Arava, 10 mg 30 pcs.

Pharmacological action:

Arava belongs to the class of basic antirheumatic drugs and has antiproliferative, immunomodulatory, immunosuppressive and anti-inflammatory properties. The active metabolite of leflunomide A771726 inhibits the enzyme dehydrorotate dehydrogenase and has antiproliferative activity. Under in vitro conditions A771726 inhibits mitogen-induced proliferation and DNA synthesis of T-lymphocytes.

The antiproliferative activity of A771726 appears to be manifested at the level of pyrimidine biosynthesis, since the addition of uridine to the cell culture eliminates the inhibitory effect of the metabolite A771726. Using radioisotope ligands, it was shown that A771726 selectively binds to the enzyme dehydrorotate dehydrogenase, which explains its ability to inhibit this enzyme and lymphocyte proliferation at the G1 stage.

Lymphocyte proliferation is one of the key steps in the development of rheumatoid arthritis.

At the same time, A771726 inhibits the expression of interleukin-2 receptors (CB-25) and Ki-67 and PCNA cell-cycle-related core antigens.

Therapeutic effects of leflunomide have been shown in several experimental models of autoimmune diseases, including rheumatoid arthritis.

Leflunomide reduces symptoms and slows the progression of joint damage in the active form of rheumatoid arthritis.
The therapeutic effect is usually seen after 4-6 weeks and may build up further over a period of 4-6 months.

Indications

As a basic treatment for adult patients with active rheumatoid arthritis to reduce the symptoms of the disease and delay the development of structural damage to the joints.

The active form of psoriatic arthritis.

Active ingredient

Composition

Active substance:

leflunomide 10 mg.

How to take, the dosage

The use of Arava should begin under the supervision of a physician experienced in the treatment of rheumatoid and psoriatic arthritis.
Treatment begins with a shock dose of 100 mg daily for 3 days. As a maintenance dose in rheumatoid arthritis, 10 to 20 mg once daily is recommended; in psoriatic arthritis, 20 mg once daily.

Therapeutic effect is seen 4 to 6 weeks after the start of therapy and may increase during 4 to 6 months. Tablets should be swallowed whole with plenty of fluid, regardless of meals. No dose adjustment is required for patients over 65 years of age and in patients with mild renal impairment.

Interaction

An increase in adverse events 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 “washout” procedure (see “Special Precautions”).

In rheumatoid arthritis patients, no pharmacokinetic interaction has been found between leflunomide (10 to 20 mg daily) and methotrexate (10 to 25 mg weekly).

Patients taking leflunomide are advised not to give colestyramine or activated charcoal, as this leads to a rapid and significant decrease in plasma concentrations of A771726 (the active metabolite of leflunomide). This is thought to be due to impaired recirculation of A771726 in the liver and small intestine and/or impaired gastrointestinal dialysis.
If the patient is already taking nonsteroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids, these can be continued after starting leflunomide treatment.

The enzymes involved in the metabolism of leflunomide and its metabolites are not exactly known. An in vivo study of its interaction with cimetidine (a non-specific cytochrome P450 inhibitor) showed no significant interaction. After concomitant administration of a single dose of leflunomide to subjects receiving multiple doses of rifampicin (a non-specific cytochrome P450 inducer), peak levels of A771726 increased by approximately 40%, whereas the area under the concentration-time curve did not change significantly. The mechanism of this effect is not clear.

In vitro studies have shown that A771726 inhibits cytochrome P4502C9 (CYP2C9) activity. No problems have been observed in clinical trials when leflunomide and NSAIDs metabolized by CYP2C9 are given together. Special caution should be exercised when giving leflunomide together with other drugs that are not NSAIDs metabolized by CYP2C9, such as phenytoin, warfarin, and tolbutamide. Increased prothrombin time has been reported with concomitant administration of leflunomide and warfarin.

In a study in which leflunomide was given to healthy female volunteers together with triphasic oral contraceptives containing 30 mcg ethinyl estradiol, no reduction in the contraceptive effect of the pills was found, and the pharmacokinetics of A771726 were completely within the intended range.

There is currently no information regarding the co-administration of leflunomide with antimalarials used in rheumatology (e.g., chloroquine and hydroxychlorine), Au drugs (intramural or oral), D-penicillamine, azathioprine and other immunosuppressive drugs (excluding methotrexate). The risks associated with combination therapy are unknown, especially with long-term treatment. Since this type of therapy may lead to additional or even synergistic toxicity (e.g., hepato- or hematoxicity), combinations of this drug with other basal drugs (e.g., methotrexate) are undesirable. 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 regarding the efficacy and safety of vaccination in the setting of leflunomide treatment. However, vaccination with live vaccines is not recommended. The long elimination half-life of Arava should be considered when planning for live vaccination after withdrawal of Arava.

Special Instructions

Before starting treatment with Arava, be aware of possible increased side effects in patients who were previously treated with other basal agents for rheumatoid arthritis that have hepatotoxic and hematotoxic effects.

The active metabolite of leflunomide, A771726, is characterized by a long half-life, typically ranging from 1 to 4 weeks. Because of the long half-life of the active metabolite of leflunomide, A771726, even when treatment with leflunomide is stopped, serious adverse effects may occur or persist (e.g., hepatotoxicity, hematoxicity, or allergic reactions, see below). In this case, a “washout” procedure should be performed.The procedure may be repeated for clinical indications. If severe immunological/allergic reactions such as Stevens-Johnson syndrome or Lyell syndrome are suspected, a complete “washout” procedure must be performed.

Therefore, if such toxicity occurs or if you switch to another basal drug (e.g. methotrexate) after treatment with leflunomide, a “washout” procedure (see below) must be performed.

Liver reactions
Since the active metabolite of leflunomide, A771726, is bound to proteins and is excreted via hepatic metabolism and bile secretion, it is thought that plasma levels of A771726 may be elevated in patients with hypoproteinemia. Arava is contraindicated in patients with severe hypoproteinemia or liver dysfunction. (See Contraindications.).

Rare cases of severe liver damage, occasionally fatal, have been reported when treated with leflunomide. Most of these cases have occurred within the first six months of treatment. Although a causal relationship of these adverse events to leflunomide has not been established, and in most cases there were several additional suspicious factors, accurate compliance with treatment monitoring recommendations is considered mandatory.
ALT levels should be checked before starting leflunomide therapy and then every 2 weeks during the first 6 months of treatment, with follow-up checks once every 6-8 weeks.

There are the following recommendations for dosing adjustment or discontinuation depending on the severity and persistence of ALT elevation.

If ALT is confirmed to be 2-3 times the upper limit of ALT, a dose reduction from 20 mg to 10 mg per day may allow continued use of leflunomide, provided that it is carefully monitored.

If 2-3 times the upper limit of ALT is still present, or if there is a confirmed ALT elevation of more than 3 times the upper limit of normal, leflunomide should be stopped and a “flush” should be initiated.

Because of possible additional hepatotoxic effects, it is recommended to refrain from drinking alcohol during treatment with leflunomide.

Hematologic reactions

A complete clinical blood count, including determination of the white blood cell count and platelet count, should be performed before treatment with leflunomide and every 2 weeks during the first 6 months of treatment and every 6-8 weeks thereafter.
In patients with previous anemia, leukopenia and/or thrombocytopenia, as well as in patients with bone marrow dysfunction or with the risk of developing such disorders, the risk of hematological disorders increases. If this occurs, a “washout” procedure should be used to reduce plasma levels of A771726.

In the event of serious hematologic reactions, including pancytopenia, Arava and any other concomitant medication that suppresses medullar hematopoiesis should be stopped and a “wash” procedure initiated.

Combined use with other treatments

. There is currently no information yet regarding the co-administration of leflunomide with antimalarials used in rheumatology (e.g., chloroquine and hydroxychloroquine), intramuscular or oral gold drugs, D-penicillamine, azathioprine, and other immunosuppressive agents (excluding methotrexate). There are no known risks associated with the administration of combination therapy, especially with long-term treatment. Since this type of therapy may lead to additional or even synergistic toxicity (e.g., hepatotoxicity or hematotoxicity), combinations of this drug with other baseline drugs (e.g., methotrexate) are not advisable.

Transitioning to other treatments

Because leflunomide persists in the body for a long time, switching to another baseline drug (e.g., methotrexate) without a proper “washout” procedure can increase the potential for additional risks even long after transition (e.g., kinetic interaction, organ toxicity).

Like, recent treatment with hepatotoxic or hematotoxic drugs (e.g., methotrexate) can lead to increased adverse events, so starting leflunomide treatment should carefully consider all the positive and negative aspects associated with taking this medication.

Skin reactions

Leflunomide should be stopped if ulcerative stomatitis develops.

Very rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported in patients receiving leflunomide. In case of skin and/or mucous membrane reactions, the administration of Arava and any other related drug should be stopped and a “washout” procedure should be initiated immediately. It is necessary to achieve complete elimination of the drug from the body. In such cases, reapplication of the drug is contraindicated.

Infections

Leflunomide-like drugs with immunosuppressive properties are known to make patients more susceptible to various types of infections, including opportunistic infections (infections caused by fungi and microorganisms that can only cause infections when immunity is reduced). Emerging infectious diseases are usually severe and require early and intensive treatment. If a severe infectious disease occurs, it may be necessary to interrupt treatment with leflunomide and begin a “washout” procedure.

Patients who test positive for tuberculin should be closely monitored because of the risk of reactivation of tuberculosis.
Respiratory reactions

Rare cases of interstitial lung disease have been reported with leflunomide therapy. Symptoms such as cough and dyspnea may be reasons for discontinuing leflunomide.

Hypertension

Hypertension should be monitored before starting treatment with leflunomide and periodically thereafter.

Interactions

Precaution should be exercised when prescribing drugs that are metabolized by CYP2C9 (phenytoin, warfarin, tolbutamide) except NSAIDs (nonsteroidal anti-inflammatory drugs).

Recommendations for men

There are no data on the risk of fetotoxicity (associated with toxic effects of the drug on paternal sperm) when leflunomide is used by men. Experimental data in this direction have not been conducted. To minimize the possible risk as much as possible, men should discontinue leflunomide and use colestyramine at 8 g 3 times a day for 11 days or 50 g of powdered activated charcoal 4 times a day for 11 days when planning to have a baby.

Contraindications

Side effects

Classification of the estimated frequency of adverse events:
very frequent (more than 1/10), frequent (more than 1/100 but less than 1/10), infrequent (more than 1/1000 but less than 1/100), rare (more than 1/10000 but less than 1/1000), very rare (less than 1/10000), unknown (cannot be estimated based on available data).

– Cardiovascular
Frequent: moderate increase in blood pressure.
Rare: marked increase in blood pressure

– Gastrointestinal tract
Frequent: diarrhea, nausea, vomiting, diseases of the oral mucosa (eg, aphthous stomatitis, ulcerated lips), pain in the abdomen.
Infrequent: taste disorders
Very rare: pancreatitis

– Respiratory system and mediastinal disorders
Rare: interstitial pulmonary process (including interstitial pneumonia), with possible fatal outcome.

– Metabolic disorders
Frequent: increased creatine phosphokinase (CPK)
Infrequent: hypokalemia, hyperlipidemia, hypophosphatemia.
Rare: increased lactate dehydrogenase (LDH)
Frequent unknown: hypouricemia

– Nervous system
Frequent: headache, dizziness, paresthesias.
Infrequent: anxiety.
Very rare: peripheral neuropathy

– Musculoskeletal system
Frequent: tendovaginitis.
Infrequent: tendon rupture

– Skin and derivatives
Frequent: increased hair loss, eczema, rash (including maculopapular rash), itching, dry skin.
Infrequent: urticaria
Very rare: toxic epidermal necrolysis (Lyell’s syndrome), erythema multiforme, Stevens-Johnson syndrome.

– Immune system
Frequent: mild allergic reactions.
Very rare: serious anaphylactic/anaphylactoid reactions, vasculitis, including cutaneous necrotic vasculitis.

– Infections and invasions
Rare: development of severe infections, including opportunistic infections and sepsis, which can be fatal.
Possible infections (particularly rhinitis, bronchitis and pneumonia) may increase.

– Blood and lymphatic system
Frequent: leukopenia (leukocytes > 2000/μl).
Infrequent: anemia, minor thrombocytopenia (platelets < 100,000/μl).
Rare: pancytopenia (probably due to antiproliferative action), leukopenia (leukocytes < 2000/μl), eosinophilia.
Very rare: agranulocytosis.
Recent, concomitant, or subsequent use of potentially myelotoxic agents may be associated with a greater risk of hematologic effects.

– Hepato-biliary system
Frequent: increased activity of “hepatic” transaminases (especially alanine aminotransferase (ALT)), less frequently, gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP), hyperbilirubinemia.
Rare: hepatitis, jaundice/cholestasis.
Very rare: severe liver damage such as liver failure, acute liver necrosis, which can be fatal;

– Changes of general
Frequent: anorexia, weight loss (usually mild), asthenia.

– Reproductive system disorders:
Frequent unknown: slight decrease in sperm concentration, total sperm count and motility

– Renal and urinary tract disorders:
Frequency unknown: renal failure

– Other
The risk of malignant, especially lymphoproliferative diseases is increased with some immunosuppressive drugs.

Overdose

Symptoms

There have been reports of chronic overdose in patients treated with leflunomide at doses up to 5 times the recommended daily dose, as well as reports of acute overdose in adults and children. In most cases of overdose, no adverse events were reported. The resulting adverse events were comparable to the safety profile of leflunomide. The most frequently observed adverse events were diarrhea, abdominal pain, leukopenia, anemia and elevated liver function tests.

Treatment

In case of overdose or toxicity, colethiramine or activated charcoal are recommended to speed up clearance.

Colestyramine taken orally by three healthy volunteers at 8 g three times daily for 24 hours reduced plasma levels of A771726 by about 40% after 24 hours and by 49% to 65% after 48 hours.

The administration of activated charcoal (powder made into a suspension) orally or through a gastric tube (50 g every 6 hours for 24 hours) was shown to reduce plasma concentrations of the active metabolite A771726 by 37% after 24 hours and by 48% after 48 hours.

These “washout” procedures can be repeated for clinical indications.

Studies with hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that A771726, the major metabolite of leflunomide, is not able to be excreted by dialysis.