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Arava

Arava
Leflunomide is a disease-modifying antirheumatic drug used to treat rheumatoid arthritis and psoriatic arthritis. It has antiproliferative, immunomodulatory and anti-inflammatory effects.

Brand: Leflunomide

Availability: In Stock
Average Delivery Time: 9 Days
Exp. Date: September 2023
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Arava 20 mg
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Arava 10 mg
240 pills - 10 mg
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$321.59 $1.34 $206.17 Add to cart
180 pills - 10 mg
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$244.79 $1.36 $151.03 Add to cart
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$165.91 $1.38 $97.97 Add to cart
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$125.93 $1.40 $71.98 Add to cart
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30 pills - 10 mg $55.95 $1.87 $10.02 Add to cart
10 pills - 10 mg $21.99 $2.20 No Add to cart

Product description

Pharmacological action of Arava Leflunomide 

Buy Arava Leflunomide in Canada

Basic antirheumatic drug. It has antiproliferative, immunomodulatory (immunosuppressive) and anti-inflammatory effects. The active metabolite of leflunomide A771726 inhibits the enzyme dehydroorotate dehydrogenase and has an antiproliferative effect. A771726 in vitro inhibits mitogen-induced proliferation and DNA synthesis of T-lymphocytes. The antiproliferative activity of A771726 is evidently manifested at the level of pyrimidine biosynthesis, since the addition of uridine to the cell culture eliminates the inhibitory effect of the A771726 metabolite. 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 at the G1 stage. Lymphocyte proliferation 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 (CB-25) and nucleus antigens Ki-67 and PCNA associated with the cell cycle.

The therapeutic effect of leflunomide has been shown in several experimental models of autoimmune diseases, including rheumatoid arthritis.

Leflunomide reduces symptoms and slows down the progression of joint damage in active rheumatoid arthritis and psoriatic arthritis.

The therapeutic effect usually appears after 4-6 weeks and may increase further over the course of 4-6 months.

Pharmacokinetics

Arava Leflunomide packaging

Absorption and distribution

When taken orally, from 82% to 95% of the drug is absorbed. Leflunomide can be taken with food. Leflunomide is rapidly converted to its active metabolite A771726 (primary metabolism in the intestinal wall and metabolism during the "first pass" through the liver). Only traces of unchanged leflunomide were seen in plasma, urine or feces. The only detectable metabolite is A771726, which is responsible for the main properties of the drug in vivo.

After a single dose, Cmax A771726 is determined after 1-24 hours. Due to the very long T1 / 2 of A771726 (about 2 weeks), a loading dose of 100 mg per day was used for 3 days. This made it possible to quickly reach an equilibrium state of the plasma concentration of A771726. Without a loading dose, a 2-month dose would be required to achieve Css. In studies with repeated administration of the drug, the pharmacokinetic parameters of A771726 were dose-dependent in the dose range from 5 to 25 mg. In these studies, the clinical effect was closely related to the plasma concentration of A771726 and the daily dose of leflunomide. At a daily dose of 20 mg, mean plasma concentrations of A771726 at equilibrium were 35 μg / ml.

In plasma, there is a rapid binding of A771726 to albumin. The unbound fraction A771726 is approximately 0.62%. The binding of A771726 is more variable and is somewhat reduced in patients with rheumatoid arthritis or chronic renal failure.

Metabolism

Leflunomide is metabolized to one major (A771726) and several minor metabolites, including 4-trifluoromethylalanine. Biotransformation of leflunomide into A771726 and the subsequent metabolism of A771726 itself is controlled by several enzymes and occurs in microsomal and other cellular fractions. Interaction studies with cimetidine (a non-specific inhibitor of cytochrome P450) and rifampicin (a non-specific inducer of cytochrome P450) have shown that in vivo CYP enzymes are involved in leflunomide metabolism only to a small extent.

Withdrawal

The elimination of A771726 from the body is slow and is characterized by a clearance of 31 ml / h. Leflunomide is excreted in feces (probably due to biliary excretion) and in urine. T1 / 2 is about 2 weeks.

Pharmacokinetics in special clinical cases

The pharmacokinetics of A771726 in patients on chronic ambulatory peritoneal dialysis is similar to that in healthy volunteers.

A faster excretion of A771726 is observed in patients on hemodialysis, which is associated not with the extraction of the drug into the dialysate, but with its displacement from the protein bond. Although the clearance of A771726 increases approximately 2-fold, the terminal T1 / 2 is similar to that in healthy individuals, since Vd increases simultaneously.

There are no data on the pharmacokinetics of the drug in patients with hepatic insufficiency.

Pharmacokinetics in individuals under 18 years of age has not been studied.

In elderly patients (65 years and older), pharmacokinetic data approximately correspond to the middle age group.

Indications of Arava®

as a basic drug for the treatment of adult patients with active 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.

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Dosage regimen of Arava Leflunomide 

Arava Leflunomide regimen

The use of the drug should begin under the supervision of a physician experienced in the treatment of rheumatoid arthritis and psoriatic arthritis.

In rheumatoid arthritis, at the beginning of treatment, the drug is prescribed in a loading dose of 100 mg (in the form of 100 mg tablets) 1 time / day for 3 days. However, excluding the use of a loading dose can reduce the risk of adverse reactions (especially from the gastrointestinal tract and the effect on the activity of hepatic enzymes in the blood). The recommended maintenance dose is 20 mg 1 time / day. When taking a maintenance dose of 20 mg 1 time / day immediately from the start of treatment (that is, without taking a loading dose), the effectiveness of the drug in rheumatoid arthritis did not decrease. In case of poor tolerance of the 20 mg dose, it is possible to reduce the dose to 10 mg 1 time / day (in the form of 10 mg or 20 mg tablets).

In psoriatic arthritis, at the beginning of treatment, the drug is prescribed in a loading dose of 100 mg 1 time / day for 3 days. The maintenance dose is 20 mg 1 time / day.

With both indications, the therapeutic effect usually appears after 4 weeks and can increase further up to 4-6 months. The therapy is usually carried out for a long time.

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

Current experience is insufficient to provide specific recommendations for dosing in patients with impaired renal function. It should be borne in mind that the active metabolite of leflunomide A771726 has a high affinity for proteins.

Patients with impaired liver function: recommendations for dose adjustment or discontinuation of the drug, depending on the severity or persistence of the increase in ALT activity while taking the drug, are given in the "Special instructions" section.


Contraindications to the use

  • of liver dysfunction;
  • severe immunodeficiency states (including AIDS);
  • severe disorders of bone marrow hematopoiesis or severe anemia, leukopenia, thrombocytopenia as a result of other causes (except for rheumatoid arthritis and psoriatic arthritis);
  • severe, uncontrolled infections;
  • renal failure of moderate and severe degree (due to little experience of clinical use);
  • severe hypoproteinemia (including with nephrotic syndrome);
  • pregnancy;
  • lactation period (breastfeeding period);
  • childbearing age in women who are not going to or are unable to use reliable methods of contraception during the period of treatment with leflunomide, and then until the plasma level of the active metabolite remains above 0.02 mg / l;
  • men who are going to conceive a child (they should be warned about the possible adverse effect of leflunomide on the sperm of the future father) (During treatment with leflunomide, it is necessary to use reliable methods of contraception);
  • age of patients less than 18 years (lack of data on efficacy and safety in this group of patients);
  • hypersensitivity to drug components.

Precautions:


  • patients with interstitial lung disease (increased risk of developing interstitial lung disease);
  • patients with anemia, leukopenia, thrombocytopenia and a history of bone marrow hematopoiesis disorders; patients who have recently received or are receiving simultaneously with leflunomide drugs with immunosuppressive or hematotoxic effects; patients with significant abnormalities of hematological parameters not associated with rheumatoid arthritis before starting treatment with leflunomide (frequent hematological monitoring is required);
  • age over 60 years, concomitant use of other neurotoxic drugs and diabetes mellitus (increased risk of developing peripheral neuropathy);
  • renal failure mild (CC less than 80 ml / min, but more than 50 ml / min) (limited clinical experience).

Application during pregnancy and lactation

There are no clinical studies evaluating leflunomide in pregnant women. 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 childbearing age who do not use reliable contraception during and for a period of time after treatment with leflunomide (waiting period or shortened washout period; see below). Ensure that you are not pregnant before starting treatment with leflunomide.

Patients should be informed that as soon as menstruation is delayed or if there is any other reason to suspect pregnancy, they should immediately inform their doctor about this in order to take a pregnancy test; If a pregnancy test is positive, the doctor should discuss with the patient the possible risks to the pregnancy. It is possible that a rapid decrease in the level of the active metabolite in the blood using the procedure for removing the drug described below will help reduce the risk to the fetus from leflunomide at the first delay in menstruation.

When taking leflunomide through negligence in the first trimester of pregnancy in patients with rheumatoid arthritis with further discontinuation of the drug and the “laundering” procedure with cholestyramine (see below), significant malformations were detected in 5.4% of live newborns compared with 4.2% of those in the group of women with rheumatoid arthritis who did not take leflunomide and 4.2% of those in the group of healthy pregnant women who did not take leflunomide.

Women taking leflunomide and wanting to become pregnant are advised to follow one of the procedures below to ensure that the fetus will not be exposed to toxic concentrations of A771726 (control concentration below 0.02 mg / L). according to available data, the concentration of the active metabolite in plasma 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 blood plasma may be higher than 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 stopping treatment with leflunomide.

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

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

Procedure "washing"

After the termination of treatment with leflunomide:

Cholestyramine 8 g is prescribed 3 times / day for 11 days;

alternatively, 50 g of powdered activated carbon is prescribed 4 times / day for 11 days.

Regardless of the "washing" procedure chosen, it is necessary to check in two separate tests with an interval of at least 14 days and wait a month and a half from the moment when the concentration of the drug in plasma is first recorded below 0.02 mg / l, until fertilization.

Women of childbearing age should be informed that it must take 2 years after stopping leflunomide treatment before they can try to become pregnant. If a 2-year waiting period with reliable contraception seems unreasonable, a preventive “laundering” procedure may be advised. Both cholestyramine and activated charcoal can interfere with the absorption of estrogens and progestogens, so reliable oral contraception is not 100% guaranteed during the washout period with cholestyramine or activated charcoal. It is recommended to use alternative methods of contraception.

Experimental studies on animals have shown that leflunomide or its metabolites are excreted in breast milk. Therefore, women who are breastfeeding should not be given leflunomide.

Depending on the importance of the treatment to the mother, a decision should be made whether to breastfeed or to start treatment with leflunomide, in which case breastfeeding should be discontinued.

Application for violations of liver functionfunction is

The use of violations of livercontraindicated.

Application for impaired renal function

Use is contraindicated in moderate or severe renal failure (due to little experience of clinical observations). No dose adjustment is required in patients with mild renal insufficiency.

Use in children

It is not recommended to use the drug in children and adolescents under the age of 18, because there are no data on efficacy and safety in this group of patients.

Use in elderly patients

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

Special instructions

Arava® can be prescribed only after a thorough medical examination.

Before starting treatment with Arava®, it is necessary to remember about the possible increase in the number of side effects in patients who previously received other basic drugs for the treatment of rheumatoid arthritis, which have hepato- and hematotoxic effects.

The active metabolite of leflunomide A771726 is characterized by a long T1 / 2 (from 1 to 4 weeks), therefore, even if treatment with leflunomide is discontinued, serious undesirable effects may occur or persist (for example, hepatotoxicity, hematotoxicity, or severe immunological / allergic reactions). If a serious adverse reaction develops, or if rapid elimination of A771726 from the body is required for any other reason, cholestyramine or activated charcoal should be prescribed as described in the section "Pregnancy and lactation", and if clinically necessary, continue or repeat taking one of them.

If severe immunological / allergic reactions such as Stevens-Johnson syndrome or Lyell's syndrome are suspected, longer use of cholestyramine or activated carbon may be required to achieve a quick and effective cleansing of the body from this metabolite.


Due to the long T1 / 2 of the active metabolite of leflunomide A771726, when switching to another basic drug (for example, methotrexate) after treatment with leflunomide, it is necessary to carry out the "laundering" procedure.

Reactions from the liver

Since the active metabolite of leflunomide A771726 has a high affinity for proteins, is metabolized in the liver and excreted in the bile, and may also have a hepatotoxic effect, the use of leflunomide in patients with impaired liver function is contraindicated. Leflunomide is not recommended for patients with liver disease.

Rare cases of severe liver damage, in some cases fatal, have been reported with leflunomide treatment. Most of these cases were observed during the first 6 months of therapy. Although the causal relationship of these adverse events to leflunomide has not been established, and in most cases there were several additional suspicious factors, strict adherence to the recommendations for monitoring treatment is considered imperative.

It is necessary to determine the activity of ALT in the blood before starting therapy with Arava®, then at least 1-2 times a month during the first 6 months of treatment and subsequently every 6-8 weeks.

Recommendations for the correction of the dosage regimen or discontinuation of the drug, depending on the severity and persistence of the increase in ALT activity.With a

confirmed 2-3-fold excess of VGN activity of ALT, reducing the dose from 20 mg to 10 mg per day may allow continued taking leflunomide, subject to careful monitoring of this indicator

If, at the same time, an increase in ALT activity 2-3 times higher than ULN persists or if there is an unconfirmed rise in ALT activity, exceeding ULN by more than 3 times, leflunomide should be discontinued. For a faster decrease in the concentration of A771726, cholestyramine or activated charcoal should be prescribed according to the "washing" scheme (as described in the section "Pregnancy and lactation").

While using Arava®, patients are advised to refrain from drinking alcohol because of the possible additional hepatotoxic effect.

Reactions from the hematopoietic system

In patients with pre-existing 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 determination of the leukocyte formula and platelet count) should be performed before starting leflunomide therapy, as well as 1-2 times a month during the first 6 months of treatment and then every 6-8 weeks.

Frequent monitoring of hematological parameters (complete blood count, including leukocyte count and platelet count) should be carried out in the following cases:

in patients with recent or concomitant use of immunosuppressive or hematotoxic drugs, as well as when taking these drugs after the end of treatment with leflunomide without a period of "washing";

  • in patients with a history of corresponding abnormalities in the blood;
  • in patients with appropriate changes in blood tests before treatment, not associated with inflammatory diseases of the joints.

In case of development of serious hematological reactions, including pancytopenia, it is necessary to stop taking the drug Arava and any other concomitant drug that suppresses bone marrow hematopoiesis, and start the "laundering" procedure.

Despite the lack of clinical data, due to the potential for immunosuppression, taking leflunomide is not recommended for patients with the following diseases:

severe immunodeficiency (eg, AIDS);

severe bone marrow dysfunction;

severe infections.

Co-administration with other therapies

There is currently no information on co-administration of leflunomide with antimalarial drugs used in rheumatology (for example, chloroquine and hydroxychloroquine), administered intramuscularly or administered orally with gold preparations, D-penicillamine, azathioprine and other immunosuppressive agents (excluding methotrexate). The risk associated with the appointment of 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 hematotoxicity), combinations of this drug with other basic drugs (for example, methotrexate) are not desirable.

Switching to other treatments

Because leflunomide persists for a long time in the body, switching to another basic therapy drug (eg methotrexate) without proper laundering may increase the possibility of additional risk even long after the switch (eg kinetic interaction, organotoxicity ).

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

Dermatological reactions

With the development of ulcerative stomatitis, the drug should be canceled.

Very rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported in patients treated with leflunomide. In case of skin reactions and / or reactions from the mucous membranes, you should stop taking the drug Arava and immediately start the "washing" procedure. It is necessary to achieve complete elimination of the drug from the body. In such cases, re-administration of the drug is contraindicated.

Infectious complications

It is known that drugs like leflunomide and having immunosuppressive properties make patients more susceptible to various kinds of infections (including opportunistic fungal infections). The resulting infectious diseases are usually difficult and require early and intensive treatment. With the development of a severe infectious process, it may be necessary to cancel the drug and carry out the "laundering" procedure.

Patients with tuberculin reactivity should be monitored because of the risk of tuberculosis activation.

Respiratory system reactions

Rare cases of interstitial pulmonary disease have been reported with leflunomide therapy. The risk of occurrence is increased in patients with a history of interstitial lung disease. Interstitial lung disease is a potentially fatal disease that can be acute in patients receiving treatment. Symptoms such as coughing and dyspnea may cause discontinuation of therapy.

Peripheral neuropathy

There have been reports of cases of peripheral neuropathy in patients treated with Arava®, which resolved in most patients after discontinuation of the drug, but in some patients symptoms persisted.

Age over 60 years, concomitant use of neurotoxic drugs, and diabetes mellitus may increase the risk of peripheral neuropathy. If peripheral neuropathy develops in a patient receiving Arava®, consideration should be given to discontinuing treatment with this drug and carrying out the drug withdrawal procedure described in the "Pregnancy and lactation" section.

Blood pressure

Before starting therapy and periodically during treatment, blood pressure should be monitored. during treatment with leflunomide, it may increase.

Interaction

Caution is needed when prescribing drugs metabolized with the participation of the isoenzyme CYP2C9 (phenytoin, warfarin, tolbutamide), with the exception of NSAIDs.

Recommendations for men

There are no data on the risk of fetotoxicity (associated with the toxic effect of the drug on the father's sperm) if leflunomide is taken by men. Experimental studies on animals in this direction have not been carried out. To minimize the possible risk, men who are planning to have a baby should stop taking leflunomide and go through the "laundering" procedure described in the "Pregnancy and lactation" section.

Effects on the ability to drive vehicles and use mechanisms

No relevant information available. However, in the event of adverse reactions from the nervous system, for example, dizziness, patients should refrain from driving vehicles and engaging in other potentially hazardous activities.

Overdose

Symptoms: chronic drug overdose has been reported in patients receiving leflunomide at a dose up to 5 times the recommended daily dose, as well as reports of acute overdose in adults and children. In most cases, the development of adverse events was not reported. The resulting adverse events were comparable to the safety profile of leflunomide. The most frequently noted diarrhea, abdominal pain, leukopenia, anemia, increased indicators of the functional state of the liver.

Treatment: in case of overdose or toxicity, it is recommended to take cholestyramine or activated charcoal to speed up the cleansing of the body. Cholestyramine, taken by three healthy volunteers orally 8 g 3 times for 24 hours, reduced the level of A771726 in blood plasma by about 40% after 24 hours and by 49-65% after 48 hours.

It was shown that the administration of activated carbon (powder, suspended) 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 by 48% after 48 hours.

It is possible to repeat the washing procedure according to clinical indications.

Studies with hemodialysis and chronic ambulatory peritoneal dialysis indicate that the major metabolite, A771726, is not excreted on dialysis.

Drug interactions

An increase in adverse reactions may occur in the case of recent or concomitant use of hepatotoxic (including alcohol) or hematotoxic and immunosuppressive drugs, or when these drugs are started after treatment with leflunomide without a "laundering" procedure.

No pharmacokinetic interaction was found between leflunomide (10-20 mg / day) and methotrexate (10-25 mg / week). However, in some (5 out of 30) patients with rheumatoid arthritis, while taking leflunomide (10-20 mg / day) and methotrexate (10-25 mg / week), there was a 2-3-fold increase in the activity of liver enzymes in the blood, and the other 5 patients showed a more than 3-fold increase in the activity of hepatic enzymes in the blood. In all cases, these phenomena disappeared, in some with continued use of both drugs, and in others after discontinuation of leflunomide. It is not recommended to prescribe cholestyramine or activated charcoal to patients receiving leflunomide, as this leads to a rapid and significant decrease in the concentration of A771726 (the active metabolite of leflunomide) in the blood plasma. It is believed that this is due to a violation of the enterohepatic recirculation of A771726 and / or a violation of its gastrointestinal dialysis.

If the patient is already taking NSAIDs and / or corticosteroids, they can be continued after starting leflunomide treatment.


The enzymes involved in the metabolism of leflunomide and its metabolites are not precisely known. An in vivo study of its interaction with cimetidine (a nonspecific inhibitor of cytochrome P450) showed no significant interaction. After concomitant administration of a single dose of leflunomide to subjects receiving multiple doses of rifampicin (a non-specific inducer of cytochrome P450), the Cmax A771726 increased by about 40%, while the AUC did not change significantly. The mechanism of this effect is not clear.

In vitro studies have shown that A771726 inhibits the activity of the CYP2C9 isoenzyme. The drugs that are metabolized with the participation of the isoenzyme CYP2C9 are phenytoin, tolbutamide, warfarin, and many NSAIDs. In clinical studies, no problems were observed with the joint administration of leflunomide and NSAIDs (metabolized by CYP2C9). With extreme caution, Arava® should be used with other drugs metabolized by CYP2C9 (phenytoin, warfarin, tolbutamide). An increase in prothrombin time has been reported with the simultaneous use of leflunomide with warfarin.

In a study in which leflunomide was given to healthy female volunteers in conjunction with three-phase oral contraceptives containing 30 μg of ethinyl estradiol, no decrease in the contraceptive effect was noted, and the pharmacokinetics of A771726 were fully within the prescribed range.


Currently, there is no data on the combined use of leflunomide with antimalarial drugs used in rheumatology (chloroquine and hydroxychloroquine), gold drugs (i / m or orally), D-penicillamine, 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 (hepato- or hematoxicity), combinations of this drug with other basic drugs (for example, methotrexate) are undesirable. Recent concomitant or subsequent use of potentially myelotoxic drugs may be associated with a greater risk of hematological reactions. Immunosuppressants increase the risk of developing infections, as well as malignant, especially lymphoproliferative diseases.

Vaccination

There are no clinical data regarding the efficacy and safety of vaccination in the setting of leflunomide therapy. However, it is not recommended to vaccinate with live vaccines. When planning vaccination with live vaccines after discontinuation of Arava®, a prolonged T1 / 2 of leflunomide should be taken into account.


Side effect

Determination of the frequency of adverse reactions: very often (> 1/10), often (> 1/100, but <1/10), infrequently (> 1/1000, but <1/100), rarely (> 1/10 000, but <1/1000), very rarely (<1/10 000), the frequency is unknown (it is not possible to estimate the frequency based on the available data).

From the side of the cardiovascular system: often - increased blood pressure.

From the digestive system: often - diarrhea, nausea, vomiting, anorexia, damage to the oral mucosa (for example, aphthous stomatitis, ulceration of the oral mucosa), abdominal pain, increased activity of hepatic transaminases (especially ALT, less often - GGT and ALP ), hyperbilirubinemia; infrequently - disturbances in taste; rarely - hepatitis, jaundice / cholestasis; very rarely - pancreatitis, severe liver damage such as liver failure, acute liver necrosis, which can be fatal.

From the respiratory system: rarely - interstitial lung disease (including interstitial pneumonitis), with a possible fatal outcome.

From the side of metabolism: often - a slight increase in CPK, weight loss; infrequently - hypokalemia, mild hyperlipidemia, mild hypophosphatemia; the frequency is unknown - a slight increase in the level of LDH, hypouricemia due to the uricosuric effect.

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

From the side of the musculoskeletal system: the frequency is unknown - tendosynovitis and tendon rupture (a causal relationship with leflunomide treatment has not been established).

On the part of 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 (at the moment, a causal relationship with leflunomide treatment has not been established, but it cannot be ruled out); frequency unknown - cutaneous lupus erythematosus, pustular psoriasis, or exacerbation of psoriasis.

Allergic reactions: often - mild maculopapular rash and other types of rash; infrequently - urticaria; very rarely - serious anaphylactic / anaphylactoid reactions, vasculitis, incl. cutaneous necrotizing vasculitis (due to the underlying disease, a causal relationship with leflunomide treatment cannot be established).

From the hematopoietic system: often - leukopenia (leukocytes> 2000 / μl); infrequently - anemia, slight thrombocytopenia (platelets <100,000 / μl); rarely - pancytopenia (probably due to antiproliferative action), leukopenia (leukocytes <2000 / μl), eosinophilia; very rarely - agranulocytosis. Recent concomitant or subsequent use of potentially myelotoxic drugs may be associated with a greater risk of hematological effects.

From the reproductive system: the frequency is unknown - a slight decrease in sperm concentration, the total number of sperm and their motility.

Infectious and parasitic diseases: rarely - the development of severe infections and sepsis, which can be fatal. Immunosuppressive drugs can make the patient more susceptible to infections, including opportunistic infections. The incidence of rhinitis, bronchitis and pneumonia may increase slightly.

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

General reactions: often - asthenia.