Arava - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate - 78.00 mg; corn starch - 50,00 mg; Povidone K 25 (polyvidon K 25) - 3.50 mg; silicon dioxide colloidal - 0.50 mg; magnesium stearate - 0.50 mg; crospovidone - 7.50 mg.

The composition of the film shell, hypromellose (methylhydroxypropylcellulose 5 mPa.s) - 2.521 mg; macrogol 8000 - 0.160 mg; titanium dioxide (E 171) - 0.630 mg; talc - 0.189 mg.

One tablet, film-coated, contains 20 mg of leflunomide as an active substance.

Excipients: lactose monohydrate - 72.00 mg; corn starch - 46.00 mg; Povidone K 25 (polyvidon K 25) - 3.50 mg; silicon dioxide colloidal - 0.50 mg; magnesium stearate - 0.50 mg; crospovidone-7.50 mg.

Composition of the film shell: hypromellose (methylhydroxypropylcellulose 5 mPa.s) - 2.516 mg; macrogol 8000 - 0.160 mg; titanium dioxide (E 171) - 0.629 mg; iron dye, yellow oxide (E 172) 0.006 mg; talc - 0.189 mg.

One tablet, film-coated, contains 100 mg leflunomide as an active substance.

Excipients: lactose monohydrate - 138.42 mg; corn starch - 86.30 mg; Povidone K 25 (polyvidon K 25) - 7.38 mg; talc - 15.50 mg; silicon colloidal dioxide -1,11 mg; magnesium stearate - 1.84 mg. crospovidone - 18.45 mg.

Composition of the film shell: hypromellose (methyl hydroxypropylcellulose 5 mPa.s) - 5.443 mg, macrogol 8000 - 0.288 mg, titanium dioxide (E 171) - 1.361 mg, talc 0.408 mg.

Description:

For the dosage of 10 mg: round tablets coated with a white or almost white film shell with the marking “ZBN” on one side.

For the dosage of 20 mg: triangular biconvex tablets, covered with film Sheath from pale yellow to pale brown with marking “ZBO” on one side.

For the dosage of 100 mg: round tablets coated with a white or almost white film shell with the marking “ZBP” on one side.

Pharmacotherapeutic group:Immunosuppressive remedy

ATX: & nbsp

L.04.A.A.13 Leflunomide

L.04.A.A Selective immunosuppressants

Pharmacodynamics:

Arava® belongs to the class of basic antirheumatic drugs and has antiproliferative, immunomodulating, immunosuppressive and anti-inflammatory properties. The active leflunomide metabolite A771726 inhibits the enzyme dehydroorotate dehydrogenase and has antiproliferative activity. А771726 in conditions in vitro inhibited by mitogens proliferation and synthesis of T-lymphocyte DNA. The antiproliferative activity of A771726 appears, apparently, at the level of pyrimidine biosynthesis, since the addition of uridine to the cell culture eliminates the inhibitory effect of the metabolite A771726. Using radioisotope ligands it was shown that A771726 selectively binds to the enzyme dehydroorotate dehydrogenase, which explains its property to inhibit this enzyme and lymphocyte proliferation in the stage G1. Proliferation of lymphocytes is one of the key stages in the development of rheumatoid arthritis. Simultaneously, A771726 inhibits the expression of receptors for interleukin-2 (CB-25) and antigens of the nucleus Ki-67 and PCNA, associated with the cell cycle.

The therapeutic effect of leflunomide was demonstrated in several experimental models of autoimmune diseases, including rheumatoid arthritis.

Leflunomide reduces symptoms and slows the progression of joint damage with an active form of rheumatoid arthritis and psoriatic arthritis.

The therapeutic effect usually manifests itself in 4-6 weeks and can grow further in 4-6 months.

Pharmacokinetics:

Leflunomide quickly turns into its active metabolite A771726 (primary metabolism in the intestinal wall and liver). In plasma, urine or feces only trace amounts of unchanged leflunomide were seen. The only detectable metabolite is A771726, responsible for the basic properties of the drug in vivo.

When ingested absorbed from 82 to 95% of the drug. The maximum plasma concentrations of A771726 are determined from 1 to 24 hours after a single dose. Leflunomide can be taken with food. Because of the very long half-life of A771726 (about 2 weeks), a loading dose of 100 mg per day was used for 3 days. This allowed us to quickly achieve the equilibrium state of the plasma concentration of A771726.Without a loading dose, it would take 2 months for the drug to reach equilibrium concentration. In studies with multiple, prescription, the pharmacokinetic parameters of A771726 were dose-dependent in the dose range of 5 to 25 mg. In these studies, the clinical effect was closely related to the plasma concentration of A771726 and the daily dose of leflunomide. At a dose of 20 mg per day, the mean plasma concentrations of A771726 at an equilibrium state were 35 μg / ml.

Plasma rapidly binds A771726 to albumins. The unbound fraction of A771726 is approximately 0.62%. Binding of A771726 is more variable and somewhat reduced in patients with rheumatoid arthritis or chronic renal insufficiency.

Leflunomide is metabolized to one major (A771726) and several secondary metabolites, including 4-trifluoromethylalanine. Biotransformation of leflunomide in A771726 and the subsequent metabolism of A771726 itself are controlled by several enzymes and occur in microsomal and other cell fractions. Investigations of interaction with cimetidine (nonspecific inhibitor of cytochrome P450) and rifampicin (a nonspecific inducer of cytochrome P450) showed that in vivo CYP-enzymes are involved in the metabolism of leflunomide only in an insignificant degree. Excretion of A771726 from the body is slow and characterized by clearance 31ml / hour. Leflunomide is excreted with feces (probably due to biliary excretion) and urine. The half-life is about 2 weeks.

The pharmacokinetics of A771726 in patients on chronic ambulatory peritoneal dialysis (HAFA) is similar to that of healthy volunteers. A faster excretion of A771726 is observed in patients on hemodialysis, which is not due to the extraction of the drug into the dialysate, but to its removal from the bond with the protein. Although the clearance of A771726 increases approximately 2-fold, the final half-life is similar to that of healthy individuals, since the volume of distribution simultaneously increases.

Data on the pharmacokinetics of the drug in patients with hepatic insufficiency are absent.

Pharmacokinetic characteristics in patients under the age of 18 years have not been studied. In elderly patients (65 years and older), the pharmacokinetic data roughly correspond to the average age group.

Indications:

As a basic treatment for adult patients withactive form of rheumatoid arthritis in order to reduce the symptoms of the disease and delay the development of structural damage to the joints.

Active form of psoriatic arthritis.

Contraindications:

- Hypersensitivity to leflunomide, teriflunomide or any of the excipients of the drug.

- Simultaneous use of leflunomide with teriflunomide is not recommended (see section "Special instructions").

- Dysfunction of the liver.

- Severe immunodeficiency (eg, AIDS).

- Serious disturbances of bone marrow hematopoiesis or severe anemia, leukopenia, neutropenia, or thrombocytopenia, not associated with rheumatoid or psoriatic arthritis.

- Severe, uncontrolled infections.

- Moderate or severe renal failure (due to small experience in clinical use).

- Severe hypoproteinemia (eg, with nephrotic syndrome).

- Pregnancy, women of reproductive age, who do not rule out the possibility of becoming pregnant during the treatment with leflunomide; after completion of treatment with leflunomide, women should not become pregnant until the plasma concentration of the active metabolite A771726 remains above 0.02 mg / l (see Fig."Application during pregnancy and during breast-feeding"). Before beginning treatment with leflunomide, pregnancy should be excluded.

- The period of breastfeeding (see "Application during pregnancy and during breastfeeding"),

- Men receiving leflunomide treatment should be warned about the possible adverse effects of leflunomide on spermatozoa. During the period of application of the drug, men need to take measures to protect their partner from pregnancy (see "Special instructions").

- The age of patients is less than 18 years (lack of data on efficacy and safety in this group of patients).

- Lactase deficiency, galactose intolerance, glucose-galactose malabsorption (since the preparation contains lactose).

Carefully:

- Patients with interstitial lung diseases (increased risk of interstitial lung disease, see "Special instructions").

- Patients with mild and moderate severity of anemia, leukopenia, neutropenia, thrombocytopenia and disorders bone marrow hematopoiesis (in including, in the anamnesis); Patients, recently received or receiving simultaneously with leflunomide medicinal drugs with immunosuppressive or hematotoxic action; patients with associated with rheumatoid arthritis significant deviations from the norm hematological parameters before treatment with leflunomide (requires frequent hematological control, see "Special instructions").

- Age over 60 years, simultaneous application other neurotoxic drugs and diabetes mellitus (increased risk of development peripheral neuropathy, "Special instructions").

- Renal failure of mild severity (limited experience in clinical use).

Pregnancy and lactation:

Pregnancy

Clinical studies to evaluate the use of leflunomide in pregnant women have not been conducted. However, A771726 has a teratogenic effect in animals (rats, rabbits) and can have a harmful effect on the fetus in humans. Leflunomide contraindicated pregnant women or reproductive age, which does not exclude the possibility of becoming pregnant during the treatment with leflunomide and some time after this treatment (waiting period or shortened period of "laundering", see below). Before starting treatment with leflunomide, you need to make sure that there is no pregnancy.

Patients should be informed that, as soon as there is a delay in menstruation or there is another reason to presume pregnancy, they should immediately notify the doctor about it to make a pregnancy test; in case of confirmation of availability the doctor should discuss with the patient the possible risk to which this pregnancy is exposed. It is possible that a rapid decrease in the concentration of A771726 in blood plasma using the procedure described below for the removal of the drug will help at the first delay of the monthly to reduce the risk to which the embryo from the leflunomide is exposed.

When taking negligently leflunomide in the first trimester of pregnancy in patients with rheumatoid arthritis with further withdrawal of the drug and the procedure for "washing" with colestyramine (see below), significant developmental defects were detected in 5.4% of the live Newborns compared with 4.2% of those in the group of women with rheumatoid arthritis who did not take leflunomide and 4.2% of those in the group of healthy pregnant women who did not take leflunomide. Women who take leflunomide and want to become pregnant, it is recommended that you follow one of the following procedures,to ensure that the fetus is not exposed to toxic concentrations of A771726 (reference concentration below 0.02 mg / L), according to available data, the concentration of the active metabolite in the plasma is less than 0.02 mg / L (0.02 μg / ml) suggests a minimal teratogenic risk.

Waiting period

It can be expected that the concentration of A771726 in the blood plasma can be above 0.02 mg / L for a long period. It is believed that its concentration may become less than 0.02 mg / L 2 years after the cessation of leflunomide treatment.

The first time the concentration of A771726 in the blood plasma is determined after a two-year waiting period.

After this, it is necessary to determine the concentration of A771726 in blood plasma, at least after 14 days.

The procedure for "laundering"

After stopping treatment with leflunomide:

- colestramine 8 g is applied 3 times a day for 11 days;

- Alternatively, 50 g of activated carbon powdered into powder is applied 4 times a day for 11 days.

Regardless of the chosen procedure for "laundering", it is necessary to double-check the determination of the concentration of A771726 in the blood plasma at intervals of at least 14 days and wait until the fertilization month and a half months from the moment when the concentration of A771726 in the plasma for the first time is fixed below 0.02 mg / l.

It is necessary to inform women of childbearing age that should pass 2 years after stopping treatment with leflunomide before they can try to become pregnant. If the 2-year waiting period with reliable contraception seems unreasonable, you can advise to carry out the procedure of "laundering" for preventive purposes.

AND colestramine, and Activated carbon can affect the absorption of estrogens and progestogens, so reliable oral contraceptives do not give 100% guarantee in the period of "laundering" through colestyramine or activated charcoal. It is recommended to use alternative methods contraception.

Breastfeeding period

Studies in animals have shown that leflunomide or its metabolites penetrate into breast milk. Therefore, women should not take breastfeeding during the period of breastfeeding leflunomide. Depending on the importance of treatment for the mother, it should be decided whether breastfeeding will be carried out or leflunomide treatment will be initiated, in which breastfeeding will have to be abandoned.

Dosing and Administration:

Treatment with leflunomide should begin under the supervision of a physician,who has experience in the treatment of rheumatoid arthritis and psoriatic arthritis.

For advice on treatment control, see "Special instructions".

Dosing regimen

Treatment of rheumatoid arthritis (RA)

Treatment with leflunomide is usually started with a single dose during the day, inside the shock dose of 100 mg for 3 days (for this there is a tablet release form of 100 mg of 3 tablets per package). However, the exclusion of a loading dose may reduce the risk of side effects (especially from the gastrointestinal tract and the effect on the activity of "hepatic" enzymes in the blood). The recommended maintenance dose is 20 mg leflunomide once a day. When receiving a maintenance dose of 20 mg once a day immediately after the start of treatment (that is, without taking a loading dose), the effectiveness of the drug in rheumatoid arthritis did not decrease, in the case of poor tolerability of 20 mg, a dose reduction of up to 10 mg once a day is possible (therefore available there are tablets of 10 mg and 20 mg).

Treatment of psoriatic arthritis (PsA)

Treatment with leflunomide PsA also begins with a loading dose of 100 mg once a day for 3 days.The maintenance dose is 20 mg leflunomide once a day.

With both indications, the therapeutic effect usually manifests itself after 4 weeks and can then increase to 4-6 months.

Therapy is usually carried out for a long time.

Special patient groups

Patients with impaired hepatic function

Recommendations for dose adjustment or drug cancellation depending on the severity or persistence of alanine aminotransferase (ALT) rise on the background of taking the drug, see section "Special instructions".

Patients with impaired renal function

The current experience is not enough to give special recommendations on the dosing regimen in patients with impaired renal function. It should be taken into account that the active metabolite leflunomide A771726 has a high affinity for proteins.

Elderly patients

Do not require dose adjustment in patients older than 65 years.

Mode of application

Tablets should be swallowed whole, with enough liquid. The ingestion of food has no effect on the absorption of leflunomide.

Side effects:

Classification of the alleged frequency of adverse events: very often (more than 1/10), often (more than 1/100, but less than 1/10),infrequently (more than 1/1000, but less than 1/100), rare (1/10000 more but less than 1/1000), very rare (less than 1/10000), the frequency is unknown (based on the available data to estimate the frequency the occurrence of an adverse event is not possible).

Infringements from digestive system

Often: diarrhea, nausea, vomiting, anorexia, lesions of the oral mucosa (e.g., aphthous stomatitis, ulceration of the oral mucosa), abdominal pain, colitis, including microscopic colitis.

Rarely: pancreatitis.

Disturbances from the liver and bile ducts

Often: increased activity of "liver" transaminases (particularly alanine aminotransferase (ALT), less often - gamma-glutamyl transferase (GGT) and alkaline phosphatase (AP)), hyperbilirubinemia.

Rarely: hepatitis, jaundice / cholestasis.

Rarely: severe liver damage, such as hepatic insufficiency, acute liver necrosis, which can be fatal.

Disorders from the cardiovascular system

Often: increase in blood pressure.

Frequency unknown: pulmonary hypertension.

Violations of the blood and lymphatic system

Often: leukopenia (number of leukocytes in peripheral blood> 2000 / μl).

Infrequently: anemia, thrombocytopenia (the number of platelets in peripheral blood < 100,000 / μl).

Rarely: leukopenia (number of leukocytes in peripheral blood <2000 / μl), eosinophilia, pancytopenia.

Rarely: agranulocytosis.

Recently, the previous, simultaneous or subsequent use of potentially myelotoxic drugs may be associated with a higher risk of adverse effects on the part of the blood.

Disturbances from the nervous system

Often: headache, dizziness, paresthesia.

Infrequently: disturbance of taste perception, anxiety.

Rarely: peripheral neuropathy.

Immune system disorders

Often: mild allergic reactions (including maculopapular rash and other types of rash), itching, eczema, dry skin cover, increased loss hair.

Infrequently: hives.

Rarely: severe anaphylactic / anaphylactoid reactions, Stevens-Johnson syndrome (erythema multiforme), toxic epidermal necrolysis (currently causal relationship with treatment could not be established,but can not be excluded), vasculitis, including skin necrotizing vasculitis (due to the underlying disease, the cause-and-effect relationship with leflunomide treatment could not be established).

Infectious and parasitic diseases

Rarely: the development of severe infections and sepsis, which can be fatal. In most of these reports, patients received other immunosuppressive therapy and, in addition to rheumatic disease, had co-morbidities that could increase the patient's predisposition to infections.

Drugs with immunosuppressive action can make a patient more susceptible to infections, including opportunistic infection.

The incidence of rhinitis, bronchitis and pneumonia may increase slightly.

Infringements from respiratory system, organs of the chest and mediastinum

Rarely: interstitial lung disease (including interstitial pneumonitis) with possible fatal outcome.

Disturbances from the skin and subcutaneous tissues

Frequency unknown: discoid lupus erythematosus, pustular psoriasis or exacerbation of psoriasis, drug reaction with eosinophilia and systemic symptoms (DRESS-syndrome) (see section "Special instructions").

Disturbances from musculoskeletal and connective tissue

Frequency unknown: tendosynovitis and tendon rupture (causal relationship with treatment leflunomide is not established).

Violations from the exchange substances and nutrition

Often: decrease in body weight.

Infrequently: hypokalemia.

Frequency unknown: insignificant hyperlipidemia, insignificant hypophosphatemia, insignificant increase in lactate dehydrogenase activity (LDH), insignificant increase in activity of creatine phosphokinase (CKF), hypo uricemia due to uricuric effect.

General disorders and disorders at the site of administration

Often: asthenia.

Violations of the genitals and mammary gland

Frequency unknown: can not exclude a slight decrease in the concentration of sperm, the total number of spermatozoa and their mobility.

Benign, malignant and unspecified neoplasms

It is known that with the use of some immunosuppressive drugs, the risk of malignancy increases, especially the risk development of lymphoproliferative diseases.

Disorders from the kidneys and urinary tract

Frequency unknown: renal insufficiency.

Overdose:

Symptoms

There were reports of chronic overdose in patients who received leflunomide in a dose up to 5 times the recommended daily dose, as well as reports of acute overdose in adults and children. In most cases, overdose has not been reported on the development of adverse events. The arising undesirable phenomena were comparable with the safety profile of leflunomide. The most frequently observed adverse events were diarrhea, abdominal pain, leukopenia, anemia and increased activity of "hepatic" enzymes.

Treatment

In case of an overdose or toxicity, it is recommended accept colestramine or Activated carbon, to accelerate the cleansing of the body. Kolestyramine, taken by three healthy volunteers orally 8 g three times a day for 24 hours, reduced the concentration of A771726 in the blood plasma by about 40% after 24 hours and at 49 - 65 % 48 hours later

It is shown that the introduction activated carbon (powder converted into suspension) orally or through a gastric tube (50 g every 6 hours for 24 hours) reduced the concentration of active metabolite A771726 in plasma by 37% after 24 hours and by 48% after 48 hours.

These procedures are "laundering" can be repeated according to clinical indications.

Studies with hemodialysis and chronic outpatient peritoneal dialysis (HAFA) showed that A771726, the main metabolite leflunomida, not able output by dialysis.

Interaction:

With hepatotoxic drugs and substances (including ethanol) or hematotoxic and immunosuppressive drugs

Increased side effects may occur in the case of recent or concomitant use of hepatotoxic drugs and substances (including ethanol) or hematotoxic and immunosuppressive drugs, or when the administration of these medicines begins after treatment with leflunomide without the procedure of "laundering" (see section "Special instructions").

With methotrexate

In some (in 5 out of 30) patients with rheumatoid arthritis with concurrent administration of leflunomide (10-20 mg per day) and methotrexate (10-25 mg per week), a 2-3-fold increase in the activity of "liver" enzymes in the blood, and in the other 5 patients there was a more than 3-fold increase in the activity of "hepatic" enzymes in the blood.In all cases, these phenomena disappeared: in 2 patients with continued use of both drugs, and in 3 patients after stopping leflunomide administration. Therefore, although, in general, there is no need for a waiting period for switching from leflunomide to methotrexate reception, careful monitoring of the activity of "hepatic" enzymes in the blood during the initial treatment phase after switching the patient from leflunomide to methotrexate is recommended.

Vaccination

There are no clinical data on the efficacy and safety of vaccination, conducted against the background of leflunomide treatment. Nevertheless, it is not recommended to conduct vaccination with live vaccines. When planning the vaccination, live the vaccine after cancellation of leflunomide should take into account its long half-life.

With warfarin

There have been reports of increased prothrombin time with the simultaneous administration of leflunomide and warfarin. In the clinical pharmacological study, pharmacodynamic interaction of warfarin with A771726 was observed (see below). Therefore, with the simultaneous use of warfarin and leflunomide careful monitoring of INR (the international normalized relationship) is recommended.

With food

The degree of absorption of leflunomide is not impaired when it is taken together with food.

The effect of other medicines on leflunomide

In vitro Studies conducted on microsomes of human liver confirmed that leflunomide is involved in the metabolism cytochrome P450 isoenzymes CYP1A2, CYP2C19 and CYP3A4. Investigation of interaction in vivo leflunomide with cimetidine (a nonspecific weak inhibitor of cytochrome P450 isoenzymes) showed no significant effect of cimetidine on the systemic exposure of A771726. After receiving a single dose of leflunomide, volunteers taking multiple doses of rifampicin (a nonspecific inducer of cytochrome P450), the maximum concentrations of A771726 in the blood increased by about 40%, while the area under the concentration-time curve (AUC) has not changed significantly. The mechanism of this effect is not clear. It should be borne in mind the possibility of continuing to increase the concentrations of leflunomide in the blood in patients who simultaneously take multiple doses of leflunomide and rifampicin. The use of colestyramine or activated charcoal leads to a rapid and significant decrease in the concentration of A771726 (active leflunomide metabolite) in blood plasma. This is due to a violation of intestinal hepatic recirculation A771726 and / or its dialysis in the gastrointestinal tract (see sections "Pregnancy and the period of breastfeeding" and the section "Overdose").

Effect of leflunomide on other drugs

Transport protein substrates for breast cancer resistance (BCRP)

Although pharmacokinetic interaction of A771726 with substrates BCRP (rosuvastatin) (see below), in 12 patients there was no pharmacokinetic interaction between leflunomide (10-20 mg per day) and methotrexate (substrate BCRP; 10 - 25 mg per week).

In studies on drug interactions, the absence of a significant drug interactions between leflunomide and three-phase oral contraceptives. AT study in which leflunomide received healthy female volunteers together with three-phase oral contraceptives containing 30 μg of ethinyl estradiol, no reduction in the contraceptive effect of the tablets was detected, and the pharmacokinetics of the A771726 fully fit into its usual range.Pharmacokinetic interaction of contraceptives with A771726 was observed (see below).

The following studies on pharmacokinetic and pharmacodynamic interactions were performed with A771726 (the main active metabolite of leflunomide). Since such drug interactions can not be excluded for leflunomide when used in recommended doses, the results presented below and the research recommendations should be taken into account in patients receiving leflunomide treatment.

Influence at repaglinide (substrate CYP2C8)

After repeated doses A771726 an increase in mean values of the maximum plasma concentration (FROM_ma_x) and AUC repaglinide (in 1,7 and 2,4 times, respectively), confirming that A771726 is an inhibitor of the isoenzyme CYP2C8 in vivo. Therefore, it is recommended that patients who take drugs metabolized with isoenzyme CYP2C8, such as repaglinide, paclitaxel, pioglitazone or rosiglitazone, since it is possible to increase their system exposure.

Influence at caffeine (substrate CYP1A2)

The use of repeated doses A771726 reduced the average values of C_m_Oh and AUC caffeine (substrate CYP1A2) by 18% and 55%, respectively, which confirms that A771726 may be a weak isoenzyme inducer CYP1A2 in vivo. Therefore, when combined with drugs metabolized by isoenzyme CYP1A2, such as duloxetine, alosetron, theophylline and tizanidine, care should be taken, as this may lead to a decrease in the effectiveness of these medicines.

Influence on the substrate of the transporter of organic anions 3 (OAT3)

After repeated doses of A771726, an increase in the mean C_m_Ohand AUC cefaclora (1.43 and 1.54 times, respectively), confirming that A771726 is an inhibitor of OAT3 in vivo. Therefore, with the simultaneous use of OAT3 substrates, such as cefaclor, benzylpenicillin, ciprofloxacin, indomethacin, ketoprofen, furosemide, cimetidine, methotrexate, zidovudine, it is recommended to be careful.

Influence on Substrates BCRP and / or organic anion transporting polypeptides B1 and B3 (OATP1B1 / B3)

After repeated doses of A771726, an increase in the mean C_m_Oh and AUC rosuvastatin (at 2.65 and 2.51 times, respectively). However, there was no significant effect of this increase in the plasma exposure of rosuvastatin on the activity of HMG-CoA reductase. With simultaneous application of a dose of rosuvastatin should not exceed 10 mg once a day. For other substrates BCRP (for example, methotrexate, topotecan, sulfasalazine, daunorubicin, doxorubicin) and the family of carrier protein carriers of organic anions (OATP), especially HMG-CoA reductase inhibitors (eg, simvastatin, atorvastatin, pravastatin, methotorexate, nateglinide, repaglinide, rifampicin), caution should be exercised when combined. Patients should be closely monitored for signs and symptoms indicating an increase in the systemic exposure of these drugs, and such patients should consider reducing the dose of these medicines.

The effect on oral contraceptives (containing 0.03 mg of ethinylestradiol and 0.15 mg of levonorgestrel)

After repeated doses of A771726, an increase in the mean C_m_Ohand AUC₀.₂4 ethinyl estradiol (1.58 and 1.54 times, respectively) and C_m_Oh and AUC0-24 levonorgestrel (in 1.33 and 1.41 times, respectively). However, the adverse effects of this interaction on effectiveness of oral contraceptives, it is recommended to consider the type of oral contraceptive used.

Influence at warfarin

Repeated doses of A771726 do not affect pharmacokinetics S-warfarin, indicating that A771726 is not an inhibitor or inducer of the isoenzyme CYP2C9. However, with the simultaneous use of A771726 and warfarin, a 25% decrease in the maximum INR values was observed, compared to that of single warfarin. Therefore, with simultaneous use with warfarin should be carefully monitored by INR.

Other interactions

If the patient is already taking nonsteroidal anti-inflammatory drugs (NSAIDs and / or glucocorticosteroids), they can be continued after the onset treatment with leflunomide.

Currently, there is no information on the combined use of leflunomide with antimalarial drugs used in rheumatology (for example, chloroquine and hydroxychloroquine), gold preparations (IM or orally), penicillamine, azathioprine, etc.immunosuppressants (except for methotrexate, see above). The risk associated with complex therapy is unknown, especially with long-term treatment. Since this kind of therapy can lead to the development of additional or even synergistic toxicity (for example, hepatotoxicity or toxic effects on the blood), combinations of this drug with other basic drugs (eg, methotrexate) are undesirable. The recent concomitant or subsequent use of potentially myelotoxic agents may be associated with a greater risk of developing blood disorders.

Special instructions:

The drug Arava® can be given to patients only after a thorough medical examination.

General Precautions

Due to the long half-life of the active metabolite leflunomide (A771726), even with discontinuation of treatment with leflunomide, serious adverse effects (eg, hepatotoxicity, toxic effects on blood or heavy immunological / allergic reactions). If a serious unwanted phenomenon develops, or if will require rapid removal from the body of A771726 for any other reason, should be applied colestramine or Activated carbon, as described in the section "Pregnancy and the period of breastfeeding", and, if clinically necessary, continue or repeat the reception of one of them.

If suspicion of severe immunological / allergic reactions is required to achieve a quick and effective cleansing of the body from this metabolite, a longer-term appointment of colestyramine or activated charcoal may be required.

Simultaneous use of teriflunomide with leflunomide is not recommended, since leflunomide is a related compound of teriflunomide.

Reactions from the liver

Since the active metabolite leflunomide A771726 has a high affinity for proteins and is excreted by metabolism in the liver and secretion with bile, and can also have a hepatotoxic effect, patients with impaired liver function leflunomide do not do it. In patients with liver disease, the use of leflunomide is not recommended. There have been reports of rare cases of severe liver damage,in some cases with a fatal outcome, in the treatment with leflunomide. Most of these cases were observed during the first six months of treatment. Although there is no causal relationship between these undesirable events and leflunomide, and in most cases there were several additional suspicious factors, the exact implementation of recommendations for control of treatment is considered mandatory.

Before the start of treatment, and also at least 1-2 times a month in the first 6 months of treatment and subsequently every 6-8 weeks should check the activity of ALT in the blood.

Recommendations for correcting the dosage regimen or stopping the drug depending on the severity and persistence of increased ALT activity

With a confirmed 2-3-fold excess of the upper limit of ALT norm, a dose reduction from 20 mg to 10 mg per day may allow further leflunomide administration provided that the indicator is closely monitored.

If a 2-3-fold excess of the upper limit of the ALT norm is maintained, or if there is an unconfirmed rise ALT activity, which exceeds the upper limit of the norm by more than 3 times, leflunomide intake should be discontinued.To reduce the concentration of A771726 more rapidly, the use of colestyramine or activated charcoal should be started according to the "laundering" scheme (see "Pregnancy and the period of breastfeeding").

Because of the possible additional hepatotoxic effects it is recommended to refrain from taking ethanol while treating leflunomide.

Hematopoietic and immune reactions

In patients with previous anemia, leukopenia and / or thrombocytopenia, as well as in patients with impaired bone marrow function or risk of suppression of bone marrow function, the risk of hematological adverse reactions increases.

A complete clinical blood test, including the determination of the leukocyte count and platelet count, should be performed prior to the initiation of leflunomide treatment, and 1-2 times per month for the first 6 months of treatment and then every 6-8 weeks.

Frequent control of hematologic indicators (general blood test, including the leukocyte formula and the number of platelets) should be conducted in the following cases: in patients with recent or simultaneously accepting immunosuppressive drugs or drugs with toxic effects on the blood,as well as when taking these medicines after the end of treatment with leflunomide without a period of "laundering"; in patients with an anamnesis of the corresponding deviations from the blood; in patients with corresponding changes in blood tests prior to treatment, not associated with inflammatory joint diseases.

In case of serious hematologic reactions, including pancytopenia, it is necessary to stop taking leflunomide and any other concomitant medication that suppresses bone marrow hematopoiesis and start the "laundering" procedure. Despite the lack of clinical data, due to the potential for immunosuppression, leflunomide is not recommended for patients who have the following diseases: severe immunodeficiency (eg AIDS); pronounced impairment of bone marrow function; severe infection.

Infections

It is known that preparations like leflunomide and possessing immunosuppressive properties make patients more susceptible to various kinds of infections, including opportunistic infections (infections caused by fungi and microorganisms that can cause infections only in conditions of decreased immunity).Emerging infectious diseases occur, as a rule, hard and require early and intensive treatment. When the occurrence of a serious infectious disease may need to interrupt treatment with leflunomide and begin the procedure of "laundering".

Before the start of treatment, all patients should be checked for active and inactive (latent) tuberculosis. It is necessary to carefully monitor patients with a history of tuberculosis because of the risk of reactivation.

Reactions from the respiratory system

In the treatment with leflunomide, rare cases of interstitial pulmonary process were noted. The risk of its occurrence increases in patients with an anamnesis of interstitial lung diseases.

Interstitial lung diseases are diseases with a potential fatal outcome, which can occur acutely during treatment with leflunomide. Symptoms such as coughing and shortness of breath can cause discontinuation of leflunomide therapy and further appropriate examination.

Peripheral Neuropathy

There have been reports of cases of peripheral neuropathy in patients treated with leflunomide, which the majority of patients after the discontinuation of leflunomide was permitted, but in some patients the symptomatology persisted. Age over 60 years, concomitant reception neurotoxic drugs and Diabetes mellitus may increase the risk of developing peripheral neuropathy. With the development of peripheral neuropathy in patient receiving leflunomide, consideration should be given to discontinuing leflunomide treatment and carrying out the drug elimination procedure described in the section "Pregnancy and the period of breastfeeding".

Renal insufficiency

Currently available experience is not enough for special recommendations on the regime dosing in patients with impaired renal function. Care should be taken when administering leflunomide to patients in this group. It should be taken into account that the active metabolite leflunomide A771726 has a high binding to blood proteins.

Skin Reactions

If ulcerative stomatitis develops, Leflunomide should be discontinued.

Stevens-Johnson syndrome, toxic epidermal necrolysis or drug reaction with eosinophilia and systemic symptoms have been reported (DRESS - syndrome) in patients who received leflunomide. If the patient receiving leflunomide, any of these reactions develop, the leflunomide should be discontinued and the procedure for "laundering" should be started immediately.

Arterial pressure

Before the start of treatment with leflunomide and periodically after its onset, it is necessary to control blood pressure, as during treatment with leflunomide it is possible to increase it.

Recommendations for men

There is no evidence of an increased risk of fetotoxic action (associated with the toxic effect of the drug on the father's spermatozoa) when leflunomide is used by men. Experimental studies in animals have not been performed to assess the specific risk of this undesirable effect. To minimize the possible risk to men, when planning the appearance of a child, it is necessary to stop taking leflunomide and undergo the procedure of "laundering" described in the section "Pregnancy and the period of breastfeeding".

Effect on the ability to drive transp. cf. and fur:

There is no relevant information. However, given the profile of side effects, such as undesirable phenomena from the nervous system eg dizziness,should refrain from driving and other activities potentially hazardous activities that require high concentration and psychomotor speed reactions.

Form release / dosage:

Tablets coated with 10 mg, 20 mg and 100 mg.

Packaging:

For dosages of 10 mg and 20 mg: 30 tablets in a plastic bottle with a screw cap. The lid is provided with a container with a moisture absorbing substance. The bottle together with the instruction for use is placed in a cardboard box.

For the dosage of 100 mg: 3 tablets in blister, consisting of laminated aluminum foil. Blister together with instructions for use are placed in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

After the expiration date, the drug can not be used.

Terms of leave from pharmacies:On prescription

Registration number:П N013884 / 01

Date of registration:18.09.2008

Expiration Date:Unlimited

The owner of the registration certificate:Sanofi-Aventis Deutschland GmbHSanofi-Aventis Deutschland GmbH Germany

Manufacturer: & nbsp

SANOFI WINTHROP INDUSTRIE France

Representation: & nbspSanofi Aventis GroupSanofi Aventis Group

Information update date: & nbsp10.09.2017

Illustrated instructions

Instructions

Arava® (Arava®)