Daklinza^® (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmstandard JSC (Russia)

Manufactured By

AstraZeneca Pharmaceuticals LP (USA)

Packaged By

BRISTOL-MYERS SQUIBB Company (USA)

Packaging and Quality Control Release

BRISTOL-MYERS SQUIBB Company (USA)

Or

ORTAT, JSC (Russia)

ATC Code

J05AP07 (Daclatasvir)

Active Substance

Daclatasvir (Rec.INN registered by WHO)

Dosage Forms

	Daklinza®	Film-coated tablets, 30 mg: 28 pcs.
		Film-coated tablets, 60 mg: 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets green, biconvex, pentagonal, engraved with “BMS” on one side and “213” on the other.

Excipients: lactose – 57.75 mg, microcrystalline cellulose – 47.85 mg, croscarmellose sodium – 7.5 mg, silicon dioxide – 1.5 mg, magnesium stearate – 2.4 mg, Opadry^® green – 6 mg (hypromellose – 3.6 mg, titanium dioxide – 1.698 mg, macrogol-400 – 0.48 mg, indigo carmine aluminum lake (FD&C Blue #2) – 0.12 mg, yellow iron oxide – 0.102 mg).

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

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

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, indigo carmine aluminum lake (FD&C Blue #2) – 0.255 mg, yellow iron oxide – 0.15 mg).

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

Clinical-Pharmacological Group

Antiviral drug active against hepatitis C virus

Pharmacotherapeutic Group

Antiviral agent

Pharmacological Action

Daclatasvir is a highly specific direct-acting agent against the hepatitis C virus and does not have pronounced activity against other RNA- and DNA-containing viruses, including the human immunodeficiency virus (HIV). Daclatasvir is an inhibitor of the non-structural protein 5A (NS5A), a multifunctional protein necessary for the replication of the hepatitis C virus, and thus suppresses two stages of the virus life cycle – viral RNA replication and virion assembly.

Based on data obtained in vitro and computer modeling data, it has been shown that Daclatasvir interacts with the N-terminus within domain 1 of the protein, which can cause structural distortions that prevent the implementation of the functions of the NS5A protein. Daclatasvir has been established to be a potent pan-genotypic inhibitor of the hepatitis C virus replication complex of genotypes 1a, 1b, 2a, 3a, 4a, 5a, and 6a with effective concentration values (50% reduction, EC₅₀) from picomolar to low nanomolar.

Amino acid substitutions causing resistance to daclatasvir in hepatitis C virus genotypes 1-6 were isolated in a replicon cell system and observed in the N-terminal region of the 100 amino acid residue of NS5A. L31V and Y93H were frequently observed in genotype 1b, and substitutions M28T, L31V/M, Q30E/H/R, and Y93C/H/N were frequently observed in genotype 1a.

Single amino acid substitutions generally cause a low level of resistance (EC₅₀ <1 nM for L31V, Y93H) for genotype 1b and higher levels of resistance for genotype 1a (up to 350 nM for Y93N). The principles of resistance development in clinical practice were similar to the principles of resistance development observed in vitro.

Pharmacokinetics

Absorption is rapid. C_max of daclatasvir is observed 1-2 hours after oral administration. AUC, C_max, and C_min in blood are dose-dependent, a stable concentration of daclatasvir in blood plasma is observed on day 4 of drug use when taken orally once/day. Absolute bioavailability is 67%. V_d of daclatasvir after a single intravenous administration of a 100 mcg dose is 47 L. Plasma protein binding is independent of dose (studied range from 1 mg to 100 mg) and is 99%.

In vitro studies have established that Daclatasvir can penetrate hepatocytes through active (predominantly) or passive transport. Active transport is carried out by organic cation transporter proteins OCT1 and other unidentified transporters, excluding organic anion transporter (OAT) 2 proteins, sodium taurocholate cotransporting polypeptide (NTCP), or organic anion transporting polypeptides (OATP). Daclatasvir is a substrate of the CYP3A isoenzyme, with CYP3A4 being the main CYP isoform responsible for the metabolism of daclatasvir.

Metabolites with a content of more than 5% of the concentration of the parent substance are absent. After oral administration of single doses of daclatasvir labeled with radioactive carbon C¹⁴ to healthy volunteers, 88% of the total radioactivity was excreted in feces (53% unchanged), 6.6% was excreted in urine (predominantly unchanged). After repeated administration of daclatasvir to patients infected with the hepatitis C virus, T_1/2 of daclatasvir ranged from 12 to 15 hours.

Indications

Treatment of chronic hepatitis C in adults in combination with other drugs for the treatment of chronic hepatitis C.

ICD codes

Dosage Regimen

Take the recommended dose of 60 mg orally, once daily.

Always use in combination with other antiviral drugs for chronic hepatitis C; do not use as monotherapy.

Select the specific combination therapy based on hepatitis C virus genotype, prior treatment history, and the presence of cirrhosis.

Adjust the dose when co-administered with moderate CYP3A inhibitors to 30 mg once daily.

Adjust the dose when co-administered with moderate CYP3A inducers to 90 mg once daily.

Do not co-administer with strong CYP3A inducers, as this leads to a significant loss of efficacy.

Take the tablet with or without food; administer at approximately the same time each day.

If a dose is vomited within 3 hours of intake, take another tablet.

If a dose is missed and it is less than 20 hours until the next scheduled dose, skip the missed dose.

If it is more than 20 hours until the next dose, take the missed dose and resume the normal schedule.

No dosage adjustment is required for patients with mild, moderate, or severe renal impairment, including those on dialysis.

No dosage adjustment is required for patients with any degree of hepatic impairment.

Adverse Reactions

Since Daclatasvir is used only as part of combination therapy regimens, adverse reactions depend on the combination of drugs included in the treatment regimen.

Contraindications

Hypersensitivity to daclatasvir; simultaneous use with strong inducers of the CYP3A4 isoenzyme and P-glycoprotein transporter, such as antiepileptic drugs (phenytoin, carbamazepine, phenobarbital, oxcarbazepine), antibacterial drugs (rifampicin, rifabutin, rifapentine), systemic corticosteroids (dexamethasone), herbal remedies (preparations based on St. John’s wort (Hypericum perforatum)); in the presence of contraindications to the use of drugs in the combination regimen (asunaprevir and/or peginterferon alfa, ribavirin, sofosbuvir); pregnancy and lactation; age under 18 years.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation.

Use in Hepatic Impairment

Dosage adjustment in patients with hepatic impairment is not required.

Use in Renal Impairment

Dosage adjustment in patients with renal impairment of any degree is not required.

Pediatric Use

Contraindicated for use under the age of 18 years.

Special Precautions

Daclatasvir should not be used as monotherapy.

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

Screening for hepatitis B virus should be performed before prescribing daclatasvir. In patients with identified serological signs of hepatitis B virus infection, monitoring and treatment of this disease should be carried out in accordance with current recommendations to avoid replication of the hepatitis B virus. In case of increased replication of the hepatitis B virus, appropriate therapy should be initiated.

During or after therapy with direct-acting antiviral drugs, patients with diabetes mellitus may experience dysglycemia, including symptomatic hypoglycemia. This may be associated with changes in blood glucose control due to improved liver function after direct-acting drug therapy. Careful monitoring of blood glucose levels is recommended during daclatasvir therapy.

Effect on ability to drive vehicles and machinery

If the patient experiences dizziness, impaired attention, blurred/decreased visual acuity, which may affect the ability to concentrate, they should refrain from driving vehicles and machinery.

Drug Interactions

Daclatasvir is a substrate of the CYP3A4 isoenzyme, so moderate and strong inducers of the CYP3A4 isoenzyme can reduce the plasma concentration of daclatasvir and the therapeutic effect of daclatasvir. Strong inhibitors of the CYP3A4 isoenzyme can increase the serum concentration of daclatasvir.

Daclatasvir is an inhibitor of Pgp, organic anion transporting polypeptide (OATP) 1B1 and 1B3, and breast cancer resistance protein (BCRP). The use of daclatasvir may increase the systemic exposure of drugs that are substrates of P-glycoprotein or organic anion transporting polypeptide 1B1/1B3 or BCRP, which may increase or prolong their therapeutic effect and enhance adverse events. Caution should be exercised when co-administering daclatasvir and substrates of the specified isoenzymes/transporters, especially in the case of a narrow therapeutic range of the latter.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.