Daklatasvir (Daklinza) is an antiviral drug, in combination with other drugs for the treatment
chronic hepatitis C in adults.
Daklintsa medicine contains an active substance Daclatasvir
Bristol-Myers Squibb, USA
Tablets, film-coated light green, biconvex, pentagonal, with chasing “the BMS” on one side and “215” on the other.
Table 1. daklatasvira digidrohlorid66 mg, which corresponds to the content daklatasvira60 mg
Excipients : Lactose – 115.5 mg Microcrystalline cellulose – 95.7 mg Croscarmellose sodium – 15 mg, silicon dioxide – 3 mg magnesium stearate – 4.8 mg, opadray® green – 15 mg (hypromellose – 8.9625 mg of titanium dioxide – 4.2825 mg macrogol-400 – 1.35 mg aluminum lake based on indigo carmine (FD & C Blue # 2) – 0.255 mg yellow iron oxide – 0.15 mg)
14 pcs. – blisters (2) – packs cardboard
Treatment of chronic hepatitis C in patients with compensated liver disease (including cirrhosis) in the following combinations daklatasvir preparation:
– with asunaprevir drug for patients with HCV genotype 1b;
– asunaprevir with drugs, peginterferon alfa and ribavirin – for patients with hepatitis C virus genotype 1
– the preparation should not be applied as a monotherapy;
– daklatasviru hypersensitivity and / or any of the auxiliary components of the drug;
– in combination with potent inducers isoenzyme CYP3A4 (due to a decrease in the blood concentration daklatasvira and reduce efficiency), such as:
– antiepileptic drugs (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)
Since the drug is used as a combined circuit, 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).
The safety of combination therapy has not been studied in patients with decompensated liver disease, and in patients after liver transplantation.
The combined use Daklinza preparation 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”).
Ppenapat Daklinza used only as part of combination therapy schemes. Should refer to a side effect of drugs included in the treatment regimen, before initiation of therapy. Adverse drug reactions (ADRs) associated with asunaprevira, peginterferon alfa and ribavirin are described in the instructions for the medical use of these formulations.
The safety of daklatasvira evaluated in 5 clinical studies on patients with chronic hepatitis C treated with 60 mg drug Daklinza 1 time / day in combination with asunaprevirom and / or peginterferon alfa and ribavirin. The safety data presented below for the application of the treatment regimes.
Daklatasvir + Asunaprevir
The safety of daklatasvira in combination with asunaprevirom evaluated in 4 studies with a median duration of treatment of 24 weeks. The most common (incidence 10% or higher) HLR observed in clinical studies using regimens Daklatasvir + Asunaprevir were headache (15%) and fatigue (12%). Most ADRs were mild to moderate in severity. 6% of patients experienced serious adverse events (SAEs), 3% of patients discontinued treatment due to occurrence of NLR. The most common adverse events (AEs) leading to discontinuation were increased ALT activity and ACT. In a clinical study therapy with Daklatasvir + Asunaprevir during the first 12 weeks of treatment the frequency of reported ADRs were similar between patients receiving placebo and those receiving said therapy.
NLR arising at ≥5% of patients with chronic hepatitis C with the combination Daklatasvir + Asunaprevir presented below. The incidence of ADRs provided in accordance with the scale: very often (≥1 / 10), often (≥1 / 100 and < 1/10)
Side reaktsiia Disorders of the nervous system It chastoGolovnaya pain (15%) Disorders of the gastrointestinal tract ChastoDiareya (9%), nausea (8%) General disorders It chastoUtomlyaemost (12%) Laboratory and instrumental data strong> ChastoPovyshenie ALT (7%), increase in the ACT (5%)
and – side reactions, whose connection with the preparation at least possible. The combined data from several studies.
Adverse reactions occurring in less than 5% of patients with chronic hepatitis C with the combination Daklatasvir + Asunaprevir: skin rash, pruritus, alopecia; zozinofiliya, thrombocytopenia, anemia; fever, malaise, chills; insomnia; loss of appetite, abdominal discomfort, constipation, pain in the upper abdomen, stomatitis, abdominal distension, vomiting; increased blood pressure; joint pain, muscle stiffness; nasopharyngitis, pain in the oropharynx; increased activity of gamma globulintransferazy, alkaline phosphatase, lipase, hypoalbuminemia.
Daklatasvir in combination with asunaprevirom, peginterferon alfa and ribavirin
The safety of daklatasvira in combination with asunaprevirom, peginterferon alfa and ribavirin was evaluated in a clinical trial HALLMARK QUAD with an average duration of 24 weeks therapy. The most common NAL (frequency of 15% and above) observed in clinical studies using regimens Daklatasvir + Asunaprevir + peginterferon alpha + Ribavirin were fatigue (39%) , headache (28%), pruritus (25%), asthenia (23%) , flu-like state (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.
The clinical trial 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. These were the only HLP, occurs with a frequency of at least 5% higher than among placebo-treated patients.
The results of laboratory tests
Abnormal laboratory abnormalities from normal grade 3-4 observed among patients with chronic hepatitis C who received the combined treatment with Daklinza presented and Table 3.
Table 3. Pathological laboratory abnormalities from the normal 3-4 degrees, observed in clinical studies of drug therapy Daklinza in combination therapy
Parameter Daklatasvir in combination with asunaprevirom n = 918 Daklatasvir in combination with asunaprevirom, peginterferon alfa ribavirin n = 398 < / strong> Increased ALT activity (> 5.1 × VGNb) 4% 3% Increase of AST activity (> 5.1 × ULN) 3% 3% Increase of total bilirubin concentration (> 2.6 ULN) 1% 1%
A – laboratory results were classified by DAIDS system for classifying the severity of adverse events of adults and children, version 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.
How to accept, acceptance rate and dosage
The recommended dosing regimen
The recommended dose Daklinza drug is 60 mg 1 time / day regardless of the write. The drug should be used in combination with other drugs (see. Table 1). Recommendations for doses of other drugs scheme given in the corresponding instructions for medical use. Recommended as a therapy for patients previously untreated chronic hepatitis C, and patients with a prior treatment failure.
Table 1. Recommended regimen Daklinza preparation when used at a dose of 60 mg 1 time / day in a combination therapy
The genotype of HCV Treatment Duration + genotype 1bdaklatacvir asunaprevir24 nedeliGenotip 1daklatacvir asunaprevir + + peginterferon alfa and ribavirin24 weeks
Change dose and suspension of therapy
After the start of therapy change the dose of the drug is not recommended Daklinza. To change the dose of other medications schemes should be read with appropriate instructions for medical use. Avoid interruption of treatment; However, if the interrupt any drug treatment scheme is necessary because of any adverse reactions, drug use Daklinza as monotherapy should not be.
During the treatment it is necessary to monitor the viral load (the amount of the RNA of HCV in the blood). Patients with inadequate virologic response during treatment with low probability of SVR, and in this group there is a chance of developing resistance. Discontinuation of therapy is recommended in patients with virologic breakthrough – an increase in HCV RNA level of more than 1 log10 from the prior
In the case of missing the next reception Daklinza dose for up to 20 hours, the patient should take the drug as soon as possible and then to adhere the original treatment regimen. If skipping doses over 20 hours has passed from the scheduled time of the drug, the patient should skip receiving this dose, the next dose should be taken in accordance with the original scheme of therapy.
Patients with renal insufficiency
Changes to the dose in patients with renal insufficiency of any degree is not required.
Patients with hepatic insufficiency
Changes to the dose in patients with mild hepatic insufficiency (class A on a scale Child-Pugh) is not required. In studies with mild (Class A according to Child-Pugh), moderate (Class B on the scale of Child-Pugh) and severe (grade C according to Child-Pugh), liver failure was no significant change in the pharmacokinetics of the drug. Efficacy and safety of use in decompensated liver disease has not been established.
Strong inhibitors isozyme 3A4 of cytochrome P450 (CYP3A4)
Dose Daklinza should be reduced to 30 mg 1 time / day in the case of simultaneous application of potent inhibitors isoenzyme CYP3A4 (used tablet 30 mg should not crush the tablet 60 mg) (see “Interaction with other drugs and other forms. interaction “). The simultaneous use of powerful and moderate inhibitors isoenzyme CYP3A4 is contraindicated for application circuits comprising drug Sunvepra.
Moderate inducers of the isoenzyme CYP3A4
Dose Daklinza should be increased to 90 mg 1 time / day (3 tablets. 30 mg or 1 tab. 60 mg and 1 tablet. 30 mg) while applying moderate inducers isoenzyme CYP3A4 (see. The section “Interaction with other drugs drugs and other forms of interaction “). Simultaneous use of inducers moderate isoenzyme CYP3A4 is contraindicated for application circuits comprising drug Sunvepra.
The drug Daklinza should not be used as monotherapy.
Of the more than 2,000 patients enrolled in clinical trials of combination therapy with the drug Daklinza, 372 patients had compensated cirrhosis (class A on a scale 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 dose modification Daklinza drug 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 liver transplant patients has not been established. There is limited experience with the drug Daklinza after liver transplantation.
Influence daklatasvira 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 application.
Do not use the drug has been studied 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.
You must use adequate contraception methods during 5 weeks after completion of therapy Daklinzoy.
Effects on ability to drive vehicles, mechanisms
Research the possible impact of the drug on the ability to drive and operate machinery has not been. 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.
Symptoms of overdose are not described.
In clinical phase I studies in the application of the drug to healthy volunteers at doses up to 100 mg for up to 14 days or a period of time to a single dose of 200 mg not 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.