Composition, form of production and packaging
The tablets covered with a film membrane of white or almost white color, round, biconcave.
1 tab.
leflunomide 10 mg
Excipients: lactose monohydrate - 80.0 mg, low-substituted giprolose 5.0 mg, tartaric acid 3.0 mg, sodium lauryl sulfate 0.5 mg, magnesium stearate 1.5 mg.
The composition of the film shell: polyvinyl alcohol - 1.3656 mg, titanium dioxide - 0.9600 mg, talc - 0.6000 mg, lecithin - 0.0600 mg, xanthan gum - 0.0144 mg.
30 pcs. - polyethylene bottles (1) - cardboard packs.
The tablets covered with a film membrane of white or almost white color, round, biconcave, with one-sided risk.
1 tab.
leflunomide 20 mg
Excipients: lactose monohydrate - 160.0 mg, low-substituted giprolose - 10.0 mg, tartaric acid - 6.0 mg, sodium lauryl sulfate - 1.0 mg, magnesium stearate - 3.0 mg.
The composition of the shell: polyvinyl alcohol - 2.7312 mg, titanium dioxide - 1.9200 mg, talc - 1.2000 mg, lecithin - 0.1200 mg, xanthan gum - 0.0288 mg.
30 pcs. - polyethylene bottles (1) - cardboard packs.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2016.
PHARMACHOLOGIC EFFECT
Elafra is a basic antirheumatic drug that modifies the course of the disease, with an antiproliferative effect. The active leflunomide metabolite - A771726 - inhibits the enzyme dihydroorotat dehydrogenase and has antiproliferative activity. A771726 in vitro inhibits mitogen-induced proliferation and 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 with the enzyme dihydroorotate dehydrogenase, which explains its property to inhibit this enzyme and lymphocyte proliferation in the G1 stage. Simultaneously, A771726 inhibits the expression of receptors for interleukin-2 and Ki-67 and PCNA core antigens associated with the cell cycle.
The therapeutic effect of leflunomide was demonstrated in several experimental models of autoimmune diseases, including rheumatoid arthritis.
PHARMACOKINETICS
Suction and distribution
Absorption of the drug is 82-95% and does not depend on food intake. The period of achieving a stable concentration of the drug in the blood plasma is approximately 2 months of daily intake, provided that the shock dose is not applied at the beginning of the treatment. Because of the long T 1/2 A771726, a loading dose of 100 mg was used for 3 days. This allowed us to quickly achieve the equilibrium state of the plasma concentration of A771726.
Pharmacokinetic parameters of A771726 have a linear dependence when applied in doses from 5 mg to 25 mg. In these studies, the clinical effect is closely related to the plasma concentration of A771726 and the daily dose of leflunomide. When applied at a dose of 20 mg / day, the average plasma concentrations of A771726 in the equilibrium state were 35 Ојg / ml. Concentration of the drug in blood plasma with repeated intake increases by 33-35 times compared with a single dose.
In plasma, A771726 binds rapidly to albumin. The unbound fraction of A771726 is 0.62%. Binding of A771726 is more variable and somewhat reduced in patients with rheumatoid arthritis or chronic renal insufficiency.
Metabolism and excretion
Leflunomide is rapidly metabolized in the intestinal wall and liver to one major (A771726) metabolite and several secondary metabolites, including 4-trifluoromethylalanine. Biotransformation of leflunomide in A771726 and subsequent metabolism of A771726 itself are controlled by several enzymes and occur in microsomal and other cell fractions.
In plasma, urine and feces, traces of leflunomide are determined. Excretion of A771726 is slow and characterized by clearance of 31 ml / h. T 1/2 - about 2 weeks.
INDICATIONS
- active form of rheumatoid arthritis.
DOSING MODE
Tablets are taken orally, swallowing whole and with enough liquid. Eating does not affect the absorption of leflunomide.
Treatment with leflunomide should begin under the supervision of a doctor who has experience in the treatment of rheumatoid arthritis. Treatment with leflunomide begins with a shock dose of 100 mg for 3 days.
The maintenance dose for rheumatoid arthritis is 10-20 mg 1 time / day.
The therapeutic effect is usually manifested in 4-6 weeks and can grow further to 4-6 months.
There are no recommendations regarding dosing of the drug in patients with mild renal insufficiency .
Do not require dose adjustment in patients older than 65 years .
SIDE EFFECT
The most common side effects (1-10%): leukopenia; allergic reactions; loss of appetite, weight loss (usually minor); fatigue (weakness), headache, dizziness, paresthesia; moderate increase in blood pressure; diarrhea, nausea, vomiting, erosive and ulcerative lesions of the oral mucosa, abdominal pain, increased liver function; increased hair loss, eczema, dry skin, rash, itching; Tendovaginitis, an increase in the activity of certain enzymes in the blood (creatine phosphokinase).
Atypical side effects (0.1-1%): a decrease in the number of erythrocytes in the blood, thrombocytopenia; decrease in the level of potassium in the blood; anxiety; a violation of taste sensations; hives; an increase in the concentration of lipids in the blood (cholesterol and triglycerides), a decrease in the level of phosphates in the blood.
Rare side effects (0.01-0.1%): eosinophilia, leukopenia, pancytopenia; a sharp increase in blood pressure; violations of liver function in the form of hepatitis, cholestasis, jaundice; sepsis (possibly fatal).
Very rare side effects (0.001% or less): agranulocytosis, severe allergic reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, vasculitis, peripheral neuropathy, pancreatitis.
CONTRAINDICATIONS
- liver failure;
- severe immunodeficient conditions (including AIDS);
- severe bone marrow function or anemia, leukopenia, neutropenia, thrombocytopenia due to other causes (except rheumatoid arthritis);
- severe infections;
- Moderate or severe renal failure;
- severe hypoproteinemia (including with nephrotic syndrome);
- Pregnancy (it is necessary to exclude pregnancy before treatment with leflunomide);
- breast-feeding;
- children and adolescence under 18;
hypersensitivity to the components of the drug.
PREGNANCY AND LACTATION
The drug is contraindicated in pregnancy and women of childbearing age who do not use reliable contraceptives.
Women need to be protected from pregnancy within 2 years after discontinuation of the drug.
It is necessary to make sure that there is no pregnancy before starting treatment. Women who take leflunomide and want to become pregnant (or already with pregnancy), it is recommended to carry out the procedure of "laundering" the drug, which will quickly reduce the level of active metabolite in the blood plasma (after stopping treatment with leflunomide appoint kolestiramin at a dose of 8 g 3 times / day for 11 days or 50 g of activated carbon powdered into powder, 4 times / day for 11 days). Then it is necessary to determine the concentration of the metabolite A771726 2 times with an interval of 14 days. From the moment when the concentration of the drug for the first time is fixed below 20 mcg / l until the time of fertilization should pass 1.5 months. It should be borne in mind that without the procedure of "washing up" the drug, a decrease in the concentration of the metabolite below 20 Ојg / l occurs after 2 years. Kolestyramine and activated charcoal can affect the absorption of estrogen and progesterone in such a way that reliable oral contraceptives do not guarantee the necessary contraception during the withdrawal period. It is recommended to use alternative methods of contraception.
Leflunomide and its metabolites penetrate into breast milk. Therefore, the use of leflunomide during breastfeeding is contraindicated.
APPLICATION FOR FUNCTIONS OF THE LIVER
There are no recommendations regarding dosing of the drug in patients with mild renal insufficiency .
Contraindicated use of the drug with moderate or severe renal failure.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Contraindicated use of the drug in liver failure.
APPLICATION FOR CHILDREN
Contraindicated in children and adolescents under 18 years.
APPLICATION IN ELDERLY PATIENTS
Do not require dose adjustment in patients older than 65 years .
SPECIAL INSTRUCTIONS
Elafra can only be administered to patients after a thorough medical examination.
Before starting treatment with Elafra, you should 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 leflunomide metabolite, A771726, is characterized by a prolonged T 1/2 , usually 1-4 weeks, which can lead to serious adverse effects (eg, hepatotoxicity, hematoxicity, or allergic reactions) even after treatment with leflunomide. In this case, the procedure for "laundering" should be followed (after ceasing the treatment with leflunomide, colestramine is prescribed at a dose of 8 g 3 times / day for 11 days or 50 g of activated carbon crushed into powder 4 times per day for 11 days).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.
If such cases of toxicity occur or when switching to another basic drug (for example, methotrexate) after treatment with leflunomide, it is necessary to carry out the "laundering" procedure.
Since the active metabolite leflunomide, A771726, binds to proteins and is excreted by hepatic metabolism and bile secretion, it is suggested that the level of A771726 in the blood plasma may increase in patients with hypoproteinemia.
There have been reports of rare cases of severe liver disease, in some cases fatal, with leflunomide treatment. Most of these cases were observed during the first 6 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 exact implementation of the treatment control recommendations is considered mandatory.
The level of ALT should be checked before beginning therapy with leflunomide, and then every 2 weeks for 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 IGN, a dose reduction from 20 mg / day to 10 mg / day may allow leflunomide to be continued, provided that this indicator is carefully monitored. If a 2-3-fold excess of ALT ALT is retained or if there is a confirmed elevation in ALT level exceeding IGN more than 3-fold, leflunomide should be stopped and "laundering" initiated.
Because of the possible additional hepatotoxic effects, it is recommended to refrain from taking alcohol while treating leflunomide.
A complete clinical blood test, including the determination of the leukocyte count and platelet count, should be performed prior to 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 Elafra and any other concomitant medication that suppresses bone marrow hematopoiesis and begin the procedure of "laundering".
Since leflunomide lasts for a long time in the body, switching to another basic drug (eg methotrexate) without an appropriate "laundering" procedure can increase the possibility of additional risk even after a long time after the transition (eg, kinetic interaction, organotoxicity). Similarly, recent treatment with hepatotoxic or hematotoxic drugs (such as methotrexate) may lead to an increase in the number of side effects, so starting treatment with leflunomide, you must carefully consider all the positive and negative aspects associated with taking this drug.
If ulcerative stomatitis develops, Leflunomide should be discontinued.
There were reports of very rare cases of Stevens-Johnson syndrome or toxic epidermal necrosis in patients receiving leflunomide. In case of skin reactions and / or reactions on the part of the mucous membranes, it is necessary to cancel the drug Elafra 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.
It is known that preparations like leflunomide and possessing immunosuppressive properties increase the susceptibility of the patient's organism to various kinds of infections, including opportunistic infections (arising only in conditions of a decrease in immunity). 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.
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.
Before the start of leflunomide treatment and periodically after its beginning, it is necessary to monitor the blood pressure level.
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. To minimize the possible risk to men, when planning the appearance of a child, it is necessary to stop taking leflunomide and use the "laundering" procedure. During the period of application of the drug, men need to take measures to protect their partner from pregnancy.
Impact on the ability to drive vehicles and manage mechanisms
Care should be taken when driving vehicles and performing work that requires an increased concentration of attention and speed of psychomotor reactions.
OVERDOSE
Symptoms: diarrhea, abdominal pain, leukopenia, anemia and an increase in liver function tests.
Treatment: in case of an overdose or toxicity, it is recommended to take colestyramine or activated charcoal to speed up the cleansing of the body. Kolestiramin, taken by three healthy volunteers orally 8 g 3 times / 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 is shown that the administration of activated coal (powder converted into 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% at 48 hours.
These procedures for "laundering" can be repeated according to clinical indications. Studies with hemodialysis and chronic outpatient peritoneal dialysis (HAFA) indicate that A771726, the main leflunomide metabolite, is not excreted by dialysis.
DRUG INTERACTION
Increased adverse reactions may occur in the case of recent or concomitant use of hepatotoxic or hematotoxic drugs, or when the administration of these drugs begins after treatment with leflunomide without the procedure for "laundering".
There was no pharmacokinetic interaction between leflunomide (10-20 mg / day) and methotrexate (10-25 mg per week).
There is no clinically significant interaction with the simultaneous use of leflunomide and three-phase oral contraceptives, NSAIDs, cimetidine, rifampicin.
In vitro studies have shown that the leflunomide metabolite A771726 depresses the activity of CYP2C9. Caution should be given leflunomide with drugs metabolized by this enzyme system (phenytoin, warfarin, tolbutamide).
Patients receiving treatment with leflunomide are not recommended to appoint colestyramine or activated charcoal, as this leads to a rapid and significant decrease in the concentration of A771726 (the active leflunomide metabolite) in the 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.
After the concomitant administration of a single dose of leflunomide, patients receiving multiple doses of rifampicin (a nonspecific inducer of cytochrome P450),Cmax A771726 increased by about 40%, while AUC did not change significantly. The mechanism of this effect is not clear.
In a study in which leflunomide was administered to healthy volunteers together with the female triphasic oral contraceptive preparations containing 30 .mu.g of ethinylestradiol, reducing contraceptive effect tablets were found, and A771726 pharmacokinetics completely fit into the prescribed range.
Currently there is no information on joint application of leflunomide with antimalarial drugs used in rheumatology (for example, chloroquine and gidroksihlorina), gold preparations (V / m or orally), D-penicillamine, azathioprine, and other immunosuppressive agents (except methotrexate). Unknown risks associated with complex therapy, especially during prolonged treatment. Since this kind of therapy may lead to the development of additional or even synergistic toxicity (e.g., hepato- or gematoksichnosti) Elafra drug combination with other DMARDs (e.g., methotrexate) are undesirable. Recent concomitant or subsequent application of potentially myelotoxicity drugs may be associated with greater risk of hematological effects.Immunosuppressants increase the risk of infections and malignancies, especially lymphoproliferative disorders.
No clinical data on the efficacy and safety of vaccinations under leflunomide treatment. However, it is not recommended to be vaccinated with live vaccines. Should be considered a long T 1/2 of leflunomide in the planning of vaccination with a live vaccine after discontinuation of the drug Elafra.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children, dry, protected from light, at a temperature of no higher than 25 В° C. Shelf life - 3 years.
