Арава®

General characteristics. Structure:

One tablet, film coated, contains 10 mg of a leflunomid as active agent.
Excipients: lactoses monohydrate - 78,00 mg; starch corn - 50,00 mg; K 25 povidone (поливидон K 25) - 3,50 mg; silicon dioxide colloid - 0,50 mg; magnesium stearate - 0,50 mg; кросповидон - 7,50 mg. Structure of a film cover: a gipromelloza (methylhydroxypropyl cellulose 5 mPa.s) - 2,521 mg; macrogoal of 8000 - 0,160 mg; titanium dioxide (Е 171) - 0,630 mg; talc - 0,189 mg.

One tablet, film coated, contains 20 mg of a leflunomid as active agent.
Excipients: lactoses monohydrate - 72,00 mg; starch corn - 46,00 mg; K 25 povidone (поливидон K 25) - 3,50 mg; silicon dioxide colloid - 0,50 mg; magnesium stearate - 0,50 mg; кросповидон-7,50 mg. Structure of a film cover: a gipromelloza (methylhydroxypropyl cellulose 5 mPa.s) - 2,516 mg; macrogoal of 8000 - 0,160 mg; titanium dioxide (Е 171) - 0,629 mg; dye ferrous oxide yellow (Е 172) - 0,006 mg; talc - 0,189 mg.

One tablet, film coated, contains 100 mg of a leflunomid as active agent.
Excipients: lactoses monohydrate - 138,42 mg; starch corn - 86,30 mg; K 25 povidone (поливидон K 25) - 7,38 mg; talc - 15,50 mg; silicon dioxide colloid - 1,11 mg; magnesium stearate - 1,84 mg. кросповидон - 18,45 mg.
Structure of a film cover: a gipromelloza (methylhydroxypropyl cellulose 5 mPa.s) - 5,443 mg, a macrogoal of 8000 - 0,288 mg, titanium dioxide (Е 171) - 1,361 mg, talc - 0,408 mg.

Description. For a dosage of 10 mg: round tablets, film coated white or almost white color with marking of "ZBN" on one party.
For a dosage of 20 mg: triangular biconvex tablets, film coated from pale yellow till pale brown color with marking of "ZBO" on one party.
For a dosage of 100 mg: round tablets, film coated white or almost white color with marking of "ZBP" on one party.

Pharmacological properties:

Pharmacodynamics. Arawa belongs to a class of basic antirheumatic drugs and has anti-proliferative, immunomodulatory, immunosuppressive and antiinflammatory properties. The active metabolite of a leflunomid of A771726 inhibits enzyme дегидрооротат a dehydrogenase and has anti-proliferative activity. A771726 in the conditions of in vitro slows down the proliferation caused by mitogens and synthesis of DNA of T lymphocytes. Anti-proliferative activity of A771726 is shown, apparently, at the level of biosynthesis of a pyrimidine as addition in cellular culture of uridine eliminates the braking action of a metabolite of A771726. With use of radio isotope ligands it is shown that A771726 selectively contacts enzyme дегидрооротат a dehydrogenase, than its property to brake this enzyme and proliferation of lymphocytes at G1 stage speaks. Proliferation of lymphocytes is one of key stages of development of a pseudorheumatism.
At the same time A771726 brakes an expression of receptors  to interleykinu-2 (SV-25) and antigens of a kernel Ki-67 and PCNA connected with a cellular cycle. Therapeutic  action  of a leflunomid    was shown  on  several experimental    models    of autoimmune    diseases,     including a pseudorheumatism.
Leflunomid reduces symptoms and slows down progressing of damage of joints at an active form of a pseudorheumatism.
The therapeutic effect is usually shown in 4-6 weeks and can increase further for 4-6 months.

Pharmacokinetics. Leflunomid quickly turns into the active metabolite of A771726 (primary metabolism in an intestinal wall and a liver). In plasma, urine or Calais only trace quantities of not changed leflunomid were noticed. The only defined metabolite is A771726 responsible for the main properties of the drug in vivo.
At intake from 82 to 95% of drug are absorbed. The maximum plasma concentration of A771726 are defined from 1 to 24 hours after once accepted dose. Leflunomid can be accepted together with food. Because of very long elimination half-life of A771726 (about 2 weeks) the load dose of 100 mg a day within 3 days was used. It allowed to reach quickly an equilibrium condition of plasma concentration of A771726. Without load dose achievement of equilibrium concentration would require 2-month administration of drug. In researches with repeated purpose of drug the pharmacokinetic A771726 parameters were dozozavisimy in the range of doses from 5 to 25 mg. In these researches the clinical effect was closely connected with plasma concentration of A771726 and a daily dose of a leflunomid. At a dose of 20 mg a day average plasma concentration of A771726 at an equilibrium state mattered 35 mkg/ml.
In plasma there is a bystry linkng of A771726 with albumine. The untied fraction A771726 makes about 0,62%. Binding of A771726 more variable and decreases at patients with a pseudorheumatism or a chronic renal failure a little.
Leflunomid is metabolized to one main (A771726) and several minor metabolites, including 4-triflyuorometilalanin. Biotransformation of a leflunomid in A771726 and the subsequent metabolism of the A771726 are controlled by several enzymes and happen in microsomal and other cellular fractions. Interaction researches with Cimetidinum (nonspecific inhibitor of P450 cytochrome) and rifampicin (the nonspecific inductor of P450 cytochrome) showed that in vivo RMS enzymes are involved in metabolism of a leflunomid only in insignificant degree.
Removal of A771726 from an organism slow is also characterized by clearance of 31 ml/hour Leflunomid is brought with excrements (possibly at the expense of biliary excretion) and with urine. The elimination half-life makes about 2 weeks. A771726 pharmacokinetics at the patients who are on HAPD is similar that at healthy volunteers. More bystry removal of A771726 is observed at the patients who are on a hemodialysis that is connected not with extraction of drug in dialyzate, and with its replacement from communication with protein. Though the clearance of A771726 increases approximately twice, the final elimination half-life is similar to that at healthy faces as distribution volume at the same time increases.
Data on drug pharmacokinetics at patients with a liver failure are absent.
Pharmacokinetic characteristics at patients more young were not studied than 18 years. At patients of advanced age (65 years are also more senior) pharmacokinetic data approximately correspond to an average age group.

Indications to use:

As basic means for treatment of adult patients with an active form of a pseudorheumatism for the purpose of reduction of symptoms of a disease and an arrest of development of structural injuries of joints. Active form of psoriasis arthritis.

Route of administration and doses:

Treatment leflunomidy has to begin under observation of the doctor having
experience of treatment of a pseudorheumatism and psoriasis arthritis.
Concerning recommendations about control of treatment watch the section "Special
instructions".
Treatment leflunomidy is begun with a single dose in a shock dose in 100 mg within 3 days. As a maintenance dose at a pseudorheumatism reception from 10 mg to 20 mg of a leflunomid is recommended once a day, at psoriasis arthritis - 20 mg of 1 times a day.
The therapeutic effect is usually shown in 4-6 weeks and can increase further up to 4 - 6 months.
There are no recommendations concerning a drug dosage for the patients having a renal failure of easy degree. No correction of a dose for patients is required 65 years are more senior. Drug has to be appointed by the specialists having necessary experience of treatment of a pseudorheumatism.
It is necessary to swallow of tablets entirely, washing down with enough liquid. Meal does not influence absorption of a leflunomid in any way.

Features of use:

Arawa can be appointed to patients only after careful medical examination.
Before an initiation of treatment drug Arawa it is necessary to remember possible increase in number of side effects at the patients who were earlier receiving other basic means for treatment of a pseudorheumatism which possess гепато - and gematotoksichesky actions.
The active metabolite of a leflunomid, A771726, is characterized by the long elimination half-life which is usually making from 1st to 4 weeks. Owing to a long elimination half-life of an active metabolite of a leflunomid, A771726, even at the treatment termination leflunomidy serious undesirable effects can arise or remain (for example, a hepatotoxic, a gematoksichnost or allergic reactions, see below). In this case it is necessary to carry out the washings procedure. The procedure can be repeated according to clinical indications. At suspicion on heavy immunological/allergic reactions like Stephens's syndrome - Johnson or a Lyell's disease holding the full washings procedure is obligatory.
Therefore at emergence of similar cases of toxicity or upon transition to reception of other basic drug (for example, a methotrexate) after treatment leflunomidy it is necessary to carry out the washings procedure (see below). Reactions of a liver
As the active metabolite of a leflunomid, A771726, is connected with proteins and is removed by means of hepatic metabolism and biliary secretion, it is supposed that the level of contents A771726 in a blood plasma can increase at patients with a hypoproteinemia. The drug Arawa is contraindicated to patients with a heavy hypoproteinemia or abnormal liver functions. (see the section "Contraindications".).
It was reported about exceptional cases of development of severe damage of a liver, in some cases from the death, at treatment leflunomidy. The majority of these cases was observed within the first six months of treatment. Though the causal interrelation of these undesirable phenomena with leflunomidy is not established, and in most cases there were several accessory suspicious factors, exact implementation of recommendations about control of treatment is considered obligatory.
The ALT level has to be checked before therapy leflunomidy, and then each 2 weeks within the first 6 months of treatment, with the subsequent check once everyone 6-8nedel.
There are following recommendations about correction of the mode of dosing or to the termination of administration of drug depending on expressiveness and firmness of increase in the ALT level.
At the confirmed 2-3 multiple exceeding of the upper bound of norm of ALT the dose decline from 20 mg to 10 mg a day is able to afford to continue reception of a leflunomid on condition of careful control of this indicator. If 2-3 multiple exceeding of the upper bound of norm of ALT remain or if there is a confirmed rise in the ALT level exceeding upper
limit of norm more than by 3 times, reception of a leflunomid it has to be stopped and it is necessary to begin the washings procedure.
Because of possible additional hepatotoxic effects it is recommended to refrain from alcohol intake at treatment leflunomidy. Hematologic reactions
Full clinical blood test, including definition of a leukocytic formula and quantity of thrombocytes, has to be carried out prior to treatment leflunomidy, and also each 2 weeks within the first 6 months of treatment and then each 6-8 weeks.
At patients with the anemia which was earlier taking place, a leukopenia and/or thrombocytopenia, and also at patients with dysfunctions of marrow or with risk of development of such disturbances, danger of emergence of hematologic disturbances increases. At emergence of this sort of the phenomena it is necessary to use the washings procedure for decrease in the A771726 level in a blood plasma.
In case of development of serious hematologic reactions, including a pancytopenia, it is necessary to stop administration of drug Arawa and any other accompanying drug suppressing    a marrowy hemopoiesis and to begin the washings procedure. Combined use with other types of treatment
Now yet there are no data of rather combined use of a leflunomid with the antimalarial drugs used in rheumatology (for example, chloroquine and hydroxychloroquine), the gold drugs entered intramusculary or orally, D-Penicillaminum, Azathioprinum and other immunodepressive means (except for a methotrexate). The risk connected with purpose of complex therapy, especially at prolonged treatment is not known. As such therapy can lead to development of additional or even synergistic toxicity (for example, gepato-or gematotoksichnost), combinations of this drug with other basic drugs (for example, a methotrexate) are not desirable.
Transition to other types of treatment
As лефлуномид in an organism, transition to reception of other basic drug long remains (for example, a methotrexate) without the corresponding holding the washings procedure can increase possibility of additional risk even later a long time after transition (for example, kinetic interaction, an organotoksichnost). Similarly recent treatment by gepatotoksichny or gematoksichny drugs (for example, a methotrexate) can lead to increase in number of by-effects therefore, beginning treatment leflunomidy, it is necessary to consider carefully all positive and negative aspects connected with reception of this drug. Skin reactions
In case of development of a stomacace it is necessary to stop reception of a leflunomid. It was reported about very exceptional cases of emergence of a syndrome of Stephens - Johnson or a toxic epidermal necrolysis at the patients receiving лефлуномид. In case of skin reactions and/or reactions from mucous membranes it is necessary to cancel administration of drug Arawa and any other related drug and to immediately begin the washings procedure. It is necessary to reach full removal of drug from an organism. In similar cases repeated purpose of drug
contraindicated.
Infections
It is known that drugs, similar to a leflunomid and having immunosuppressive properties, do patients more sensitive to different infections, including opportunistic infections (the infection caused by the fungi and microorganisms capable to cause infections only in the conditions of decrease in immunity). The arisen infectious diseases proceed, as a rule, hard and demand early and intensive treatment. When developing a serious infectious disease it can be necessary to interrupt treatment leflunomidy and to begin the washings procedure.
It is necessary to watch carefully patients with positive reaction to tuberculine because of risk of reactivation of tuberculosis. Reactions of respiratory tracts
At therapy leflunomidy exceptional cases of intersticial pulmonary process were celebrated. Such symptoms as cough and диспноэ can serve as the reason of the termination of reception of a leflunomid. Arterial pressure
Before an initiation of treatment leflunomidy and periodically after its beginning
it is necessary to control the level of arterial pressure.
Interactions
It is necessary to be careful at purpose of the drugs which are metabolized under the influence of CYP2C9 (Phenytoinum, warfarin, Tolbutamidum) except for NPVS (non-steroidal anti-inflammatory drugs). Recommendations for men
There is no emergence of the fetotoksichnost (connected with toxic influence of drug on the father's spermatozoa) given about risk when using a leflunomid by men. Experimental data in this direction were not carried out. For the maximum reduction of possible risk men when planning appearance of the child need to stop reception of a leflunomid and to use Colestyraminum on 8 g 3 times a day within 11 days or 50 g of the absorbent carbon crushed in powder 4 times a day within 11 days.

Side effects:

Classification of estimated frequency of by-effects: 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), it is unknown (on the basis of the available data it is impossible to estimate).

Cardiovascular system
Frequent: moderate increase in arterial pressure. Rare: the expressed increase in arterial pressure
Digestive tract
Frequent: diarrhea, nausea, vomiting, diseases of a mucous oral cavity (for example, aphthous stomatitis, ulceration of lips), abdominal cavity pains. Infrequent: disturbances of flavoring feelings Very rare: pancreatitis
Respiratory system and mediastinal disturbances
Rare: intersticial pulmonary process (including intersticial pneumonia), with a possible lethal outcome. Metabolism disturbances
Frequent: increase in a kreatinfosfokinaza (KFK) Infrequent: hypopotassemia, lipidemia, hypophosphatemia. Rare: increase in level of a lactate dehydrogenase (LDG) Frequency is unknown: hypolithemia Nervous system
Frequent: headache, dizziness, paresthesias.
Infrequent: concern.
Very rare: peripheral neuropathy
Musculoskeletal system
Frequent: tendovaginitis.
Infrequent: rupture of sinews
Skin and derivatives
Frequent: the strengthened hair loss, eczema, rash ( including makulopapulezny rash), an itch, a xeroderma. Infrequent: small tortoiseshell
Very rare: toxic epidermal necrolysis  (Lyell's disease),
multiformny erythema, Stephens's syndrome - Johnson.
Immune system
Frequent: easy allergic reactions.
Very rare: serious anaphylactic/anaphylactoid reactions, vasculitis, including skin necrotic vasculitis. Infections and invasions
Rare: development of heavy infections, including opportunistic, and sepsis which can be fatal.
The number of possible infections can increase (in particular, rhinitis, bronchitis and pneumonia).
System of a hemopoiesis and lymphatic system
Frequent: leukopenia (leukocytes> 2000/mkl).
Infrequent: anemia, small thrombocytopenia (thrombocytes <100 000/мкл). Rare: a pancytopenia (it is probable due to anti-proliferative action), a leukopenia (leukocytes <2000/mkl), an eosinophilia. Very rare: agranulocytosis.
The recent, accompanying or subsequent use of potentially miyelotoksichny agents can be associated with a bigger risk degree of hematologic effects. Gepato-biliarnaya system
Frequent: increase in activity of "hepatic" transaminases (especially alaninaminotranspherases (ALT)), is more rare - gamma глютамилтранспептидазы (GGT) and the alkaline phosphatase (AP), a hyperbilirubinemia. Rare: hepatitis, jaundice/cholestasia.
 Very rare: severe damages of a liver, such as liver failure, acute necrosis of a liver which can be fatal; Changes of the general character
Frequent: anorexia, loss of body weight (usually insignificant), adynamy. From reproductive system:
Frequency is unknown: insignificant decrease in concentration of sperm, the general
numbers of spermatozoa and their mobility
From kidneys and urinary tract:
Frequency is unknown: renal failure
Other
The risk of developing of malignant, especially limfoproliferativny diseases, increases when using some immunodepressive drugs.

Interaction with other medicines:

Strengthening of by-effects can take place in case of the recent or accompanying use gepatotoksichny (including alcohol) or gematotoksichny and immunosuppressive drugs or when reception of these drugs is begun after treatment leflunomidy without the washings procedure (see. "Special instructions").
At patients with a pseudorheumatism no pharmacokinetic interaction between leflunomidy (10 - 20 mg a day) and a methotrexate was revealed (10 - 25 mg a week).
The patients accepting лефлуномид are recommended not to give Colestyraminum or absorbent carbon as it leads to bystry and considerable decrease in concentration of A771726 (an active metabolite of a leflunomid) in a blood plasma. It is considered that it is caused by disturbance of recirculation of A771726 in a liver and a small bowel and/or disturbance of its gastrointestinal dialysis.
If the patient already accepts non-steroidal anti-inflammatory drugs (NPVS) and/or corticosteroids, they can continue to be accepted after an initiation of treatment leflunomidy.
The enzymes participating in metabolism of a leflunomid and its metabolites are definitely not known. The research in vivo of its interaction with Cimetidinum (not specific inhibitor of P450 cytochrome) showed lack of essential interaction. After the accompanying introduction of a single dose of a leflunomid to the subjects receiving repeated doses of rifampicin (not the specific inductor of P450 cytochrome), the peak A771726 levels increased approximately for 40% whereas the area under a curve concentration time significantly did not change. The mechanism of this effect is not clear. The researches in vitro showed that A771726 oppresses activity of P4502C9 (CYP2C9) cytochrome. In clinical tests no problems at joint introduction of a leflunomid and NPVS which are metabolized CYP2C9 were observed. With extra care it is necessary to give
лефлуномид together with other drugs which are not NPVP which are metabolized by means of CYP2C9 such as Phenytoinum, warfarin and Tolbutamidum. It was reported about increase in a prothrombin time at co-administration of a leflunomid and warfarin.
In a research in which лефлуномид gave to female healthy volunteers together with the three-phase peroral contraceptives containing 30 mkg acetenyl of oestradiol of any decrease in contraceptive effect of tablets it was revealed not, and A771726 pharmacokinetics completely kept within the provided range. Now there are no data of rather combined use of a leflunomid with the antimalarial drugs used in rheumatology (for example, chloroquine and hydroxychlorine), the drugs Au (in oil or orally), D-Penicillaminum, Azathioprinum, etc. immunodepressive medicines (except for a methotrexate). The risk connected with performing complex therapy, especially at prolonged treatment is unknown. As such therapy can lead to development of additional or even synergistic toxicity (for example, gepato-or gematoksichnost), combinations of this drug with other basic drugs (for example, a methotrexate) are undesirable. The recent accompanying or subsequent use of potentially miyelotoksichny agents can be connected with a bigger risk degree of hematologic influences. Immunodepressants increase risk of development of infections, and also malignant, especially limfoproliferativny diseases. Vaccination
There are no clinical data on effectiveness and safety of vaccination in the conditions of treatment leflunomidy. Nevertheless, it is not recommended to carry out vaccination by live vaccines. It is necessary to consider a long elimination half-life of drug Arawa when planning vaccination by a live vaccine after drug withdrawal Arawa.

Contraindications:

The drug Arawa should not be used at patients with hypersensitivity to a leflunomid or any other component of drug.
Drug is contraindicated:
- at patients with abnormal liver functions;
- at patients with a heavy immunodeficiency (for example, AIDS);
- at patients with considerable disturbances of a marrowy hemopoiesis or with the expressed anemia, a leukopenia or thrombocytopenia as a result of other reasons (except a pseudorheumatism);
- at patients with heavy, uncontrollable infections;
- at patients with a moderate or heavy renal failure (in view of small experience of clinical observation);
- at patients with a heavy hypoproteinemia (for example, at a nephrotic syndrome);
- at pregnant women or women of childbearing age who are not using reliable contraception during treatment leflunomidy and then until the plasma level of an active metabolite remains higher than 0,02 mg/l (see. "Pregnancy and feeding by a breast"). Pregnancy has to be excluded before an initiation of treatment leflunomidy.
Reception of a leflunomid during breastfeeding is contraindicated (see. "Pregnancy and feeding by a breast".)
The men receiving treatment leflunomidy have to be warned about the possible fetotoksichesky effect of drug (connected with its possible influence on the father's spermatozoa) and about need of use of nadezhy contraceptives.
Arawa is not recommended to use at patients 18 years as data on efficiency and safety in this group of patients are absent are younger.

Pregnancy and feeding by a breast
Leflunomid pregnant women or women of childbearing age who do not use reliable contraception at treatment leflunomidy and any time after this treatment (the period of expectation or the reduced period of "washing" cannot appoint; see below). It is necessary to be convinced of lack of pregnancy prior to treatment leflunomidy.
Patients need to be informed that as soon as there comes the delay monthly or if there is other reason to assume pregnancy approach, they have to report immediately about it to the doctor to make the test for pregnancy; in case of positive test for pregnancy the doctor has to discuss about sick possible risk to which this pregnancy is exposed. It is possible that bystry decrease in level of maintenance of an active metabolite in blood by means of the procedure of removal of drug described below will help monthly to reduce risk to which the fruit from a leflunomid is exposed at the first delay.
To women  who  accept  лефлуномид  and  want  to become pregnant, it is recommended to follow one of stated below procedures to be confident that the fruit will not be subject to influence of toxic concentration of A771726 (control concentration lower than 0,02 mg/l). Expectation period
It is possible to expect that concentration of A771726 in a blood plasma can be higher than 0,02 mg/l during the long period. It is considered that its concentration can become less than 0,02 mg/l in 2 years after the treatment termination leflunomidy.
The first time concentration of A771726 is measured in a blood plasma after the two-year period of expectation.
After that it is necessary to measure concentration of A771726 in a blood plasma as
at least, in 14 days. If the size of both measurements is lower than 0,02 mg/l, not
it is expected any teratogenic risk.
Washings procedure
After the treatment termination leflunomidy:
•  Colestyraminum of 8 g is entered 3 times a day within 11 days;
•  as an alternative 50 g of the absorbent carbon crushed in
powder, is entered 4 times a day within 11 days. Irrespective of the chosen washings procedure it is necessary to carry out an inspection two separate tests with an interval, at least, in 14 days and to wait one and a half months since that moment when concentration of drug in plasma is for the first time recorded lower than 0,02 mg/l, until fertilization.
It is necessary to inform women of the genital period on what has to pass 2 years after the treatment termination leflunomidy before they can try to become pregnant. If the 2-year period of expectation at reliable contraception seems unreasonable, it is possible to advise to carry out the washings procedure in the preventive purposes. Both Colestyraminum, and absorbent carbon can influence absorption of estrogen and progestogens therefore well-tried peroral contraceptives do not give an absolute guarantee during "washing" by means of Colestyraminum or absorbent carbon. It is recommended to use alternative methods of contraception. Researches on animals showed that лефлуномид or its metabolites pass into breast milk. Therefore the women nursing should not accept лефлуномид.

Overdose:

Symptoms
The patients receiving лефлуномид in a dose had messages on chronic overdose, to 5 times the exceeding recommended daily dose, and also messages on acute overdose for adults and children. In most cases the overdose was not reported about development of the undesirable phenomena. The arising undesirable phenomena were comparable to a profile of safety of a leflunomid. Diarrhea, abdominal pains, a leukopenia, anemia and increase in indicators of tests functional a condition of a liver were the most often observed undesirable phenomena. Treatment
  In case of  overdose  or  toxicity  it is recommended  to accept Colestyraminum or absorbent carbon to accelerate clarification of an organism. Colestyraminum accepted by three healthy volunteers orally on 8 g three times a day within 24 hours reduced the level of contents A771726 in a blood plasma approximately by 40% in 24 hours and for 49 - 65% in 48 hours. It is shown that administration of absorbent carbon (the powder turned into suspension) orally or through a gastric tube (to 50 g there are each 6 hours within a day) reduced concentration of an active metabolite of A771726 in plasma by 37% in 24 hours and for 48% in 48 hours.
These washings procedures can be repeated according to clinical indications. Researches with a hemodialysis and COPPD (chronic out-patient peritoneal dialysis) specify that A771726, the main metabolite of a leflunomid, is not capable to be removed by dialysis.

Storage conditions:

To store at a temperature not above 25 °C. To store medicine in the place, unavailable to children. Period of validity 3 years. After a period of validity drug cannot be used.

Issue conditions:

According to the recipe

Packaging:

Tablets, coated on 10 mg, 20 mg and 100 mg.

For dosages of 10 mg and 20 mg: on 30 tablets in a polyethylene bottle with the screw-on cover. The cover is supplied with a container with the moisture absorbing substance. The bottle together with the application instruction is placed in a cardboard pack.

For a dosage of 100 mg: on 3 tablets in the blister consisting of the laminated aluminum foil. The blister together with the application instruction is placed in a cardboard pack.