Arabia

Active material: leflunomide
When ATH: L04AA13
CCF: Basic antirheumatic drug
ICD-10 codes (testimony): M05, M07
When CSF: 05.02
Manufacturer: Sanofi-Aventis Germany GmbH (Germany)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Pills, Film-coated white or nearly white, round, labeled “BAJ” on one side.

1 tab.
leflunomide10 mg

Excipients: lactose monohydrate, corn starch, povidone (polyvidone K25), colloidal silicon dioxide, magnesium stearate, krospovydon.

The composition of the shell: gipromelloza, macrogol 8000, Titanium dioxide (E171), talc.

30 PC. – plastic bottles (1) – packs cardboard.
100 PC. – plastic bottles (1) – packs cardboard.

Pills, Film-coated from pale yellow to pale brown, Triangular, lenticular, labeled “ZBO” on one side.

1 tab.
leflunomide20 mg

Excipients: lactose monohydrate, corn starch, povidone (polyvidone K25), colloidal silicon dioxide, magnesium stearate, krospovydon.

The composition of the shell: gipromelloza, macrogol 8000, Titanium dioxide (E171), iron oxide yellow (E172), talc.

30 PC. – plastic bottles (1) – packs cardboard.
100 PC. – plastic bottles (1) – packs cardboard.

Pills, Film-coated white or nearly white, round, labeled “The PBA” on one side.

1 tab.
leflunomide100 mg

Excipients: lactose monohydrate, corn starch, povidone (polyvidone K25), talc, colloidal silicon dioxide, magnesium stearate, krospovydon.

The composition of the shell: gipromelloza, macrogol 8000, Titanium dioxide (E171), talc.

3 PC. – packings Valium planimetric (1) – packs cardboard.

Pharmacological action

Basic antirheumatic drug. It has anti-proliferative, immunomodulatory (immunosuppressive) and anti. The active metabolite of leflunomide A771726 inhibits the enzyme degidroorotat dehydrogenase and has antiproliferative effects. A771726 in vitro inhibits mitogen-induced proliferation and DNA synthesis of T lymphocytes. The antiproliferative activity appears A771726, apparently, level pyrimidine biosynthesis, since the addition of cell culture eliminates the inhibitory effect of uridine metabolite A771726. With the use of radioisotope ligand shown, that A771726 selectively binds to the enzyme dehydrogenase degidroorotat, which explains its property to inhibit this enzyme and lymphocyte proliferation in G1. Lymphocyte proliferation is one of the key stages in the development of rheumatoid arthritis.

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

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

Leflunomide decreases the symptoms and slow the progression of joint damage in the form of active rheumatoid arthritis.

The therapeutic effect is usually manifested through 4-6 weeks and may increase in the future, for 4-6 Months.

Pharmacokinetics

Absorption and distribution

Once inside absorbed from the gastrointestinal tract on 82-95%. Eating does not affect the absorption of leflunomide. Leflunomide is rapidly metabolized to the active metabolite A771726. Cmax metabolite A771726 is determined for 1-24 h after a single dose of the dose. In plasma, A771726 quickly bound to albumin. Unbound fraction of A771726 0.62%. Binding of A771726 more variable and somewhat reduced in patients with rheumatoid arthritis or chronic renal insufficiency.

Due to the long T1/2 A771726 used a loading dose 100 mg for 3 days. This allows you to quickly access Css A771726. Pharmacokinetic parameters A771726 are linear at doses from 5 mg 25 mg. In these studies, the clinical effect is closely related to the plasma concentration of A771726 and a daily dose of leflunomide. At a dose of 20 mg / day, mean Css A771726 was 35 ug / ml.

Metabolism

Leflunomide is rapidly metabolized in the intestinal wall and liver to one of the main (A771726) metabolite, and several minor metabolites, including 4-trifluorometilalanin. The biotransformation of leflunomide to A771726 and subsequent metabolism of A771726 are controlled by several enzymes.

Deduction

In the plasma, urine and feces are determined by trace amounts of leflunomide. Withdrawal A771726 slow, clearance is 31 ml / h. T1/2 – about 2 weeks.

Pharmacokinetics in special clinical situations

Patients, hemodialysis, there is a more rapid elimination, due to the displacement of A771726 its association with proteins. Although the clearance of A771726 is increased about 2 times, T he final1/2 It is similar to that of healthy individuals, tk. at the same time increasing the volume of distribution.

The data on the pharmacokinetics of the drug in patients with hepatic insufficiency are absent.

The pharmacokinetics in patients younger than 18 years has not been studied.

Elderly patients (65 and older) pharmacokinetic data correspond approximately to the middle age group.

Testimony

- As a reference drug for the treatment of adult patients with active rheumatoid arthritis to reduce symptoms and the delay of progression of structural damage of joints;

- The active form of psoriatic arthritis.

Dosage regimen

Use of the drug should start by a physician, with experience in the treatment of rheumatoid arthritis and psoriatic.

Treatment starts with a destination in shock dose 100 mg daily for 3 days. As a maintenance dose in revmatoidnom ARTHRO receiving recommended dose of 10 to 20 mg 1 time / day; at psoriatic arthritis – 20 mg 1 time / day.

The therapeutic effect is manifested through 4-6 weeks from the beginning of reception, and can grow over 4-6 Months.

The tablets should be swallowed whole, drinking plenty of fluids, regardless of the meal.

No dose adjustment is required for older patients 65 years and in patients with mild renal insufficiency.

Side effect

Classification of the anticipated frequency of side effects: typical – 1-10%, untypical – 0.1-1%, few – 0.01-0.1%, very rare – 0.01% less.

Cardio-vascular system: typical – a moderate increase in blood pressure; few – marked increase in blood pressure; very rare – vasculitis (due to the presence of underlying disease causal relationship to leflunomide reception could not be established).

From the digestive system: typical – diarrhea, nausea, vomiting, anorexia, lesions of the oral mucosa (thrush, ulceration of the mouth), abdominal pain, increase in liver transaminases (particularly ALT), less often – GGT, Alkaline phosphatase, giperʙiliruʙinemija; few – hepatitis, jaundice, cholestasis; very rare – severe liver injury (hepatic failure, acute liver necrosis, that can lead to death), pancreatitis.

The respiratory system: very rare – interstitial pulmonary process (including interstitial pneumonia) which can be fatal.

Metabolism: typical – weight loss, asthenia; untypical – kaliopenia.

From the central and peripheral nervous system: typical – headache, dizziness, astenii, paresthesia; untypical – taste disturbance, anxiety; very rare – perifericheskaya neuropathy.

On the part of the musculoskeletal system: typical – tendinitis; untypical – tendon rupture.

Dermatological reactions: typical – increased hair loss, eczema, xerosis; very rare – erythema multiforme.

Allergic reactions: typical – mild allergic reactions, rash (incl. macular-papular), itch; untypical – hives; very rare – Stevens-Johnson syndrome, Lyell's syndrome.

From the hematopoietic system: typical – leukopenia (leukocytes >2000/l); untypical – anemia, thrombocytopenia (platelets <100 000/l); few – eozinofilija, leukopenia (leukocytes <2000/l), pancytopenia; very rare – agranulocytosis. The risk of haematological disorders is increased by the recent, accompanying and subsequent application myelotoxic drugs.

Other: very rare – the development of severe infections (including opportunističeskie) and sepsis; may increase the incidence of possible infections (coryza, bronchitis and pneumonia).

The risk of cancer, particularly lymphoproliferative disorders, increases with the use of certain immunosuppressive drugs.

There may be a slight hyperlipidemia. The level of uric acid is usually reduced. Laboratory data (not confirmed clinically) show a slight increase in LDH, CPK. Atypical is hypophosphatemia.

We can not exclude the possibility of a reversible decrease in sperm concentration, the total number of spermatozoa and their motility.

Contraindications

- Abnormal liver function;

- Severe immunodeficiency states (incl. AIDS);

- The expressed disturbances of bone marrow blood or anemia, leukopenia, thrombocytopenia due to other causes (except rheumatoid arthritis);

- Heavy, nekontroliruemыe infections;

- Moderate or severe renal insufficiency (due to the small experience of clinical observations);

- Severe hypoproteinemia (incl. nephrotic syndrome);

- Pregnancy;

- Lactation (breastfeeding);

- Hypersensitivity to leflunomide or any other component of the drug.

The drug is contraindicated in women of childbearing age, not using reliable contraception during treatment with leflunomide and then until, while the plasma levels of the active metabolite remains above 0.02 mg / l. Pregnancy must be excluded before the start of leflunomide treatment.

Men, receiving treatment with leflunomide, You should be warned about the possible effects of the drug foetotoxic (related to its possible impact on the father's sperm) and the need to use reliable contraception.

It is not recommended to use the drug in children and adolescents under the age of 18 years, tk. data on efficacy and safety in this patient group no.

Pregnancy and lactation

The drug should not be prescribed during pregnancy and women of childbearing age, which do not use reliable contraception (Contraception is necessary until, until the concentration of the active metabolite in plasma remains >20 ug / l). It is necessary to ensure the absence of pregnancy prior to treatment.

Patients should be informed, that in cases of suspected pregnancy should consult a doctor immediately and take a pregnancy test. If the test is positive, the doctor should inform the patient about the possible risks to the fetus.

Women, who take leflunomide and want to get pregnant (or even at the ensuing pregnancy), recommended procedure “money” product, which allows to quickly reduce the level of the active metabolite in the blood plasma (After stopping treatment with leflunomide administered at a dose of cholestyramine 8 g 3 times / day for 11 days or 50 g of activated charcoal, powdered, 4 times / day for 11 days).

Next you need to determine the concentration of the metabolite A771726 2 times at intervals 14 days. With time, when the concentration of the drug for the first time will be fixed <20 ug / l, up to the moment of fertilization must pass 1.5 Months.

It should be taken into account, Without treatments “money” reducing the concentration of drug metabolite <20 ug / L occurs via 2 year.

Colestyramine and active carbon can affect the absorption of the estrogen and progesterone thus, that reliable birth control pills do not guarantee the necessary contraception during Withdrawal. It is recommended to use alternative methods of contraception.

Animal studies have shown, that leflunomide or its metabolites are excreted in breast milk. Therefore, if necessary, the appointment during lactation should decide the issue of termination of breastfeeding.

Cautions

The drug Arava® may be given only after a thorough medical examination.

Before starting treatment with Arava® You should be aware of a possible increase in the number of side effects in patients, previously treated with other basic facilities for the treatment of rheumatoid arthritis, which have hepato- and gematotoksicheskim action.

The active metabolite of leflunomide A771726 is characterized by a duration T1/2 (from 1 to 4 weeks), therefore serious side effects may occur or persist even after the cessation of drug treatment. In the event of such cases of toxicity or migrating to receive another reference drug after treatment with leflunomide should carry out the procedure “money” (After stopping treatment with leflunomide administered at a dose of cholestyramine 8 g 3 times / day for 11 days or 50 g of activated charcoal, powdered, 4 times / day for 11 days). The procedure “money” It can also be performed as clinically indicated. If you suspect a severe allergic / immunopathological reaction (Stevens-Johnson syndrome or Lyell's syndrome) conducting the procedure “money” necessarily.

Reactions co Liver

Unnecessarily. active metabolite of leflunomide bound to plasma proteins, metabolized by the liver and excreted in the bile, It assumed, that the level of A771726 plasma levels may be increased in patients with hypoproteinaemia or impairment of liver function.

It was reported about rare cases of severe liver injury, in some cases, fatal. Most of these cases occurred in the first 6 months of therapy. The exact causal relationship between these adverse events with taking leflunomide is not installed, in most cases, there are several additional factors. It is necessary to determine the level of ALT before therapy Arabia®, every 2 during the first week 6 months of treatment, and then 1 once every 6-8 weeks. Upon confirmation of 2-3 times the upper limit of normal ALT levels should be carried out with dose reduction 20 mg 10 mg per day, that can afford to continue receiving Arava with careful monitoring for this indicator. If the increase in ALT activity 2-3 times above ULN persists or if the ULN ALT exceeds more than 3 times, leflunomide should be discontinued and the start procedure “money”.

Against the background of the drug Arava® should not drink alcohol because of the possible additional hepatotoxicity.

Reactions from the hematopoietic system

Complete blood count (including the determination of leukocyte and platelet counts) should be conducted prior to initiating therapy with leflunomide, every 2 during the first week 6 months of treatment and every 6-8 weeks. The risk of hematologic reactions is increased in patients, with a history of anemia, leukopenia and / or thrombocytopenia, in patients with impaired bone marrow blood or with an increased risk of its development. With the development of severe haematological reactions (including pancytopenia) drug Arava® should be abolished and start the procedure “money”.

The combined use with other treatments

The combination of the drug Arava® with other drugs for the treatment of basal (chloroquine, hydroxychloroquine, gold preparations, D-Penicillamine, azathioprine, other immunosuppressive agents, isklyucheniem for methotrexate) not recommended, tk. data on clinical use and is not unknown risk, associated with (especially long) such combinations.

Switching to other treatments

The transition to the use of another drug without a basic treatment of the procedure “money” It may increase the risk of toxic reactions, even after a long time after the transition (eg, kinetic interaction, organotoksichnost). The question of the appointment of the drug Arava® patients, recently received basic therapy with other drugs with hepatotoxic or gematotoksicheskim action, It is decided only after a thorough assessment of the expected benefits and potential risks of such therapy.

Dermatological reactions

With the development of ulcerative stomatitis drug should be discontinued.

It was reported about rare cases of Stevens-Johnson syndrome or Lyell's syndrome patients, treated with leflunomide. In the event of dermatological reactions drug Arava® and any other related drug should be discontinued and carry out the procedure “money”. It is necessary to achieve the complete elimination of the drug from the body. In such cases, the re-appointment of the drug is contraindicated.

Infectious complications

Known, that drugs, like leflunomide and having immunosuppressive properties make patients more susceptible to various infections (including opportunistic fungal infections). Arisen infections occur, usually, difficult and require early and intensive treatment. With the development of severe infection may require removal of the drug and conduct procedures “money”.

It is necessary to monitor patients with tuberculin reactivity due to the risk of activation of tuberculosis.

Reactions on the part of the respiratory system

In therapy lenflunomidom it was noted rare cases of interstitial pulmonary process. Symptoms such as cough and dyspnea may cause discontinuation of therapy.

Blood pressure

Before starting treatment and periodically during treatment should control blood pressure.

Advice for Men

Currently there is no information, confirming the association between the drug Arava® men and foetotoxic effect of the drug. Experimental studies in this area have not been conducted. To minimize the risk of men when planning a baby should stop taking leflunomide and use of cholestyramine 8 mg 3 times / day for 11 days or 50 g of powdered activated carbon 4 times / day for 11 days.

Overdose

Symptoms: There were reports of chronic overdose in patients, treated at a dose of leflunomide 5 times the recommended daily dose, and reports of acute overdose in adults and children. In most cases, no reports of adverse events. Emergent adverse events were comparable to the safety profile of leflunomide. The most frequently observed diarrhea, stomach ache, leukopenia, anemia, improving the functional state of the liver.

Treatment: in the event of an overdose or toxicity it is recommended to use cholestyramine or powdered activated carbon. Cholestyramine, three healthy volunteers received orally 8 mg 3 times during the day, A771726 reduced levels in the blood plasma of about 40% through 24 and h 49-65% through 48 no.

Displaying, that introduction of activated carbon or orally by gavage (50 g every 6 hours within a day) decreasing the concentration of the active metabolite in the plasma A771726 37% through 24 and h 48% through 48 no.

Possible repetition of the procedure “money” as clinically indicated.

Studies with hemodialysis and chronic ambulatory peritoneal dialysis indicate, that the main metabolite A771726 is not displayed during dialysis.

Drug Interactions

Increased side effects may occur in case of recent or concomitant use of hepatotoxic or haematological and immunosuppressive drugs or when taking these drugs after the start of treatment with leflunomide without the procedure “money”.

There were no pharmacokinetic interaction between the leflunomide (10-20 mg / day) and metotreksatom (10-25 mg per week).

The simultaneous use of leflunomide with colestyramine or activated carbon leads to rapid and substantial reduction in the concentration in blood plasma A771726. It is believed, it is due to an impaired recycling A771726 in the liver and small intestine and / or violation of its gastrointestinal dialysis.

If a patient is already taking NSAIDs and corticosteroids, the joint application can be extended.

Enzymes, involved in the metabolism of leflunomide and its metabolites, unknown. In vivo studies of its interaction with cimetidine (a non-specific inhibitor of cytochrome P450) showed no significant interaction. Following concomitant administration of a single dose of leflunomide to subjects, Gets multiple doses of rifampicin (non-specific cytochrome P450 inducer), Cmax A771726 rose about 40%, while the AUC did not change significantly. The mechanism of this effect is not clear.

Studies in vitro have shown, A771726 that inhibits the activity of CYP2C9. In clinical trials, there was not any problems with the co-administration of leflunomide and NSAIDs (метаболизирующихся CYP2C9). Special care should be given Arava® with other drugs, метаболизирующимися CYP2C9 (phenytoin, warfarin, tolbutamid). Reported an increase in prothrombin time, while the use of leflunomide with warfarin.

The study, in which leflunomide was allowed healthy female volunteers together with triphasic oral contraceptives, containing 30 g etiniestradiola, no decrease in the contraceptive effect is not observed, and pharmacokinetics of A771726 completely fit into the prescribed range.

There is currently no data on the joint use of leflunomide with antimalarials, used in rheumatology (chloroquine and hydroxychloroquine), Gold preparations (/ m or orally), D-penïcïllamïnom, azathioprine, and other immunosuppressive drugs (isklyucheniem for methotrexate). Unknown risk, associated with complex therapy, especially when long-term treatment. Unnecessarily. such treatment may lead to the development of additional or even synergistic toxicity (scarp- Ili gyemotoksichnosti), combination of the drug with other DMARDs (eg, metotreksatom) undesirable. Recent concomitant or subsequent use of potentially myelotoxic agents may be associated with a higher risk of haematological reactions. Immunosuppressive drugs increase the risk of infections, and malignant, particularly lymphoproliferative disorders.

Vaccination

There are no data on the effectiveness and safety of the vaccine under therapy with leflunomide. Nonetheless, it is not recommended to vaccinate with live vaccines. When planning a vaccination with live vaccines after the drug Arava® should be considered a long half-life of leflunomide.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored at temperatures not exceeding 25 ° C. Shelf life – 3 year.

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