Sevalveo^® (Tablets) Instructions for Use

Marketing Authorization Holder

Promomed Rus LLC (Russia)

Manufactured By

Biokhimik, JSC (Russia)

ATC Code

J05AP57 (Glecaprevir and Pibrentasvir)

Active Substances

Glecaprevir (Rec.INN registered by WHO)

Pibrentasvir (Rec.INN registered by WHO)

Dosage Form

Sevalveo®

Tablets, film-coated 100 mg+40 mg

Dosage Form, Packaging, and Composition

Tablets, film-coated

21 pcs. – jars – cardboard packs (21 pcs.) – Prescription only
3 pcs. – blister packs (28 pcs.) – cardboard packs (84 pcs.) – Prescription only
7 pcs. – blister packs (12 pcs.) – cardboard packs (84 pcs.) – Prescription only
7 pcs. – blister packs (3 pcs.) – cardboard packs (21 pcs.) – Prescription only
84 pcs. – jars – cardboard packs (84 pcs.) – Prescription only

Clinical-Pharmacological Group

Antiviral drug active against hepatitis C virus

Pharmacotherapeutic Group

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

Pharmacological Action

Combined antiviral drug. It contains two pangenotypic direct-acting antiviral agents in fixed doses – Glecaprevir (NS3/4A protease inhibitor) and Pibrentasvir (NS5A inhibitor), which act on different stages of the hepatitis C virus life cycle.

Glecaprevir is an inhibitor of the hepatitis C virus (HCV) NS3/4A protease, which is necessary for the proteolytic cleavage of the HCV-encoded polyprotein (for further conversion into mature forms of NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. In biochemical studies, Glecaprevir inhibited the proteolytic activity of recombinant HCV NS3/4A proteases from clinical isolates of genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, and 6a with IC₅₀ values ranging from 3.5 to 11.3 nM.

Pibrentasvir is a pangenotypic inhibitor of the HCV NS5A protein, which is necessary for viral RNA replication and virion assembly. The mechanism of action of pibrentasvir was studied in cell culture antiviral activity studies and drug resistance characterization studies.

Pharmacokinetics

T_max of glecaprevir and pibrentasvir is 5 h. When taken with food, compared to fasting, the absorption of glecaprevir and pibrentasvir increases by 83-163% and 40-53%, respectively. Plasma protein binding of glecaprevir and pibrentasvir is high and is 97.5% and >99.9%, respectively; blood/plasma distribution coefficient is 0.57 and 0.62, respectively. Glecaprevir undergoes metabolism, Pibrentasvir is not metabolized.

The main route of elimination is via feces. T_1/2 at steady state for glecaprevir is 6-9 h, for pibrentasvir – 23-29 h.

Glecaprevir is a substrate for transporters – P-glycoprotein, BCRP and OATP1B1/3, Pibrentasvir – for P-glycoprotein, and possibly BCRP.

The bioavailability of pibrentasvir when co-administered with glecaprevir is 3 times higher compared to pibrentasvir alone. Glecaprevir showed less influence from pibrentasvir.

Indications

Treatment of chronic hepatitis C in adults and children aged 12 years and older.

ICD codes

Dosage Regimen

For oral administration.

Take the tablets once daily with food.

The recommended adult and pediatric (12 years and older) dose is three 100 mg/40 mg tablets, totaling 300 mg glecaprevir and 120 mg pibrentasvir.

Swallow the tablets whole; do not crush, split, or chew.

For patients without cirrhosis and not previously treated, administer for 8 weeks.

For patients with compensated cirrhosis (Child-Pugh A), administer for 8 weeks if treatment-naive.

For treatment-experienced patients with compensated cirrhosis (Child-Pugh A), administer for 16 weeks.

For patients with chronic kidney disease, including those on dialysis, no dose adjustment is required.

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

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.

This regimen is contraindicated in patients with severe hepatic impairment (Child-Pugh class C).

Discontinue use if hepatitis B virus reactivation occurs.

Adverse Reactions

Nervous system disorders very common – headache.

Gastrointestinal disorders common – nausea, diarrhea.

General disorders and administration site conditions very common – fatigue; common – asthenia.

Contraindications

Hypersensitivity to the components of the combination; severe hepatic impairment (Child-Pugh class C); concomitant use with the following drugs: atazanavir, atorvastatin, simvastatin, dabigatran etexilate, drugs containing estradiol, carbamazepine, St. John’s wort preparations, phenobarbital, phenytoin, primidone; children under 12 years of age.

Not recommended for concomitant use with omeprazole (40 mg), darunavir/ritonavir, efavirenz, lopinavir/ritonavir, lovastatin, cyclosporine (>100 mg/day).

Use with caution with the following drugs: digoxin, pravastatin, rosuvastatin, fluvastatin, pitavastatin, tacrolimus.

Use in Pregnancy and Lactation

Data on the use of glecaprevir or pibrentasvir in pregnant women are limited or absent. During studies, there were less than 300 cases of pregnancy. Studies of glecaprevir and pibrentasvir in rats and mice did not demonstrate direct toxic effects on reproductive function. Toxic effects on pregnant females followed by miscarriage were observed in rabbits with glecaprevir use, which precluded further studies. As a precaution, this combination is not recommended during pregnancy.

It is unknown whether Glecaprevir or Pibrentasvir is excreted in human breast milk. Available data from animal pharmacokinetic studies showed excretion of glecaprevir and pibrentasvir in milk, so a risk to newborns and infants cannot be excluded. A decision should be made to either discontinue breastfeeding or discontinue/abstain from therapy with this combination, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother.

Use in Hepatic Impairment

Contraindication: severe hepatic impairment (Child-Pugh class C).

Special Precautions

During treatment with direct-acting antiviral agents, reactivation of hepatitis B virus has been reported, in some cases with a fatal outcome. Before starting therapy, all patients should be tested for HBV. Patients co-infected with HBV/HCV are at risk of HBV reactivation, so they should be monitored and managed according to current guidelines.

Effect on ability to drive vehicles and operate machinery

This combination has no or negligible influence on the ability to drive and use machines.

Drug Interactions

Glecaprevir and Pibrentasvir are inhibitors of P-glycoprotein (Pgp), breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 1B1/3.

Concomitant use with this combination may lead to increased plasma concentrations of drugs that are substrates of P-glycoprotein (dabigatran etexilate, digoxin), BCRP (rosuvastatin) or OATP1B1/3 (atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin).

Glecaprevir and Pibrentasvir are weak inhibitors of CYP3A and UGT1A1 isoenzymes in vivo. No clinically significant increase in systemic exposure was noted for sensitive CYP3A (midazolam, felodipine) and UGT1A1 (raltegravir) substrates when co-administered with this combination.

Use of glecaprevir and pibrentasvir inhibits the bile salt export pump (BSEP) in vitro.

During treatment with this combination, liver function may change, so careful monitoring of INR is recommended in patients receiving vitamin K antagonists.

Drugs that are strong inducers of P-glycoprotein and CYP3A (rifampicin, carbamazepine, St. John’s wort, phenobarbital, phenytoin and primidone) may cause a significant decrease in plasma concentrations of glecaprevir and pibrentasvir, leading to a reduction in the therapeutic effect of this combination and loss of virological response. Concomitant use of such drugs with this combination is contraindicated.

Use of this combination concomitantly with drugs that are moderate inducers of P-glycoprotein and CYP3A may cause a decrease in plasma concentrations of glecaprevir and pibrentasvir (oxcarbazepine, eslicarbazepine, lumacaftor, crizotinib). Concomitant use with moderate inducers is not recommended.

Glecaprevir and Pibrentasvir are substrates of the efflux transporters P-glycoprotein and/or BCRP. Glecaprevir is also a substrate of the hepatic uptake transporters OATP1B1/3. Use of this combination concomitantly with drugs that are inhibitors of P-glycoprotein and BCRP (cyclosporine, cobicistat, dronedarone, itraconazole, ketoconazole, ritonavir) may slow the elimination of glecaprevir and pibrentasvir and may cause an increase in plasma exposure of the antiviral drugs. Drugs that are inhibitors of OATP1B1/3 (elvitegravir, cyclosporine, darunavir, lopinavir) may cause an increase in the systemic concentration of glecaprevir.

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.