Composition, form of production and packaging
The tablets covered with a film membrane of green color, biconcave, pentagonal, with engraving "BMS" on one side and "213" on the other.
1 tab.
daklatasvira dihydrochloride 33 mg,
which corresponds to the content of daklatasvir 30 mg
Auxiliary substances: lactose - 57.75 mg, microcrystalline cellulose - 47.85 mg, croscarmellose sodium 7.5 mg, silicon dioxide 1.5 mg, magnesium stearate 2.4 mg, opadrai В® green 6 mg (hypromellose 3.6 mg, titanium dioxide 1.698 mg, Macrogol-400 - 0.48 mg, aluminum varnish based on indigo carmine (FD & C Blue # 2) - 0.12 mg, iron oxide yellow - 0.102 mg).
14 pcs. - blisters (2) - packs of cardboard.
The tablets covered with a film cover of light green color, biconcave, pentagonal, with engraving "BMS" on one side and "215" on another.
1 tab.
daklatasvira dihydrochloride 66 mg,
which corresponds to the content of daklatasvira 60 mg
Excipients: lactose 115.5 mg, microcrystalline cellulose 95.7 mg, croscarmellose sodium 15 mg, silicon dioxide 3 mg, magnesium stearate 4.8 mg, opadrai В® green 15 mg (hypromellose 8.9625 mg, titanium dioxide 4.2825 mg, Macrogol-400 - 1.35 mg, aluminum varnish based on indigo carmine (FD & C Blue # 2) - 0.255 mg, iron oxide yellow - 0.15 mg).
14 pcs. - blisters (2) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
PHARMACHOLOGIC EFFECT
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). Daklatasvir is an inhibitor of the non-structural protein 5A (NS5A), a multifunctional protein required for HCV replication, and thus suppresses the two stages of the viral life cycle-viral RNA replication and virion assembly. Based on in vitro data and computer simulation data, it has been shown that daklataswir interacts with the N-terminus within domain 1 of the protein, which can cause structural distortions that interfere with the function of the NS5A protein. It was found that the preparation is a potent panthenotypic inhibitor of the hepatitis C virus replication of the genotypes 1a, 1b, 2a, 3a, 4a, 5a and 6a with effective concentrations (50% reduction, EC50) from picomolar to low nanomolar. In cell quantitative replicon assays, EC 50 values ​​of 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. In addition, daklataswir inhibits the hepatitis C virus of genotype 2a (JFH-1) at an EC50 value of 0.020 nM. In genotype 1a, a single dose of 60 mg daklataswir in the infected untreated patients leads to an average decrease in the viral load, measured after 24 hours, by 3.2 log 10 IU / ml.
Cell culture studies also showed an increase in the antiviral effect of the drug when combined with interferon alpha and NS3 protease inhibitors, non-nucleoside HCV NS5B inhibitors, and NS5B nucleoside analogues. 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 genotype 1b, and the substitutions of M28T, L31V / M, Q30E / H / R and Y93C / H / N were often observed in genotype 1a. Single amino acid substitutions in general cause a low level of resistance (EC 50 <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 vilro
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 the naturally occurring initial substitutions of NS5A (polymorphism) and the outcome of the treatment revealed that the effect of NS5A polymorphism depends on the therapy regimen.
Therapy with a combination of drugs Daklatasvir + Asunaprevir
In clinical studies of Phase II-III, the efficacy of the combination of daklatasvir + asunaprevir was reduced in patients infected with HCV genotype 1b with original NS5A L31 and / or Y93M substitutions. 40% (48/119) of patients with NS5A L31 and / or Y93H substitutions achieved a sustained virologic response (SVR12) compared with 93% (686/742) patients without these polymorphisms. The initial prevalence of NS5A L3 I and Y93H substitutions was 14%; 4% for L31 separately, 10% for Y93H separately and 0.5% for L31 + Y93H. Of the 127 cases of virological inefficiency with the original replacement of NS5A, 16% had only L31, 38% - only Y93H and 2% - L31 + Y93H.
Therapy with a combination of drugs Daklatasvir + Asunaprevir + Peginterferon alfa + Ribavirin
Of the 373 patients who underwent sequencing, 42 patients had initial substitutions associated with resistance to daklatasvir in the study of this combination. Of the 42 patients, 38 achieved SVR12, 1 had non-vascular inefficiency, and 3 patients had virological inefficiency (1 patient with genotype 1a had NS5A-L31M substitutions and 1 had NS5A-Y93F at baseline, 1 patient with genotype 1b there was a replacement of NS5A-L31M at the initial level).
PHARMACOKINETICS
The pharmacokinetic properties of daklataswir were evaluated in adult healthy volunteers and in patients with chronic hepatitis C virus infection. After repeated oral daklataswir intake 60 mg 1 time / day in combination with peginterferon alfa and ribavirin, the average value (variability factor,%) of C max daklataswir was 1534 (58) ng / ml, the area under the concentration-time curve (AUC 0-24h ) was 14122 (70) ng h / ml and C min was 232 (83) ng / ml.
Suction
Absorption is fast. C max daklatasvira is observed 1-2 hours after ingestion. AUC, РЎ max , C min in the blood are dose-dependent, stable level of daklatasvira in blood plasma is observed on the 4th day of application of the drug for ingestion 1 time / day. Studies have not revealed differences in the pharmacokinetics of the drug in patients with hepatitis C and healthy volunteers. In vitro studies with human Caco-2 cells have shown that daklataswir is a substrate for P-glycoprotein (P-gp).Absolute bioavailability of the drug is 67%.
In studies on healthy volunteers, a single dose of daklataswir 60 mg 30 minutes after a high-fat meal (about 1000 Kcal with a fat content of about 50%) reduced the Cmax drug in the blood by 28% and the 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
V d daklatasvira after a single IV injection of 100 Ојg 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% .
Metabolism
In vitro studies have shown that daklatasvir is a substrate of the CYP3A isoenzyme, with CYP3A4 being the main isoform of CYP responsible for the metabolism of the drug. Metabolites with more than 5% of the initial substance concentration are absent.
Excretion
After oral ingestion of single doses of daklataswir labeled with radioactive carbon C14 ([ 14 C] -diclatasvir) by healthy volunteers, 88% of all radioactivity was excreted with feces (53% unchanged), 6.6% excreted in the urine (mostly unchanged).
After repeated daklatasvir administration of HCV-infected patients, T 1/2 of daklataswir varied from 12 to 15 hours. In patients who took daklatasvir in tablets of 60 mg followed by iv administration of 100 Ојg of [ 13 C, 15 N] -daclactasvir, the total the clearance was 4.24 l / h.
Patients with impaired renal function
Comparison of the AUC value in patients with HCV infection and normal kidney function (CK 90 ml / min) and patients with HCV infection with impaired renal function (QC 60, 30 and 15 ml / min) showed an AUC increase of 26%, 60% and 80 % (unrelated AUC - 18%, 39%, 51%), respectively. In patients with end-stage renal disease requiring hemodialysis, an AUC increase of 27% (associated -20%) was observed compared to patients with normal renal function. Statistical population analysis of patients with HCV infection showed an increase in AUC in patients with mild to moderate renal failure, but the magnitude of this increase is not clinically relevant 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 conducted with the participation of patients with hepatitis C with mild, moderate and severe hepatic insufficiency (classes A-C on the Child-Pugh scale) in comparison with patients without disturbing the liver function. Values ​​of C max and AUC of daklataswir (free and protein-bound) were lower in the presence of hepatic insufficiency 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 were involved (310 people were 65 years of age or older, and 20 were aged 75 years and older). 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 the overall clearance (CL / F) of daklataswir, with CL / F in women being lower, but this difference is not clinically significant.
INDICATIONS
Treatment of chronic hepatitis C in patients with compensated liver disease (including cirrhosis) in the following combinations of daklatasvir:
- with the drug asunaprevir for patients with the hepatitis virus of genotype 1b;
- with drugs asunaprevir, peginterferon alfa and ribavirin - for patients with the hepatitis virus of genotype 1.
DOSING MODE
Recommended dosing regimen
The recommended dose of Daklins is 60 mg 1 time / day, regardless of the intake of the food. The drug should be used in combination with other medicines (see Table 1). Recommendations for doses of other drug regimens are given in the relevant instructions for medical use. Therapy is recommended both for patients who have not previously received treatment for chronic hepatitis C, and for patients with previous ineffectiveness of therapy.
Table 1. Recommended regimens for the therapy of Daklinsa when used at a dose of 60 mg 1 time / day as part of combination therapy
Genotype of HCV Treatment Duration
Genotype 1b daklatasvir + asunaprevir 24 weeks
Genotype 1 daclatacsvir + asunaprevir + peginterferon alfa and ribavirin 24 weeks
Dose change and suspension of therapy
After the start of therapy, a change in the dose of Daklins is not recommended. To change the dose of other drugs of the regimen, it is necessary to familiarize yourself with the relevant instructions for medical use. Interruption of treatment should be avoided; However, in the event that the interruption of treatment with any preparation of the scheme is necessary because of the adverse reactions that have arisen, Daclins should not be used as monotherapy.
During treatment, it is necessary to monitor the viral load (the amount of PNK HCV in the patient's blood). Patients with an inadequate virologic response during treatment with a low degree of probability have achieved SVR, and this group is also likely to develop resistance. Discontinuation of treatment is recommended in patients with a virologic breakthrough - an increase in the level of HCV RNA by more than 1 log 10 from the previous level.
Dose skip
If you miss a dose of Daklins for a period of up to 20 hours, the patient should take the drug as soon as possible and then adhere to the original therapy. If a dose has passed more than 20 hours 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 scheme of therapy.
Patients with renal insufficiency
Dose changes in patients with renal failure of any degree are not required.
Patients with hepatic insufficiency
Dose changes in patients with mild liver failure (class A on the Child-Pugh scale) are not required. In studies with mild (class A on the Child-Pugh scale), moderate (class B on the Child-Pugh scale), and severe (class C on the Child-Pugh scale), hepatic insufficiency did not reveal significant changes in the pharmacokinetics of the drug. Efficacy and safety of use in decompensated liver failure is not established.
Concomitant therapy
Strong inhibitors of the 3A4 isoenzyme of the cytochrome P450 system (CYP3A4)
The dose of Daklins should be reduced to 30 mg once a day if used simultaneously with potent inhibitors of the isoenzyme CYP3A4 (use the 30 mg tablet, do not break the 60 mg tablet) (see "Interactions with other drugs and other forms of interaction"). . Simultaneous use of potent and moderate inhibitors of the isoenzyme CYP3A4 is contraindicated in the use of schemes involving the preparation of Sunvepra.
Moderate inducers of the isoenzyme CYP3A4
The dose of Daklins should be increased to 90 mg once a day (3 tablets 30 mg or 1 tablets 60 mg and 1 table 30 mg), while using moderate inducers of the isoenzyme CYP3A4 (see "Interaction with other drugs and other forms of interaction "). Simultaneous use of moderate inducers of the CYP3A4 isoenzyme is contraindicated in the use of schemes involving the preparation of Sunvepra.
SIDE EFFECT
Daklens transplant 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 asunaprevir, peginterferon alfa and ribavirin are described in the instructions for the medical use of these drugs.
The safety of daklataswir was evaluated in 5 clinical trials in patients with chronic hepatitis C who received 60 mg of Daklins 1 time / day in combination with 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) HLR observed in clinical studies using the scheme of therapy of Daklatasvir + Asunaprevir were headache (15%) and 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. At the same time, the most common adverse events (AEs) leading to discontinuation of treatment were an increase in ALT and ACT activity. In the clinical study of daklutasvir + Asunaprevir therapy during the first 12 weeks of treatment, the frequency of reported HLR was similar between patients receiving placebo and patients receiving this therapy.
NLR occurring in ≤5% of patients with chronic hepatitis C when using the combination of daklatasvir + 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).
Table 2.
Adverse reactions a
Disturbances from the nervous system
Very often Headache (15%)
Disorders from the digestive tract
Often Diarrhea (9%), nausea (8%)
General disorders
Very often Fatigue (12%)
Laboratory and instrumental data
Often, an increase in ALT (7%), an increase in ACT (5%)
a - adverse 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 using the combination of daklatasvir + asunaprevir: skin rash, skin itch, alopecia; zosinophilia, 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, hypoalbuminemia.
Daklatasvir in 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 of HALLMARK QUAD with an average duration of 24 weeks. The most common NLR (frequency 15% and higher) observed in clinical studies using the therapy scheme of daklatasvir + asunaprevir + peginterferon alfa + ribavirin were: increased fatigue (39%) , headache (28%), pruritus (25%), asthenia (23%) , flu-like condition (22%), insomnia (21%), anemia (19%), rash (18%), alopecia (16%), irritability (16%) and nausea (15%). Further side effects arising in patients with chronic hepatitis C using regimens Daklatasvir + Asunaprevir + peginterferon alpha + Ribavirin were: dry skin (15%), anorexia (12%), muscle pain (14%), fever (15% ), cough (13%), dyspnea (11%), neutropenia (14%), lymphopenia (1%), diarrhea (14%), arthralgia (9%). Most ADRs were mild to moderate in severity. 6% of patients were recorded CHYA. 5% of patients discontinued treatment due to adverse events, the most common adverse events. leading to treatment discontinuation were rash, malaise, dizziness and neutropenia.
In a clinical study therapy Daklatasvir Asunaprevir + + + peginterferon alfa ribavirin frequency of reported adverse reactions was similar between patients receiving placebo and those receiving said therapy, except 2-HLP - asthenia and flu-like state. Given HLP were the only occurs with a frequency of at least 5% higher than among patients receiving placebo.
Results of laboratory investigations
pathological laboratory abnormalities from normal grade 3-4 observed among patients with chronic hepatitis C who received the combined treatment with Daklinza, and Table 3 are presented.
Table 3. Pathologic laboratory abnormalities from normal grade 3-4 observed in clinical studies Daklinza therapy with combination therapy
parameter and Daklatasvir in combination with asunaprevirom n = 918 Daklatasvir in combination with asunaprevirom, peginterferon alfa ribavirin n = 398
Increased ALT (?> 5.1 ULN b ) 4% 3%
Increased AST activity (> 5.1 ULN?) 3% 3%
Increased total bilirubin concentration (> 2.6 ULN) 1% 1%
and - results of laboratory studies were classified by DAIDS system for the classification of t tin adverse events adults and children, 1.0
b - the upper limit of normal
If any of these instructions are compounded in ADRs or if you notice any other side effects not mentioned in the instructions, tell your doctor.
CONTRAINDICATIONS
- the preparation should not be applied as a monotherapy;
- daklatasviru hypersensitivity and / or any of the auxiliary components of the formulation;
- in combination with potent inducers isoenzyme CYP3A4 (due to a decrease in the blood concentration daklatasvira and reduce efficiency), such as:
- antiepileptics (phenytoin, carbamazepine, phenobarbital, oxcarbazepine);
- antibacterials (rifampicin, rifabutin, rifapentim);
- systemic corticosteroids (dexamethasone);
- vegetable products (drugs based on St. John's wort (Hypericum perforatum)).
- simultaneous application of moderate isoenzyme inducers of CYP3A4 is contraindicated for application circuits comprising asunaprevir (see user manual for preparation Sunvepra.);
- with contraindications to the use of combination preparations circuit (asunaprevir and / or ribavirin, peginterferon alfa +) - see for appropriate preparations instructions;.
- Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
- pregnancy and lactation;
- the age of 18 years (effectiveness and safety have been studied).
Carefully
Because the drug is applied in the form of a combined scheme, combination therapy should be used with caution in conditions described in the instructions for use of each drug, part of the circuit (asunaprevir and / or peginterferon alfa and ribavirin).
Safety of combined therapy has not been studied in patients with decompensated liver disease, and in patients after liver transplantation.
The combined use of the drug Daklinza with other drugs may lead to changes in concentration of both daklatasvira and other active ingredients of drugs (see. The sections "Contra" and "interaction with other drugs").
PREGNANCY AND LACTATION
Daklatasvir + Asunaprevir
No adequate and well-controlled studies in pregnant women. In animal studies, the application daklatasvira in doses exceeding the recommended therapeutic (4.6 times (rats) and 16 times (rabbits)), no observed adverse effects on fetal development, while still higher concentrations of the drug (25 times (rats) and 72 times (rabbits)) revealed negative effects for the mother and the fetus. Women of childbearing age should use effective contraception during treatment prsparatom Daklinza and within five weeks after its completion.
Use of a combination Daklatasvir + Asunaprevir contraindicated in pregnancy. It is unknown whether daklatasvir into breast milk. Daklatasvir passes into breast milk of lactating rats at concentrations greater than the maternal plasma concentrations in 1.7-2 times, so at the time of treatment with Daklinza breast-feeding should be discontinued.
Daklatasvir Asunaprevir + + + peginterferon alfa ribavirin
Use of ribavirin can cause birth defects, intrauterine death, abortion, so care should be taken when applying rigorous regimen comprising ribavirin. The need to prevent pregnancy like themselves patients and women whose sexual partners have indicated therapy. Therapy with ribavirin should not begin until as long as the patient, fertility, and sexual male partners will not use at least two effective contraceptive method, it is necessary to both throughout therapy and for at least 6 months after its completion. During this period necessary to perform the standard tests for pregnancy.When using oral contraceptives as a means of preventing pregnancy recommended to use high doses of oral contraceptives (containing not less than 30 mcg of ethinyl estradiol in combination with norethindrone acetate / norethindrone).
A study of interferon in animal studies associated with the abortive effects, the possibility of which in humans can not be ruled out. Therefore, when used as a therapy to patients and their partners should use adequate contraception.
APPLICATION FOR FUNCTIONS OF THE LIVER
dose modification in patients with renal insufficiency of any degree is not required.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
No need to change the dose in patients with impaired liver function.
APPLICATION FOR CHILDREN
Use of the drug for children and adolescents under the age of 18 years is contraindicated (efficacy and safety have not been studied).
SPECIAL INSTRUCTIONS
Daklinza The drug should not be used as monotherapy.
Of the more than 2000 patients enrolled in clinical studies of combination therapy with the drug Daklinza, 372 patients had compensated cirrhosis (Class A according to Child-Pugh). Differences in safety and efficacy of therapy in patients with compensated cirrhosis and patients without cirrhosis were observed. Safety and effectiveness of Daklinza drug in patients with decompensated cirrhosis is not installed. Not required drug dose Daklinza changes in patients with mild (Class A according to Child-Pugh), moderate (Class B of Child-Pugh) or severe (grade C in Child-Pugh) liver dysfunction.
The safety and efficacy of combination therapy with Daklinza in patients with liver transplant has not been established. There is limited experience with the drug Daklinza after liver transplantation.
Daklatasvira Effect on QTc interval was evaluated in a randomized, placebo-controlled study in healthy volunteers. Daklatasvira Single doses of 60 mg and 180 mg had no clinically significant effect on interval QTc, Frederick adjusted by formula (QTcF). There was no significant relationship between increased concentrations in plasma and daklatasvira change QTc. Thus a single dose of 180 mg daklatasvira corresponds to the maximum expected concentration of drug in blood plasma in clinical use.
Not studied the use of the drug for the treatment of chronic hepatitis C in patients co-infected with hepatitis B virus or human immunodeficiency virus. Daklinza formulation contains lactose: 1 tab. 60 mg (daily dose) contained 115.50 mg of lactose.
It is necessary to use adequate contraception during Daklinzoy 5 weeks after completion of therapy.
Influence on ability to drive vehicles, mechanisms
Studies of the possible effect of the drug on the ability to drive and operate with mechanisms not conducted. If a patient experiences dizziness, impaired attention, blurred / decreased visual acuity data AEs reported with the treatment regimen with peginterferon alpha), which may affect the ability to concentrate, he should refrain from driving vehicles and mechanisms.
OVERDOSE
Overdosage symptoms is not described.
In clinical phase I studies in the application of the drug to healthy volunteers at doses up to 100 mg for a period of up to 14 days or a single dose up to 200 mg of an unexpected adverse reactions were noted. Antidote to daklatasviru absent. Treatment of overdose should include general supportive measures, including monitoring of vital signs and observation of clinical status. Due to the high binding daklatasvira plasma proteins, dialysis is not recommended in overdose.
DRUG INTERACTION
Because Daklinza drug is used in combined treatment regimens should be familiar with possible interactions with each of the drugs scheme. In the appointment of concomitant therapy should follow the most conservative recommendations.
Daklatasvir a substrate izofermeta CYP3A4, however moderate and strong inducers of CYP3A4 isoenzyme may reduce daklatasvira plasma levels and therapeutic effect daklatasvira. Strong inhibitors of CYP3A4 isoenzyme may increase serum concentrations daklatasvira. Daklatasvir substrate transport is also P-glycoprotein (P-gp), but the joint use of drugs which affect only the properties of P-gp (without a simultaneous effect on isoenzyme CYP3A), not enough to obtain clinically significant effect on the plasma concentration daklatasvira.
Daklatasvir an inhibitor of P-gp, a transport polypeptide organic anions (TPOA) 1B1 and 1B3 and the protein resistant breast cancer (BCRP). Application Daklinza drug can increase the systemic exposure of drugs that are substrates of P-glycoprotein polypeptide or transport of organic anions 1B1 / 1B3 or BCRP, which may increase or prolong their therapeutic effect and increase undesirable phenomena. Care must be taken when used together daklatasvira these isoenzymes and substrates / carriers, particularly in the case of the last narrow therapeutic range.
Formulations which use together with the preparation Daklinza contraindicated, listed in Table 4 (see also "Contra" section.)
Table 4. Formulations use of which in conjunction with the drug contraindicated Daklinza
The interactions result of interaction Medicaments contraindicated for use in conjunction with the preparation Daklinza a
strong induction of isoenzyme CYP3A by the co-drug employed The combined use can lead to a reduction daklatasvira plasma concentrations that can lead to a lack of virological response to daklatasvir antiepileptic drugs carbamazepine, Okskarbaz Yeping, phenobarbital, phenytoin Antibacterials Rifampitsip, rifabutin, Rifapentine Corticosteroids Dexamethasone herbal remediesFormulations Hypericum perforatum (Hypericum perforatum)
and - it is a complete list of substances which induce CYP3A4 isozyme
Table 5 presents the clinical guidelines for established and potentially significant drug interactions Daklinza preparation with other drugs. Clinically significant increase of concentration are marked with a "*", a clinically significant reduction - symbol "v" and the absence of clinically significant changes - "-" icon.
Table 5. Installed potentially significant drug-drug interaction
class concomitant drug / drug name Effect on concentration Note clinical significance interaction
Antivirals, HCV
Asunaprevir - daklatasvir - asunaprevir Changes dose asunaprevira not required
peginterferon alfa 180 mg 1 time per week and ribavirin 500 mg or 600 mg of 2 times / day - daklatasvir - peginterferon alfa - ribavirin Changes dose daklatasvira, peginterferon alfa or ribavirin is not required
Simeprevir - daklatasvir - simeprevir Changes dose daklatasvira and simeprevira not required
sofosbuvir - daklatasvir - GS-331007 (the major metabolite sofosbuvir) dose changes daklatasvira and sofosbuvir not required
telaprevir ^ daklatasvir - telaprevir joint th application daklatasvira increases the concentration in plasma
HIV and HBV (hepatitis B) antivirals
Protease inhibitors: Atazanavir / ritonavir ^ daklatasvir daklatasvira dose should be reduced to 1 to 30 mg once / day with concomitant use of atazanavir / ritonavir, or other strong CYP3A4 isoenzyme inhibitor
darunavir / r Lopinavir / ritonavir No interaction was investigated. It is expected in view of inhibiting the isozyme CYP3A4 protease inhibitors: ^ daklatasvir Due to the lack of data and sharing application Daklinzy darunavir or lopinavir not recommended
Boceprevir No interaction was investigated. Expected ^ daklatasvir view iigibirovaniya isoenzyme SUR3A4 boceprevir Daklinza drug dose should be reduced to 1 to 30 mg once / day with concomitant use boceprevir or other strong CYP3A4 isoenzyme inhibitors
Nucleoside reverse transcriptase inhibitors (NRTI)
Tenofovir - daklatasvir - Change dose tenofovir and tenofovir daklatasvira not required
Lamivudine Zidovudine Abacavir Didanosine Emtricitabine Stavudine interaction has not been studied. Expected: - daklatasvir - Change NRTI and NNRTI daklatasvira dose not required
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz v daklatasvir daklatasvira dose should be increased to 90 mg 1 time / day with concomitant use of efavirenz or other moderate isoenzyme CYP3A4 inducers
