Daklinsa® (Daklinza®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceDaklataswirDaklataswir
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  • Daklinsa®
    pills inwards 
    Bristol-Myers Squibb Company     USA
    • Dosage form: & nbspfilm-coated tablets
    Composition:

    Each film-coated tablet contains:

    Active substance: daklatasvira dihydrochloride 33.00 mg or 66.00 mg, respectively (in terms of daklatasvir 30.00 mg and 60.00 mg);

    Excipients: lactose 57.75 / 115.50 mg, microcrystalline cellulose 47.85 / 95.70 mg, croscarmellose sodium 7.50 / 15.00 mg, silicon dioxide 1.50 / 3.00 mg, magnesium stearate 2.40 / 4 , 80 mg, Opadrai® green membrane (hypromellose 3.6 / 8.9625 mg, titanium dioxide 1.698 / 4.2825 mg, macrogol-400 0.48 / 1.35 mg, aluminum lignol based on indigo carmineFD&C Blue # 2) 0.12 / 0.255 mg, iron oxide yellow 0.102 / 0.150 mg) 6.00 / 15.00 mg.

    Description:

    Tablets 30 mg: Pentagonal biconvex tablets, covered with a film shell of green color, engraved with "BMS"on one side and" 213 "on the other side.

    Tablets of 60 mg: Pentagonal biconvex tablets, covered with a film shell of light green color, engraved with "BMS"on one side and" 215 "on the other side.

    Pharmacotherapeutic group:Antiviral agent
    ATX: & nbsp

    J.05.A.X.14   Daklataswir

    Pharmacodynamics:

    Daklatasvir is a highly specific direct action agent against hepatitis C virus (HCV) and has no pronounced activity against other RNA and DNA containing viruses, including the human immunodeficiency virus (HIV). Daklataswir is an inhibitor of non-structural protein 5A(NS5A), a multifunctional protein required for HCV replication, and thus suppresses two stages of the life cycle of the virus - viral RNA replication and virion assembly. Based on the data obtained in vitro, and computer simulation data it is shown that daklataswir interacts with N-the end within the domain 1 of the protein, which can cause structural distortions that impede the function of the protein NS5A. It is established that the preparation is a potent panthenotypic inhibitor of the hepatitis C virus replication complex of genotypes la, lb, 2a, 3a, 4a, 5a and 6a with effective concentration values ​​(50% reduction, EU50) from picomolar to low nanomolar. In cell quantitative analyzes of replicons, the EU values50 daklataswir vary from 0.001 to 1.25 nM in genotypes 1a, 1b, 3a, 4a, 5a and 6a and from 0.034 to 19 nM in genotype 2a. Besides, daklataswir inhibits hepatitis C virus of genotype 2a (JFH-1) at the value EU50, 0.020 nM. In genotype 1a in infected patients who had not received previous treatment, a single dose of daklatasvira 60 mg resulted in an average decrease in the viral load measured after 24 hours by 3.2 log10 IU / ml.

    Studies on cell culture also showed an increase in the antiviral effect of the drug when combined with interferon alpha and protease inhibitors NS3, non-nucleoside inhibitors of HCV NS5B, nucleoside analogues NS5B. With all these groups of drugs, antagonism of the antiviral effect was not observed.

    Resistance in cell culture

    Amino acid substitutions causing resistance to daklatasvir in genotypes of HCV 1-6 were isolated in the replicon cell system and were observed in the N-terminal region of the 100 amino acid residue of NS5A. L31V and Y93H were frequently observed in the lb genotype, and the substitutions of M28T, L31V / M, Q30E / H / R and Y93C / H / N were often observed in genotype 1a. Single changes in amino acids generally cause a low level of resistance (EC50<1 nM for L31V, Y93H) for genotype 1b and higher resistance levels for genotype 1a (up to 350 nM for Y93N). Principles of the emergence of resistance in clinical practice were similar to the principles of the emergence of resistance, observed in vitro.

    Resistance in clinical trials

    The effect of the initial polymorphism of HCV in response to therapy

    In the course of the study, the relationship between naturally occurring initial substitutions NS5A (polymorphism) and the outcome of the treatment, it was found that the effect NS5A polymorphism depends on the scheme of therapy.

    Combination Therapy daklataswir+ Asunaprevir

    In clinical trials II-III phase efficiency combination daklatasvir + asunaprevir was reduced in patients infected with HCV genotype 1b with original substitutions NS5A L31 and / or Y93H. 40% of patients with replacements NS5A L31 (F, I, M or V) and / or Y93H achieved a stable virologic response (SVR12) compared with 93% of patients without these kinds of polymorphism. Initial replacement prevalence NS5A L31 and Y93H was 14%; 4% - for L31F/I/M/V separately, 10% - for Y93H separately and 0.5% - L31F/I/M/V + Y93H. Of all cases of virological inefficiency in the initial replacement NS5A 15% had only L31F/I/M/V, in 38% - only Y93H and 2% - L31F/I/M/V + Y93H.

    Combination Therapy daklataswir+ sophosbuvir

    In clinical studies in patients treated with daklutasvir and sophosbuvir with or without ribavirin for 12 or 24 weeks, the baseline NS5A polymorphism in amino acid positions associated with resistance to daklatasvir was observed in 19% of patients (11% genotype 1a, 20% genotype lb, 90% genotype 2, 16% genotype 3, 67% genotype 4 and 100% genotype 6) with available baseline data. These polymorphisms NS5A included M28T/V, Q30E/H/L/R, L31M or Y93C/H/L/N/S in patients with a genotype la; R30K/M/Q, L31M or Y93H in patients with genotype 1b; F28L or L31M in patients with genotype 2; M28V, A30E/K/S/T/V, L31M or Y93H in patients with genotype 3; L28M or L30R in patients with genotype 4; F28M/V and R30S in patients with genotype 6.

    The total percentage of SVR12 in patients with or without initial polymorphism NS5A in positions 28, 30, 31 or 93 were 88% and 96%, respectively.

    In patients without cirrhosis with or without an initial NS5A polymorphism, a high sustained virologic response was observed: 95% and 99%, respectively. In patients with cirrhosis of the liver with or without an initial NS5A of the polymorphism of VBIO12 was 53% and 85%, respectively. In 10 patients with liver cirrhosis with ineffective therapy, specific initial NS5A polymorphisms were observed in the following positions: M28T (n = 1), L31M (n = 2, Child-Pugh class B) and Y93N (n = 1) in patients with a genotype la; A30K (n = 1), Y93H (n = 3) and AZOTn = 1) in patients with genotype 3; and L31M (n = 1, Child-Pugh class C) in a patient with genotype 2. All described NS5A replacements for genotypes 1a, 2 and 3 caused a 100-fold decrease in the activity of daklatasvir in vitro, except for the replacement of A30T, which was fixed only initially, but not at the time of failure. Of the 14 patients with liver cirrhosis who did not have the initial polymorphism NS5A, in 6 patients there was cirrhosis of class C according to Child-Pugh.

    In clinical trials in patients in the original NS5B sequence there was no fixed replacement S282T, which causes resistance to cofosbuvir.

    Table. Influence of initial NS5A polymorphisms (at positions 28, 30, 31 or 93) on SVR12 in patients with or without initial cirrhosis receiving daklatasvir and sophosbuvir with or without ribavirin 12-24 weeks

    VDU level12 the patients with NS5A consistency

    With known initial NS5A polymorphisms

    Without known initial NS5A polymorphisms

    Generally

    102/116 (88%)

    469/489 (96%)

    Patients with cirrhosis

    11/21 (52%)

    77/91 (85%)

    Genotype 1a

    2/6 (33%)

    42/48 (88%)

    Genotype 1b

    0

    12/12(100%)

    Genotype 2

    5/6 (83%)

    0

    Genotype 3

    2/7 (29%)

    22/30 (73%)

    Genotype 4

    2/2 (100%)

    1/1 (100%)

    Patients without cirrhosis

    83/87 (95%)

    350/353 (99%)

    Genotype 1a

    24/24 (100%)

    186/186 (100%)

    Genotype lb

    11/11 (100%)

    42/42 (100%)

    Genotype 2

    27/27 (100%)

    3/3 (100%)

    Genotype 3

    19/23 (83%)

    118/121 (98%)

    Genotype 4

    2/2 (100%)

    1/1 (100%)

    Combination Therapy daklataswirasunaprevir+ peginterferon alfa +ribavirin

    In patients who underwent sequencing prior to treatment, in a study of this combination, 11% of patients had initial substitutions associated with resistance to daklatasvir. 90% of the patients achieved SVR12, 2.4% had non-viral inefficiency, and 7.2% had virological inefficiency (2.4% of patients with genotype 1a had substitutions NS5A-L31M and 2.4% - NS5A-Y93F at the initial level; in 2.4% of patients with a genotype lb there was a substitution NS5A-L31M at the initial level).

    Combination Therapy daklataswir+ peginterferon alfa +ribavirin

    Initial NS5A polymorphism, leading to a loss of sensitivity to daklatasvir in vitro (genotype la: M28T, Q30H/R, L31M/V, Y93H/N; genotype 1b: L31M, Y93C/H; genotype 4: L28M, L30C/R, M31V), was observed in 7% of patients with HCV genotype 1a, 16% - in patients with HCV genotype 1b and 63% in patients with genotype 4 who were not previously treated. Most patients (56% with genotype 1a, 75% with genotype 1b and 83% with genotype 4) with initial NS5A polymorphisms have reached SVR12.

    Pharmacokinetics:

    The pharmacokinetic properties of daklataswir were evaluated in adult healthy volunteers and in patients with chronic hepatitis virus infection FROM. After repeated oral administration of daklataswir at a dosage of 60 mg once daily in combination with peginterferon alfa and ribavirin, the mean (variability factor,%) of the maximum concentration (CmOh) of daklataswir was 1534 (58) ng / ml, the area under the concentration-time curve (AUC0-24h) was 14,122 (70) ng.h / ml and minimum concentration (Cmin) was 232 (83) ng / ml.

    Suction

    Absorption is fast.The maximum concentration of daklatasvir is observed 1-2 hours after ingestion. AUC, CmOh and Cmin in the blood are dose-dependent, a stable concentration of daklatasvir in the blood plasma is observed on the 4th day of application of the drug for ingestion once a day. Studies have not revealed differences in the pharmacokinetics of the drug in patients with hepatitis C and healthy volunteers. Research in vitro, carried out with human Casso-2 cells, showed that daklataswir is a substrate for P-glycoprotein (P-gp). Absolute bioavailability of the drug is 67%.

    In studies on healthy volunteers, it was found that a single dose of daklatasvira 60 mg 30 minutes after a meal with a high fat content (about 1000 Kcal with a fat content of about 50%) lowers CmOh of the drug in the blood by 28% and AUC by 23%. Taking the drug after a light meal (275 kcal with a fat content of about 15%) did not change the concentration of the drug in the blood.

    Distribution

    The volume distribution of daklataswir (Vss) after a single intravenous injection of 100 μg of the drug is 47 liters. The connection with plasma proteins is not dose-dependent (the range studied is from 1 mg to 100 mg) and is 99%. In studies in vitro determined that daklataswir is able to penetrate into hepatocytes due to active (predominantly) or passive transport. Active transport is carried out by proteins-transports of organic cations OST1 and other unidentified transports, except for the transport proteins of organic anions (OAT) 2, sodium-taurocholate cotransport polypeptide (NTCP) or transport polypeptides of organic anions (OATP).

    Metabolism

    In studies in vitro determined that daklataswir is a substrate of isoenzyme CYP3A, wherein CYP3A4 is the main isoform CYP, responsible for the metabolism of the drug. Metabolites with more than 5% of the initial substance concentration are absent.

    Excretion

    After oral administration by healthy volunteers of single doses of daklatasvir labeled with radioactive carbon C14 ([14FROM]- daklataswir), 88% of the total radioactivity was excreted with feces (53% unchanged), 6.6% was excreted in the urine (mostly unchanged).

    After repeated administration of daklataswir with HCV-infected patients, the half-life of daklatasvir ranged from 12 to 15 hours. In patients who took daklataswir in tablets of 60 mg followed by intravenous administration of 100 μg [13C, 15N] -diclataswira, the total clearance was 4.24 l / h.

    Patients with impaired renal function

    Comparison of AUC in patients with HCV infection and normal kidney function (creatinine clearance 90 ml / min) and patients with HCV infection with impaired renal function (QA 60, 30 and 15 ml / min) showed an increase AUC by 26%, 60% and 80% (unrelated AUC - 18%, 39%, 51%), respectively. In patients with terminal stage of kidney disease requiring hemodialysis, there was an increase AUC by 27% (related - by 20%) compared to patients with normal renal function. Statistical population analysis of patients with HCV infection showed an increase AUC in patients with mild to moderate renal insufficiency, but the magnitude of this increase is not clinically significant for the pharmacokinetics of daklataswir. Due to the high degree of binding of daklatasvir to proteins, hemodialysis does not affect its concentration in the blood. Changes in the dose of the drug in patients with renal failure are not required.

    Patients with impaired hepatic function

    Daklataswir pharmacokinetics studies at a dose of 30 mg were performed with patients with hepatitis FROM with mild, moderate and severe hepatic impairment (classes A-C by Child-Pugh) in comparison with patients without disturbance of liver function. Values FROMmOh and AUC daklataswir (free and protein-bound) were lower in the presence of liver failure compared to the values ​​of these indices in healthy volunteers, but this decrease in concentration was not clinically significant. There is no need to change the dose of the drug in patients with impaired liver function.

    Elderly patients

    In clinical trials, elderly patients (65 years and older) participated. Changes in pharmacokinetics, as well as profiles of efficacy and safety of the drug in elderly patients were not observed.

    Floor

    There are differences in overall clearance (CL/F) daklatasvira, while CL/F women are lower, but this difference is not clinically significant.

    Indications:

    Treatment of chronic hepatitis C (CHC) in adults in combination with other drugs for HCV treatment.

    Contraindications:

    - The drug should not be used as a monotherapy;

    - gand sensitivity to daklatasvir and / or any of the auxiliary components of the drug;

    - at Combinations with strong isoenzyme inducers CYP3A4 and the P-glycoprotein transporter (due to a reduction in daklatasvir concentration in the blood and a decrease in efficacy), such as (which include but are not limited to the drugs listed below):

    - PIn the presence of contraindications to the use of drugs combined scheme (asunaprevir and / or peginterferon alfa, ribavirin, sophosbuvier) - see instructions for the use of appropriate drugs;

    - dlactase inhibitor, lactose intolerance, glucose-galactose malabsorption;

    - bVariability and lactation period;

    - atozrast to 18 years (efficiency and safety not studied).

    Carefully:

    Since the drug is used as a combined regimen, combined therapy should be used with caution under the conditions described in the instructions for use of each preparation included in the scheme (sophosbuvier, asunaprevir and / or peginterferon alfa and ribavirin).

    Joint use of Daklins® with other drugs can lead to a change in the concentration of both daklatasvir and the active substances of other drugs (see the section "Interaction with other drugs").

    Pregnancy and lactation:

    Pregnancy

    There are no adequate and well-controlled studies involving pregnant women. Animal studies using daklatasvir showed embryotoxic and teratogenic effects. The potential risk to humans is unknown. Daklinsa® is contraindicated during pregnancy and for women who do not use contraception. Women of childbearing age should use effective contraceptive methods during treatment with Daclins® and within 5 weeks after completion.

    Use of a combination of drugs containing daklataswir, with pregnancy is contraindicated.

    For detailed recommendations regarding pregnancy and contraception for combination regimens, see instructions for the use of appropriate drugs.

    Breast-feeding

    It is not known whether the daklataswir in breast milk. Daklataswir penetrated the breast milk of lactating rats in concentrations exceeding the plasma maternal concentrations by a factor of 1.7-2, and therefore, breastfeeding should be discontinued for the duration of treatment with Daclins®.

    Dosing and Administration:

    Recommended dosing regimen

    The recommended dose of Daklins® is 60 mg once a day, regardless of food intake. Tablets must be swallowed whole. Tablets should not be chewed or grinded. The drug should be used in combination with other medicines (see table below). Recommendations for doses of other drug regimens are given in the relevant instructions for medical use. Therapy is recommended for patients who have not previously received treatment for chronic hepatitis C, and with previous ineffectiveness of therapy.

    Table. Recommended Daclins regimensa® when used at a dose of 60 mg once a day as part of a combination therapy for patients, infected with HCV or with co-infection of HCV and HIV1

    Mode / Genotype of HCV / Patient population

    Duration

    Daklutasvir + sophosbuvir

    Genotypes 1, 2, 3, 4;

    patients without cirrhosis, as previously untreated chronic hepatitis C, and with previous ineffectiveness of therapy2

    12 weeks

    Daklatasvir + sophosbuvier + ribavirin

    Genotypes 1, 2, 3, 4;

    patients with cirrhosis (classes A or B Chayld- Pugh) as previously untreated chronic hepatitis C, and with the previous treatment failure2

    12 weeks

    Therapy daklatasvirom sofosbuvir and without ribavirin may be considered for patients with cirrhosis of the liver at Class A Child-Pugh.

    For genotype 3, it is possible to extend therapy to 24 weeks, with or without ribavirin.

    Genotypes 1, 2, 3, 4;

    Patients with cirrhosis of the P Child-Pugh as previously untreated chronic hepatitis C, and with the previous treatment failure2

    24 weeks

    For patients with ribavirin intolerance, daklatasvir and sophosbuvir therapy without ribavirin can be considered for 24 weeks.

    Genotypes 1, 2, 3, 4;

    patients after liver transplantation with relapse of HCV infection

    12 weeks

    Daklatasvir + asunaprevir

    Genotype 1b;

    patients without cirrhosis or with compensated cirrhosis, as previously untreated for chronic hepatitis C, and with previous ineffectiveness of therapy2

    24 weeks

    Daklatasvir + asunaprevir + peginterferon alfa + ribavirin

    Genotype 1;

    patients without cirrhosis or with compensated cirrhosis, as previously untreated for chronic hepatitis C, and with previous ineffectiveness of therapy2

    24 weeks

    Daklatasvir + peginterferon alfa + ribavirin

    Genotype 1;

    patients without cirrhosis or with compensated cirrhosis who had not previously received therapy

    24 weeks of use

    daklatasvira in combination with a 24-48-week application

    peginterferon alfa and ribavirin.3

    1 - Recommendations for dosing in patients with co-infection may differ depending on the antiretroviral therapy used. For recommendations on dose changes, see "Interaction with Other Drugs".

    2 - Ineffectiveness of previous therapy with ribavirin and peginterferon alfa. The daklatasvir / cofosbuvir regimen with or without ribavirin may also be recommended for patients with a previous failure of a regimen containing a protease inhibitor (PI).

    3 - If at both the 4th and the 12th week of the treatment the patient does not have HCV RNA, then the combination therapy should be continued for all of the three drugs within 24 weeks.If the patient achieves a condition where there is no HCV RNA, but only one of these (4 or 12), then after therapy with daklatasvir (24 weeks), continue therapy with peginterferon alfa and ribavirin until 48 weeks.

    The daily dose of ribavirin when used in combination with daklatasvir depends on the patient's body weight and is 1000 mg for patients with a body weight of <75 kg or 1200 mg for patients with a body weight of ≥ 75 kg (see instructions for ribavirin).

    For patients with grade-A, C, or C liver cirrhosis in Child-Pugh, as well as relapse of HCV infection after liver transplantation, the recommended initial daily dose of ribavirin is 600 mg during meals. In case of satisfactory tolerability of the initial dose, the dose of ribavirin can be gradually increased to 1000-1200 mg / day (depending on the weight - more or less 75 kg). In case of unsatisfactory tolerability of the initial dose, the dose of ribavirin should be reduced according to clinical indications on the basis of measurement of hemoglobin level and creatinine clearance (see table below).

    Table. Recommended doses of ribavirin when used in conjunction with the Daclins® preparation for patients with cirrhosis or after liver transplantation

    Laboratory test data / Clinical criteria

    The recommended dose of ribavirin

    Hemoglobin

    > 12 g / dL

    600 mg / day

    > 10 to ≤12 g / dL

    400 mg / day

    > 8.5 to ≤10 g / dL

    200 mg / day

    ≤ 8.5 g / dL

    Suspension of ribavirin therapy

    Creatinine clearance

    > 50 ml / min

    Follow the recommendations above for hemoglobin

    > 30 to ≤50 ml / min

    200 mg every other day

    ≤30 ml / min or hemodialysis

    Suspension of ribavirin therapy

    Dose change and suspension of therapy

    After the start of therapy, a change in the dose of Daklins® is not recommended. Interruption of treatment should be avoided; However, in the event that the interruption of treatment with any drug of the scheme is necessary because of the adverse reactions that have arisen, use Daklins® in the form of monotherapy or only with ribavirin should not be. It is unlikely that patients with an insufficient virologic response to treatment will achieve a sustained virologic response (SVR); for such patients, discontinuation of therapy is recommended. Recommendations for cessation of therapy for regimens daklataswir + sophosbuvier, daklataswir + asunaprevir, daklataswir + asunaprevir + peginterferon alfa and ribavirin are absent.The HCV RNA levels at which initiation of discontinuation of therapy with daklatasvir, peginterferon alfa and ribavirin are presented in the table below.

    Table. Principles of suspension of therapy for patients receiving daklataswir, peginterferon alfa and ribavirin with an inadequate virological response.

    HCV RNA

    Act

    4 week of treatment:> 1000 IU / ml

    Suspend daklatasvira, peginterferon alfa and ribavirin

    12th week of treatment: ≥25 IU / ml

    Suspend daklatasvira, peginterferon alfa and ribavirin

    24th week of treatment: ≥25 IU / ml

    Suspend the use of peginterferon alfa and ribavirin (daklatawir therapy is completed at week 24)

    Dose skip

    If a dose of Daklins® is missed for up to 20 hours, the patient should take the drug as soon as possible and then adhere to the original therapy regimen. If, when a dose is missed, more than 20 hours have elapsed from the planned time of taking the drug, the patient should skip this dose, the next dose of the drug should be taken in accordance with the initial therapy regimen.

    Patients with impaired renal function

    Dose changes in patients with renal failure of any degree are not required.

    Patients with impaired hepatic function

    Dose changes in patients with hepatic insufficiency are not required. In studies with a mild (Child-Pugh class A), moderate (Child-Pugh class B) and severe (Child-Pugh class C) liver failure, no significant changes in the pharmacokinetics of the drug were found.

    Concomitant therapy

    Strong inhibitors of the 3A4 isoenzyme of the cytochrome P450 system (CYP3A4)

    Daklins Dose® should be reduced to 30 mg once a day in the case of simultaneous use with strong inhibitors of isoenzyme CYP3A4 (use a tablet of 30 mg, do not break the tablet 60 mg) (see section "Interaction with other drugs").

    Moderate inductance inducers CYP3A4

    The dose of Daclins® should be increased to 90 mg once daily (three 30 mg tablets or one 60 mg tablet and one 30 mg tablet), while using moderate isoenzyme inducers CYP3A4 (see section "Interaction with other medicinal products").

    Side effects:

    Daklinsa ® is used only as part of combined therapy regimens.It is necessary to get acquainted with the side effect of the medications included in the treatment regimen before the initiation of therapy. Unwanted drug reactions (NLR) associated with the use of sophosbuvira, asunaprevir, peginterferon alfa and ribavirin are described in the instructions for use of these drugs.

    The safety of daklataswir was evaluated in clinical studies in patients with chronic hepatitis C who received 60 mg of Daklins® once a day in combination with sophosbuvir; asunaprevir and / or peginterferon alfa and ribavirin. The safety data are presented below for treatment regimens.

    Daklatasvir + asunaprevir

    The safety of daklataswir in combination with asunaprevir was evaluated in 4 studies with an average duration of 24 weeks. The most common (frequency of 10% and higher) of NLR observed in clinical trials using a therapy regimen daklataswirasunaprevir, were headache (15%) and increased fatigue (12%). Most NLDs were mild and moderate in severity. 6% of patients experienced serious adverse events (SLE), 3% of patients discontinued treatment due to the occurrence of NLP.In this case, the most common adverse events (AEs) leading to discontinuation of treatment were an increase in the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (ACT). In a clinical study of therapy daklataswir + asunaprevir during the first 12 weeks of treatment, the reported frequency of HLR was similar between patients receiving placebo and patients receiving this therapy.

    NLR, which occurred in ≥5% of patients with chronic hepatitis C with the combination daklataswir + asunaprevir, are presented below. The frequency of occurrence of NLR is shown in accordance with the scale: very often (≥ 1/10), often (≥ 1/100 and <1/10).

    Adverse Reactionsa

    Disturbances from the nervous system

    Often

    Headache (15%)

    Disorders from the gastrointestinal tract

    Often

    Diarrhea (9%), nausea (8%)

    General disorders

    Often

    Fatigue (12%)

    Laboratory and instrumental data

    Often

    Increased ALT activity (7%), increased activity ACT (5%)

    a side reactions, the relationship of which with the use of the drug is at least possible. Combined data from several studies.

    Undesirable reactions occurring in less than 5% of patients with chronic hepatitis C when combined daklataswir + Asunaprevir: skin rash, itchy skin, alopecia; eosinophilia, thrombocytopenia, anemia; fever, malaise, chills; insomnia; decreased appetite, abdominal discomfort, constipation, upper abdominal pain, stomatitis, bloating, vomiting; increased blood pressure; pain in the joints, stiff muscles; nasopharyngitis, pain in the oropharynx; increased activity of gamma globulin transferase, alkaline phosphatase, lipase, and hypoalbuminemia.

    Daklutasvir + sophosbuvir

    The safety of daklataswir in combination with sophosbuvir has been evaluated in clinical studies involving a patient with HCV genotypes 1, 2, 3, 4 or 6, including patients with co-infection with HCV and HIV, patients with severe cirrhosis, and patients with relapse of HCV infection after liver transplantation . The duration of therapy was 8, 12 or 24 weeks. The most common NLR (frequency 10% and higher) were increased fatigue (19%), headache (15%) and nausea (11%). Most NLDs were mild and moderate in severity.In 5% of patients, SNRI was registered. Four percent of patients discontinued treatment because of AEs, only one of which is considered to be relevant to the study therapy.

    NLR, which occurred in ≥5% of patients with chronic hepatitis C with the combination daklataswir + sophosbuvier (with or without ribavirin) are presented below. The frequency of occurrence of NLR is shown in accordance with the scale: very often (≥ 1/10), often (≥ 1/100 and <1/10).

    System of organs / frequency of occurrence of NLR

    Adverse Reactionsa

    daklatasvir + sophosbuvier + ribavirinb

    daklatasvir + sophosbuvirb

    Violations of the blood and lymphatic system

    Often

    Anemia

    Disorders from the metabolism and nutrition

    Often

    Decreased appetite

    Disorders of the psyche

    Often

    Insomnia, irritability

    Insomnia

    Disturbances from the nervous system

    Often

    Headache

    Headache

    Often

    Dizziness, migraines

    Dizziness, migraines

    Vascular disorders

    Often

    "Tides"

    Disturbances from the respiratory system, chest and mediastinal organs

    Often

    Shortness of breath, shortness of breath with physical exertion, cough, nasal congestion

    Disorders from the gastrointestinal tract

    Often

    Nausea

    Often

    Diarrhea, vomiting, abdominal pain, gastroesophageal reflux disease, constipation, dry mouth, flatulence

    Nausea, diarrhea, abdominal pain

    Disturbances from the skin and subcutaneous tissues

    Often

    Rash, alopecia, itching, dry skin

    Disturbances from musculoskeletal and connective tissue

    Often

    Joint pain, muscle pain

    Joint pain, muscle pain

    General disorders

    Often

    Fatigability

    Fatigability

    a - adverse reactions, the relationship of which with the use of the drug, at least, is possible. Combined data from several studies.

    b - 43% of patients in clinical trials took ribavirin in addition to the combination daklutasvir + sophosbuvir: there have been no cases of anemia.

    Daklataswir at combination with asunaprevir, peginterferon alfa and ribavirin

    The safety of daklataswir in combination with asunaprevir, peginterferon alfa and ribavirin was evaluated in a clinical trial HALLMARK QUAD with an average duration of 24 weeks. The most common NLRs (frequency 15% and higher), observed in clinical studies using a therapy regimen daklatasvir + asunaprevir + peginterferon alfa + ribavirin were: fatigue (39%), headache (28%), pruritus (25%), asthenia (23%), flu-like condition (22%), insomnia (21%), anemia (19%), rash (18 %), alopecia (16%), irritability (16%), nausea (15%). Additional side effects that occurred in patients with chronic hepatitis C when using a therapy regimen daklataswir + asunaprevir + peginterferon alfa + ribavirin, dry skin (15%), decreased appetite (12%), muscle pain (14%), fever (15%), cough (13%), dyspnea (11%), neutropenia (14%), lymphopenia (1%), diarrhea (14%), joint pain (9%). Most NLDs were mild and moderate in severity. In six percent of patients, SNAP was registered. Five percent of patients discontinued treatment due to AE, the most common AEs leading to discontinuation of treatment were rash, malaise, dizziness and neutropenia.

    In a clinical study of therapy daklataswir + asunaprevir + peginterferon alfa +ribavirin the frequency of reported HLR was similar between patients receiving placebo and patients receiving this therapy, with the exception of 2 NLP-asthenia and influenza-like conditions.These HLR were the only ones that occurred at a minimum rate of 5% higher than among patients receiving a placebo.

    Daklatasvir in combination with peginterferon alfa and ribavirin

    The safety of daklataswir was evaluated in 10 clinical trials in patients with chronic hepatitis C who received 60 mg of Daklins® once a day in combination with peginterferon alfa and ribavirin. The most common NLR (frequency 15% and higher) were fatigue (37%), headache (28%), itching (23%), anemia (22%), flu-like condition (22%), nausea (20%), insomnia (20%), neutropenia (20%), asthenia (20%), rash (19%), loss of appetite (18%), dry skin (18%), alopecia (17%) and fever (15%).

    In clinical trials, no NLR was detected with a frequency of at least 5% higher in patients receiving therapy including daklataswir, compared with patients receiving placebo, peginterferon alfa and ribavirin. In patients receiving placebo in conjunction with peginterferon alfa and ribavirin, grade 3-4 ILD occurred more often (24%) than in patients treated with a combination daklataswir + peginterferon alfa + ribavirin (20%).

    The incidence of fixed SLE associated with the therapy received, as well as the suspension of therapy for AEs, were similar in both of the above groups of patients.

    The level of AE in subgroups of patients with cirrhosis who received combination therapy daklataswir + peginterferon alfa + ribavirin, was similar to that in patients treated with placebo in combination with peginterferon alfa and ribavirin (92% against 96% respectively).

    Laboratory results

    The abnormal laboratory abnormalities from the norm of 3-4 degrees, observed among patients with HCV who received combined treatment with Daclins®, are presented below.

    Pathological deviations of laboratory indicators from the norm of 3-4 degrees, observed in clinical studies of therapy with Daklinsa ® in combination therapy

    Parametera

    Daklatasvir in combination with asunaprevir

    Daklutasvir in combination with sophosbuvir ± ribavirin

    Hemoglobin

    <1%

    1%

    Increased activity of ALT (> 5.1 x VGNb)

    4%

    <1%

    Increased activity ACT (> 5.1 x VGN)

    3%

    <1%

    An increase in the level of total bilirubin (> 2.6 VGN)

    <1%

    3%*

    * - an increase in the level of total bilirubin of grade 3-4 was registered only in patients with HIV coinfection who received co-infection atazanavir oozeu in patients with cirrhosis who received ribavirin.

    Parametera

    Daklatasvir in combination with asunaprevir, peginterferon alfa, ribavirin

    Daklatasvir in combination with peginterferon alfa, ribavirin

    Increased activity of ALT (> 5.1 x VGN6)

    3%

    2%

    Increased activity ACT (> 5.1 x VGN)

    3%

    2%

    An increase in the level of total bilirubin (> 2.6 VGN)

    1 %

    6%*

    a - The results of laboratory studies were classified according to the DAIDS system for classification of the severity of adverse events in adults and children, version 1.0.

    b - the upper limit of the norm

    * - an increase in the level of total bilirubin was registered in patients with HIV coinfection who received co-infection atazanavir.

    Post-marketing research data

    During post-marketing studies of daklataswir, the following AEs were detected at an unidentified frequency.

    Daklataswir +acyon the contraryup

    Disturbances from the skin and subcutaneous tissues: erythema multiforme.

    Daklatasvir +sophosbuvier when combined with amiodarone

    Disorders from the heart: cardiac arrhythmias, including severe bradycardia and cardiac blockade. (See the sections on "Specific guidance" and "Interaction with other medicinal products", as well as instructions for the use of drugs amiodarone and sophosbuvier).

    If any of the specified NLR instructions are aggravated, or you notice any other side effects not listed in the manual, inform the doctor about it.

    Overdose:

    Symptoms of overdose are not described.

    In Phase 1 clinical studies, when the drug was administered in healthy volunteers at doses up to 100 mg for a period of up to 14 days or a single dose of up to 200 mg, there were no unforeseen side effects. Antidote to daklatasvir is absent. Treatment of drug overdose should include general supportive measures, including monitoring of vital signs and monitoring the clinical state of the patient. In view of the high binding of daklatasvir to plasma proteins, dialysis in case of an overdose is not effective.

    Interaction:

    In view of the fact that Daklinsa ® is used as a part of combined treatment regimens, it is necessary to familiarize yourself with possible interactions with each of the regimen preparations. When prescribing concomitant therapy, the most conservative recommendations should be observed.

    Daklatasvir is a substrate of isoenzyme CYP3A4, so moderate and strong isoenzyme inducers CYP3A4 can reduce the concentration of daklatasvir in plasma and the therapeutic effect of daklatasvir. Strong inhibitors of isoenzyme CYP3A4 can increase the serum concentration of daklatasvir. Daklataswir is also a substrate of P-glycoprotein (P-gp) and the transporter protein of organic cations (OCT) 1, but the joint use of agents that affect only properties P-gp or OST 1 (without simultaneous impact on CYP3A) is not sufficient to produce a clinically significant effect on the concentration of daklatasvir in plasma.

    Daklatasvir is an inhibitor P-gp, a transport polypeptide of organic anions (OATP) 1B1 and 1B3 and a breast cancer resistance protein (BCRP). The use of the drug Daclins® can increase the systemic effect of drugs that are substrates of the P-glycoprotein or transport polypeptide of organic anions 1B1 / 1B3 or BCRP, which can increase or prolong their therapeutic effect and intensify undesirable phenomena. Caution should be exercised in the joint use of daklatasvir and substrates of these isoenzymes / vectors, especially in the case of a narrow therapeutic range of the latter.

    Drugs, which are contraindicated in conjunction with Daklins® are listed in the table below (see also "Contraindications"):

    Table. Preparations, the use of which is contraindicated in conjunction with the drug Daclins®

    The mechanism of interaction

    Result interactions

    Drugs that are contraindicated for use with Daclins®a

    Strong induction of isoenzyme CYP3A from the side of the jointly used medicinal product

    Co-administration may lead to a reduction in the concentration of daklatasvir in the blood plasma, which may lead to a lack of a virological response to daklatasvir

    Antiepileptic agents

    Carbamazepine, Oxcarbazepine, Phenobarbital, Phenytoin

    Antibacterial agents

    Rifampicin, Rifabutin, Rifapentin

    Systemic glucocorticosteroids

    Dexamethasone

    Herbal products

    Preparations of St. John's Wort (Hypericum perforatum)

    a - not a complete list of substances that induce isoenzyme CYP3A4

    The table below provides clinical recommendations for the established and potentially significant drug interactions of Daklinsa® with other drugs.Clinically significant increases in concentration are indicated by the sign "↑" clinically significant decreases - with the "↓" symbol and the absence of clinically significant changes - with the "↔" symbol.

    Table. Established potentially significant inter-drug interactions

    Class of concomitant drug /

    Name of the medicinal product

    Effect on concentration

    Comment on the clinical significance of interaction

    ANTI-VIRAL DRUGS, HCV

    Protease Inhibitors

    Asunaprevir

    ↔ daklutasvir

    ↔ asunaprevir

    Changes in the dose of asunaprevir are not required.

    Boceprevir

    The interaction was not studied. Is expected due to inhibition of the isoenzyme CYP3A4 bocetrevir:

    ↑ daklutasvir

    The dose of Daklins® should be reduced to 30 mg once daily with the concomitant use of bocetrevir or other strong inhibitors of the CYP3A4 isoenzyme.

    Symeprevir 150 mg once daily (daklataswir 60 mg once daily)

    ↔ daklataswir

    ↔ simeprevir

    Changes in the dose of daklataswir and simeprevir are not required.

    Telaprevir 500 mg every 12 hours (daklataswir 20 mg once daily)

    ↑ daklutasvir

    ↔ telaprevir

    Co-administration increases the concentration of daklatasvir in plasma.The dose of Daklins® should be reduced to 30 mg once daily with the concomitant use of telaprevir or other strong inhibitors of the CYP3A4 isoenzyme.

    Telaprevir 750 mg every 8 hours (daklataswir 20 mg once daily)

    Peginterferon and ribavirin

    Peginterferon alfa 180 μg once a week and ribavirin 500 mg or 600 mg twice daily (daklataswir 60 mg once daily)

    ↔ daklataswir

    ↔ peginterferon alfa

    ↔ ribavirin

    Changes in the dose of daklatasvira, peginterferon alfa or ribavirin are not required.

    Nucleotide polymerase inhibitor

    Sofosbuvir 400 mg once daily (daklataswir 60 mg once daily)

    ↔ daklutasvir

    ↔ GS-331007 (the main metabolite of sophosbuvira)

    Changes in the dose of daklatasvir and sophosbuvir are not required.

    Antiviral drugs, HIV and HBV (hepatitis B virus)

    Protease Inhibitors

    Atazanavir 300 mg / ritonavir 100 mg once daily (daklataswir 20 mg once daily)

    ↑ daklutasvir

    The dose of daklataswir should be reduced to 30 mg once daily with the concomitant use of atazanavir / ritonavir or atazanavir / co-bicystate or other strong inhibitors of the CYP3A4 isoenzyme.

    Atazanavir / cobicystate

    The interaction was not studied. Is expected due to inhibition of the isoenzyme CYP3A4 atazanavir / cobicystate:

    ↑ daklataswir.

    Darunavir 800 mg / ritonavir 100 mg once daily (daklataswir 30 mg once daily)

    ↔ daklataswir

    ↔ darunavir

    ↔ lopinavir

    Changes in the dose of daklatasvira, darunavir / ritonavir, lopinavir / ritonavir, darunavir / co-bicystate are not required.

    Lopinavir 400 mg / ritonavir 100 mg twice daily (daklataswir 30 mg once daily)

    Darunavir / cobicystate

    The interaction was not studied. Expected:

    ↔ daklutasvir

    Nucleoside reverse transcriptase inhibitors (NRTIs)

    Tenofovir disoproxil fumarate 300 mg once daily (daklataswir 60 mg once daily)

    ↔ daklutasvir

    ↔ tenofovir

    Changes in the dose of daklatasvir and tenofovir are not required.

    Lamivudine

    Zidovudine

    Emtricitabine

    Abacavir

    Didanosine

    Stavudine

    The interaction was not studied. Expected:

    ↔ daklataswir

    ↔ NRTI

    Changes in the dose of daklatasvir and NRTI are not required.

    Non-nucleoside inhibitors reverse transcriptase (NNRTI)

    Efavirenz 600 mg once daily (daklataswir 60 mg once daily / 120 mg once daily)

    ↓ daklutasvir

    Daklatasvira dose should be increased to 90 mg once a day with concomitant use of efavirenz or other moderate isoenzyme inducers CYP3A4.

    Etravirine

    Nevirapine

    The interaction was not studied. Is expected due to induction of isoenzyme CYP3A4 etravirine and nevirapine:

    ↓ daklataswir.

    In the absence of data, the combined use of daklatasvira and etravirine or nevirapine is not recommended.

    Rilpivirine

    The interaction was not studied. Expected

    ↔ daklutasvir

    ↔ Rilpivirine

    Changes in the dose of daklatasvir and rilpivirin are not required.

    Integrase inhibitors

    Dolutegravir 50 mg once a day (daklataswir 60 mg once daily)

    ↔ daklutasvir

    ↑ dolutegravir

    Changes in the dose of daklatasvir and dolutegravir are not required.

    Raltegravir

    The interaction was not studied. Expected

    ↔ daklataswir

    ↔ raltegravir

    Doklatasvir and raltegravir dose changes are not required.

    Elvitegravir + cobicystate + emtricitabine+ tenofovir

    The interaction was not studied. Is expected due to inhibition of the isoenzyme CYP3A4 by a cobicystate:

    ↑ daklatasvir.

    The dose of Daklins® should be reduced to 30 mg once daily with the concomitant use of a co-bicystate or other strong inhibitors of the isoenzyme CYP3A4.

    Inhibitor of fusion

    Enfuvirtide

    The interaction was not studied. Expected

    ↔ daklataswir

    ↔ enfuvirtide

    Doklatasvir and enfuvirtide dose changes are not required.

    Antagonist CCR5 receptors

    Maraviroc

    The interaction was not studied. Expected

    ↔ daklataswir

    ↔ maraviroc

    Changes in the dose of daklatasvira and maraviroc are not required.

    DRUGS SUPPRESSING ACID FORMATION

    The antagonist of H2-gistaminovyh receptors

    Famotidine 40 mg once (daklataswir 60 mg once)

    ↔ daklutasvir

    Doklataswir dose changes are not required.

    Proton Pump Inhibitors

    Omeprazole 40 mg once daily (daklataswir 60 mg once daily)

    ↔ daklutasvir

    Doklataswir dose changes are not required.

    ANTIBACTERIAL PREPARATIONS

    Clarithromycin

    Telithromycin

    The interaction was not studied. Is expected due to inhibition of the isoenzyme CYP3A4 antibiotics:

    ↑ daklatasvir.

    The dose of Daklins® should be reduced to 30 mg once daily with the concomitant use of clarithromycin, telithromycin or other strong inhibitors of the isoenzyme CYP3A4.

    Erythromycin

    The interaction was not studied. Is expected due to inhibition of the isoenzyme CYP3A4 antibiotic:

    ↑ daklataswir.

    Joint use of Daklins® and erythromycin may increase the concentration of daklatasvir. Use with caution.

    Azithromycin

    Ciprofloxacin

    The interaction was not studied. Expected

    ↔ daklutasvir

    ↔ azithromycin

    ↔ Ciprofloxacin

    Changes in the dose of daklatasvira and azithromycin or ciprofloxacin are not required.

    ANTICOAGULANTS

    Dabigatran etexilate

    The interaction was not studied. Expected due to inhibition P-gp daklatasvir:

    ↑ dabigatran etexilate.

    It is recommended to carefully monitor the safety of the application at the beginning of the application of Daklins® in patients taking dabigatran etexilate or other P- gp with a narrow therapeutic range.

    Warfarin

    The interaction was not studied. Expected

    ↔ daklataswir

    ↔ warfarin

    Doklataswir and warfarin dose changes are not required.

    ANTI-DEPRESSANTS

    Selective serotonin reuptake inhibitors

    Escitalopram 10 mg once daily (daklataswir 60 mg once daily)

    ↔ daklataswir

    ↔ escitalopram

    Doklatasvir and escitalopram dose changes are not required.

    Anti-fouling CRARES

    Ketoconazole 400 mg once daily (daklataswir 10 mg once)

    ↑ daklutasvir

    Suppression of isoenzyme CYP3A and P-gp from the side of ketoconazole

    The dose of Daklins® should be reduced to 30 mg once a day with the concomitant use of ketoconazoleor other strong inhibitors of the CYP3A4 isoenzyme.

    Itraconazole

    Posaconazole

    Voriconazole

    The interaction was not studied. Is expected due to inhibition of the isoenzyme CYP3A antifungal agents:

    ↑ daklutasvir

    Fluconazole

    The interaction was not studied. Is expected due to inhibition of the isoenzyme CYP3A antifungal agents

    ↑ daklutasvir

    When combined, a moderate increase in the concentration of daklatasvir in the blood is expected, which does not require a change in the dose of both drugs.

    CARDIOVASCULAR RESOURCES

    Antiarrhythmics

    Amiodarone

    The interaction was not studied.

    For patients without an alternative variant of antiarrhythmic therapy, careful monitoring of safety in the joint use of amiodarone and combination daklataswir + sophosbuvir

    Digoxin 0.125 mg once daily (daklataswir 60 mg once daily)

    ↑ digoxin

    Suppression P-gp from daklata-virra

    Digoxin and other substrates P-gp with a narrow therapeutic range should be used with caution when used in conjunction with daklatasvir.

    The lowest dose of digoxin should be administered and the digoxin concentration in the blood plasma should be monitored. To achieve the desired therapeutic effect, dose titration should be used.

    Blocks of "slow" calcium channels

    Diltiazem

    Nifedipine

    Amlodipine

    The interaction was not studied.

    Is expected due to inhibition of the isoenzyme CYP3A blockers of "slow" calcium channels:

    ↑ daklutasvir

    The use of Daklinsa ® together with blockers of "slow" calcium channels can lead to an increase in the concentration of daklatasvir in blood plasma. Such combinations must be used with caution.

    Verapamil

    The interaction was not studied.

    Is expected due to inhibition of the isoenzyme CYP3A and P-gp verapamil:

    ↑ daklutasvir

    Application of the drug

    Daklins® together with the drug verapamil can lead to an increase in the concentration of daklatasvir in blood plasma. Such combinations must be used with caution.

    ORALAL KOHTPACEPTIVES

    Ethinylestradiol 35 μg once daily + norgestimate 0.180 / 0.215 / 0.250 mg once a day for 7/7/7 days (daklatavir 60 mg once daily)

    ↔ ethinyl estradiol

    ↔ noregestromine

    ↔ Norgestrel

    Joint use has no clinically significant effect on the pharmacokinetics of daklatasvir.

    Ethinylestradiol 30 μg once daily / norethindrone acetate 1.5 mg once daily (high-dose contraceptive)

    ↔ ethinylestradiol *

    ↔ norethindrone *

    ↔ ethinyl estradiol *

    ↔ norethindrone *

    * The pharmacokinetics of ethinylestradiol / norethindrone in the combined use of high doses of oral contraceptives with asunaprevir and daklatasvir compared with the pharmacokinetics of ethinyl estradiol / norethindrone with only low doses of oral contraceptives (ethinylestradiol 20 μg once daily / norethindrone 1 mg once daily).

    IMMUNosUPPRESSORS

    Ciclosporin 400 mg once a day (daklatavir 60 mg once daily)

    ↔ daklutasvir

    ↔ cyclosporine

    Doklatasvir and cyclosporine dose changes are not required.

    Tacrolimus 5 mg once daily (daklatavir 60 mg once daily)

    ↔ daklutasvir

    ↔ tacrolimus

    Doklatasvir and tacrolimus dose changes are not required.

    Sirolimus

    Mycophenolate mofetil

    The interaction was not studied. Expected

    ↔ daklutasvir

    ↔ immunosuppressant

    Changes in the dose of daklatasvir and immunosuppressants are not required.

    HYPOLIPIDEMIC MEANS

    Inhibitors of HMG-CoA reductase

    Rosuvastatin 10 mg once (daklatavir 60 mg once daily)

    ↑ rosuvastatin

    Caution should be exercised when using the combination of Daklins® and rosuvastatin or other substrates of OATP1B1, OATP1B3 and BCRP.

    Atorvastatin

    Fluvastatin

    Simvastatin

    Pitavastatin

    Pravastatin

    The interaction was not studied.

    An increase in the concentration of statins in the plasma is expected due to inhibition of OATP 1B1 and / or BCRP daklataswir

    NARCOTIC ANALGETICS

    Buprenorphine / naloxone, from 8/2 mg to 24/6 mg once daily, the individual dose (daklataswir 60 mg once daily)

    ↔ daklataswir

    AUC: ↔

    FROMmOh: ↔

    Cmin: ↔

    ↔ Buprenorphine

    ↔ Norbuprenorphine

    Changes in the dose of daklatasvir and buprenorphine are not required.

    Methadone, a stable maintenance dose of 40-120 mg once daily (daklataswir 60 mg once daily)

    ↔ daklutasvir

    ↔ R-methanone

    Changes in the dose of daklatasvira and methadone are not required.

    ESSENTIAL MEANS

    Benzodiazepines

    Midazolam 5 mg once (daklataswir 60 mg once daily)

    ↔ midazolam

    Changes in the dose of midazolam and other substrates of the CYP3A4 isoenzyme are not required.

    Triazolam

    Alprazolam

    The interaction was not studied. Expected

    ↔ triazolam

    ↔ alprazolam

    Clinically significant effects on pharmacokinetics are not expected with the combined use of daklatasvir with the following drugs: phosphodiesterase-5 inhibitors, ACE inhibitors (eg, enalapril), angiotensin antagonists II receptors (e.g., losartan, irbesartan, olmesartan, candesartan, valsartan), disopyramide, propafenone, flecainide, mexiletine, quinidine, antacids.

    Special instructions:

    The drug Daclins® should not be used in the form of monotherapy.

    In general, in clinical studies, there was no significant difference in safety and efficacy among patients with compensated cirrhosis and patients without cirrhosis. In the study using the regimen of therapy daklataswir + sophosbuvier for 12 weeks in patients with genotype 3 and cirrhosis, a lower incidence of SVR was observed than in patients without cirrhosis. Also in the study using the daklataswirsophosbuvierribavirin for 12 weeks in patients with cirrhosis (A, B, C in Child-Pugh), in patients with decompensated grade C Cirrhosis in Child-Pugh, a lower incidence of SVR was observed than in patients with Child-Pugh class A and B cirrhosis.

    There is no need to change the dose of Daklins® in patients with a weak (Child-Pugh class A), moderate (class B on the Child-Pugh scale) or severe (class C in Child-Pugh) impaired liver function.

    The clinical study established the safety and efficacy of Daklins® treatment in combination with sophosbuvir and ribavirin in patients with transplanted liver. The safety and efficacy of daklataswir in patients with other transplanted organs has not been established.

    Effect of daklatasvir on the interval QTc was evaluated in a randomized, placebo-controlled study on healthy volunteers. Single dose daklatasvira 60 mg and 180 mg had no clinically significant effect on the interval QTc, corrected according to Frederick's formula (QTcF). There was no significant relationship between increased daklataswir concentrations in plasma and changes in QTc. In this case, a single dose of daklatasvira 180 mg corresponds to the maximum expected concentration of the drug in the blood plasma for clinical use.

    Daklins preparation® contains lactose: 1 tablet 60 mg (daily dose) contains 115.50 mg of lactose.

    Appropriate contraceptive methods should be used during treatment and for 5 weeks after completion of Daklins® therapy.

    Therapy with a combination of drugs containing ribavirin

    The use of ribavirin can cause fetal malformations, intrauterine death and abortion, so careful care should be taken when using a therapy regimen that includes ribavirin. It is necessary to prevent the onset of pregnancy both in the patients themselves and in women whose sexual partners receive this therapy. Ribavirin therapy should not begin until patients capable of childbearing and their male sexual partners will not use at least 2 effective methods of contraception, which is necessary both throughout the therapy and for at least 6 months after it completion. During this period, it is necessary to perform standard pregnancy tests. When using oral contraceptives as one of the ways to prevent pregnancy, it is recommended to use high doses of oral contraceptives (containing at least 30 micrograms of ethinylestradiol in combination with norethindrone acetate / norethindrone).

    Therapy with a combination of drugs containing peginterferon alfa

    Investigation of interferons in animal experiments was associated with abortive effects, the possibility of which development in humans can not be ruled out.Therefore, when using therapy, both patients and their partners should use adequate contraception.

    Bradycardia when treated with a combination of preparations containing sophosbuvir

    In patients receiving amiodarone together with combination therapy daklataswir + sophosbuvier with or without concomitant therapy with other medications that reduce the heart rate, cases of severe bradycardia and cardiac blockade were documented. The occurrence of bradycardia was usually observed from several hours to several days after initiation of hepatitis C therapy in patients taking amiodarone. Usually bradycardia stopped after the suspension of therapy with hepatitis C. The mechanism of bradycardia is not established.

    Amiodarone may be taken together with daklatasvir and sophosbuvir only if alternative antiarrhythmic therapy is contraindicated or not tolerated. For patients without an alternative variant of antiarrhythmic therapy, careful safety monitoring is recommended. Patients should be under constant monitoring in a hospital during the first 48 hours of joint intake of these drugs,followed by outpatient monitoring or self-monitoring of heart rate on a daily basis at least in the first 2 weeks of treatment.

    Due to the long half-life of amiodarone, patients who stopped taking amiodarone immediately before starting therapy with a combination of daklataswir and sophosbuvier, should also be monitored as described above.

    All patients receiving daklataswir and sophosbuvier in combination with amiodarone, should be warned of the symptoms of bradycardia and cardiac blockade, as well as the need to urgently consult a doctor in case of such symptoms. (See also the sections "Side effect" and "Interaction with other medicinal products", as well as instructions for the use of amiodarone and sophosbuvira).

    Development of hepatotoxicity in combination with drugs containing asunaprevir

    When treated with a combination of drugs containing asunaprevir, in a number of cases, severe drug-induced liver damage was observed. Recommendations for monitoring the state of the liver are given in the instructions for the use of Sunvepra®.During the application of daklatasvir in combinations that do not contain asunaprevir, the incidence of clinically significant increases in ALT or ACT activity was comparable to that in patients receiving placebo.

    Use in patients with concomitant infections

    The use of the drug for the treatment of chronic hepatitis C in patients with concomitant hepatitis B virus infection has not been studied.

    Increases in hepatitis B virus replication (including fatal cases) were documented during and after therapy with direct-acting antivirals for the treatment of chronic hepatitis C. Before prescribing Daklins® a screening for the presence of hepatitis B virus should be performed in all patients. In patients with identified serological signs of infection with hepatitis B virus, it is necessary to monitor and treat the disease in accordance with current recommendations to avoid replication of the hepatitis B virus. In the case of increased replication of the hepatitis B virus, appropriate therapy should be initiated.

    Repeated course of treatment with daklatasvir

    The efficacy of daklataswir in the repeated course of treatment of patients with previous ineffective treatment with NS5A protease inhibitors has not been studied.

    Effect on the ability to drive transp. cf. and fur:

    Studies of the possible effect of the use of the drug on the ability to drive vehicles and work with mechanisms have not been carried out. If the patient experiences dizziness (noted with the Sofosbuvir treatment regimen) and dizziness, attention impairment, blurred / decreased visual acuity (noted with the peginterferon alfa and ribavirin treatment regimen) that may affect the ability to concentrate, he should refrain from management of vehicles and mechanisms.

    Form release / dosage:Film coated tablets, 30 and 60 mg.
    Packaging:

    For 14 tablets in a perforated blister of PVC / Aklar® and aluminum foil.

    2 perforated blisters together with instructions for use in a cardboard bundle.

    Storage conditions:

    At a temperature of no higher than 30 ° C.

    Keep out of the reach of children.
    Shelf life:

    2 years.

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

    Terms of leave from pharmacies:On prescription
    Registration number:LP-003088
    Date of registration:14.07.2015 / 12.08.2016
    Expiration Date:14.07.2020
    The owner of the registration certificate:Bristol-Myers Squibb CompanyBristol-Myers Squibb Company USA
    Manufacturer: & nbsp
    Representation: & nbspBRISTOL-Majers SKVIBB, LLCBRISTOL-Majers SKVIBB, LLCRussia
    Information update date: & nbsp20.04.2017
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