Ralef - instructions for use, doses, side effects, contraindications

Excipients: hypromellose (hydroxypropylmethylcellulose) 16,0 mg / 32.0 mg, lactose anhydrous 39.0 mg / 78.0 mg, corn starch 22.8 mg / 45.6 mg, crospovidone 8.0 mg / 16.0 mg, silicon dioxide colloidal anhydrous (aerosil) 2,0 mg / 4.0 mg, talc 2.0 mg / 4.0 mg, magnesium stearate 0.2 mg / 0.4 mg;

excipients for the shell: giprolose (hydroxypropylcellulose) 2.16 mg / 4.32 mg, macrogol 6000 (polyethylene glycol 6000) 0.14 mg / 0.28 mg, titanium dioxide 0.54 mg / 1.08 mg, talc 0.16 mg / 0.32 mg.

Description:

Round biconvex tablets, covered with a film coat of white or almost white color. On the cross section, the nucleus is white or almost white in color.

Pharmacotherapeutic group:Immunosuppressive remedy

ATX: & nbsp

L.04.A.A.13 Leflunomide

L.04.A.A Selective immunosuppressants

Pharmacodynamics:

Leflunomide is a basic antirheumatic drug 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. At the same time, A771726 inhibits the expression of receptors for interleukin-2 (Cd-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 leflunomide in vivo.

When ingested, 82 to 95% leflunomide is absorbed. The maximum plasma concentrations of A771726 are determined from 1 to 24 hours after a single dose. Leflunomide can be used together 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, achieving a steady-state concentration would require a 2-month leflunomide.In studies with multiple prescriptions of leflunomide, the pharmacokinetic parameters of A771726 were dose-dependent in the dose range of 5 mg 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%. The binding of A771726 is more variable and slightly decreased in patients with rheumatoid arthritis or chronic renal failure.

Leflunomide is metabolized to one major metabolite 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 (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 a clearance of 31 ml / h. Leflunomide is excreted with feces (probably due to biliary excretion) and with urine. The half-life of leflunomide is about 2 weeks.

In patients who are on chronic outpatient peritoneal dialysis (HAPS), the pharmacokinetics of A771726 is similar to that of healthy volunteers. The faster excretion of A771726 is observed in patients on hemodialysis, which is not due to its extraction into the dialysate, but to the displacement 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.

In patients with hepatic insufficiency data on the pharmacokinetics of leflunomide are absent.

Patients under the age of 18 years pharmacokinetic characteristics were not studied.

In elderly patients (65 years and older) pharmacokinetic data roughly correspond to the average age group.

Indications:

As a basic agent for the treatment of adult patients with active 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 and teriflunomida or to any other component of the drug.

Impaired liver function, pre-existing liver disease.

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.

Renal insufficiency of moderate and severe severity (due to the small experience of clinical observation).

Severe hypoproteinemia (eg, with nephrotoxic syndrome).

Pregnancy.

For women of reproductive age who do not rule out the possibility of becoming pregnant during the treatment with leflunomide, after the end of leflunomide treatment, women should not become pregnant as long as the plasma concentration of the active metabolite remains above 0.02 mg / l.

Pregnancy should be excluded before treatment with leflunomide begins.

Breastfeeding period.

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.

Age to 18 years (due to lack of data on efficacy and safety in this group of patients).

Lactose intolerance, lactase deficiency, glucose-galactose malabsorption (since the formulation contains lactose anhydrous).

Carefully:

Patients with interstitial lung diseases (increased risk of interstitial lung injury).

Patients with mild to moderate severity of anemia, leukopenia, neutropenia, thrombocytopenia and bone marrow hematopoiesis disorders (including history); patients who have recently received or are receiving concomitantly with leflunomide drugs with immunosuppressive or hematotoxic action; patients with abnormalities from the norm of hematological parameters before the beginning of treatment with leflunomide, not associated with inflammatory diseases of the joints (frequent hematological control is required).

Age over 60 years, simultaneous use of other neurotoxic drugs and diabetes mellitus (increased risk of peripheral neuropathy).

Mild renal insufficiency (creatinine clearance (CC) is less than 80 ml / min, but more than 50 ml / min), due to limited clinical experience.

Pregnancy and lactation:

Pregnancy

Clinical studies on the evaluation 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 pregnancy or in women of childbearing age who do not use reliable contraception in leflunomide treatment and for some time after treatment (waiting period or shortened period of "laundering", see below). Before the treatment with leflunomide, it is necessary to make sure that there is no pregnancy. Patients should be informed that as soon as the menstrual cycle is delayed or if there is another reason to presume pregnancy, they should immediately inform the doctor about it to make a pregnancy test. 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 concentration of the active metabolite in the blood using the "laundering" procedure described below will help in the first delay of the menstrual cycle 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 live births compared with 4.2% 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), 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 blood plasma is measured after a two-year waiting period.

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

The procedure for "laundering"

After stopping treatment with leflunomide:

- Colestyramine 8 g is administered 3 times a day for 11 days;

- as an alternative, 50 g of activated charcoal, powdered, is administered 4 times a day for 11 days.

Regardless of the selected "laundering" procedure, two separate tests should be tested at intervals of at least 14 days and wait one and a half months from the moment when the concentration of A771726 in the blood plasma for the first time is fixed below 0.02 mg / l, until 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 a two-year waiting period with reliable contraception seems unreasonable, It may be advisable to carry out the procedure of "laundering" in preventive purposes.

AND colestramine, and Activated carbon can affect the absorption of estrogens and progestogens, so reliable oral contraceptives do not give a hundred percent guarantee during the "laundering" period with the help of kolestiramine or activated charcoal. It is recommended to use alternative methods contraception.

Breastfeeding period

Studies in animals have shown that leflunomide or its metabolites pass into breast milk. Therefore, the use of leflunomide during breastfeeding is contraindicated. 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:

Inside, swallowing whole, with enough liquid. The ingestion of food has no effect on the absorption of leflunomide.

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

Recommendations for monitoring treatment are indicated in the section "Special instructions".

Dosing regimen

Treatment of rheumatoid arthritis (RA)

The recommended dose is 20 mg leflunomide once a day. When taking a dose of 20 mg once a day immediately after the start of treatment (that is, without taking a loading dose), the efficacy of leflunomide in RA 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.

Treatment of psoriatic arthritis (PsA)

The recommended dose is 20 mg leflunomide once a day.

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

Therapy is usually carried out for a long time.

Special patient groups

Patients with hepatic impairment

Recommendations for dose adjustment or drug cancellation depending on the severity or persistence of alanine aminotransferase (ALT) elevation when leflunomide is taken are listed in the 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 for patients older than 65 years.

Side effects:

The incidence of adverse reactions is as follows: very often (≥1 / 10 cases), often (≥1 / 100 and <1/10 cases) infrequently (≥1 / 1000 and <1/100 cases), rarely (≥1 / 10000 and <1/1000 cases) and very rarely (<1/10000 cases). Undesirable reactions, the frequency of development of which can not be estimated from available data, have the designation "frequency is unknown".

From the cardiovascular system: often - increased blood pressure.

From the gastrointestinal tract: often diarrhea, nausea, vomiting, anorexia, damage to the oral mucosa (eg, aphthous stomatitis, ulceration of the oral mucosa), abdominal pain; infrequently - a violation of taste sensations; very rarely - pancreatitis.

From the respiratory system, chest and mediastinum: rarely - interstitial lung diseases (including interstitial pneumonitis), with possible fatal outcome.

From the side of metabolism and nutrition: often - a slight increase in creatine phosphokinase (CK), weight loss; infrequently - hypokalemia, insignificant hyperlipidemia,minor hypophosphataemia; frequency unknown - a slight increase in lactate dehydrogenase (LDH) activity, hypo uricemia.

From the nervous system: often - headache, dizziness, paresthesia; infrequently - anxiety; very rarely - peripheral neuropathy.

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

From the skin and subcutaneous tissues: often - increased hair loss, eczema, itching, dry skin; very rarely - toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme, Stevens-Johnson syndrome (so far causal relationship with leflunomide treatment has not been established, but it can not be excluded); frequency unknown - discoid lupus erythematosus, pustular psoriasis or exacerbation of psoriasis, drug reaction with eosinophilia and systemic symptoms (DRESS-syndrome).

From the immune system: often - mild allergic reactions, including a maculopapular rash and other types of rash; infrequently - hives; very rarely - serious anaphylactic / anaphylactoid reactions, vasculitis, including,cutaneous vasculitis (due to the underlying disease, the causal relationship with leflunomide treatment can not be established).

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

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.

From the side of the blood and lymphatic system: often - leukopenia (leukocytes> 2000 / μl); infrequently - anemia, small thrombocytopenia (platelets <100 000 / μL); rarely - pancytopenia (probably due to antiproliferative action), leukopenia (leukocytes <2000 / μl), eosinophilia; very rarely - agranulocytosis.

The recent concomitant or subsequent use of potentially myelotoxic drugs may be associated with a greater risk of hematological effects.

From the liver and bile ducts: often - an increase in the activity of "hepatic" transaminases (especially alanine aminotransferase (ALT), less often gamma-glutamyltranspeptidase (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 lethal.

From the genitals and the breast: frequency is unknown - a slight decrease in the concentration of sperm, the total number of spermatozoa and their mobility.

From the side of the kidneys and urinary tract: frequency unknown - renal failure.

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.

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

If any of the unwanted reactions listed in the manual is aggravated, or if you notice other undesirable reactions not listed in the manual, 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 overdose or toxicity, it is recommended to take colestramine or Activated carbon, to accelerate the cleansing of the body.

Kolestiramin, taken by three healthy volunteers orally 8 g three times a day for 24 hours, reduced the level 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 suspension) either 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 HAD (chronic ambulatory peritoneal dialysis) indicate that A771726, the main metabolite of leflunomide, is not able to be eliminated by dialysis.

Interaction:

Increased adverse reactions may occur in the case of recent or concomitant use of hepatotoxic (including alcohol) or hematotoxic and immunosuppressive drugs, or when taking these drugs after treatment with leflunomide without the procedure for "laundering" (see "Special instructions").

There was no pharmacokinetic interaction between leflunomide (10-20 mg per day) and methotrexate (10-25 mg per week). However, in some (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 "hepatic" enzymes in the blood, and in the other 5 patients there was more than a 3-fold increase in the activity of "hepatic" enzymes in the blood. In all cases, these phenomena disappeared, in some cases, with the continuation of taking both drugs, and in others after stopping the leflunomide.

Patients receiving leflunomide, it is recommended not to give colestramine or Activated carbon, as this leads to a rapid and significant decrease in the concentration of A771726 (the active metabolite leflunomide) in blood plasma.It is believed that this is due to a violation of intestinal hepatic recirculation of A771726 in the liver and / or a violation of its gastrointestinal dialysis.

If the patient is already taking non-steroidal anti-inflammatory drugs (NSAIDs) and / or glucocorticosteroids, they can continue to be taken after treatment with leflunomide.

The enzymes involved in the metabolism of leflunomide and its metabolites are not exactly known. Study in vivo its interaction with cimetidine (nonspecific inhibitor of cytochrome P450) showed no significant interaction. After the concomitant administration of a single dose of leflunomide to subjects receiving 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 did not change significantly. The mechanism of this effect is not clear.

Research in vitro showed that A771726 depresses the activity of the isoenzyme CYP2C9. Drugs metabolized by isoenzyme CYP2C9, are the phenytoin, tolbutamide, warfarin and many NSAIDs.In clinical studies, there were no problems with the simultaneous administration of leflunomide and NSAIDs metabolized by isoenzyme CYP2C9. With extreme caution should be applied leflunomide with phenytoin and tolbutamide, since it is impossible to exclude the possibility of their interaction with leflunomide at the level of metabolism, although there is no clinical data on such an interaction. An increase in prothrombin time was reported with the simultaneous use of leflunomide and warfarin.

Repeated doses of A771726 (active leflunomide metabolite - teriflunomide) lowered the average value of C_m_Oh and AUC for caffeine (substrate isoenzyme CYP1A2) by 18% and 55% %, respectively, suggesting that A771726 induces less isoenzyme CYP1A2 in vivo. Therefore, drugs metabolized by isoenzyme CYP1A2 (such as duloxetine, alosetron, theophylline and tizanidine) during treatment with A771726 should be used with caution, as this may lead to a decrease in the effectiveness of these products.

An increase in the average value of C_max and AUC for repaglinide (1.7 and 2.4 times, respectively) after taking multiple doses of A771726, suggesting that A771726 acts as an inhibitor of the isoenzyme CYP2C8 in vivo. Therefore, against the designation of A771726, drugs metabolized by the isoenzyme CYP2C8, such as repaglinide, paclitaxel, pioglitazone or rosiglitazone, should be used with caution.

An increase in the value of C_m_Oh and AUC (2.64 and 2.51-fold, respectively) of rosuvastatin (substrate transport protein resistance of breast cancer (BCRP), after the introduction of repeated doses of A771726. However, there was no apparent effect of this increase in rosuvastatin exposure in plasma on activity HMG-CoA reductase. For rosuvastatin, a dose reduction of 50% is recommended for joint administration with A771726.

There is an increase in the concentration of C_m_Oh and AUC (1.43 and 1.54-fold, respectively) of cefaclor after repeated doses of A771726, suggesting that A771726 is an inhibitor of organic anion transporters 3 (OAT3) in vivo. Therefore, precautions should be taken when using A771726 together with substrates of OATS, such as cefaclor, benzylpenicillin, ciprofloxacin, indomethacin, ketoprofen, furosemide, cimetidine, methotrexate and zidovudine.

In a study in which leflunomide gave female healthy volunteers in conjunction with three phase oral contraceptive containing 30 .mu.g of ethinylestradiol, no reduction in contraceptive effect was found, and A771726 pharmacokinetics completely fit into a normal range.

Currently there is no information regarding the simultaneous use of leflunomide with antimalarial drugs used in rheumatology (for example, chloroquine and hydroxychloroquine), gold preparations (intramuscular or oral), penicillamine, azathioprine, and other immunosuppressive agents (except methotrexate, supra.). The risk associated with complex therapy is unknown, especially with long-term treatment. Since this kind of therapy may lead to the development of additional or even synergistic toxicity (e.g., hepato- or gematotoksichnosti), leflunomide combination with other DMARDs (e.g., methotrexate) are undesirable. The recent concomitant or subsequent use of potentially myelotoxic agents may be associated with a greater risk of hematologic effects.Immunosuppressants increase the risk of infections, as well as malignant, especially lymphoproliferative diseases.

Vaccination

There are no clinical data on the efficacy and safety of vaccination in the treatment of 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.

Special instructions:

Leflunomide can be used only after a thorough medical examination of patients.

Before starting treatment, it is necessary to remember the possible increase in the number of unwanted reactions in patients who previously received baseline therapy of rheumatoid arthritis with other drugs that have hepato- and hematotoxic effects.

General Precautions

Due to the long half-life of the active metabolite leflunomide, A771726, serious adverse reactions (eg, hepatotoxicity, hematotoxicity or severe immunological / allergic reactions) may occur or persist even after treatment with leflunomide has ceased.If a serious unwanted reaction 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 "Application during pregnancy and during breastfeeding", and with the clinical need to continue or repeat the reception of one of them.

If suspicion of severe immunological / allergic reactions such as Stevens-Johnson syndrome or Lyell's syndrome is required to achieve a rapid and effective cleansing of the body from this metabolite, a longer-term administration of colestyramine or activated charcoal may be required.

Due to the long half-life of the active metabolite leflunomide, A771726, when proceeding to receive another basic drug (eg methotrexate) after treatment with leflunomide, it is necessary to carry out the procedure of "laundering".

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, the use of leflunomide in patients with impaired hepatic function is contraindicated.

There have been reports of rare cases of severe liver damage, in some cases fatal, with leflunomide treatment. Most of these cases were observed during the first six months of treatment. Although no causal relationship has been established between these undesirable events and leflunomide, and in most cases there were several additional suspicious factors, the exact implementation of the recommendations for treatment control is considered mandatory.

Before the start of treatment, and at least 1-2 times a month in the first 6 months of treatment, and then 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 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 leflunomide administration to be continued, 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 elevation in the ALT level that exceeds the upper limit of the norm by more than 3 times, leflunomide intake should be discontinued.To reduce the level of A771726 more quickly, you should start taking colestyramine or activated charcoal according to the procedure for "laundering" (see section "Use during pregnancy and during breastfeeding").

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

Renal insufficiency

In view of the limited experience of clinical observation, Ralef is contraindicated in patients with moderate and severe renal insufficiency. In patients with mild renal insufficiency (creatinine clearance (CC) less than 80 ml / min, but more than 50 ml / min), the drug should be taken with caution.

Hematologic and immune reactions

In patients with previous anemia, leukopenia and / or thrombocytopenia, as well as in patients with impaired bone marrow function or at risk of suppression of bone marrow function, the risk of hematological disorders 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 with recent or concomitant use of immunosuppressive or hematotoxic drugs, as well as with the administration of these drugs after the end of leflunomide treatment 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.

Simultaneous application with other types of treatment

At present, there is still no information on the simultaneous use of leflunomide with antimalarial drugs used in rheumatology (for example, chloroquine and hydroxychloroquine) administered intramuscularly or orally with gold preparations, Dpenicillamine, azathioprine and other immunosuppressive agents (with the exception of methotrexate). There is no known risk associated with the appointment of complex therapy, especially with long-term treatment. Since this type of therapy can lead to the development of additional or even synergistic toxicity (eg, hepatotoxicity or hematotoxicity), combinations of leflunomide with other basic drugs (eg methotrexate) are not desirable.

Transition to other types of treatment

Because the leflunomide long remains in the body, switching to another basic drug (for example, methotrexate) without an appropriate procedure for "laundering" can increase the possibility of additional risk even after a long time after the transition (for example, kinetic interaction, organotoxicity).

Similarly, the recent treatment with hepatotoxic or hematotoxic drugs (eg methotrexate) may lead to an increase in the number of adverse reactions, therefore, when starting leflunomide treatment, it is necessary to carefully consider all the positive and negative aspects associated with taking this drug.

Skin Reactions

If ulcerative stomatitis develops, Leflunomide should be discontinued. Very rare cases of Stevens-Johnson syndrome or toxic epidermal necrosis have been reported in patients who received leflunomide. Have patients receiving leflunomide possible development of a drug reaction with eosinophilia and systemic symptoms (DRESS-syndrome).

In case of skin reactions and / or reactions from the mucous membranes, it is necessary to cancel the drug and immediately begin the procedure of "laundering". It is necessary to achieve complete removal of leflunomide from the body. In such cases, the repeated administration of leflunomide is contraindicated.

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 reduced 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".

It is necessary to carefully monitor patients with a positive reaction to tuberculin because of the risk of reactivation of tuberculosis.

Reactions from the respiratory system

In the treatment with leflunomide, rare cases of interstitial pulmonary process were noted. The risk of occurrence increases in patients with a history of interstitial lung diseases. Interstitial lung diseases are diseases with a potential fatal outcome, which can be acute in patients receiving treatment. Symptoms such as coughing and shortness of breath can cause cessation of leflunomide therapy and further examination if necessary.

Peripheral Neuropathy

There were reports of cases of peripheral neuropathy in patients treated with leflunomide, which was resolved in most patients after discontinuation, 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, consideration should be given to discontinuing leflunomide treatment and conducting the "laundering" procedure described in the section on "Application during pregnancy and during breastfeeding".

Arterial pressure

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

Interaction with other drugs

Caution should be exercised in prescribing drugs metabolized by isoenzyme CYP2C9 (phenytoin, warfarin, tolbutamide), with the exception of NSAIDs (also see "Interactions with Other Drugs"). An increase in prothrombin time was reported with the simultaneous use of leflunomide and warfarin.When used simultaneously with warfarin, the international normalized relationship (MNO) should be closely monitored. Because the leflunomide is the starting compound for teriflunomide, the combined administration of leflunomide with teriflunomide is not recommended.

Recommendations for men

There are no confirmed data on the increased risk of fetotoxic action (associated with the toxic effect of the drug on the sperm of the father) when leflunomide is used in men. Experimental studies in animals have not been conducted. 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 "Use during pregnancy during breastfeeding".

Effect on the ability to drive transp. cf. and fur:It is necessary to take into account the possibility of developing unwanted reactions from the nervous system, for example, dizziness, and therefore, in the event of such undesirable reactions, one should refrain from managing vehicles, mechanisms and engaging in potentially hazardous activities,requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

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

Packaging:

By 3, 10, 15, 30 tablets in a planar cell packaging made of polyvinylchloride film and aluminum foil printed lacquered.

According to 1, 2, 3, 5, 6 contour mesh packages together with instruction for use in pack of cardboard.

Storage conditions:

In a dry, protected from light place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:2 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002702

Date of registration:10.11.2014

The owner of the registration certificate:EvoFarm Ltd.EvoFarm Ltd. Russia

Manufacturer: & nbsp

EvoFarm Ltd. Russia

Information update date: & nbsp13.11.2015

Illustrated instructions

Instructions

Ralef® (Ralef)