Lefomide - instructions for use, dose, side effects, contraindications

Excipients, lactose monohydrate (milk sugar) - 38 mg, 55 mg, 70 mg, croscarmellose sodium (impellosis) - 5 mg, 7.5 mg, 13.5 mg, povidone (polyvinylpyrrolidone low molecular weight medical 12600 + 2700, plasdon-K 17) 3.6 mg, 5.4 mg, 14.5 mg, talc - 3 mg, 4.5 mg, 8.1 mg, calcium stearate - 1 mg, 1 , 5 mg, 2.7 mg, corn starch - 39.4 mg, 56.1 mg, 61.2 mg;

Shell composition: hypromellose (hydroxypropylmethylcellulose, methocel) 1.9 mg. 3.1 mg, 5 mg, macrogol 4000 (polyethylene oxide 4000, polyethylene glycol 4000) - 0.8 mg. 1.3 mg, 2 mg, titanium dioxide (titanium dioxide) - 0.3 mg, 0.6 mg, 1 mg.

Description:Round biconvex tablets, covered with a film membrane white or almost white.On the cross-section, one layer of white or almost white color is visible.

Pharmacotherapeutic group:Immunosuppressive remedy

ATX: & nbsp

L.04.A.A.13 Leflunomide

L.04.A.A Selective immunosuppressants

Pharmacodynamics:

Leflunomide belongs to the class of basic antirheumatic drugs and has anti-proliferative, immunomodulating, immunosuppressive and anti-inflammatory properties. The active leflunomide metabolite A771726 inhibits the enzyme dehydroorotate dehydrogenase and has antiproliferative activity. А771726 in conditions in vitro inhibits proliferation caused by mitogens and T-lymphocyte DNA synthesis. Antiproliferative activity of A771726 is 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 dehydroorotate dehydrogenase, which explains its property to inhibit this enzyme and lymphocyte proliferation in the stage G1. Proliferation of lymphocytes is one of the key stages in the development of rheumatoid arthritis. Simultaneously, A771726 inhibits the expression of receptors for interleukin-2 (CB-25) and antigens of the nucleus Ki-67 and MSNA, associated with the cell cycle.

Leflunomide reduces symptoms and slows the progression of joint damage with an active form of rheumatoid and psoriatic arthritis.

The therapeutic effect usually manifests itself in 4-6 weeks and can grow further in 4-6 months.

Pharmacokinetics:

Leflunomide quickly turns into its active metabolite A771726 (primary metabolism in the intestinal wall and liver). In plasma, urine or feces trace amounts of unchanged leflunomide are found. The only detectable metabolite is A771726, responsible for the basic properties of the drug in vivo When ingested absorbed from 82 to 95% of the drug. Maximum plasma concentrations of A771726 are determined from 1 to 24 hours after a single dose. The intake of food does not affect absorption. Due to the very long half-life of A771726 (about 2 weeks), a loading dose of 100 mg per day for 3 days is used. This allows us to quickly reach the equilibrium state of the plasma concentration A771726. Without a loading dose, it would take 2 months for the drug to reach an equilibrium concentration.Pharmacokinetic parameters A771726 have a linear dependence in a dose of 5-25 mg. At a dose of 20 mg per day, the mean plasma concentrations of A771726 at an equilibrium state are 35 μg / ml.

Plasma rapidly binds A771726 to albumins. Unrelated fraction A771726 is 0.62%. Binding of A771726 is more variable and somewhat reduced in patients with rheumatoid arthritis or chronic renal insufficiency.

Leflunomide is metabolized to one major (A771726) and several secondary metabolites, including 4-trifluoromethanol laslin. Biotransformation of leflunomide in A771726 and subsequent metabolism of A771726 is controlled by several enzymes and occurs in microsomal and other cell fractions CYP-enzymes are involved in the metabolism of leflunomide only in an insignificant degree.

Excretion A771726 from an organism slow and is characterized by a clearance of 31 ml / hour. Leflunomide is excreted by the kidneys and through the intestine. The half-life period is about 2 weeks.

The pharmacokinetics of A771726 in patients on chronic outpatient peritoneal dialysis is similar to that of healthy individuals. Faster elimination A771726 is observed in patients on hemodialysis, which is due not to the extraction of the drug in the dialysate, but to its displacement from the bond with the protein. Although the clearance of A771726 increases approximately 2-fold, the final half-life is similar to that in healthy individuals, since the volume of distribution simultaneously increases.

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

Indications:

- Active form of rheumatoid arthritis (to reduce symptoms of the disease and delay the development of structural damage to the joints).

- Active form of psoriatic arthritis.

Contraindications:

- Hypersensitivity to leflunomide or other components of the drug, including teriflunomide;

- impaired liver function;

- severe immunodeficiency (eg, AIDS);

- significant disorders of bone marrow hematopoiesis or severe anemia, leukopenia, neutropenia or thrombocytopenia not associated with rheumatoid or psoriatic arthritis;

- severe, uncontrolled infections;

- renal failure of moderate to severe severity;

- severe hypoproteinemia (eg, with nephrotoxic syndrome);

- pregnancy;

- reproductive age in women who do not use reliable contraceptives for the leflunomide treatment period, and then as long as the plasma level of the active metabolite remains above 0.02 mg / L. Pregnancy should be excluded before treatment with leflunomide;

- the period of breastfeeding;

- men receiving treatment with leflunomide should be warned about the possible toxic effect of the drug on spermatozoa. During the period of application of the drug, it is necessary for men to take measures to protect their partner from pregnancy,

- deficiency of lactase, lactose intolerance, glucose-galactose malabsorption;

- age to 18 years.

Carefully:

- Patients with interstitial lung diseases (increased risk of interstitial lung disease);

- patients with mild to moderate severity of anemia, leukopenia, neutropenia, thrombocytopenia and disorders of bone marrow hematopoiesis (including in the anamnesis); patients who have recently received or are receiving concomitantly with leflunomide drugs with immunosuppressive or hematotoxicaction; patients with non-rheumatoid arthritis significant deviations from the norm of hematological parameters before treatment with leflunomide (frequent hematological control is required);

- age over 60 years, simultaneous use of other neurotoxic drugs and diabetes mellitus (increased risk of peripheral neuropathy);

- renal failure of mild severity (creatinine clearance less than 80 ml / min but more than 50 ml / min) (limited clinical experience).

Pregnancy and lactation:

Leflunomide is contraindicated in pregnant women or women of reproductive age who do not use reliable contraception in leflunomide treatment and for some time after this treatment (waiting period or a shortened period of "laundering"). It is necessary to be convinced of absence of pregnancy before the beginning of leflunomide treatment. Patients should be informed that as soon as a delay in menstruation occurs or there is another reason to presume pregnancy, they should immediately inform the doctor about it. In the case of a positive pregnancy test, the doctor should discuss with the patient the possible risk to which this pregnancy is exposed.It is possible that a rapid decrease in the active metabolite level in the blood with the help of the "laundering" procedure will help in the first delay of menstruation to reduce the risk to which the embryo from the leflunomide is exposed. Women who take leflunomide and want to become pregnant, it is recommended that you follow one of the following procedures to be sure that the fetus is not will be exposed to toxic concentrations A771726 (the control concentration is below 0.02 mg / l).

Waiting period

It can be expected that the concentration of L771726 in blood plasma can be above 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 the cessation of leflunomide treatment.

The first time the concentration of L771726 in the blood plasma is measured but the expiration of a two-year waiting period. After this, it is necessary to determine the concentration of L771726 in the blood plasma, at least after 14 days.

The procedure for "laundering"

After stopping treatment with leflunomide:

- Colestyramine 8 g is administered 3 times a day for 11 days,

- as an alternative, 50 g of activated charcoal powdered (as a suspension) is introduced 4 times per day for 11 days.

Regardless of the chosen "laundering" procedure, two separate tests should be tested at intervals of at least 14 days and wait one and a half months from the moment when the concentration of the drug in the plasma is first recorded below 0.02 mg / L, until fertilization.

It is necessary to inform women of childbearing age about what should take 2 years after stopping treatment with leflunomide before they can attempt to become pregnant. If the 2-year waiting period with reliable contraception seems unreasonable, it is possible to carry out the "laundering" procedure for preventive purposes AND colestramine, and Activated carbon can affect the absorption of estrogens and progestogens, so reliable oral contraceptives do not give a 100% guarantee during the "laundering" It is recommended to use alternative methods of contraception.

Leflunomide and its metabolites pass into breast milk, so women who breast-feed should not take leflunomide. Depending on the importance of treatment for the mother, it should be decided whether breastfeeding will be carried out or leflunomide treatment will be started, in which breastfeeding will have to be abandoned.

Dosing and Administration:

Treatment with leflunomide should begin under the supervision of a physician with experience in the treatment of rheumatoid and psoriatic arthritis.

The drug is taken orally, regardless of food intake. Tablets should be swallowed whole, with enough liquid.

Treatment of rheumatoid arthritis

Treatment with leflunomide usually begins with a single dose of 100 mg per day during the day for 3 days, then goes to maintenance treatment. However, exclusion of the loading dose may reduce the risk of side effects (especially from the gastrointestinal tract and the effect on the activity of "hepatic" enzymes in the blood).

When receiving a maintenance dose of 20 mg once a day immediately began treatment (ie, without taking a loading dose), the effectiveness of the drug in rheumatoid arthritis decreases. 13 In the case of a poor tolerance of 20 mg, a dose reduction of up to 10 mg once a day is possible.

Treatment of psoriatic arthritis

Treatment with leflunomide also begins with a loading dose of 100 mg once a day for 3 days. The maintenance dose is 20 mg once a day.

With both indications, the therapeutic effect usually manifests itself after 4 weeks and can grow further in 4-6 months.

Therapy is usually carried out for a long time.

Special patient groups

Patients with impaired hepatic function

Recommendations for dose adjustment or drug cancellation depending on the severity or persistence of alanine aminotransferase elevation on the background of taking the drug are described in the section "Special instructions"

Patients with impaired renal function

There are no special recommendations but the dosing regimen in patients with impaired renal function. It should be taken into account that the active metabolite leflunomide A771726 has a high affinity for proteins.

Elderly patients

Do not require dose adjustment in patients older than 65 years.

Side effects:

Classification of the alleged frequency of side effects:

very often - 1/10 appointments (≥ 10%), often - 1/100 appointments (≥ 1%, but <10%), infrequently - 1/1000 appointments (≥0.1%, <1%), rarely - 1/10000 prescriptions (≥0.01%, but <0.1%), very rarely - less than 1/10000 prescriptions (<0.01%), the frequency is not known (based on the available data, to estimate the incidence of side effect not it is possible).

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

From the skin: often - increased hair loss, eczema, itching, dry skin; very rarely - toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme, Stevens-Johnson syndrome; frequency is not known - discoid lupus erythematosus, pustular psoriasis or exacerbation of psoriasis, drug reaction with eosinophilia and systemic symptoms (DRESS-syndrome).

From the genitourinary system: frequency is not known - a slight decrease in the concentration of sperm, the total number of spermatozoa and their mobility.

From the urinary system: frequency not known - renal failure.

From the side of metabolism: often - a slight increase in creatine phosphokinase, a decrease in the mass of the green; infrequently - hypokalemia, insignificant hyperlipidemia, insignificant hypophosphatemia; frequency is not known - increased lactate dehydrogenase activity, hypouricemia.

From the musculoskeletal system: frequency is not known - tendosynovitis and rupture of tendons.

From the digestive system: often - diarrhea, nausea, vomiting, anorexia, damage to the oral mucosa (aphthous stomatitis, ulceration of the mucosa),pain in the abdominal cavity; increased activity of "liver" transaminases (especially alanine aminotransferase, less often gamma-glutamintransferase and alkaline phosphatase), hyperbilirubinemia; rarely - hepatitis, jaundice / cholestasis; very rarely - severe liver damage, such as hepatic insufficiency, acute liver necrosis, which can be fatal, pancreatitis.

From the hematopoiesis: often - leukopenia (leukocytes> 2000 / μl); infrequently - anemia, small thrombocytopenia (platelets <100000 / μl); rarely - eosinophilia, leukopenia (leukocytes <2000 / μl), pancytopenia (due to antiproliferation action); very rarely - agranulocytosis.

The recent concomitant or subsequent use of potentially myelotoxic drugs may be associated with a greater risk of hematological effects.

From the respiratory system: rarely - interstitial lung diseases (including interstitial pneumonia), with possible legal outcome.

From the sense organs: infrequently - a violation of taste.

From the cardiovascular system: often - increased blood pressure.

From the immune system: often - mild allergic reactions, including maculopapular rash and other types of rash, infrequently - hives, very rarely - serious anaphylactic / anaphylactoid reactions, vasculitis, including cutaneous necrotic vasculitis.

Other: rarely - the development of severe infections and sepsis, which can be lethal. Medicines with immunosuppressive action can make the patient more susceptible to infections, including opportunistic infections. The incidence of rhinitis, bronchitis and pneumonia may increase slightly.

When using some immunosuppressive drugs, the risk of malignancy increases, especially the risk of developing lymphoproliferative diseases.

Overdose:

Symptoms: diarrhea, abdominal pain, leukopenia, anemia, increased activity of "liver" enzymes.

Treatment: In case of an overdose or toxicity, colestramine Activated carbon, to accelerate the cleansing of the body. Kolestyramine, taken orally 8 g three times a day for 24 hours, reduces the level of A771726 in blood plasma by about 40% after 24 hours and at 49-65% after 48 hours.The administration of activated charcoal (as a suspension) orally or through a gastric tube (50 g every 6 hours for 24 hours) reduces the concentration of active metabolite A771726 in plasma by 37% after 24 hours and 48% after 48 hours.

These procedures for "laundering" can be repeated according to clinical indications. Studies with hemodialysis and chronic outpatient peritoneal dialysis indicate that A771726, the main leflunomide metabolite, can not be excreted by dialysis.

Interaction:

Enhancement of side effects may occur in the case of recent or concomitant use of hepatotoxic (including alcohol) or hematotoxic and immunosuppressive drugs, or when the administration of these drugs begins after treatment with leflunomide without the procedure for "laundering".

Colestyramine and Activated carbon rapidly and significantly reduce the concentration of A771726 (active metabolite leflunomide) in the plasma. It is believed that this is due to a violation of enteric-liver recirculation A771726 and / or a violation of its gastrointestinal dialysis.

Possible joint use with non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticosteroids.

The enzymes involved in the metabolism of leflunomide and its metabolites are not known exactly. Clinically significant interaction with cimetidine (nonspecific inhibitor of cytochrome P450) is absent. After the concomitant administration of a single dose of leflunomide against a background of multiple doses of rifampicin (a nonspecific inducer of cytochrome P450), the maximum concentrations of A771726 increase by approximately 40%, while the area under the concentration-time curve does not change significantly. A771726 inhibits the activity of cytochrome P4502C9 (CYP2C9). With extreme caution should be taken leflunomide with other drugs that are not NSAIDs metabolized using CYP2C9. such as phenytoin, tolbutamide, since it is impossible to exclude the possibility of their interaction with leflunomide at the level of metabolism. The simultaneous use of leflunomide and warfarin may lead to an increase in prothrombin time.

There is no reduction in the contraceptive effect when combined with three-phase oral contraceptive medications containing 30 μg of ethinylestradiol, while pharmacokinetics A771726 does not change.

There is no information on the combined use of leflunomide with antimalarial drugs used in rheumatology (for example, chloroquine and hydroxychloroquine), gold preparations (intramuscularly or orally), penicillamine, azathioprine and other immunosuppressive drugs (excluding methotrexate). The risk associated with complex therapy is not known, especially for long-term treatment. Because such therapy can lead to the development of additional or even synergistic toxicity (eg, hepatotoxicity or hematotoxicity), combinations of this drug with other basic drugs (eg methotrexate) are undesirable.

In patients with rheumatoid arthritis, there was no pharmacokinetic interaction between leflunomide (10-20 mg / day) and methotrexate (10-25 mg / week).

The 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.

There is no data on the efficacy and safety of vaccination against leflunomide treatment. However, vaccination with live vaccines is not recommended. When planning vaccination with live vaccine, the long half-life of the drug should be taken into account after its elimination.

Effect of leflunomide on substrates of transport protein resistance of breast cancer (BCRP)

After repeated doses of L771726, the average values of the maximum plasma concentration and the area under the concentration-time curve of rosuvastin increase (by 2.65 and 2.51 times, respectively).

However, there is no noticeable effect of this increase in the plasma exposure of rosuvastin on the activity of HMG-CoA reductase. With simultaneous application of a dose of rosuvastin should not exceed 10 mg once a day.

Effect of leflunomide on caffeine (substrate FROMYR1A2)

The use of repeated doses of A771726 reduces the average values of the maximum plasma concentration and the area under the concentration-time curve of caffeine (substrate CYP1A2) by 18% and 55%, respectively, which confirms that A771726 may be a weak isoenzyme inducer CYPIA2 in vivo. Therefore, when combined with drugs metabolized by isoenzyme CYP1A2, such as duloxetine, alosetron, theophylline and tizanidine, care should be taken, as this may lead to a decrease in the effectiveness of these drugs

Effect of leflunomide on repaglinide (substrate CYP2C8)

After repeated doses of A771726, the average values of the maximum plasma concentration and the area under the concentration-time curve of repaglinide increase by 1.7 and 2.4 times, respectively, confirming that A771726 is an inhibitor of the isoenzyme CYP2C8 in vivo. Therefore, it is recommended that patients who take drugs metabolized with isoenzyme CYP2C8, such as repaglinide, paclitaxel, pioglitazone or rosiglitazone, since it is possible to increase their system exposure.

The effect of leflunomide on the substrates of the carrier of organic anions 3 (OAT3)

After repeated doses of A771726, the average values of the maximum plasma concentration and the area under the concentration-time curve of cefaclor increased (by 1.43 and 1.54 times, respectively), confirming that A771726 is an inhibitor of OAT3 in vivo. Therefore, with the simultaneous use of OAT substrates, such as cefaclor, benzylpenicillin, ciprofloxacin, furosemide, zidovudine, indomethacin, ketoprofen, cimetidine, methotrexate, it is recommended to be careful.

Special instructions:

The drug should be administered only after a thorough medical examination. Before starting treatment, it is necessary to remember about the possible increase in the number of side effects in patients who received earlier basic medicines for the treatment of rheumatoid arthritis, which have hepato- and hematotoxic effects.

General Precautions

Due to the long half-life of the active metabolite leflunomide A771726, Even with the cessation of treatment with leflunomide, serious adverse effects (eg, hepatotoxicity, hematoxicity, or severe immunological / allergic reactions) may or may not occur. Therefore, when such cases of toxicity occur or when switching to another basic drug after treatment with leflunomide, it is necessary to carry out the procedure of "laundering".

If suspicion of severe immunological / allergic reactions such as Stevens-Johnson syndrome orLyell's syndrome to achieve rapid and effective cleansing of the body from the metabolite A771726 may require a longer appointment of colestyramine or activated charcoal.

When used simultaneously with warfarin, the international normalized relationship should be closely monitored.

Simultaneous use of teriflunomide with leflunomide is not recommended, since leflunomide is a related compound of teriflunomide.

Reactions of the liver

Since the active metabolite leflunomide A771726 has a high affinity for proteins and is excreted by metabolism in the liver and secretion with bile, and can also have a hepatotoxic effect, the use of leflunomide in patients with impaired hepatic function is contraindicated. The use of leflunomide is not recommended in patients with liver disease.

It is necessary to strictly follow the recommendations for monitoring patients during treatment.

Before the start of treatment, and also at least 1-2 times a month in the first 6 months of treatment, and subsequently every 6-8 weeks, the activity should be checked alanine aminotransferase (ALT) in the blood.

Recommendations for correcting the regimen of subsidization or discontinuation of the drug depending on the severity and persistence of increasing ALT levels

With a confirmed 2-3-fold excess of the upper limit of the ALT norm, a decrease in the dosota from 20 mg to 10 mg per day may allow further leflunomide administration provided that the indicator is closely monitored.

If 2-3 times the upper limit of the ALT norm is maintained, or if there is a confirmed elevation in ALT levels that exceeds the upper limit of the norm by more than 3 times, the leflunomide should be discontinued and the "laundering" procedure should begin.

Because of the possible additional hepatotoxic effects, it is recommended to refrain from taking alcohol.

Hematologic and immune reactions

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.

A complete clinical blood test, including the determination of the leukocyte count and platelet count, should be performed prior to treatment, and every 2 weeks for the first 6 months of treatment and then every 6-8 weeks.

Frequent monitoring of hematologic parameters (general blood test, including leukocyte count and platelet count) should be performed in the following cases:

- in patients with recent or concomitantly receiving immunosuppressive or hematotoxic drugs, as well as when taking these drugs after treatment with leflunomide without a period of "laundering",

- in patients with an anamnesis of the corresponding deviations from the blood;

- in patients with corresponding changes in blood tests prior to treatment, not associated with inflammatory joint diseases.

In case of serious hematologic reactions, including pancytopenia, it is necessary to stop taking leflunomide and any other concomitant medication depressing bone marrow hematopoiesis and begin the procedure for washing.

Transition to other types of treatment

Because the leflunomide long remains in the body, switching to another basic drug (for example, methotrexate) without the appropriate procedure for "laundering" can increase the possibility of additional risk even after a long time after the transition (eg, kinetic interaction, organotoxicity).

Similarly, the recent treatment with hepatotoxic or hematoxic drugs (eg methotrexate) may lead to an increase in the number of side effects, therefore, in treating leflunomide, all the positive and negative aspects associated with taking this drug should be carefully considered.

Skin Reactions

In patients receiving leflunomide, it is possible to develop a drug reaction with eosinophilia and systemic symptoms (DRESS-syndrome).

If ulcerative stomatitis develops, Leflunomide should be discontinued.

In the event of Stevens-Johnson syndrome, epidermal necrolysis, or other skin reactions and / or reactions from the mucous membranes, it is necessary to cancel leflunomide intake and immediately begin the procedure of "washing". It is necessary to achieve complete removal of the drug from the body. In such cases, the repeated administration of the drug is contraindicated.

Infections

Preparations like leflunomide and possessing immunosuppressive properties make patients more susceptible to various kinds of infections, including opportunistic infections (infections caused by fungi and microorganisms that can cause infections only in conditions of decreased immunity).Emerging infectious diseases are severe and require early and intensive treatment. In the event of a serious infectious disease, it may be necessary to interrupt the 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.

Respiratory tract reaction

In the treatment with leflunomide, rare cases of interstitial pulmonary process were noted. The risk of occurrence increases in patients with a history of interstitial lung diseases. Interstitial lung diseases are diseases with a potential fatal outcome, which can occur acutely in patients receiving treatment. Symptoms such as cough and shortness of breath can be a reason for stopping leflunomide therapy and further examination if necessary.

Pperipheral neuropathy

Age over 60 years, the concomitant use of neurotoxic drugs and diabetes can increase the risk of peripheral neuropathy. With the development of peripheral neuropathy in patient receiving leflunomide, consideration should be given to discontinuing drug treatment and conducting a "laundering" procedure.

Arterial pressure

Before the start of treatment with leflunomide and periodically after its onset, it is necessary to control blood pressure, as during treatment with leflunomide it is possible to increase it.

Recommendations for men

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 in planning the appearance of a child, it is necessary to stop taking leflunomide and carry out the procedure of "laundering".

Renal insufficiency

The current experience is not enough for special recommendations on the dosing regimen in patients with impaired renal function. When prescribing leflunomide, patients of this group should be careful. It should be taken into account that the active metabolite leflunomide A771726 has a high connection with blood proteins.

Effect on the ability to drive transp. cf. and fur:During treatment, care should be taken when driving vehicles and other potentially hazardous speciesactivities.

Form release / dosage:

Tablets film-coated 10 mg, 20 mg, 100 mg.

Packaging:

For 3 tablets with a dosage of 100 mg, 10 or 20 tablets with a dosage of 10 mg and 20 mg in a contiguous cell pack of a polyvinylchloride film and aluminum foil printed lacquered.

For 3 or 30 tablets with a dosage of 100 mg, 30 or 100 tablets with a dosage of 10 mg and 20 mg in a can of polymer.

Each jar, 1 circuit cell package with 100 mg tablets, 3 out-of-round packs of 10 tablets or 5 out-of-round cell packs of 20 tablets with a dosage of 10 mg, 20 mg with instructions for use are placed in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002966

Date of registration:21.04.2015 / 01.03.2017

Expiration Date:21.04.2020

The owner of the registration certificate:MEDIMPEX, CJSC MEDIMPEX, CJSC Russia

Manufacturer: & nbsp

SYNTHESIS, OJSC Russia

Information update date: & nbsp05.03.2018

Illustrated instructions

Instructions

Lefomide® (Lefomid)