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

One tablet contains:
Leflunomide	10.0 mg	20.0 mg	100.0 mg
Excipients:
Lactose Monohydrate	100.0 mg	90.0 mg	120.0 mg
Corn starch	20.0 mg	20.0 mg	40.0 mg
Povidone-K25	4.0 mg	4.0 mg	8.0 mg
Microcrystalline cellulose	14.5 mg	14.5 mg	29.0 mg
Magnesium stearate	1.5 mg	1.5 mg	3.0 mg
Total: Composition of the film jacket:	150 mg	150 mg	300 mg
Advantia Prime 190100BA01 [hypromellose - 65%, titanium dioxide - 25%, macrogol -10%]	4.5 mg	4.5 mg	9.0 mg
Weight of film-coated tablet	154.5 mg	154.5 mg	309 mg

Description:Tablets are round, biconvex, covered with a film coat, white. Two layers are visible on the section.

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 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.

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 an equilibrium concentration. In studies with multiple prescription of the drug, 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 plasma concentration of A771726 and a 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 (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 urine. The half-life is about 2 weeks.

The pharmacokinetics of A771726 in patients on the HADS 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 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:

Leflunomide should not be used in patients with hypersensitivity to leflunomide or any other component of the drug.

The drug is contraindicated:

in patients with impaired hepatic function;

in patients with severe immunodeficiency (eg, AIDS);

in patients with significant disorders of bone marrow hematopoiesis, or with severe anemia, leukopenia or thrombocytopenia due to other reasons (other than rheumatoid arthritis);

in patients with severe, uncontrolled infections; in patients with moderate or severe renal failure (due to the small experience of clinical observation);

in patients with severe hypoproteinemia (eg, with nephrotic syndrome);

in pregnant women or women of childbearing age who are not using adequate contraception during treatment leflunomide, and then as long as the plasma level of the active metabolite remains above 0.02 mg / l (cm. "Pregnancy and lactation"). Pregnancy should be excluded before treatment with leflunomide begins. Leflunomide reception contraindicated during breastfeeding (cm. "Pregnancy and lactation").

Men being treated with leflunomide should be warned about the possible foetotoxic effect of the drug (related to its possible impact on the father's sperm) and the need to use reliable contraception. Leflunomide is not recommended for use in patients under 18 years of age, as there is no data on efficacy and safety in this group of patients.

Pregnancy and lactation:

Leflunomide should not be given to pregnant women or women of childbearing age who do not use reliable contraception in leflunomide treatment and for some time after this treatment (waiting period or abbreviated period of "laundering", see below). It is necessary to be convinced of absence of pregnancy before the beginning of leflunomide treatment. Patients should be informed that as soon as there is a delay in menstruation or if there is another reason to presume pregnancy, they should immediately inform the doctor about it, in order 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 level of active metabolite in the blood using the procedure described below for the removal of the drug will help at the first delay of the month to reduce the risk to which the fetus is exposed by 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).

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. If the value of both measurements is less than 0.02 mg / l, no teratogenic risk is expected.

The procedure for "laundering"

After stopping treatment with leflunomide: colestramine 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 chosen "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 the drug in the plasma for the first time is fixed below 0.02 mg / l, until fertilization.

It is necessary to inform women of childbearing age that they should go 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, it may be advisable to carry out the "laundering" procedure for 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 of contraception.

Studies in animals have shown that leflunomide or its metabolites pass into breast milk. Therefore, breastfeeding women should not take leflunomide.

Dosing and Administration:

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

For recommendations on treatment control, see the section "Special instructions". Treatment with leflunomide begins with a single oral dose of a shock dose of 100 mg for 3 days.As a maintenance dose for rheumatoid arthritis, it is recommended to take 10 mg to 20 mg leflunomide once a day, with psoriatic arthritis - 20 mg once a day.

The therapeutic effect usually manifests itself in 4-6 weeks and can then increase to 4-6 months.

There are no recommendations regarding the dosage of the drug for patients with mild renal insufficiency.

No dose adjustment is required for patients over 65 years of age.

The drug should be prescribed by specialists who have the necessary experience of treating rheumatoid arthritis.

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

Side effects:

Determination of the frequency of adverse reactions: very often (≥1 / 10), often (≥1 / 100, but <1/10), sometimes (≥1 / 1000, but <1/100), rarely (≥1 / 10,000, but <1/1000), very rarely (<1/10 000), the frequency is unknown (based on the available data can not be estimated).

From the cardiovascular system: often - a moderate increase in blood pressure; rarely a marked increase in blood pressure.

From the digestive system: often diarrhea, nausea, vomiting, diseases of the oral mucosa (eg, aphthous stomatitis, ulceration of the lips),pain in the abdominal cavity; infrequently - a violation of taste sensations; very rarely - pancreatitis.

From the hepatobiliary system: often, an increase in the activity of hepatic transaminases (especially ALT, less often GGT and APF, hyperbilirubinemia, rarely hepatitis, jaundice / cholestasis, very rarely severe liver damage such as hepatic insufficiency, acute liver necrosis, which can be fatal.

From the respiratory system: rarely - interstitial pulmonary process (including interstitial pneumonia), with possible fatal outcome.

From the side of metabolism: often - increased activity of CK; infrequently - hypokalemia, hyperlipidemia, hypophosphatemia; rarely - increase in LDH; frequency unknown - hypo-uricemia.

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

From the musculoskeletal system: often - tendovaginitis; infrequently - rupture of tendons.

Dermatological reactions: often - increased hair loss, eczema, rash (including maculopapular rash), itching, dry skin; very rarely - toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme, Stevens-Johnson syndrome.

From the immune system: often - mild allergic reactions; infrequently - hives; very rarely - serious anaphylactic / anaphylactoid reactions, vasculitis, incl. cutaneous necrotic vasculitis.

Infections and infestations: rarely - the development of severe infections, including opportunistic infections, and sepsis, which can be fatal. May increase the number of possible infections (in particular, rhinitis, bronchitis and pneumonia).

On the part of the hematopoiesis system: often - leukopenia (> 2000 / μL to the lower limit of the norm); 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, concurrent or subsequent use of potentially myelotoxic agents may be associated with a greater risk of hematologic effects.

On the part of the reproductive system: frequency is unknown - a slight decrease in the concentration of sperm, the total number of spermatozoa and their mobility.

From the urinary system: frequency unknown - renal failure.

General changes: often - anorexia, weight loss (usually minor), asthenia.

Other: the risk of malignant, especially lymphoproliferative diseases, increases with the use of certain immunosuppressive drugs.

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 an increase in liver function tests.

Treatment

In case of overdose or toxicity, it is recommended to take colestramine or activated charcoal 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 carbon (a powder converted 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 HAD (chronic ambulatory peritoneal dialysis) indicate that A771726, the main metabolite of leflunomide, is not able to be eliminated by dialysis.

Interaction:

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

In patients with rheumatoid arthritis, there was no pharmacokinetic interaction between leflunomide (10-20 mg per day) and methotrexate (10-25 mg per week).

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 recirculation of A771726 in the liver and small intestine and / or disruption of its gastrointestinal dialysis.

If the patient is already taking non-steroidal anti-inflammatory drugs (NSAIDs) and / or corticosteroids, 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 (not a specific 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 (not a specific cytochrome P450 inducer), the peak levels of A771726 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 inhibits the activity of cytochrome P4502C9 (CYP2C9). In clinical trials, there were no problems with co-administration of leflunomide and NSAIDs metabolized CYP2C9. With extreme caution should be given leflunomide together with other drugs that are not NSAIDs metabolized by CYP2C9, such as phenytoin, warfarin and tolbutamide. An increase in prothrombin time was reported with the simultaneous administration of leflunomide and warfarin.

In a study in which leflunomide were given to 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 found, and the pharmacokinetics of the A771726 were completely within the prescribed range.

Currently, there is no information on the combined use of leflunomide with antimalarial drugs used in rheumatology (for example, chloroquine and hydroxychlorine), drugs Au (w / m or orally), Dpenicillamine, azathioprine and other immunosuppressive drugs (with the exception of methotrexate). 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,hepato- or hematoxicity), 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 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. Consider the long half-life of the drug leflunomide when planning vaccination with live vaccine after discontinuation of the drug leflunomide.

Special instructions:Leflunomide can be given to patients only after a thorough medical examination.

Before starting treatment with the drug Leflunomide it is necessary to remember the possible increase in the number of side effects in patients who previously received other basic agents for the treatment of rheumatoid arthritis who have hepatotoxic and hematotoxic effects.The active leflunomide metabolite, A771726, is characterized by a long half-life, usually from 1 to 4 weeks. Due to the long half-life of the active metabolite leflunomide, A771726, serious adverse effects (eg, hepatotoxicity, hematoxicity or allergic reactions, see below) may occur or persist after treatment with leflunomide has ceased. In this case, the "laundering" procedure should be followed. The procedure can be repeated according to clinical indications. If suspected of severe immunological / allergic reactions such as Stevens-Johnson syndrome or Lyell's syndrome, a full procedure for "laundering" is mandatory.

Therefore, when such cases of toxicity occur or when switching to another basic drug (eg methotrexate) after treatment with leflunomide, it is necessary to carry out the procedure of "laundering" (see below).

Reactions of the liver

'Since the active metabolite leflunomide A771726, is associated with proteins and is excreted through hepatic metabolism and bile secretion, it is suggested that the level of A771726 in the blood plasma may increase in patients with hypoproteinemia.

A drug Leflunomide contraindicated in patients with severe hypoproteinemia or impaired liver function, (see "Contraindications.").

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 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.

The ALT level should be checked before starting leflunomide therapy, and then every 2 weeks during the first 6 months of treatment, followed by a check once every 6-8 weeks.

There are the following recommendations for correcting the dosage regimen or stopping the drug depending on the severity and persistence of increasing ALT levels. 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 2-3 times the upper limit of the ALT norm is maintained, or if there is a confirmed elevation in ALT levels that exceeds the upper limit of the norm by more than 3 times, the leflunomide should be discontinued and the "laundering" procedure should begin.

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

Hematologic reactions

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

In patients with previous anemia, leukopenia and / or thrombocytopenia, as well as in patients with impaired bone marrow function or the risk of developing such disorders, the risk of hematological disorders increases. If such a phenomenon occurs, you should use the "laundering" procedure to reduce the level of A771726 in blood plasma.

In case of serious hematologic reactions, including pancytopenia, it is necessary to stop taking the drug Leflunomide and any other concomitant drug suppressing bone marrow hematopoiesis, and begin the procedure of "laundering".

Joint application with other types of treatment

At present, there is still no information on the combined use of leflunomide with antimalarials 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. Because this type of therapy may lead to the development of additional or even synergistic toxicity (eg, hepato- or hematotoxicity), combinations of this drug 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, recent treatment with hepatotoxic or hematoxic drugs (eg methotrexate) may lead to an increase in the number of side effects, therefore, starting treatment with leflunomide, 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. In case of skin reactions and / or reactions from the mucous membranes, it is necessary to cancel the drug intake Leflunomide and any other drug associated with it and immediately begin the procedure of "laundering". It is necessary to achieve complete removal of the drug from the body. In such cases, the repeated administration of the drug is contraindicated.

Infections

It is known that preparations like leflunomide and possessing immunosuppressive properties,make patients more susceptible to various types 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.

Respiratory system reactions

In the treatment with leflunomide, rare cases of interstitial pulmonary process were noted. Symptoms such as cough and dyspnea may be the reason for stopping leflunomide.

Arterial pressure

Before the start of treatment with leflunomide and periodically after its beginning, it is necessary to control the level of arterial pressure.

Interactions

You should be careful when prescribing drugs that are metabolized by the action of CYP2C9 (phenytoin, warfarin, tolbutamide), with the exception of NSAIDs (non-steroidal anti-inflammatory drugs).

Recommendations for men

There is no data on the risk of fetotoxicity (associated with the toxic effect of the drug on the father's spermatozoa) when leflunomide is used by men. Experimental data in this direction were not carried out. To minimize the possible risk to men in planning the appearance of a child, it is necessary to stop taking leflunomide and use colestramine 8 g 3 times a day for 11 days or 50 g powdered activated carbon 4 times a day for 11 days.

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

When treating the drug Leflunomide the speed of psychomotor reactions and the ability to concentrate due to side effects (dizziness) may be impaired. In such cases, the patient needs to refrain from driving vehicles and working with potentially dangerous mechanisms.

Form release / dosage:

Tablets of 10 mg, 20 mg or 100 mg.

Packaging:

For tablets with a dosage of 10 mg and 20 mg, 10 tablets each, for tablets with a dosage of 100 mg, 3 tablets per contour cell pack of polyvinylchloride film and aluminum foil.

For tablets with a dosage of 10 mg and 20 mg - 30 or 100 tablets per can of polymer for medicines.

For tablets with a dosage of 100 mg - 3 tablets per can of polymer for medicines.

For tablets with a dosage of 10 mg and 20 mg - 30 or 100 tablets per can of orange glass. For tablets with a dosage of 100 mg - 3 tablets per can of orange glass.

Free space in the banks is filled with cotton absorbent medical cotton.

For tablets with a dosage of 10 mg and 20 mg, each jar, 3 or 10 out-of-round cell packs, together with the instructions for use, are placed in a pack of cardboard.

For tablets with a dosage of 100 mg, each jar or 1 circuit cell package, together with the instructions for use, is placed in a pack of cardboard.

Storage conditions:

The drug should be stored in a dry, protected from light 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-000820

Date of registration:07.10.2011

The owner of the registration certificate:TECHNOLOGY OF DRUGS, LTD. TECHNOLOGY OF DRUGS, LTD. Russia

Manufacturer: & nbsp

TECHNOLOGY OF DRUGS, LTD. Russia

Information update date: & nbsp13.11.2015

Illustrated instructions

Instructions

Leflayd (Leflaid)