Daklinza

General characteristics. Structure:

Active ingredient: 66 mg of a daklatasvir of dihydrochloride that corresponds to 60 mg of a daklatasvir.

Excipients: lactose, cellulose microcrystallic, croscarmellose sodium, silicon dioxide, magnesium stearate, опадрай® green (a gipromelloza, titanium dioxide, a macrogoal-400, an aluminum varnish on the basis of indigo carmine (FD&C Blue #2), iron oxide yellow).

Pharmacological properties:

Pharmacodynamics. Daklatasvir represents highly specific means of direct action against the hepatitis C virus (HCV) and has no the expressed activity against other RNA and DNA of the containing viruses, including the human immunodeficiency virus (HIV). Daklatasvir is inhibitor of the nonstructural protein 5A (NS5A), a multipurpose protein necessary for replication of VGS, and thus suppresses two stages of a life cycle of a virus - replication of virus RNA and assembly of virions. On the basis of the data obtained by in vitro, and data of computer modeling it is shown what даклатасвир interacts with the N-end within the domain of 1 protein which can cause the structural distortions interfering implementation of functions of protein of NS5A. It is established that drug is powerful pan-genotypic inhibitor of a complex of replication of a virus of hepatitis From genotypes 1a, 1b, 2a, 3a, 4a, 5a and 6a with values of effective concentration (50% decrease, EC50) from pikomolyarny to low nanomolar. At cellular quantifications of replicons of EC50 value of a daklatasvir vary from 0.001 to 1.25 nanometers at genotypes 1a, 1b, 3a, 4a, 5a and 6a and from 0.034 to 19 nanometers at a genotype 2a. Besides, даклатасвир inhibits a hepatitis virus From a genotype 2a (JFH-1) at the EC50 value equal to 0.020 nanometers. At a genotype 1a at the infected patients who were not receiving before treatment, the single dose of a daklatasvir of 60 mg leads to average decrease in the virus load measured in 24 h of 3.2 log10 ME/ml.

Researches on culture of cells also showed strengthening of antiviral effect of drug at combined use with interferon an alpha and NS3 protease inhibitors, the VGS NS5B nenukleozidny inhibitors, nukleozidny analogs of NS5B. With all listed groups of drugs antagonism of antiviral effect was not noted.

Resistance in culture of cells. The replacements of amino acids causing resistance to a daklatasvir in VGS 1-6 genotypes were allocated in cellular system of replicon and were observed in N-terminal area 100 of the amino-acid rest of NS5A. L31V and Y93H were often observable in a genotype 1b, and replacements of M28T, L31V/M, Q30E/H/R and Y93C/H/N were often observable in a genotype 1a. Single replacements of amino acids in general cause the low level of a rezistentost (EC50 <1 nanometers for L31V, Y93H) for a genotype 1b and higher levels of resistance for a genotype 1a (to 350 nanometers for Y93N). The principles of emergence of resistance in clinical practice were similar to the principles of emergence of resistance observed by in vilro

Resistance in clinical trials. Effect of initial polymorphism of VGS in response to therapy. During the conducted communication research between naturally arising initial replacements of NS5A (polymorphism) and the result of treatment it was established that influence of NS5A of polymorphism depends on the scheme of therapy.

Therapy by a combination of drugs Daklatasvir + Asunaprevir. In clinical trials of the II-III phase efficiency of a combination Daklatasvir + Asunaprevir was reduced at the patients infected with genotype VGS 1b with initial replacements of NS5A L31 and/or Y93M. 40% (48/119) patients with replacements of NS5A L31 and/or Y93H reached the steady virologic answer (UVO12) in comparison with 93% (686/742) patients without these types of polymorphism. Initial prevalence of replacements of NS5A L3 I and Y93H made 14%; 4% - for L31 separately, 10% - for Y93H separately and 0.5% - L31+Y93H. From 127 cases of virologic inefficiency at initial replacement of NS5A 16% had only L31, at 38% - only Y93H and at 2% - L31+Y93H.

Therapy by a combination of drugs Daklatasvir + Asunaprevir + Peginterferon alpha + Ribavirin. From 373 patients to whom sequenation was carried out in a research of this combination 42 patients had initial replacements connected with resistance to a daklatasvir. From these 42 patients 38 reached UVO12, at 1 patient was nevirusologicheskaya inefficiency and at 3 patients virologic inefficiency was observed (1 patient with a genotype 1a had replacements of NS5A-L31M and at 1 - NS5A-Y93F at the initial level; 1 patient with a genotype 1b had a replacement of NS5A-L31M at the initial level).

Pharmacokinetics. Pharmacokinetic properties of a daklatasvir were estimated at adult healthy volunteers and patients with persistent infection a hepatitis C virus. After multiple oral administration of a daklatasvir in a dose of 60 mg of 1 times/days in a combination with peginterferon an alpha and ribaviriny average value (coefficient of variability, %) Cmax of a daklatasvir made 1534 (58) ng/ml, concentration time (AUC0-24ch) made the areas under a curve 14122 (70) нг×ч/мл and Cmin made 232 (83) ng/ml.

Absorption. Absorption is bystry. Cmax of a daklatasvir is observed in 1-2 h after intake. AUC, Cmax, Cmin in blood are dozozavisimy, the stable level of a daklatasvir in a blood plasma is observed for the 4th day of use of drug at intake of 1 times/days. Researches did not reveal distinctions in drug pharmacokinetics at patients with hepatitis C and healthy volunteers. The researches in vitro conducted with human cells of Saso-2 showed what даклатасвир is substrate for the R-glycoprotein (P-gp). Absolute bioavailability of drug makes 67%.

In researches on healthy volunteers it was established that the single dose of a daklatasvir of 60 mg in 30 min. after meal with the high content of fat (about 1000 Kcal with the content of fats about 50%) lowers drug Cmax in blood by 28% and AUC for 23%. Administration of drug after easy meal (275 Kcal with the content of fats about 15%) did not change concentration of drug in blood.

Distribution. Vd of a daklatasvir after drug, single in/in introductions of 100 mkg, makes 47 l. Communication with proteins of plasma does not depend on a dose (the studied range from 1 mg to 100 mg) and makes 99%.

Metabolism. In the researches in vitro it is established what даклатасвир is CYP3A isoenzyme substrate, at this CYP3A4 is the main CYP isoform responsible for drug metabolism. Metabolites with contents more than 5% of concentration of initial substance are absent.

Removal. After oral administration by healthy volunteers of single doses of a daklatasvir, marked C14 radiocarbon ([14C] - даклатасвир), 88% of all radioactivity were removed with a stake (53% in not changed look), 6.6% were allocated with urine (preferential in not changed look).

After multiple dose of a daklatasvir VGS-infitsirovannymi patients, T1/2 of a daklatasvir varied from 12 to 15 h. At patients who accepted даклатасвир in tablets 60 mg with the subsequent in/in introduction of 100 mkg [13C, 15N] - daklatasvira the general clearance made 4.24 l/h.

Patients with a renal failure. Comparison of the size AUC at patients with an infection of VGS and normal function of kidneys (KK of 90 ml/min.) and patients with VGS infection with renal failures (ml/min. KK 60, 30 and 15) showed increase in AUC by 26%, 60% and 80% (untied AUC - 18%, 39%, 51%) respectively. Patients with an end-stage have diseases of kidneys, demanding carrying out a hemodialysis, increase in AUC for 27% (connected - for 20%) in comparison with patients with normal function of kidneys was observed. The statistical population analysis of patients with an infection of VGS showed increase in AUC at patients with a slight and moderate renal failure, however the size of this increase is not clinically significant for pharmacokinetics of a daklatasvir. In view of high extent of linkng of a daklatasvir with proteins, carrying out a hemodialysis does not influence its concentration in blood. Change of a dose of drug with a renal failure is not required from patients.

Patients with an abnormal liver function. Researches of pharmacokinetics of a daklatasvir in a dose of 30 mg were conducted with participation of patients with hepatitis C with easy, moderate and heavy degree of a liver failure (classes A-with on a scale of Chayld-Pyyu) in comparison with patients without abnormal liver function. Cmax and AUC values of a daklatasvir (free and connected with proteins) were lower in the presence of a liver failure in comparison with values of these indicators at healthy volunteers, however this decrease in concentration was not clinically significant. There is no need of change of a dose of drug at patients with the broken function of a liver.

Elderly patients. Patients of advanced age took part in clinical trials (310 people were at the age of 65 years and is more senior, and 20 - at the age of 75 years and is more senior). Change of pharmacokinetics, and also profiles of efficiency and safety of drug at elderly patients was not observed.

Floor. Distinctions in the general clearance (CL/F) of a daklatasvir are observed, at the same time CL/F at women is lower, however this distinction is not clinically significant.

Indications to use:

Treatment of chronic hepatitis C at patients with the compensated liver disease (including cirrhosis) in the following combinations of drug даклатасвир:

— with drug асунапревир for patients with a genotype hepatitis virus 1b;

— with drugs асунапревир, peginterferon an alpha and рибавирин - for patients with a virus of hepatitis of a genotype 1.

Route of administration and doses:

The recommended dosing mode. The recommended dose of drug of Daklinz makes 60 mg of 1 times/days irrespective of reception write. Drug should be used in combination with other medicines (see Table 1). Recommendations about doses of other medicines of the scheme are made in the corresponding instructions on a medical use. Therapy is recommended as the patients who were earlier not receiving treatment of chronic hepatitis C and patients with the previous inefficiency of therapy.

Table 1. The recommended schemes of therapy of drug of Daklinz when using in a dose of 60 mg of 1 times/days as a part of a combination therapy

Change of a dose and suspension of therapy. After the beginning of therapy change of a dose of drug of Daklinz is not recommended. For change of a dose of other medicines of the scheme it is necessary to study the corresponding instructions on a medical use. It is necessary to avoid treatment interruption; however if treatment interruption by any drug of the scheme is necessary because of the arisen undesirable reactions, it is not necessary to use Daklinz's drug in the form of monotherapy.

During treatment it is necessary to carry out monitoring of virus loading (quantity of PNK VGS to the patient's blood). Patients with the inadequate virologic answer during treatment with low degree of probability will reach UVO, also this group has a probability of development of resistance. The termination of treatment is recommended at patients with virologic break - increase in the VGS RNA level at more than 1 _log10 from the previous level.

Admission of a dose. In case of the admission of reception of the next dose of drug of Daklinz for a period of up to 20 h, the patient should accept drug as soon as possible and further to adhere to the initial scheme of therapy. If at the admission of a dose there passed more than 20 h from the planned time of administration of drug, the patient should miss reception of this dose, the following dose of drug has to be accepted according to the initial scheme of therapy.

Patients with a renal failure. Change of a dose with a renal failure of any degree is not required from patients.

Patients with a liver failure. Change of a dose with easy degree of a liver failure (a class A on a scale of Chayld-Pyyu) is not required from patients. In researches at easy (a class A on a scale of Chayld-Pyyu), moderated (a class B on a scale of Chayld-Pyyu) and heavy (a class C on a scale of Chayld-Pyyu) a liver failure significant changes of pharmacokinetics of drug were not revealed. Efficiency and safety of use at a dekompensirovanny liver failure is not established.

The accompanying therapy. Strong inhibitors of an isoenzyme 3A4 of system of P450 (CYP3A4) cytochrome. The dose of drug of Daklinz should be lowered to 30 mg of 1 times/days in case of simultaneous use with powerful inhibitors of an isoenzyme CYP3A4 (to use a tablet of 30 mg; it is not necessary to break a tablet of 60 mg) (see the section "Interaction with Other Medicines and Other Forms of Interaction"). Simultaneous use of powerful and moderate inhibitors of an isoenzyme of CYP3A4 is contraindicated at use of the schemes including Sunvepr's drug.

Moderate inductors of an isoenzyme CYP3A4. It is necessary to increase a dose of drug of Daklinz to 90 mg of 1 times/days (3 таб. 30 mg or 1 таб. 60 mg and 1 таб. 30 mg) at simultaneous use of moderate inductors of an isoenzyme of CYP3A4 (see the section "Interaction with Other Medicines and Other Forms of Interaction"). Simultaneous use of moderate inductors of an isoenzyme of CYP3A4 is contraindicated at use of the schemes including Sunvepr's drug.

Features of use:

Use at pregnancy and feeding by a breast. Daklatasvir + Asunaprevir. There are no adequate and well controlled researches with participation of pregnant women. In researches on animals at use of a daklatasvir in the doses exceeding recommended therapeutic (by 4.6 times (rat) and by 16 times (rabbits)) the negative impact on pre-natal fetation while higher concentration of drug (by 25 times (rat) and by 72 times (rabbits)) revealed negative effects both for mother, and for a fruit is noted. Women of childbearing age should use effective methods of contraception during treatment prsparaty Daklinza and within five weeks after its end.

Use of a combination Daklatasvir + Asunaprevir at pregnancy is contraindicated. It is unknown whether gets даклатасвир into breast milk. Daklatasvir got into breast milk of the lactating rats in the concentration exceeding plasma maternal concentration by 1.7-2 times therefore for the period of treatment by Daklinz's drug feeding by a breast should be stopped.

Daklatasvir + Asunaprevir + Peginterferon alpha + Ribavirin. Use of a ribavirin can cause fruit malformations, pre-natal death and abortions therefore it is necessary to observe the careful care at use of the scheme of therapy including рибавирин. Prevention of approach of pregnancy both at patients is necessary, and at women whose sexual partners receive the specified therapy. Therapy ribaviriny should not begin until the patients capable to a child-bearing, and their male sexual partners do not use at least 2 effective methods of contraception that is necessary both throughout all therapy, and within not less than 6 months after its end. During this period it is necessary to carry out standard tests for pregnancy. When using peroral contraceptives as one of ways of contraception it is recommended to use high doses of the peroral contraceptives (containing not less than 30 mkg of ethinylestradiol in a combination from norethindrone acetate/norethindrone).

The research of interferon in animal experiments was associated with abortal effects which possibility of development in the person cannot be excluded. Therefore at use of therapy both to patients, and their partners it is necessary to apply adequate contraception.

Use at abnormal liver functions. There is no need of change of a dose of drug at patients with the broken function of a liver.

Use at renal failures. Change of a dose with a renal failure of any degree is not required from patients.

Use for children. Drug use aged up to 18 years is contraindicated to children and teenagers (efficiency and safety are not studied).

Special instructions. Daklinz's drug should not be used in the form of monotherapy. From more than 2000 patients included in clinical trials of a combination therapy with Daklinz's drug 372 patients had the compensated cirrhosis (a class A on a scale of Chayld-Pyyu). Distinctions in indicators of safety and efficiency of therapy among patients with the compensated cirrhosis and patients without cirrhosis were not observed. Safety and efficiency of use of drug Daklinza at patients with dekompensirovanny cirrhosis is not established. Change of a dose of drug of Daklinz is not required from patients with weak (a class A on a scale of Chayld-Pyyu), moderated (a class B on a scale of Chayld-Pyyu) or heavy (a class C on a scale of Chayld-Pyyu) an abnormal liver function.

Safety and efficiency of a combination therapy Daklinza at patients with a transplantirovanny liver is not established by drug. There is a limited experience of use of drug of Daklinz after transplantation of a liver.

Influence of a daklatasvir on an interval of QTc was estimated in randomized placebo - a controlled research on healthy volunteers. Single doses of a daklatasvir of 60 mg and 180 mg had no clinically significant influence on the QTc interval corrected on Frederik's (QTcF) formula. There was no significant interrelation between the increased concentration of a daklatasvir in plasma and QTc change. At the same time the single dose of a daklatasvir of 180 mg corresponds to most expected concentration of drug in a blood plasma at a clinical use.

Use of drug for treatment of chronic hepatitis C at patients with the accompanying infection of a virus of hepatitis B or a human immunodeficiency virus was not studied. Daklinz's drug contains lactose: in 1 таб. 60 mg (daily dose) contain 115.50 mg of lactose.

It is necessary to use adequate methods of contraception within 5 weeks after completion of therapy by Daklinza.

Influence on ability to manage vehicles, mechanisms. Researches of possible influence of use of drug on ability to manage vehicles and to work with mechanisms were not conducted. If the patient tests dizziness, disturbance of attention, illegibility/decrease in visual acuity data of NYa were noted when using the scheme of treatment with peginterferon an alpha) which can affect ability to concentration of attention, it should refrain from control of vehicles and mechanisms.

Side effects:

Ppenapat Daklinza is applied only as a part of schemes of a combination therapy. It is necessary to examine side effect of the medicines entering the scheme of treatment prior to therapy. The Undesirable Medicinal Reactions (UMR) connected using an asunaprevir, peginterferon an alpha and a ribavirina are described in instructions on a medical use of these drugs.

Safety of use of a daklatasvir was estimated in 5 clinical trials on patients with chronic hepatitis From the receiving 60 mg of drug of Daklinz of 1 times/days at combinations with asunapreviry and/or peginterferon an alpha and ribaviriny. The uses given on safety are given below on the treatment modes.

Daklatasvir + Asunaprevir. Safety of use of a daklatasvir with asunapreviry was estimated at combinations in 4kh researches with an average duration of therapy of 24 weeks. (Frequency of 10% and above) NLR observed in clinical trials when using the scheme of therapy Daklatasvir + Asunaprevir the headache (15%) and increased fatigue (12%) were the most widespread. The majority of NLR were weak and moderate on weight. 6% of patients tested the serious undesirable phenomena (SUP), 3% of patients stopped treatment on NLR origin. At the same time the most widespread undesirable phenomena (UP) leading to the treatment termination were increase in activity of ALT and ACT. In clinical trial of therapy by drugs Daklatasvir + Asunaprevir during the first 12 weeks of treatment the frequency of the reported NLR was similar between the patients receiving placebo and the patients receiving the specified therapy.

NLR arising at ≥5% of patients with chronic hepatitis C at use of a combination Daklatasvir + Asunaprevir are given below. Frequency of emergence of NLR is specified according to a scale: very often (≥1/10), it is frequent (≥1/100 and <1/10).

Table 2.

^and - side reactions which communication using drug is at least possible. Integrated data on several researches.

The undesirable reactions arising less than at 5% of patients with chronic hepatitis C at use of a combination Daklatasvir + Asunaprevir: skin rash, skin itch, alopecia; zozinofiliya, thrombocytopenia, anemia; fervescence, indisposition, fever; sleeplessness; a loss of appetite, discomfort in a stomach, a lock, pain in an upper part of a stomach, stomatitis, abdominal distention, vomiting; increase in the ABP; joint pain, muscle tension; a nasopharyngitis, pain in a stomatopharynx; increase in activity gamma глобулинтрансферазы, ShchF, lipases, hypoalbuminemia.

Daklatasvir in a combination with asunapreviry, peginterferon an alpha and ribaviriny. Safety of use of a daklatasvir in combinations with asunapreviry, peginterferon an alpha and ribaviriny was estimated in clinical trial of HALLMARK QUAD with an average duration of therapy of 24 weeks. The most widespread NLR (frequency of 15% and above) observed in clinical trials when using the scheme of therapy Daklatasvir + Asunaprevir + Peginterferon an alpha + Ribavirin were: increased fatigue (39%), headache (28%), itch (25%), adynamy (23%), grippopodobny state (22%), sleeplessness (21%), anemia (19%), rash (18%), alopecia (16%), irritability (16%) and nausea (15%). The additional side effects arising at patients with chronic hepatitis C when using the scheme of therapy Daklatasvir + Asunaprevir + Peginterferon an alpha + Ribavirin were: xeroderma (15%), loss of appetite (12%), muscle pain (14%), fever (15%), cough (13%), asthma (11%), neutropenia (14%), lymphopenia (1%), diarrhea (14%), joint pain (9%). The majority of NLR were weak and moderate on weight. 6% of patients were registered by SNYa. 5% of patients stopped treatment because of NYa, at the same time the most widespread NYa. leading to the treatment termination, were rash, an indisposition, dizziness and a neutropenia.

In clinical trial of therapy Daklatasvir + Asunaprevir + Peginterferon an alpha + Ribavirin frequency reported to side reaction was similar between the patients receiving placebo and the patients receiving the specified therapy except for 2 NLR - an adynamy and a grippopodobny state. The specified NLR were only, arising with a frequency is at least 5% higher, than among the patients receiving placebo.

Results of laboratory researches. Pathological deviations of laboratory indicators from norm 3-4 degrees observed among the patients with chronic hepatitis C receiving the combined treatment by Daklinz's drug are presented also to table 3.

Table 3. Pathological deviations of laboratory indicators from norm 3-4 degrees observed in clinical trials of therapy by Daklinz's drug in a combination therapy.

^and - results of laboratory researches were classified by the DAIDS system for classification of weight of the undesirable phenomena of adults and children, version 1.0
- the upper bound of norm

If any of NLR specified in the instruction are aggravated or you noticed any other side effects which are not specified in the instruction, report about it to the doctor.

Interaction with other medicines:

In view of the fact that Daklinz's drug is used as a part of the combined schemes of treatment, it is necessary to examine possible interactions with each of scheme drugs. At purpose of the accompanying therapy it is necessary to observe the most conservative recommendations.

Daklatasvir is substrate of an izofermet CYP3A4 therefore moderate and strong inductors of an isoenzyme CYP3A4 can reduce the level of a daklatasvir in plasma and therapeutic effect of a daklatasvir. Strong inhibitors of an isoenzyme CYP3A4 can increase serumal concentration of a daklatasvir. Daklatasvir is also substrate of a transport P-glycoprotein (R-gp), but combined use of the means influencing only R-gp properties (without simultaneous influence on CYP3A isoenzyme), there is not enough for receiving clinically significant influence on concentration of a daklatasvir in plasma.

Daklatasvir is P-gp inhibitor, the transport polypeptide of organic anions (TPOA) 1B1 and 1B3 and protein of resistance of a breast cancer (BCRP). Use of drug of Daklinz can increase system influence of the medicines which are substrates of the R-glycoprotein or transport polypeptide of organic anions 1B1/1B3 or BCRP that can increase or prolong their therapeutic effect and strengthen the undesirable phenomena. It is necessary to be careful at combined use of a daklatasvir and substrates of the specified isoenzymes/carriers, especially in case of the narrow therapeutic range of the last.

Drugs use of which together with Daklinz's drug is contraindicated, are listed in table 4 (see also section "Contraindications"):

Table 4. Drugs which use together with Daklinz's drug is contraindicated.

^and - not the full list of the substances inducing CYP3A4 isoenzyme is provided

Clinical recommendations for the established and potentially significant medicinal interactions of drug of Daklinz with other medicines are presented in table 5. Clinically significant increases in concentration are designated by a badge "↑", clinically significant reduction - a badge "↓" and lack of clinically significant changes - a badge "↔".

Table 5. The established potentially significant intermedicinal interactions.

Contraindications:

— drug should not will be applied in the form of monotherapy;

— hypersensitivity to a daklatasvir and/or any of auxiliary components of drug;

— in a combination with strong inductors of an isoenzyme CYP3A4 (owing to decrease in concentration of a daklatasvir in blood and decrease in efficiency), such, as:

- antiepileptic means (Phenytoinum, carbamazepine, phenobarbital, окскарбазепин);

- antibacterial agents (rifampicin, рифабутин, rifapenty);

- system GKS (dexamethasone);

- vegetable means (drugs on the basis of the St. John's Wort of made a hole (Hypericum perforatum)).

— simultaneous use of moderate inductors of an isoenzyme of CYP3A4 is contraindicated at use of the schemes including асунапревир (see the instruction on Sunvepr's drug);

— in the presence of contraindications to use of drugs of the combined scheme (асунапревир and/or peginterferon an alpha + рибавирин) - see application instructions of the corresponding drugs;

— deficit of lactase, lactose intolerance, glyukozo-galaktozny malabsorption;

— pregnancy and period of a lactation;

— age up to 18 years (efficiency and safety are not studied).

With care. As drug is used in the form of the combined scheme, the combination therapy should be applied with care at the states described in application instructions of each drug which is a part of the scheme (асунапревир and/or peginterferon an alpha and рибавирин).

Safety of use of a combination therapy was not studied at patients with dekompensirovanny diseases of a liver, and also at patients is after transplantation of a liver.

Can lead combined use of drug of Daklinz with other drugs to change of concentration both a daklatasvir, and active ingredients of other drugs (see sections of "Contraindication" and "Interaction with Other Medicines").

Overdose:

Symptoms of overdose are not described.

In clinical trials of a phase I at use of drug for healthy volunteers in doses to 100 mg during a span lasting up to 14 days or a single dose to 200 mg unexpected side reactions were not noted. The antidote to a daklatasvir is absent. Overdose treatment by drug has to include the general supporting measures, including monitoring of indicators of the vital functions and observation of a clinical condition of the patient. In view of high linkng of a daklatasvir with proteins of a blood plasma, carrying out dialysis at overdose is not recommended.

Storage conditions:

Drug should be stored in the place, unavailable to children, at a temperature not above 30 °C. A period of validity - 2 years. Not to use drug after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

14 pieces - blisters (2) - packs cardboard.