2010/09/21

Arava

Composition, structure and packing

Tablets, film-coated white or almost white, round, marked "ZBN" on one side.

1 tab. leflunomide 10 mg.

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

The composition of the shell: gipromelloza, macrogol 8000, titanium dioxide (E171), talc. Tablets, film-coated from pale yellow to pale-brown, triangular, biconvex, labeled "ZBO" on one side.

1 tab. leflunomide 20 mg.

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

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

Tablets, film-coated white or almost white, round, marked "ZBP" on one side.

1 tab. leflunomide 100 mg.

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

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

Clinico-pharmacological group: Base antirheumatic drug.

Pharmacological action

Base antirheumatic drug. Has antiproliferative, immunomodulatory (immunosuppressive) and anti-inflammatory effect.

Active metabolite of leflunomide A771726 inhibits the enzyme degidroorotat dehydrogenase and has antiproliferative activity. A771726 in vitro inhibits mitogen induced proliferation and DNA synthesis of T-lymphocytes. Antiproliferative activity A771726 seen, apparently at the level of 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 degidroorotat dehydrogenase, which explains its property to inhibit this enzyme and the proliferation of lymphocytes at the stage of G1. 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 antigen Ki-67 nuclei and PCNA, associated with cell cycle. The therapeutic effect of leflunomide has been shown in several experimental models of autoimmune diseases, including rheumatoid arthritis.

Leflunomide decreases the symptoms and slow the progression of joint damage in the active form of rheumatoid arthritis. The therapeutic effect usually appears within 4-6 weeks and may grow further for 4-6 months.

Pharmacokinetics

Absorption and distribution

After intake is absorbed from the gastrointestinal tract in 82-95%. Eating does not affect the absorption of leflunomide. Leflunomide is rapidly metabolized with the formation of the active metabolite A771726. Cmax metabolite A771726 is determined within 1-24 h after a single dose adopted. In the plasma A771726 rapidly binds to albumin. Untie A771726 fraction is 0.62%.

Linking A771726 more variable and somewhat lower in patients with rheumatoid arthritis or chronic renal insufficiency. Due to the long T1 / 2 A771726 used loading dose of 100 mg for 3 days. This has quickly reach Css A771726.

Pharmacokinetic parameters A771726 have a linear relationship at doses from 5 mg to 25 mg. In these studies, the clinical effect is closely related to plasma concentration of A771726 and a daily dose of leflunomide. At a dose of 20 mg / day average 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 secondary metabolites, including 4-trifluorometilalanin. Biotransformation of leflunomide to A771726 and A771726 of the subsequent metabolism are controlled by several enzymes.

Withdrawal

In the plasma, urine and feces determined trace amounts of leflunomide.

Putting A771726 slow clearance is 31 ml / h. T1 / 2 - about 2 weeks.

Pharmacokinetics in special clinical situations

Patients who are on hemodialysis, there is a more rapid elimination, which is associated with the displacement A771726 from its relationship with proteins. Although clearance A771726 increases approximately 2 times, the end of its T1 / 2 is similar to that in healthy individuals, because simultaneously increases the amount of distribution. Data on the pharmacokinetics of the drug in patients with hepatic insufficiency are absent.

Pharmacokinetics in patients younger than 18 years has not been studied. Elderly patients (65 years and older) pharmacokinetic data correspond approximately to the middle age group.

Statement
as the reference drug for the treatment of adult patients with active forms of rheumatoid arthritis to reduce symptoms and delay the development of structural damage of joints;
active psoriatic arthritis.

Dosage regimen

The product should start under the supervision of a physician with experience treating rheumatoid and psoriatic arthritis. Treatment starts with the appointment of a shock dose of 100 mg daily for 3 days. As a maintenance dose recommended for rheumatoid arthritis receiving a dose of 10 to 20 mg 1 time / day, with psoriatic arthritis - 20 mg 1 time / day.

The therapeutic effect appears in 4-6 weeks from the start of the reception and can grow within 4-6 months. Tablets should be swallowed whole, drinking plenty of fluids, regardless of the meal. No dose adjustment for patients older than 65 years and in patients with renal insufficiency mild.

Side effect

Classification of the alleged frequency of side effects: typical - 1-10%, atypical - 0.1-1%, rare - 0.01-0.1%, very rare - 0.01% or less.

Since the cardiovascular system: typical - a moderate increase in blood pressure; rare - pronounced increase in blood pressure, and very rare - vasculitis (because of the underlying disease causation from receiving leflunomide could not be established).

On the part of the digestive system: typical - diarrhea, nausea, vomiting, anorexia, lesions of the oral mucosa (thrush, mouth ulceration), abdominal pain, increased activity of hepatic transaminases (particularly ALT), rarely - GGT, alkaline phosphatase, hyperbilirubinemia; rare - hepatitis, jaundice, cholestasis, very rare - serious liver disease (hepatic failure, acute liver necrosis, which can be fatal), pancreatitis.

On the part of the respiratory system: very rare - interstitial pulmonary process (including interstitial pneumonitis), with possible fatal outcome.

On the part of metabolism: typical - weight loss, asthenia, atypical - hypokalemia.

From the central nervous system and peripheral nervous system: typical - headache, dizziness, asthenia, paresthesia, atypical - a violation of taste, anxiety, and very rare - Peripheral neuropathy.

On the part of the musculoskeletal system: typical - abscess, atypical - tendon rupture.

Dermatological reactions: typical - increased hair loss, eczema, dry skin, very rare - erythema multiforme.

Allergic reactions: typical - light allergic reactions, rash (including Makulo-papular), itching, unusual - urticaria, very rare - Stevens-Johnson syndrome, Lyell's syndrome.

On the part of the hemopoietic system: typical - leukopenia (leukocytes> 2000/mkl), atypical - anemia, thrombocytopenia (platelets <100 000/mkl); rare - eosinophilia, leukopenia (WBC <2000/mkl), pancytopenia, and very rare - agranulocytosis. The risk of hematologic disorders increased with the recent, companion and subsequent application myelotoxic drugs.

Other: very rare - the development of severe infections (including opportunistic), and sepsis, may increase the frequency of possible infections (rhinitis, bronchitis and pneumonia). The risk of cancer, particularly lymphoproliferative diseases, increases with the use of some immunosuppressive drugs. Perhaps, a slight hyperlipidemia.

The level of uric acid is usually reduced. Laboratory data (not clinically confirmed) indicate a slight increase in LDH, CPK. Non-typical is hypophosphataemia. We can not exclude the possibility of a reversible decrease in sperm concentration, total sperm count and motility.

Contraindications
liver problems;
severe immunodeficiency states (including AIDS);
marked disturbances of bone marrow hematopoiesis or anemia, leukopenia, thrombocytopenia due to other causes (other than rheumatoid arthritis);
severe, uncontrolled infections;
moderate or severe renal insufficiency (because of the short experience of clinical observations);
severe hypoproteinemia (including with nephrotic syndrome);
Pregnancy
Lactation (breastfeeding);
Hypersensitivity to the drug's components.

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

Men receiving leflunomide therapy, should be warned about the possible effect of fetotoksicheskom (related to its possible effect on sperm father) and the need to use reliable contraception. Do not use the drug in children and adolescents under the age of 18 years, since data on efficacy and safety in this group of patients lacking.

Pregnancy and lactation

The drug should not be prescribed during pregnancy and women of childbearing age who do not use reliable contraception (contraception is required until such time until the concentration of active metabolite in plasma is> 20 ug / l). You must verify the absence of pregnancy before starting treatment. Patients should be informed that if you suspect a pregnancy should consult a doctor immediately and do a pregnancy test.

If the test is positive, the physician should inform the patient about the possible risk to the fetus. Women who take leflunomide and want to become pregnant (or already in the ensuing pregnancy), recommended procedure laundering drug that would quickly reduce the levels of active metabolite in blood plasma (after cessation of treatment prescribed kolestiramin leflunomide at a dose of 8 g 3 times / day for 11 days or 50 g of activated charcoal, crushed into powder, 4 times / day for 11 days). Next, determine the concentration of metabolite A771726 2 times with an interval of 14 days.

From the moment when the concentration of the drug for the first time will be fixed <20 mg / l, up to the moment of fertilization must take 1.5 months. Note that without the procedure of "laundering" drug decrease in metabolite concentrations <20 mg / l occurs in 2 years. Kolestiramin and activated carbon can affect the absorption of estrogen and progesterone in such a way that reliable oral contraceptives do not guarantee appropriate contraception during the removal of the drug.

It is recommended to use alternative methods of contraception. Animal studies have shown that leflunomide or its metabolites are excreted with breast milk. Therefore, the need to designate a lactation should resolve the issue of termination of breastfeeding.

Application for violations of liver function

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

Application for violations of renal function

Do not use this for violations of kidney function.

Cautions

The preparation is Arava may be imposed only after a thorough medical examination. Before starting treatment with Arava should be mindful of possible increase in the number of side effects in patients treated before other basic drugs for the treatment of rheumatoid arthritis, which have hepato-and gematotoksicheskim action. Active metabolite of leflunomide A771726 characterized by a long T1 / 2 (from 1 to 4 weeks), so the serious side effects may occur or persist even after cessation of drug treatment.

If you have any similar cases of toxicity or migrating to receive another basic drug after treatment with leflunomide should be the procedure of "laundering" (after cessation of treatment prescribed kolestiramin leflunomide at a dose of 8 g 3 times / day for 11 days or 50 g of activated charcoal, crushed into powder , 4 times / day for 11 days). The procedure laundering can be conducted also on clinical indications. If you suspect a severe allergic / immunological (Stevens-Johnson syndrome or Lyell's syndrome) a procedure of "money" is mandatory.

Reactions of co Liver

Since active metabolite of leflunomide is associated with plasma proteins, metabolized in the liver and excreted in the bile, it is expected that the level of A771726 in plasma may be elevated in patients with hypoproteinemia or disorders of the liver.

Reported rare cases of severe liver injury, in some cases fatal. Most of these cases was observed during the first 6 months of therapy. The exact causal relationship of these adverse events from receiving leflunomide has not been established, in most cases, there were several additional factors. Need to determine the level of ALT before therapy Arawa, every 2 weeks during the first 6 months of treatment and then 1 time every 6-8 weeks.

If confirmed by 2-3-fold excess of the upper limit of normal ALT levels should be reducing the dose from 20 mg to 10 mg per day, which could allow to continue receiving Arava with careful monitoring of this indicator. If this increase in activity of ALT was 2-3 times higher FHG persist or if ALT exceeds FHG more than 3 times, leflunomide should be abolished and begin the process laundering. Against the background of the drug Arava should not drink alcohol because of possible additional hepatotoxic action.

The reaction of the hemopoietic system

Complete blood count (including differential and platelet count) should be conducted before therapy of leflunomide, every 2 weeks during the first 6 months of treatment and then 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 disorders of the bone marrow or blood with an increased risk of its development.

With the development of serious hematologic reactions (including pancytopenia) drug Arava should be abolished and begin the process laundering.

Combined use with other therapies

The combination of the drug Arava with other drugs to standard treatment (chloroquine, Hydroxychloroquine, gold preparations, D-penicillamine, azathioprine immunosuppressive other means, except methotrexate) is not recommended, because Data on the clinical use and no known risk associated with the use of (especially long-term) of such combinations.

Switching to other treatments

The transition to the use of another drug of basic therapy without the procedure of money-may increase the risk of toxic reactions, even long after the transition (eg, the kinetic interaction organotoksichnost). The appointment of the drug Arava patients have recently received basic therapy with other drugs with hepatotoxic or gematotoksicheskim action, decided only after careful assessment of expected benefits and potential risks of such therapy.

Dermatological reactions

With the development of ulcerative stomatitis drug should be abolished. It has been reported on very rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis syndrome patients treated with leflunomide. If you have any dermatological reactions drug Arava and any other related product should be abolished and a procedure for "laundering". Necessary to achieve complete elimination of the drug from the body. In such cases, the re-appointment of the drug is contraindicated.

Infection

It is known that drugs such as leflunomide and having immunosuppressive properties make patients more susceptible to various infections (including opportunistic fungal infections). Arisen infections occur, usually hard and require early and intensive treatment. With the development of severe infection may require removal of the drug and conducting the procedure laundering. Need to monitor patients with tuberculin reactivity due to the risk of activating tuberculosis.

Reactions of the respiratory system

In therapy lenflunomidom were noted rare cases of interstitial pulmonary process. Symptoms such as coughing and dyspnea may cause discontinuation of therapy. Blood pressure before therapy and periodically during treatment should be monitored blood pressure.

Recommendations for Men

There is currently no information confirming the relationship between drug intake Arava men and fetotoksicheskim action of the drug. Experimental studies in this direction have been conducted.

To minimize the risk of men for planning a baby should stop taking leflunomide and use kolestiramin to 8 mg 3 times / day for 11 days or 50 g of powdered activated charcoal 4 times / day for 11 days.

Overdose

Symptoms: There were reports of chronic overdose in patients treated with leflunomide at a dose of up to 5 times the recommended daily dose, as well as reports of acute overdose in adults and children. In most cases, not reported on the development of adverse events. Emerging adverse events were comparable to the safety profile of leflunomide.

The most frequently reported diarrhea, abdominal pain, leukopenia, anemia, elevation in liver functional state.

Treatment: In case of overdose or toxicity is recommended to use kolestiramina or powdered activated carbon. Kolestiramin, taken three healthy volunteers administered orally to 8 mg 3 times during the day, reduced levels of A771726 in plasma by approximately 40% after 24 h and 49-65% after 48 h.

Shown that introduction of activated charcoal by mouth or through a stomach tube (50 g every 6 h during the day) reduced the concentration of the active metabolite A771726 in plasma by 37% after 24 h and 48% after 48 hours of procedure may be repeated laundering on clinical testimony. 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 the case of recent or concomitant use of hepatotoxic or gematotoksicheskih and immunosuppressive drugs, or when their drug use began after leflunomide treatment without resorting to "money". No pharmacokinetic interaction was found between leflunomide (10-20 mg / day) and methotrexate (10-25 mg / week). The simultaneous use of leflunomide with kolestiraminom or activated charcoal leads to a rapid and significant decrease in the concentration of A771726 in blood plasma.

It is believed that this was due to a violation of recycling A771726 in the liver and small intestine and / or breach of its gastrointestinal dialysis. If the patient is already taking NSAIDs and GCS, the joint application can continue.

Enzymes involved in the metabolism of leflunomide and its metabolites are unknown. Study in vivo of its interaction with cimetidine (a nonspecific inhibitor of cytochrome P450) showed no significant interaction. After accompanying a single dose of leflunomide the subjects who received multiple doses of rifampicin (a nonspecific inducer of cytochrome P450), Cmax A771726 increased by about 40%, whereas the AUC has not changed.

The mechanism of this effect is not clear. Studies in vitro have shown that A771726 inhibits the activity of CYP2C9. In clinical trials not observed any problems with the combined administration of leflunomide and NSAIDs (metabolized CYP2C9).

With great care should be given the Arava with other drugs, is metabolized CYP2C9 (phenytoin, warfarin, tolbutamide). Reported an increase in prothrombin time, while the use of leflunomide with warfarin. In a study in which leflunomide was given to healthy female volunteers, together with three-phase oral contraceptives containing 30 mcg etiniestradiola, any loss of contraceptive effect is not observed, and pharmacokinetics of A771726 fully fit into the prescribed range.

Currently there are no data on the joint application of leflunomide with antimalarials used in rheumatology (chloroquine and Hydroxychloroquine), gold preparations (IM or oral), D-penicillamine, azathioprine and other immunosuppressive drugs (except methotrexate).

Unknown risks associated with the combined therapy, especially during prolonged treatment.

Since such therapy may lead to the development of additional or even synergistic toxicity (hepatitis or gemotoksichnosti), a combination of the drug with other basic drugs (eg, methotrexate) are undesirable. Recent concomitant or subsequent use of potentially myelotoxicity funds may be associated with greater risk of hematologic reactions.

Immunosuppressants increase the risk of infections and cancer, particularly lymphoproliferative diseases.

Vaccination

There are no data on the effectiveness and safety of the vaccine in therapy of leflunomide. Nevertheless, not recommended for vaccinations with live vaccines.

When planning a vaccination with live vaccines after discontinuation of the drug Arava should take into account the long half-life of leflunomide.

Terms and Conditions of storage

The drug should be stored at temperatures not above 25 ° C. Shelf life - 3 years.