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

Excipients: lactose (anhydrous) 57.25 mg, sodium lauryl sulfate 2.25 mg, crospovidone (XL-10) 6.5 mg, silicon dioxide colloid 2 mg, magnesium stearate 2 mg; film coating: opadray white 21K58794 2 mg [hypromellose 49.2%, titanium dioxide (E171) 31.25%, ethyl cellulose 12.3%, triacetin 7.25%].

Each tablet, film-coated, 20 mg contains:

active substance: leflunomide 20 mg;

Excipients: lactose (anhydrous) 57.25 mg, sodium lauryl sulfate 2.25 mg, crospovidone (XL-10) 6.5 mg, silicon dioxide colloid 2 mg, magnesium stearate 2 mg; film coating: opadray white 21K58794 1.94 mg [hypromellose 49.2%, titanium dioxide (E171) 31.25%, ethyl cellulose 12.3%, triacetin 7.25%], iron oxide yellow oxide (E172) 0.06 mg.

Description:

Dosage of 10 mg: round, biconvex tablets, coated with a film coat from white to almost white.

On a cross-section of a tablet from white up to almost white color.

Dosage of 20 mg: round, biconvex tablets, covered with a film membrane from white with a yellowish tint to yellow color.

On a cross-section of a tablet from white up to almost white color.

Pharmacotherapeutic group:Immunosuppressive remedy

ATX: & nbsp

L.04.A.A.13 Leflunomide

L.04.A.A Selective immunosuppressants

Pharmacodynamics:

Leflunomide 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 inhibits proliferation caused by mitogens and the synthesis of T-lymphocyte DNA. The antiproliferative activity of A771726 is manifested 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 intreleukin-2 (CB-25) and antigens of the nucleus Ki-67 and PCNA, associated with the cell cycle.

Leflunomide reduces symptoms and slows the progression of joint damage with an active form of rheumatoid 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 trace amounts of unchanged leflunomide are found. 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 taken. Eating does not affect absorption.Due to the very long half-life of A771726 (about 2 weeks), a loading dose of 100 mg per day for 3 days is used.

This allows us to quickly achieve an equilibrium state of the plasma concentration A771726. Without a loading dose, it would take 2 months for the drug to reach an equilibrium concentration. Pharmacokinetic parameters of A771726 have a linear dependence in a dose of 5-25 mg. At a dose of 20 mg per day, the mean plasma concentrations of A771726 at an equilibrium state are 35 μg / ml.

Plasma rapidly binds A771726 to albumins. The unbound fraction of A771726 is 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 subsequent metabolism of A771726 itself is controlled by several enzymes and occurs in microsomal and other cell fractions. 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 a clearance of 31 ml / h. Leflunomide is excreted by the kidneys and through the intestine. The half-life is about 2 weeks.

Pharmacokinetics of A771726 in patients on chronic outpatient peritoneal dialysis is similar to pharmacokinetics in healthy individuals. 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.

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

Indications:

- Active form of rheumatoid arthritis (to reduce symptoms of the disease and delay the development of structural damage to the joints);

- active form of psoriatic arthritis.

Contraindications:

- Hypersensitivity to leflunomide or other components of the drug, including teriflunomide;

- simultaneous application of leflunomide with teriflunomide (see.section "Special instructions");

- impaired liver function;

- severe immunodeficiency (eg, AIDS);

- significant disorders of bone marrow hematopoiesis or severe anemia, leukopenia, neutropenia or thrombocytopenia, not associated with rheumatoid or psoriatic arthritis;

- severe, uncontrolled infections;

- renal failure of moderate and severe severity;

- severe hypoproteinemia (eg, with nephrotic syndrome);

- pregnancy;

- reproductive age in women who do not use reliable contraceptive methods for the treatment with leflunomide, and then as long as the plasma level of the active metabolite remains above 0.02 mg / L. Pregnancy should be excluded before treatment with leflunomide;

- the period of breastfeeding;

- men receiving treatment with leflunomide should be warned about the possible toxic effects of the drug on spermatozoa. During the period of application of the drug, men need to take measures to protect their partner from pregnancy;

- deficiency of lactase, lactose intolerance, glucose-galactose malabsorption;

- age under 18 years (no data on efficacy and safety in this group of patients).

Carefully:

- Patients with interstitial lung diseases (increased risk of interstitial lung injury);

- patients with mild to moderate severity of anemia, leukopenia, neutropenia, thrombocytopenia and disorders of bone marrow hematopoiesis (including in history); patients who have recently received or are receiving concomitantly with leflunomide drugs with immunosuppressive or hematotoxic action; patients with non-rheumatoid arthritis significant deviations from the norm of hematological parameters before treatment with leflunomide (frequent hematological control is required);

- age over 60 years, simultaneous use of other neurotoxic drugs and diabetes mellitus (increased risk of peripheral neuropathy);

- 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 is contraindicated in pregnant women or women of reproductive age, not excluding the possibility of becoming pregnant during the treatment with leflunomide and some time after this treatment (waiting period or shortened period of "laundering"). It is necessary to be convinced of absence of pregnancy before the beginning of leflunomide treatment. Patients should be informed that as soon as a delay in menstruation occurs or there is another reason to presume pregnancy, they should immediately inform the doctor about it. In the case of a positive pregnancy test, 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 level of active metabolite content by means of the "laundering" procedure will help in the first delay of menstruation to reduce the risk to which the embryo from the leflunomide is exposed.

When taking leflunomide by negligence in the first trimester of pregnancy in patients with rheumatoid arthritis with further withdrawal of the drug and the procedure of "washing" with colestyramine, significant developmental defects were detected in 5.4% of live births 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 (a control concentration of less than 0.02 mg / L), because the available concentration of active metabolite in 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 blood plasma is measured after a two-year waiting period. After this, it is necessary to determine the concentration of A771726 in the blood plasma after at least 14 days.

The procedure for "laundering"

After stopping treatment with leflunomide:

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

- As an alternative, 50 g of activated carbon powdered (as a suspension), 4 times a day for 11 days is used.

Regardless of the procedure of "washing" it is necessary to inspect two separate tests at intervals of at least 14 days and to wait six weeks from the moment when the concentration of drug in plasma is first recorded below 0.02 mg / L, prior to fertilization.

It is necessary to inform women of childbearing age about what should happen 2 years after stopping treatment with leflunomide before they can try to become pregnant. If the 2-year waiting period with reliable contraceptive methods seems to be unreasonable, you can conduct a "laundering" procedure.

AND colestramine, and Activated carbon may affect the absorption of estrogen and progesterone, so reliable oral contraceptives does not give an absolute guarantee of the period of "money" by using cholestyramine or activated charcoal. It is recommended to use alternative methods of contraception.

Breastfeeding period

Studies in animals have shown that leflunomide and its metabolites penetrate into breast milk, so women during breast-feeding should not take leflunomide. Depending on the importance of treatment for a woman, it should be decided whether breastfeeding will be carried out or leflunomide treatment will be initiated, in which it will be necessary to refuse breastfeeding.

Dosing and Administration:

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

The drug is taken orally, regardless of food intake. Tablets should be swallowed whole, with enough liquid.

Treatment of rheumatoid arthritis

Treatment with leflunomide usually begin with a single dose of 100 mg per day during the day for 3 days, then switch to maintenance treatment. 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).

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 does not decrease. In the case of poor tolerability of 20 mg, a dose reduction of up to 10 mg once a day is possible.

Treatment of psoriatic arthritis

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

With both indications, the therapeutic effect usually manifests itself after 4 weeks and can grow further in 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 withdrawal depending on the severity or persistence of alanine aminotransferase elevation on the background of taking the drug are set out in the section "Special instructions".

Patients with impaired renal function

There are no 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.

Side effects:

The following undesirable phenomena are distributed according to the frequency of occurrence in accordance with the following gradation: very often (≥ 1/10), often (from ≥ 1/100 to <1/10), infrequently (from ≥ 1/1000 to <1/100) , rarely (from ≥ 1/10000 to <1/1000), very rarely (<1/10000), frequency is unknown (it is not possible to estimate the incidence of side effects from the available data).

Infectious and parasitic diseases: rarely - the development of severe infections and sepsis, which can be fatal.

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

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

In most of these cases, patients received another immunosuppressive therapy and, in addition to rheumatic disease, had co-morbidities that could increase the patient's predisposition to infections.

Benign, malignant and unspecified neoplasms: It is known that using some immunosuppressive drugs increases the risk of malignancy, especially the risk of developing lymphoproliferative diseases.

Violations from 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 <100000 / μl); rarely - leukopenia (number of leukocytes in peripheral blood <2000 / μl), eosinophilia, pancytopenia; very rarely - agranulocytosis.

The recent, concomitant or subsequent use of potentially myelotoxic drugs may be associated with a greater degree of risk of unwanted effects from the blood.

Immune system disorders: often - mild allergic reactions, including maculopapular rash and other types of rash, itching, eczema, dry skin, increased hair loss; infrequently - hives; very rarely - severe anaphylactic / anaphylactoid reactions, Stevens-Johnson syndrome (erythema multiforme), toxic epidermal necrolysis (currently a causal relationship with the treatment has not been established but can not be ruled out), vasculitis, including cutaneous necrotizing vasculitis ( because of the underlying disease, a cause-and-effect relationship with leflunomide treatment has not been established).

Disorders from the metabolism and nutrition: often - weight loss; infrequently - hypokalemia; frequency unknown - slighthyperlipidemia, insignificant hypophosphatemia, insignificant increase in lactate dehydrogenase activity (LDH), insignificant increase in creatine phosphokinase activity (CKF), hypo uricemia due to uricosuric effect.

Impaired nervous system: often - headache, dizziness, paresthesia; infrequently - disorders of taste perception, anxiety; very rarely - peripheral neuropathy.

Disorders from the cardiovascular system: often - increased blood pressure.

Disturbances from the respiratory system, chest and mediastinal organs: rarely - interstitial lung diseases (including interstitial pneumonitis) with possible fatal outcome; frequency unknown - pulmonary hypertension.

Disorders from the gastrointestinal tract: often diarrhea, nausea, vomiting, anorexia, damage to the oral mucosa (eg, aphthous stomatitis, ulceration of the oral mucosa), abdominal pain, colitis, including microscopic colitis; very rarely - pancreatitis.

Disorders from the liver and bile ducts: often - increased activity of "liver" transaminases (especiallyalanine aminotransferase (ALT), less often gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALF)), hyperbilirubinemia; rarely - hepatitis, jaundice / cholestasis; very rarely - severe liver damage, such as hepatic insufficiency, acute liver necrosis, which can be fatal.

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 the musculoskeletal and connective tissue: frequency unknown - tendosynovitis and rupture of tendons (causal relationship with leflunomide treatment not established).

Disorders from the kidneys and urinary tract: frequency unknown - renal failure.

Violations of the genitals: frequency is unknown - can not exclude a slight decrease in the concentration of sperm, the total number of spermatozoa and their mobility.

General disorders and disorders at the site of administration: often - asthenia.

If any of the side effects listed in the manual are aggravated or you notice any other side effects not listed in the instructions, inform the doctor about it.

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 to take 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 by 49 - 65% after 48 hours.

It was shown that the administration of activated charcoal (powder turned into a suspension) orally or through a gastric tube (50 g every 6 hours during the day) reduced the concentration of the active metabolite A771726 in plasma by 37% after 24 hours and 48% after 48 hours.

These procedures for "laundering" can be repeated according to clinical indications.Studies with hemodialysis and chronic outpatient peritoneal dialysis (HAPA) have shown that A771726, the main leflunomide metabolite, can not be excreted by dialysis.

Interaction:

FROM 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").

FROM methotrexate

In some (in 5 out of 30) patients with rheumatoid arthritis with simultaneous administration of leflunomide (10-20 mg per day) and methotrexate (10-25 mg per week) there was 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 given the treatment with leflunomide. However, vaccination with live vaccines is not recommended. When planning vaccination with live vaccine after the cancellation of leflunomide, its long half-life should be taken into account.

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. Therefore, with the simultaneous use of warfarin and leflunomide careful monitoring of INR (the international normalized relationship) is recommended.

FROM food

The degree of absorption of leflunomide is not affected by its joint intake with food.

The effect of other drugs on leflunomide

In vitro Studies conducted on human liver microsomes confirmed that cytochrome P450 isoenzymes participate in leflunomide metabolism CYP1A2, CYP2C19 and CYP3A4. Interaction Studies in vivo leflunomide with cimetidine (a nonspecific weak inhibitor of cytochrome P450 isoenzyme) 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 curveAUC) 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 A771726 (active metabolite leflunomide) in the blood plasma. This is due to violation of intestinal-hepatic recirculation of A771726 and / or its dialysis in the gastrointestinal tract (see section "Application during pregnancy and during breast-feeding" and section "Overdose").

Effect of leflunomide on other drugs

Transport protein substrates for breast cancer resistanceBCRP)

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

In studies on drug interaction, the absence of significant drug interaction between leflunomide and three-phase oral contraceptives was demonstrated. In a 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. 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 ruled out for leflunomide when administered at the 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 of A771726, the average values of the maximum plasma concentration (C_m_Oh) and AUC repaglinide (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 CYPC8, 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 of A771726 reduced the mean 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 application 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_Oh and 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 (e.g., methotrexate, topotecan, sulfasalazine, daunorubicin,doxorubicin) and a family of protein-organic anion transporter substrates (OATR), especially HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin, pravastatin, methotrexate, nateglinide, repaglinide, rifampin) should also be cautious in their joint application. 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_Oh and AUC_0-24ethinyl estradiol (1.58 and 1.54 times, respectively) and C_m_Oh and AUC_0-24 levonorgestrel (in 1.33 and 1.41 times, respectively). However, the adverse effect of this interaction on the efficacy of oral contraceptives is not expected, it is recommended to take into account the type of oral contraceptive used.

Effect on 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 concomitant 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 non-steroidal anti-inflammatory drugs (NSAIDs and / or glucocorticosteroids), they can continue to be taken after the start of 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 (intramuscularly or orally), penicillamine, azathioprine and other immunosuppressants (excluding methotrexate). The risk associated with complex therapy is unknown, especially with long-term treatment. Since this type of therapy can lead to the development of additional or even synergistic toxicity (eg, hepatotoxicity or toxic effects on the blood),combinations of this drug with other basic drugs (eg, methotrexate) are undesirable. Recent concomitant or subsequent use of potentially myelotoxic agents may be associated with a greater risk of developing blood disorders.

Special instructions:

The drug Arresto® 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 if leflunomide treatment is discontinued, serious adverse effects (eg, hepatotoxicity, toxic effects on blood or severe immunological / allergic reactions) may or may not persist. If a serious unwanted phenomenon develops, or if rapid removal from the body of A771726 is required for any other reason, colestramine or Activated carbon, as described in the section "Use during pregnancy and during 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 should take 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 development 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 precise implementation of the treatment control recommendations is considered mandatory.

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

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 increase in ALT activity exceeding 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 section "Application during pregnancy and during breast-feeding").

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 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 monitoring of hematologic parameters (general blood test, including leukocyte count and platelet count) should be performed in the following cases:

- in patients recently or simultaneously taking 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 hematological reactions, including pancytopenia, it is necessary to stop taking leflunomide and any other concomitant medication that suppresses bone marrow hematopoiesis and begin the procedure of "laundering".

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. If a serious infectious disease occurs, it may be necessary 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 cough and shortness of breath can be a reason for stopping leflunomide therapy and further appropriate testing.

Peripheral Neuropathy

There were reports of cases of peripheral neuropathy in patients treated with leflunomide, which was resolved in most patients after the ceasing of leflunomide, but in some patients the symptomatology persisted. Age over 60 years, the concomitant use of neurotoxic drugs and diabetes mellitus may increase the risk of peripheral neuropathy.In the development of peripheral neuropathy in a patient receiving leflunomide, consideration should be given to discontinuing leflunomide treatment and carrying out the drug removal procedure described in the section on "Application during pregnancy and during breastfeeding".

Renal insufficiency

The current experience is not enough for special recommendations on the dosing regimen 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 connection with 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. In order to minimize the possible risk, men should stop taking leflunomide and plan the "laundering" procedure described in the section "Pregnancy and Breastfeeding" when planning the appearance of the baby.

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

No relevant information is available. However, given the profile of side effects, such as undesirable phenomena on the part of the nervous system, for example dizziness, one should refrain from driving and other potentially hazardous activities requiring increased attention and speed of psychomotor reactions.

Form release / dosage:

Tablets, film-coated, 10 mg, 20 mg.

Packaging:

10 tablets per strip (aluminum / aluminum). For 1, 3 or 10 strips, together with the instructions for use are placed in a cardboard box.

For 10, 30 or 100 tablets in a sealed, transparent plastic bag together with a desiccant is placed in a bottle of high-density polyethylene, sealed with aluminum foil with the manufacturer's logo in English, closed with a plastic lid. One bottle together with the instruction for use is placed in a cardboard box.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the product after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004312

Date of registration:29.05.2017

Expiration Date:29.05.2022

The owner of the registration certificate: Simpex Pharma Pvt Ltd. Simpex Pharma Pvt Ltd. India

Manufacturer: & nbsp

SIMPEX PHARMA, Pvt. Ltd. India

Representation: & nbspKORAL-MED, CJSCKORAL-MED, CJSC

Information update date: & nbsp22.06.2017

Illustrated instructions

Instructions

Arresto® (Arresto®)