Daclinza, 60 mg 28 pcs.

Daclatasvir (Daklinza) is an antiviral drug in combination with other medicines to treat
chronic hepatitis C in adults.
The drug Daklinza contains the active ingredient Daclatasvir

Indications

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

— with the drug asunaprevir for patients with hepatitis virus genotype 1b;

– with the drugs asunaprevir, peginterferon alfa and ribavirin – for patients with hepatitis virus genotype 1.

Pharmacological effect

Daclatasvir (Daklinza) is an antiviral drug in combination with other drugs to treat
chronic hepatitis C in adults.
The medicine Daklintsa contains the active substance Daclatasvir

Special instructions

Daklinza should not be used as monotherapy.

Of more than 2,000 patients included in clinical trials of combination therapy with Daklinza, 372 patients had compensated cirrhosis (Child-Pugh class A). There were no differences in the safety and efficacy of therapy between patients with compensated cirrhosis and patients without cirrhosis. The safety and effectiveness of Daklinza in patients with decompensated cirrhosis have not been established. No change in the dose of Daklinza is required in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment.

The safety and effectiveness of combination therapy with Daclinza in liver transplant patients has not been established. There is limited experience with the use of Daklinza after liver transplantation.

The effect of daclatasvir on the QTc interval was assessed in a randomized, placebo-controlled trial in healthy volunteers. Single doses of daclatasvir 60 mg and 180 mg had no clinically significant effect on the QTc interval adjusted by the Frederick formula (QTcF). There was no significant relationship between increased plasma concentrations of daclatasvir and changes in QTc. In this case, a single dose of daclatasvir 180 mg corresponds to the maximum expected concentration of the drug in blood plasma during clinical use.

The drug has not been studied for the treatment of chronic hepatitis C in patients with concomitant infection with hepatitis B virus or human immunodeficiency virus. The drug Daklinza contains lactose: 1 tablet. 60 mg (daily dose) contains 115.50 mg of lactose.

Adequate contraception must be used for 5 weeks after completion of Daklinza therapy.

Impact on the ability to drive vehicles and machinery

There have been no studies of the possible effect of the drug on the ability to drive vehicles and operate machinery. If the patient experiences dizziness, impaired attention, blurred/decreased visual acuity (aEs noted when using a treatment regimen with peginterferon alfa), which may affect the ability to concentrate, he should refrain from driving vehicles and machinery.

Active ingredient

Daclatasvir

Composition

The film-coated tablets are light green, biconvex, pentagonal, engraved with “BMS” on one side and “215” on the other.

1 tablet of daclatasvir dihydrochloride 66 mg, which corresponds to the content of daclatasvir 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, opadry® 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, yellow iron oxide – 0.15 mg).

14 pcs. – blisters (2) – cardboard packs.

Contraindications

— the drug should not be used as monotherapy;

– hypersensitivity to daclatasvir and/or any of the auxiliary components of the drug;

– in combination with strong inducers of the CYP3A4 isoenzyme (due to a decrease in the concentration of daclatasvir in the blood and a decrease in effectiveness), such as:

– antiepileptic drugs (phenytoin, carbamazepine, phenobarbital, oxcarbazepine);

– antibacterial agents (rifampicin, rifabutin, rifapentim);

– systemic corticosteroids (dexamethasone);

– herbal remedies (preparations based on St. John’s wort (Hypericum perforatum)).

– simultaneous use of moderate inducers of the CYP3A4 isoenzyme is contraindicated when using regimens that include asunaprevir (see instructions for the drug Sunvepra);

– if there are contraindications to the use of drugs in a combination regimen (asunaprevir and/or peginterferon alfa + ribavirin) – see the instructions for use of the corresponding drugs;

– lactase deficiency, lactose intolerance, glucose-galactose malabsorption;

— pregnancy and lactation;

– age under 18 years (efficacy and safety have not been studied).

With caution

Because the drug is administered as a combination regimen, combination therapy should be used with caution for the conditions described in the instructions for use of each drug included in the regimen (asunaprevir and/or peginterferon alfa and ribavirin).

The safety of combination therapy has not been studied in patients with decompensated liver disease, as well as in patients after liver transplantation.

The combined use of Daklinza with other drugs may lead to changes in the concentration of both daclatasvir and the active ingredients of other drugs (see sections “Contraindications” and “Interaction with other drugs”).

Side Effects

Penapat Daklinza is used only as part of combination therapy regimens. You should become familiar with the side effects of medications included in the treatment regimen before starting therapy. Adverse drug reactions (ADRs) associated with the use of asunaprevir, peginterferon alfa and ribavirin are described in the instructions for medical use of these drugs.

The safety of daclatasvir was assessed in 5 clinical studies in patients with chronic hepatitis C who received 60 mg of Daklinza once a day in combination with asunaprevir and/or peginterferon alfa and ribavirin. Safety data are presented below by treatment regimen.

Daclatasvir+Asunaprevir

The safety of daclatasvir in combination with asunaprevir was assessed in 4 studies with an average duration of therapy of 24 weeks. The most common (incidence of 10% or greater) ADRs observed in clinical trials using the Daclatasvir + Asunaprevir regimen were headache (15%) and fatigue (12%). Most ADRs were mild to moderate in severity. 6% of patients experienced serious adverse events (SAEs), and 3% of patients discontinued treatment due to an ADR. At the same time, the most common adverse events (AEs) leading to treatment discontinuation were increased ALT and AST activity. In a clinical study of Daclatasvir+Asunaprevir therapy during the first 12 weeks of treatment, the incidence of reported ADRs was similar between patients receiving placebo and patients receiving the indicated therapy.

ADRs that occurred in ≥5% of patients with chronic hepatitis C when using the combination Daclatasvir + Asunaprevir are presented below. The incidence of ADRs is given according to the scale: very often (≥1/10), often (≥1/100 and <1/10).

Table 2.

Adverse reactions Nervous system disorders Very common Headache (15%) Gastrointestinal disorders Often Diarrhea (9%), nausea (8%) General disorders Very common Fatigue (12%) Laboratory and instrumental data Often Increased ALT (7%), increased AST (5%)

a – adverse reactions, the connection of which with the use of the drug is at least possible. Pooled data from multiple studies.

Adverse reactions occurring in less than 5% of patients with chronic hepatitis C when using the combination Daclatasvir + Asunaprevir: skin rash, itching, alopecia; Zosinophilia, thrombocytopenia, anemia; increased body temperature, malaise, chills; insomnia; loss of appetite, abdominal discomfort, constipation, pain in the upper abdomen, stomatitis, bloating, vomiting; increased blood pressure; joint pain, muscle stiffness; nasopharyngitis, pain in the oropharynx; increased activity of gamma globulin transferase, alkaline phosphatase, lipase, hypoalbuminemia.

Daclatasvir in combination with asunaprevir, peginterferon alfa and ribavirin

The safety of daclatasvir in combination with asunaprevir, peginterferon alfa and ribavirin was assessed in the HALLMARK QUAD clinical trial with a median duration of therapy of 24 weeks. The most common ADRs (incidence 15% or higher) observed in clinical trials using the Daclatasvir + Asunaprevir + Peginterferon alfa + Ribavirin treatment regimen 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%). Additional side effects that occurred in patients with chronic hepatitis C when using the Daclatasvir + Asunaprevir + Peginterferon alfa + Ribavirin treatment regimen were: dry skin (15%), decreased appetite (12%), muscle pain (14%), fever (15%), cough (13%), shortness of breath (11%), neutropenia (14%), lymphopenia (1%), diarrhea (14%), pain in joints (9%). Most ADRs were mild to moderate in severity. 6% of patients were registered as CHF. 5% of patients discontinued treatment due to AEs, with AEs being the most common. leading to discontinuation of treatment were rash, malaise, dizziness and neutropenia.

In a clinical trial of Daclatasvir + Asunaprevir + Peginterferon alfa + Ribavirin, the incidence of reported adverse reactions was similar between patients receiving placebo and patients receiving the indicated therapy, with the exception of 2 ADRs – asthenia and influenza-like illness. These ADRs were the only ones that occurred at a rate at least 5% higher than among patients receiving placebo.

Laboratory results

Pathological deviations of laboratory parameters from the norm of 3-4 degrees, observed among patients with chronic hepatitis C who received combination treatment with Daklinza, are presented in Table 3.

Table 3. Pathological deviations of laboratory parameters from the norm of 3-4 degrees observed in clinical studies of therapy with Daklinza in combination therapy

ParametersDaklatasvir in combination with asunaprevir n=918Daklatasvir in combination with asunaprevir, peginterferon alfa, ribavirin n=398Increased ALT activity (>5.1×ULNb)4%3%Increased AST activity (>5.1×ULN)3%3%Increased total bilirubin concentration (>2.6 VGN)1%1%

a – laboratory test results were classified according to the DAIDS system for classifying the severity of adverse events in adults and children, version 1.0
b – upper limit of normal

If any of the NDRs listed in the instructions get worse or you notice any other side effects not listed in the instructions, tell your doctor.

Overdose

Overdose symptoms have not been described.

In phase I clinical studies, no unexpected adverse reactions were observed in healthy volunteers at doses up to 100 mg over a period of up to 14 days or a single dose up to 200 mg. There is no antidote for daclatasvir. Treatment of drug overdose should include general supportive measures, incl. monitoring vital signs and monitoring the clinical condition of the patient. Due to the high binding of daclatasvir to plasma proteins, dialysis in case of overdose is not recommended.

Manufacturer

Bristol-Myers Squibb Holdings Pharma, Ltd. Liabil, USA