 years of age.
Pediatric population
Arava is not recommended in patients below 18 years of age as efficacy and safety in juvenile rheumatoid arthritis (ARJ) have not been established (see sections 5.1 and 5.2).
Method of administration
Arava tablets should be taken whole with a sufficient amount of liquid. The extent of absorption of leflunomide is not affected by food intake.
04.3 Contraindications
• Hypersensitivity to the active substance (especially a history of Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme) or to any of the excipients listed in section 6.1.
• Patients with hepatic insufficiency.
• Patients with severe immunodeficiency (eg AIDS).
• Patients with significantly impaired bone marrow function or with severe anemia, leukopenia, neutropenia or thrombocytopenia, of an etiology other than rheumatoid arthritis or psoriatic arthritis.
• Patients with severe infections (see section 4.4).
• Patients with moderate to severe renal insufficiency, because insufficient clinical experience is available in this patient group.
• P.patients with severe hypoproteinemia, for example in nephrotic syndrome.
• Pregnant women or women of childbearing age who do not use reliable methods of contraception during treatment with leflunomide. After discontinuation of leflunomide treatment, pregnancy is contraindicated until plasma concentrations of the active metabolite exceed 0.02 mg / l (see section 4.6). Before starting treatment with leflunomide, it is recommended to exclude pregnancy.
• Breastfeeding women (see section 4.6).
04.4 Special warnings and appropriate precautions for use
Concomitant administration of DMARDs, hepatotoxic or haematotoxic (e.g. methotrexate) is not recommended.
The active metabolite of leflunomide, A771726, has a long half-life, usually between 1 and 4 weeks. Serious side effects (e.g. hepatotoxicity, haematotoxicity or allergic reactions, see below) could occur, even if treatment with leflunomide has been stopped. Therefore, when such toxic reactions occur or if for any other reason it is necessary to eliminate A771726 rapidly from the body, the washout procedure should be followed. This procedure can be repeated if clinically necessary.
For washout procedures and other recommended actions in the event of a planned or unexpected pregnancy see section 4.6.
Hepatic reactions
Rare cases of severe liver injury, including fatalities, have been reported with leflunomide treatment. Many of these cases occurred within the first 6 months of treatment. Concomitant treatments with other hepatotoxic drugs were frequently present. It is considered essential that the control recommendations are carefully followed.
ALT (SGPT) levels should be checked before starting treatment with leflunomide and at the same frequency as the complete blood test (every 2 weeks) during the first 6 months of therapy and every 8 weeks thereafter.
For ALT (SGPT) elevations of 2 to 3 times the upper limit of normal, dose reduction of Arava from 20 to 10 mg should be considered and weekly monitoring should be performed. If the ALT (SGPT) elevation greater than 2 times the upper limit of normal persists or if the elevation is greater than 3 times, leflunomide should be discontinued and the washout procedure initiated. It is recommended that liver enzyme monitoring be performed after stopping leflunomide treatment until liver enzyme levels are normalized.
Given the possibility of accentuating the hepatotoxic effects, it is recommended to refrain from the intake of alcoholic beverages during treatment with leflunomide.
Since the active metabolite of leflunomide, A771726, is highly bound to plasma proteins and is eliminated via hepatic metabolism and biliary secretion, plasma levels of A771726 may increase in patients with hypoproteinaemia. Arava is contraindicated in patients with severe hypoproteinaemia or hepatic insufficiency (see section 4.3).
Hematological reactions
In conjunction with ALT levels, a complete blood test including leukocyte formula and platelets should be performed before the start of treatment, as well as every 2 weeks for the first 6 months of therapy and every 8 weeks thereafter.
In patients with pre-existing anemia, leukopenia, and / or thrombocytopenia as well as in patients with impaired bone marrow function or who are at risk of suppression of bone marrow activity, the risk of haematological changes is increased. should consider a washout (see below) to reduce plasma levels of A771726.
In the event of severe blood reactions, including pancytopenia, Arava and any other concomitant myelosuppressive treatment should be discontinued and an Arava washout procedure initiated.
Association with other treatments
The use of leflunomide with antimalarials used in rheumatic diseases (eg chloroquine and hydroxychloroquine), intramuscularly or orally administered gold, D-penicillamine, azathioprine and other immunosuppressants including TNF-alpha inhibitors is not It has been adequately studied in randomized trials (except for methotrexate, see section 4.5). The risk associated with combination therapy, particularly for long-term treatment, is unknown. As such therapy may cause additive or even synergistic toxicity ( eg hepato- or haematotoxicity), association with another DMARD (eg methotrexate) is not recommended.
Caution should be used when leflunomide is administered with other drugs such as NSAIDs metabolised by CYP2C9, such as phenytoin, warfarin, phenprocoumon and tolbutamide.
Switching to other therapies
Since leflunomide remains in the body for a long time, switching to another DMARD (e.g. methotrexate) without performing the washout procedure (see below) may increase the possibility of addictive risks even for a long period of time after the substitution (i.e. interactions kinetics, organ toxicity).
Similarly, recent treatment with hepatotoxic or haematotoxic drugs (eg methotrexate) may lead to an increase in undesirable effects; therefore, initiation of leflunomide treatment should be carefully considered for these benefit / risk aspects and very close monitoring is recommended in the initial phase after switching to another treatment.
Skin reactions
In case of ulcerative stomatitis, the administration of leflunomide should be discontinued.
Very rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported in patients receiving leflunomide. As soon as skin and / or mucosal reactions are observed which raise suspicion of such severe reactions, Arava and other treatments potentially associated with such reactions should be discontinued and a leflunomide washout procedure initiated immediately. complete is essential in such cases Re-exposure to leflunomide is contraindicated in such cases (see section 4.3).
Pustular psoriasis and worsening of psoriasis have been reported after use of leflunomide. Discontinuation of treatment may be considered in relation to the patient's disease and medical history.
Infections
Immunosuppressive medicinal products - such as leflunomide - are known to predispose patients to danger of infections, including opportunistic infections. More serious infections can occur in nature and for this reason may require early and aggressive treatment. In the event of a severe and uncontrolled infection, it may be necessary to discontinue treatment with leflunomide and to implement an accelerated elimination procedure as described below.
Rare cases of Progressive Multiform Leukoencephalopathy (PML) have been reported in patients taking leflunomide concomitantly with other immunosuppressants.
The risk of tuberculosis must be considered. For those patients with other risk factors for tuberculosis, a tuberculin test should be performed.
Respiratory reactions
Cases of interstitial lung disease have been reported during treatment with leflunomide (see section 4.8). The risk of this occurring is greater in patients with a history of interstitial lung disease. Interstitial lung disease is a life-threatening disease that can occur acutely during therapy. Pulmonary symptoms such as cough and dyspnoea may be a reason for discontinuing therapy and for further investigation.
Peripheral neuropathy
Cases of peripheral neuropathy have been reported in patients receiving Arava. Most patients improved after 'discontinuation of Arava. However' there was' wide variability in the clinical course, ie in some patients the neuropathy resolved and some patients had persistent symptoms. Age over 60 years, Concomitant neurotoxic drugs and diabetes may increase the risk of peripheral neuropathy. If a patient receiving Arava develops peripheral neuropathy, consider discontinuing Arava therapy and performing the drug elimination procedure (see section 4.4).
Blood pressure
Blood pressure should be checked before starting leflunomide therapy and periodically thereafter.
Procreation (recommendations for men)
Male patients should be advised of possible male-mediated fetal toxicity. Reliable contraception must also be ensured during treatment with leflunomide.
There are no specific data on the risk of male-mediated fetal toxicity. However, no animal experiments have been carried out to assess this specific risk. To minimize any possibility of risk, the patient who intends to generate must stop taking leflunomide and, at the same time, take 8 g of cholestyramine 3 times a day for 11 days or 50 g of activated charcoal powder 4 times a day for 11 days.
Subsequently, in both cases, the plasma concentration of A771726 is measured for the first time. Therefore, the plasma concentration of A771726 must be determined again after an interval of at least 14 days.If both plasma concentrations are below 0.02 mg / l and after an additional waiting period of at least 3 months, the risk of fetal toxicity is very low.
Washout procedure
8 g of cholestyramine should be administered 3 times a day. Alternatively, 50 g of powdered activated charcoal should be administered 4 times a day. The duration of a complete washout is usually 11 days. The duration may vary according to clinical or laboratory variables.
Lactose
Arava contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults.
In case of recent or concomitant use of hepatotoxic or haematotoxic drugs or when treatment with leflunomide is followed by treatment with such drugs without a washout period (see also the course of action for the association with other treatments, see section 4.4), may increase the frequency of undesirable effects, therefore closer monitoring of liver enzymes and haematological parameters is recommended in the initial phase after switching to another treatment.
In a study in a small number of patients (n = 30), in which the administration of leflunomide (10-20 mg / day) was combined with that of methotrexate (10-25 mg / week), the concentration liver enzymes were increased by 2-3 times in 5 out of 30 patients. In all cases these elevations were reversed by continuing to take both drugs (2 cases) or by stopping the administration of leflunomide (3 cases). An increase of more than 3 times was observed in 5 patients: these increases regressed with continuing the intake of both drugs (2 cases) or with discontinuing the administration of leflunomide (3 cases).
In patients with rheumatoid arthritis, no pharmacokinetic interaction was observed between leflunomide (10-20 mg / day) and methotrexate (10-25 mg / week).
It is recommended that patients receiving leflunomide are not treated with cholestyramine or powdered activated charcoal as this results in a rapid and significant decrease in plasma concentration of A771726 (the active metabolite of leflunomide; see also section 5). It is believed that the mechanism responsible for this behavior is to be found in the interruption of the enterohepatic recirculation and / or in the gastrointestinal dialysis of A771726.
Previous administration of non-steroidal anti-inflammatory drugs (NSAIDs) and / or corticosteroids may be continued even after starting treatment with leflunomide.
The enzymes involved in the metabolization process of leflunomide and its metabolites are not yet known exactly. A study in vivo on the possible interaction with cimetidine (substance that non-specifically inhibits cytochrome P450) showed no significant interaction. After concomitant administration of a single dose of leflunomide to subjects receiving multiple doses of rifampicin (non-specific inducer of cytochrome P450 ) increases in peak concentrations of A771726 of approximately 40% were observed, with no significant changes in the area under the curve (AUC). The mechanism that determines this effect is not yet known.
Education in vitro indicate that A771726 inhibits the activity of cytochrome P4502C9 (CYP2C9). In clinical trials, no safety concerns were identified when co-administered with leflunomide and NSAIDs metabolised by CYP2C9. Caution is advised when co-administered leflunomide. to drugs other than NSAIDs, metabolised by CYP2C9, such as phenytoin, warfarin, phenprocoumon and tolbutamide.
In a study conducted on healthy volunteers, which involved the concomitant administration of leflunomide and a triphasic contraceptive for oral use containing 30 mcg of ethinylestradiol, no reduction whatsoever in the contraceptive activity of the aforementioned drug was observed; the pharmacokinetic parameters of A771726 were within the expected values.
Vaccinations
No clinical data are available on the efficacy and safety of vaccinations during treatment with leflunomide. However, vaccination with live attenuated vaccines is not recommended. For administration of a live attenuated vaccine, even if following discontinuation of Arava treatment, it is recommended that should take into account the prolonged half-life of leflunomide.
04.6 Pregnancy and lactation
Pregnancy
The active metabolite of leflunomide, A771726, is thought to cause serious birth defects when administered during pregnancy.
Arava is contraindicated in pregnancy (see section 4.3).
Women of childbearing potential must use effective contraception during and up to 2 years after treatment (see "Waiting period" below) or up to 11 days after treatment (see shortened "washout period" below).
The patient must be informed that, in the presence of any delay in menstrual flow or for any other reason that suggests a pregnancy in progress, she must immediately inform the doctor who will prescribe a pregnancy test. If this is positive, the doctor and patient should discuss the risks that may be associated with this situation. It is possible that the rapid reduction in the concentration of the active metabolite in the blood (by carrying out the drug elimination procedure described below), performed at the first delay in menstrual flow, may decrease the risks to the fetus from leflunomide.
In a small prospective study in women (n = 64) who became inadvertently pregnant during treatment with leflunomide, taken for no more than three weeks after conception and who underwent the drug elimination procedure, no significant differences were observed (p = 0.13) in the overall rate of major structural defects (5.4%) compared to both comparison groups (4.2% in the group with the disease [n = 108] and 4.2% in healthy volunteers [n = 78]).
In the case of women treated with leflunomide and wishing to become pregnant, one of the following procedures is recommended to ensure that the fetus is not exposed to toxic concentrations of A771726 (reference concentration below 0.02 mg / l).
Waiting period
Plasma levels of A771726 may remain above 0.02 mg / l for an extended period. The concentration may decrease to below 0.02 mg / l approximately 2 years after stopping treatment with leflunomide.
After a 2-year waiting period, the plasma concentration of A771726 is measured for the first time. Therefore, the plasma concentration of A771726 must still be determined after an interval of at least 14 days. No teratogenic risk is foreseeable if both plasma concentrations are below 0.02 mg / l.
For further information on the samples to be analyzed, please contact the Marketing Authorization Holder or their local representative (see section 7).
Washout procedure
After stopping treatment with leflunomide:
• 8 g of cholestyramine should be administered 3 times a day for a period of 11 days,
• Alternatively, 50 g of powdered activated charcoal should be administered 4 times a day for a period of 11 days.
However, following both washout procedures, verification by 2 tests separated by an interval of at least 14 days and a waiting period of one and a half months between the first time a plasma concentration below 0 is obtained is required. 02 mg / l and fertilization.
Women of childbearing potential should be advised that a waiting period of 2 years is required after stopping treatment before deciding to become pregnant. If a waiting period of approximately 2 years with implementation of reliable forms of contraception is not considered possible. , the adoption of the washout procedure may be recommended.
Both cholestyramine and powdered activated charcoal can affect the absorption of estrogens and progestogens in such a way that reliable contraception with oral contraceptives may not be guaranteed during the washout procedure with either cholestyramine or activated charcoal powder. use of alternative methods of contraception.
Feeding time
Animal studies indicate that leflunomide or its metabolites pass into breast milk. Breastfeeding women should therefore not take leflunomide.
04.7 Effects on ability to drive and use machines
In case of undesirable effects such as dizziness, the patient's ability to concentrate and react promptly may be impaired. In these cases, patients must refrain from driving cars and using machines.
04.8 Undesirable effects
Summary of the safety profile
The most frequently reported undesirable effects with leflunomide are: modest increase in blood pressure, leukopenia, paraesthesia, headache, dizziness, diarrhea, nausea, vomiting, oral mucosal changes (e.g. aphthous stomatitis, mouth ulcers), abdominal pain, increased hair loss, eczema, rash (including maculopapular rash), pruritus, dry skin, tenosynovitis, increased CPK, anorexia, weight loss (usually not significant), asthenia, mild allergic reactions and increased liver enzymes (transaminases ( especially ALT), less often gamma-GT, alkaline phosphatase, bilirubin).
Classification of the expected frequency values:
very common (≥1 / 10); common (≥1 / 100,
Within each frequency class, undesirable effects are reported in descending order of severity.
Infections and infestations
Rare: serious infections, including sepsis which can be fatal.
Like other potential immunosuppressive agents, leflunomide may increase susceptibility to infections, including opportunistic infections (see also section 4.4). Therefore, the overall incidence of infections may increase (particularly of rhinitis, bronchitis and pneumonia).
Neoplasms benign, malignant and unspecified (including cysts and polyps)
The use of some immunosuppressive agents increases the risk of developing malignancies, especially of the lymphoproliferative type.
Disorders of the blood and lymphatic system
Common: leukopenia (leukocytes> 2 G / l)
Uncommon: anemia, mild thrombocytopenia (platelets
Rare: pancytopenia (possibly due to an antiproliferative mechanism), leukopenia (leukocytes eosinophilia
Very rare: agranulocytosis
Recent, concomitant or consecutive use of potentially myelotoxic drugs may be associated with a higher risk of haematological effects
Disorders of the immune system
Common: mild allergic reactions
Very rare: severe anaphylactic / anaphylactoid reactions, vasculitis, including necrotizing cutaneous vasculitis
Metabolism and nutrition disorders
Common: increase in CPK values
Uncommon: hypokalaemia, hyperlipidaemia, hypophosphataemia
Rare: increase in LDH values
Not known: hypouricemia
Psychiatric disorders
Uncommon: anxiety
Nervous system disorders
Common: paraesthesia, headache, dizziness, peripheral neuropathy
Cardiac pathologies
Common: modest increase in blood pressure
Rare: severe increase in blood pressure
Respiratory, thoracic and mediastinal disorders
Rare: interstitial lung disease (including interstitial pneumonia) which can be fatal
Gastrointestinal disorders
Common: diarrhea, nausea, vomiting, oral mucosal changes (e.g. aphthous stomatitis, mouth ulcerations), abdominal pain.
Uncommon: taste disturbances
Very rare: pancreatitis
Hepatobiliary disorders
Common: increased liver function indices (transaminases [especially ALT], less often gamma-GT, alkaline phosphatase, bilirubin)
Rare: hepatitis, jaundice / cholestasis
Very rare: severe liver damage such as liver failure and acute liver necrosis which can 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 of psoriasis
Musculoskeletal and connective tissue disorders
Common: tenosynovitis
Uncommon: tendon rupture
Renal and urinary disorders
Not known: renal failure
Diseases of the reproductive system and breast
Not known: marginal (reversible) decrease in sperm concentration, total sperm count and rapid progressive motility
General disorders and administration site conditions
Common: anorexia, weight loss (usually not significant), asthenia
04.9 Overdose
Symptoms
Cases of chronic overdose have been reported in patients taking Arava at daily doses up to five times the recommended daily dose, and acute overdose have been reported in adults and children. No adverse events were reported in the majority of reported overdose cases. Adverse events consistent with the safety profile of leflunomide were: abdominal pain, nausea, diarrhea, elevated liver enzymes, anemia, leukopenia, pruritus and rash.
Treatment
In the event of an overdose or toxicity, the use of cholestyramine or activated charcoal is recommended to accelerate the elimination of the drug. Oral administration of cholestyramine to three healthy volunteers at a dose of 8 g three times a day for 24 hours decreased plasma A771726 levels by approximately 40% in 24 hours and from 49% to 65% in 48 hours.
Activated charcoal (powder in suspension), administered orally or via nasogastric tube (50 g every 6 hours, for 24 hours), has been shown to reduce plasma concentrations of A771726, the active metabolite of leflunomide, 37% in 24 hours and 48% in 48 hours.
If clinically needed, these washout procedures can be repeated.
Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that A771726, the primary metabolite of leflunomide, is not dialysable.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: substances with selective immunosuppressive action.
ATC code: L04AA13.
Human Pharmacology
Leflunomide is a disease-modifying antirheumatic agent with antiproliferative properties.
Animal Pharmacology
In experimental models of rheumatoid arthritis and other autoimmune diseases and in transplants, leflunomide is mainly active when administered during the sensitization phase. The substance has characteristics of immunomodulation / immunosuppression, has antiproliferative action and has anti-inflammatory properties.
Leflunomide exhibits its best protective effects in animal models with autoimmune diseases when administered in the early stage of disease progression.
In vivo, leflunomide 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 human dihydroorotate dehydrogenase (DHODH) enzyme and exhibits antiproliferative activity.
Clinical efficacy and safety
Rheumatoid arthritis
The efficacy of Arava in the treatment of rheumatoid arthritis has been demonstrated in 4 controlled trials (one phase II and three phase III). In the phase II trial, study YU203, 402 subjects with rheumatoid arthritis were randomized to placebo (n = 102), leflunomide 5 mg / day (n = 95), 10 mg / day (n = 101) or 25 mg / day (n = 104). The treatment duration was 6 months.
All patients who received leflunomide in the phase III trials received a starting dose of 100 mg for 3 days.
Study MN301 randomized 358 subjects with active rheumatoid arthritis to treatment with leflunomide 20 mg / day (n = 133), sulfasalazine 2 g / day (n = 133), or placebo (n = 92). The treatment duration was 6 months.
Study MN303 was an optional 6-month blinded continuation of study MN301 without the placebo group in order to have 12-month comparative results between leflunomide and sulfasalazine.
In study MN302, 999 subjects with active rheumatoid arthritis were randomized to treatment with leflunomide 20 mg / day (n = 501) or methotrexate 7.5 mg / week, increased to 15 mg / week (n = 498). The addition of folate was optional and was used in only 10% of patients. The duration of treatment was 12 months.
In study US301, 482 subjects with active rheumatoid arthritis were randomized to treatment with leflunomide 20 mg / day (n = 182), methotrexate 7.5 mg / week, increased to 15 mg / week (n = 182), or placebo (n = 118). All patients took folate 1 mg twice daily. The 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 decreasing the signs and symptoms of rheumatoid arthritis in all three placebo-controlled trials. The American College of Rheumatology (ACR) response rates in study YU203 were 27.7% for placebo, 31.9% for 5 mg / day, 50.5% for 10 mg / day and 54.5% for 25 mg / day of leflunomide.In 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 of active treatment, the response rates according to the ACR in patients treated with leflunomide were 52.3% (studies MN301 / 303), 50.5% (study MN302) and 49.4% (study US301), compared to 53.8% (studies MN301 / 303) in patients treated with sulfasalazine, and 64.8% (study MN302) and 43.9% (study US301) in patients treated with methotrexate. In study MN302, leflunomide was significantly less effective than methotrexate. However, no significant difference was observed between leflunomide and methotrexate in primary efficacy parameters in study US301. No difference was observed between leflunomide and sulfasalazine (study MN301). The effect of leflunomide treatment was evident after 1 month, stabilized between 3 and 6 months and continued throughout treatment.
A randomized, 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 is possible to conclude that the efficacy results of the maintenance dose of 20 mg were more favorable while, on the other hand, the safety results were more favorable to the maintenance dose of 10 mg.
Pediatric population
Leflunomide was studied in a multicentre, controlled vs active, randomized, double-blind study involving 94 patients (47 per arm) with polyarticular course juvenile rheumatoid arthritis. Patients were 3-17 years old with polyarticular course active juvenile rheumatoid arthritis regardless of onset and had not previously been treated with methotrexate or leflunomide. In this study, the loading and maintenance dose of leflunomide was calculated based on three weight categories: 40 kg. After 16 weeks of treatment, the difference in response rate according to the Definition of Improvement for Juvenile Rheumatoid Artitis (DOI ≥30%) was statistically significant ( p = 0.02) for the methotrexate group. In responding patients, this response was maintained for 48 weeks (see section 4.2).
The adverse event profile appeared similar with leflunomide and with methotrexate; however the dose used in lower weight patients resulted in relatively low exposure (see section 5.2). These data do not allow for recommending an effective and safe dose.
Psoriatic arthritis
The efficacy of Arava was demonstrated in a controlled, randomized, double-blind study (3L01) in 188 psoriatic arthritis patients treated with 20 mg per day. The treatment duration was 6 months.
Leflunomide 20 mg daily was significantly superior to placebo in reducing symptoms of arthritis in patients with psoriatic arthritis: PsARC (psoriatic arthritis treatment response criteria) found 59% of responders in the group treated with leflunomide versus 29.7% in the placebo group at 6 months (p
Post-marketing studies
A randomized study evaluated the clinical efficacy of the response rate in new DMARD patients (n = 121) with initial RA, who received double-blind in two parallel groups either 20 mg or 100 mg of leflunomide during the first three days of treatment. The initial phase was followed by an open-label maintenance period of three months during which both groups received 20 mg of leflunomide daily. No increase in overall benefit was observed in the group of patients who received received the loading dose therapy. The safety data obtained from both treatment groups were consistent with the known safety profile of leflunomide, however, the incidence of gastrointestinal side effects and liver enzyme elevations had the tendency to be higher in patients who received a 100 mg loading dose of leflunomide.
05.2 "Pharmacokinetic properties
Leflunomide is rapidly converted to its active metabolite, A771726, by first pass (ring opening) metabolism which occurs in the intestinal wall and liver.
In a study with 14C-labeled leflunomide in three healthy volunteers, no unchanged leflunomide was detected in plasma, urine and faeces. In other studies, the finding of unchanged leflunomide in plasma was rare and, however, with levels in the order of magnitude of ng / ml. The only radiolabelled metabolite present in plasma was A771726. This metabolite is responsible for essentially all of the plasma. "Arava business in vivo.
Absorption
The excretion data obtained from the 14C study indicate an absorption of not less than 82-95% of the administered dose. The time it takes for the plasma concentration of A771726 to reach peak values varies greatly; peak plasma levels can be seen between 1 and 24 hours after single administration. Leflunomide can be administered concomitantly with food as the extent of absorption is similar after food and fasting. Given the very long half-life of A771726 (approximately 2 weeks) in clinical trials A loading dose of 100 mg was used for 3 days to facilitate rapid achievement of steady-state of the concentrations of A771726. In the absence of a loading dose, it is estimated that nearly 2 months of dosing are required to reach steady state plasma concentrations. The results obtained in studies with repeated dose administration to patients with rheumatoid arthritis have shown that the pharmacokinetic parameters of A771726 show a linear trend within the range of doses used (5-25 mg). In these studies, the clinical effect it correlated closely with A771726 plasma concentrations and daily dose of leflunomide. With doses of 20 mg / day, the mean plasma concentration of A771726 allo steady-state is about 35 mcg / ml. At the steady-state plasma concentrations are approximately 33-35 times those related to the administration of a single dose.
Distribution
In human plasma, A771726 is extensively bound to proteins (albumin). The unbound fraction of A771726 is approximately 0.62%. Binding of A771726 is linear at concentrations in the therapeutic range. Binding is slightly lower and more variable in plasma from patients with rheumatoid arthritis or chronic renal failure. The extensive binding of A771726 to proteins could cause displacement of other drugs. with high protein binding. However, plasma protein binding interaction studies conducted in vitrousing clinically significant warfarin concentrations they did not demonstrate interactions. Similar studies have shown that ibuprofen and diclofenac do not displace A771726, while the free fraction of A771726 undergoes a 2-3 fold increase in the presence of tolbutamide. A771726 is able to displace ibuprofen, diclofenac and tolbutamide, but the free fraction of these drugs is only increased by 10-50%. There are no indications that these effects are clinically relevant. Consistent with its marked protein binding. , A771726 has a low apparent volume of distribution (approximately 11 liters) There is no preferential uptake by erythrocytes.
Biotransformation
Metabolization of leflunomide results in the formation of a primary metabolite (A771726) and several minor metabolites, including TFMA (4-trifluoromethylalanine). The metabolic biotransformation of leflunomide to A771726 and subsequent metabolization of A771726 are not controlled by a single enzyme and have been shown to occur in microsomal and cytosolic cell fractions. Interaction studies conducted with cimetidine (non-specific cytochrome P450 inhibitor) and rifampicin (non-specific cytochrome P450 inducer) have shown that, in vivo, CYP enzymes are not involved except to a limited extent in the metabolism of leflunomide.
Elimination
Elimination of A771726 occurs slowly and is characterized by an apparent clearance of approximately 31 ml / h. In patients, the elimination half-life is approximately 2 weeks. Following administration of a radiolabelled dose of leflunomide, radioactivity is excreted in equal amounts in faeces (probably via biliary elimination) and urine. A771726 was detected in faeces and urine even 36 days after a single administration. The main urinary metabolites are made up of glucuronide products derived from leflunomide (mainly present in samples taken in the first 24 hours) and from a derivative of the oxanyl acid of A771726. The main component found in the faeces is A771726.
In humans, oral administration of a suspension of activated charcoal powder or cholestyramine has been observed to induce a rapid and significant increase in the elimination rate of A771726 and decline in plasma concentration (see section 4.9). is due to a gastrointestinal dialysis mechanism and / or to the interruption of enterohepatic recirculation.
Kidney failure
Leflunomide was administered as a single oral dose (100 mg) to 3 hemodialysis patients and 3 patients on continuous ambulatory peritoneal dialysis (CAPD). The pharmacokinetics of A771726 in CAPD subjects appeared similar to that of healthy volunteers: A more rapid elimination of A771726 was observed in subjects on hemodialysis, this elimination was not caused by the extraction of the drug in dialysis fluids.
Hepatic insufficiency
No data are available on the treatment of patients with hepatic insufficiency. The active metabolite, A771726, binds strongly to plasma proteins and is eliminated by biliary excretion following hepatic metabolism; these processes can be compromised by hepatic dysfunction.
Pediatric population
The pharmacokinetics of A771726 following oral administration of leflunomide were evaluated in 73 pediatric patients with polyarticular course juvenile rheumatoid arthritis aged 3-17 years. The results of a "population pharmacokinetic analysis of these clinical studies showed that pediatric patients with body weight ≤40 kg have a reduced" systemic exposure to A771726 (assessed by Css) compared to adult patients with rheumatoid arthritis (see section 4.2). .
Senior citizens
Pharmacokinetic data from elderly patients (> 65 years) are limited but show good correspondence with those obtained in young adults.
05.3 Preclinical safety data
Acute toxicity studies were conducted by oral and intraperitoneal administration of leflunomide in mice and rats. Repeated oral administration of leflunomide to mice (up to 3 months), rats and dogs (up to 6 months) and monkeys (up to 1 month) showed that the main target organs of toxicity are the spinal cord, blood, gastrointestinal tract, skin, spleen, thymus and lymph nodes. The main effects (represented by anemia, leukopenia, reduction in the number of platelets and panmyelopathy) reflect the basic mechanism of action of the drug (inhibition of DNA synthesis). Heinz and / or corpuscles have been identified in the rat and dog. Howell-Jolly corpuscles Other effects affecting the heart, liver, cornea and respiratory tract can be interpreted as infections induced by immunosuppression Toxicity in animals has been shown at doses equivalent to human therapeutic doses.
Leflunomide is not mutagenic. However, the secondary metabolite TFMA (4-trifluoromethylalanine) induced in vitro clastogenicity and point mutations. Currently, insufficient information is available on its ability to have a similar effect in vivo.
In a rat carcinogenicity study, leflunomide was shown to have no carcinogenic potential. In a similar study in mice, a higher frequency of malignant lymphomas was found in males in the higher-dose group: this effect was attributed to the immunosuppressive activity of leflunomide. A dose-dependent increase in incidence was observed in female mice. bronchioloalveolar adenomas and lung carcinomas. The relevance of the results of the rat studies in the clinical practice of leflunomide is questionable.
Leflunomide did not exhibit antigenic properties in animal models.
At doses proper to the human therapeutic setting, leflunomide exhibited embryotoxic and teratogenic properties when administered to rats and rabbits. Furthermore, in toxicity studies, repeated administration of leflunomide induced adverse effects on the male reproductive organs. Fertility did not was reduced.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablets:
Cornstarch
Povidone (E1201)
Crospovidone (E1202)
Anhydrous colloidal silica
Magnesium stearate (E470b)
Lactose monohydrate.
Coating:
Talc (E553b)
Hydroxypropylmethylcellulose (E464)
Titanium dioxide (E171)
Macrogol 8000
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Blisters: Store in the original package.
Bottle: keep the container tightly closed.
06.5 Nature of the immediate packaging and contents of the package
Blister packs: aluminum foil / aluminum foil. Pack sizes: 30 and 100 film-coated tablets.
Bottle: 100ml wide neck high density polyethylene bottle with screw cap with integrated desiccant container, containing either 30 or 100 film-coated tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions for disposal.
07.0 MARKETING AUTHORIZATION HOLDER
Sanofi-Aventis Deutschland GmbH, D-65926 Frankfurt am Main, Germany
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/99/118 / 001-004
034702011
034702023
034702035
034702047
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 02 September 1999
Last renewal date: 02 September 2009
10.0 DATE OF REVISION OF THE TEXT
December 2012
