Konesko^® (Tablets) Instructions for Use

Marketing Authorization Holder

Khimrar Pharma, LLC (Russia)

Manufactured By

Chemical Diversity Research Institute LLC (Russia)

ATC Code

J05AP13 (Ravidasvir)

Active Substance

Ravidasvir (Rec.INN registered by WHO)

Dosage Form

Konesko®

Film-coated tablets 200 mg

Dosage Form, Packaging, and Composition

Film-coated tablets

28 pcs. – bottles – cardboard packs (28 pcs.) – By prescription

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; antiviral agents for the treatment of hepatitis C

Pharmacological Action

Ravidasvir is an inhibitor of the non-structural protein 5A (NS5A), a multifunctional protein that is an essential component of the HCV replication complex. Ravidasvir inhibits the replication of HCV variant replicons encoding resistance mutations to other major classes of direct-acting antivirals against HCV. HCV variants with reduced susceptibility to ravidasvir remain fully susceptible to other classes of HCV inhibitors.

Pharmacokinetics

After oral administration of increasing single doses (80-320 mg) by healthy subjects, Ravidasvir was relatively rapidly absorbed with a mean T_max of 1.5-2 hours after administration. The C_max and AUC of ravidasvir increased proportionally with the dose, and plasma concentrations 24 hours after dose administration were above the ravidasvir EC₉₀ values for HCV genotypes 1 through 7. The mean T_max was slightly delayed for absorption after food compared to absorption under fasting conditions (3.0 vs. 2.0 hours).

Ravidasvir is highly bound to plasma proteins, with the unbound fraction estimated to be 1.9%; it does not distribute or bind in extravascular tissues. The apparent V_d values were approximately 100 L. In vivo animal studies suggest that distribution to the liver, an important target organ for antiviral efficacy, is higher than in plasma.

Metabolism in liver microsomes of all species was minimal, and oxidative metabolism of ravidasvir by human liver S9 fractions did not result in the formation of detectable glutathione conjugates. Mono-oxidation was the predominant metabolic pathway in all species tested; however, the metabolite profiles differed between species. Ravidasvir is metabolically very stable, with only moderate (~2%) metabolite formation detected. The most common metabolites in humans (M6 and M7, both of minor importance) are formed by mono-oxidation of ravidasvir.

Biliary excretion of ravidasvir appears to be the main route of elimination of the absorbed dose, while renal excretion is negligible. Administration for 5 days does not lead to significant accumulation or induced elimination of ravidasvir.

Indications

In combination with sofosbuvir for the treatment of chronic hepatitis C (CHC).

Not to be used as monotherapy.

ICD codes

Dosage Regimen

Administer orally at a dose of 200 mg once daily in combination with sofosbuvir.

Take the tablet with or without food; food does not significantly affect absorption.

Adhere to the standard treatment duration of 12 weeks for most patients with chronic hepatitis C.

For patients with specific clinical characteristics, such as compensated cirrhosis, extend the treatment duration to 24 weeks based on clinical assessment.

Swallow the tablet whole with water; do not crush or chew.

If a dose is missed and less than 18 hours have passed since the scheduled time, take the missed dose immediately.

If more than 18 hours have passed, skip the missed dose and take the next dose at the regular time.

Do not take a double dose to make up for a missed one.

Complete the full course of therapy as prescribed, even if viral load becomes undetectable early during treatment.

Discontinuation of therapy prior to the recommended duration may lead to virologic relapse.

Monitor hepatic function and HCV RNA levels as per standard clinical practice during treatment.

Adverse Reactions

Metabolism and nutrition disorders Uncommon – decreased appetite

Psychiatric disorders Common – insomnia; Uncommon – irritability.

Nervous system disorders Common – headache, dizziness, lethargy, somnolence.

Cardiac disorders Uncommon – palpitations, flushing.

Gastrointestinal disorders Common – dyspepsia, nausea, diarrhea, abdominal pain, vomiting, constipation.

Skin and subcutaneous tissue disorders Common – pruritus, rash, dermatitis.

General disorders and administration site conditions Very common – fever; Common – fatigue.

Investigations Common – increased plasma AST activity; Uncommon – increased plasma INR.

Contraindications

Hypersensitivity to ravidasvir; concomitant use with strong P-glycoprotein (P-gp) inducers, such as carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin, and St. John’s wort (Hypericum perforatum), as it will lead to a decrease in the plasma concentration of ravidasvir, which may result in reduced efficacy of ravidasvir; children and adolescents under 18 years of age.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Women of childbearing potential should use effective methods of contraception prior to initiation of ravidasvir therapy and continue to use them for 1 month after completion of ravidasvir treatment.

Use in Hepatic Impairment

Dosage adjustment of ravidasvir is not required in patients with mild hepatic impairment. The safety and efficacy of ravidasvir were evaluated in patients with compensated cirrhosis but have not been evaluated in patients with decompensated cirrhosis. The safety and efficacy of ravidasvir use in patients with severe hepatic impairment have not been evaluated.

The safety and efficacy of ravidasvir in the treatment of hepatitis C virus (HCV) infection in patients who have undergone liver transplantation have not been evaluated. Treatment should be based on an assessment of the benefit-risk ratio for each individual patient.

Use in Renal Impairment

Studies on the use of ravidasvir in patients with serum creatinine levels more than 1.5 times the upper limit of normal or with end-stage renal disease have not been conducted. Treatment with ravidasvir should be based on an assessment of the benefit-risk ratio for each individual patient.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Clinical experience with ravidasvir in patients over 65 years of age is limited. Treatment with ravidasvir should be based on an assessment of the benefit-risk ratio for each individual patient.

Special Precautions

All patients should be screened for HBV before starting therapy. Patients co-infected with HBV/HCV are at risk of HBV reactivation and should be monitored and managed according to current clinical guidelines.

Patients with diabetes may experience improved glycemic control, which may lead to symptomatic hypoglycemia after initiation of HCV direct-acting antiviral therapy. The physician responsible for the diabetic patient’s treatment should be informed about the initiation of therapy.

Effect on ability to drive and use machines

Studies on the effect of ravidasvir on the ability to drive and operate machinery have not been conducted. Dizziness, lethargy, somnolence, and blurred vision may occur during ravidasvir therapy. If these symptoms occur, refrain from driving vehicles and operating machinery.

Drug Interactions

Ravidasvir is a substrate of P-glycoprotein (P-gp).

Drugs that are strong inducers of P-gp (e.g., carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin, and herbal preparations containing St. John’s wort extract (Hypericum perforatum)) may decrease the plasma concentration of ravidasvir, leading to a reduction in the therapeutic effect of ravidasvir. Concomitant use of such drugs with ravidasvir is contraindicated.

Drugs that are moderate inducers of P-gp (e.g., oxcarbazepine or rifapentine) may decrease the plasma concentration of ravidasvir, leading to a reduction in the therapeutic effect of ravidasvir. Concomitant use of Ravidasvir with moderate P-gp inducers is not recommended.

Concomitant administration with drugs that inhibit P-gp may increase the plasma concentration of ravidasvir. However, clinically significant interaction with P-gp inhibitors is not expected.

Ravidasvir is an inhibitor of the breast cancer resistance protein (BCRP). Concomitant administration of ravidasvir with drugs that are substrates of BCRP may increase their effect.

Ravidasvir is a weak inhibitor of the organic anion transporting polypeptide (OATP) 1B1 and 1B3, as well as CYP450 – CYP3A, CYP2C19, and UGT1A1. Clinically significant interaction between ravidasvir and substrates of BCRP, OATP, CYP, or UGT1A1 enzymes is not expected.

As liver function may change during ravidasvir therapy, careful monitoring of INR values is recommended in patients receiving vitamin K antagonists.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°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.