Pigleriya^® (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmasintez, JSC (Russia)

ATC Code

J05AP57 (Glecaprevir and Pibrentasvir)

Active Substances

Glecaprevir (Rec.INN registered by WHO)

Pibrentasvir (Rec.INN registered by WHO)

Dosage Form

Pigleriya®

Tablets, film-coated 100 mg+40 mg

Dosage Form, Packaging, and Composition

Tablets, film-coated

21 pcs. – jars – cardboard packs (21 pcs.) – In-Bulk
3 pcs. – contour packs (28 pcs.) – cardboard packs (84 pcs.) – By prescription

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

A combined antiviral drug. It contains two pangenotypic direct-acting antiviral agents in fixed doses – Glecaprevir (an NS3/4A protease inhibitor) and Pibrentasvir (an 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 subsequent 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 has been studied in antiviral activity assays in cell cultures and in studies to determine the pattern of drug resistance.

Pharmacokinetics

The T_max of glecaprevir and pibrentasvir is 5 hours. When taken with food, compared to fasting, the absorption of glecaprevir and pibrentasvir increases by 83-163% and 40-53%, respectively. The plasma protein binding of glecaprevir and pibrentasvir is high and is 97.5% and >99.9%, respectively; the 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. The T_1/2 at steady state for glecaprevir is 6-9 hours, for pibrentasvir – 23-29 hours.

Glecaprevir is a substrate for the 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 the use of 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 dose is three 100 mg/40 mg tablets, providing a total daily dose of 300 mg glecaprevir and 120 mg pibrentasvir.

Swallow the tablets whole; do not crush or chew.

The duration of treatment is 8 weeks for adult and pediatric patients (12 years and older) with chronic hepatitis C virus infection without cirrhosis and who are not previously treated with an NS5A inhibitor.

Extend the treatment duration to 12 weeks for patients with compensated cirrhosis (Child-Pugh A).

Extend the treatment duration to 16 weeks for patients who are previous treatment failures with an HCV regimen containing an NS5A inhibitor and who do not have cirrhosis.

For patients who are previous treatment failures with an NS5A inhibitor and have compensated cirrhosis, the optimal duration is not established; consider 16 weeks of therapy.

Confirm the presence or absence of cirrhosis prior to initiating therapy.

Assess the HCV genotype and prior treatment history to determine the appropriate treatment duration.

This regimen is prescribed for use in adults and pediatric patients 12 years of age and older or weighing at least 45 kg.

Initiate and conduct treatment under the supervision of a physician experienced in the management of chronic hepatitis C.

Adverse Reactions

Nervous system disorders very common – headache.

Gastrointestinal disorders common – nausea, diarrhea.

General disorders 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.

It is not recommended to use concomitantly with omeprazole (40 mg), darunavir/ritonavir, efavirenz, lopinavir/ritonavir, lovastatin, cyclosporine (>100 mg/day).

Use with caution should be exercised 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 a direct toxic effect on reproductive function. The presence of a toxic effect on the pregnant female with subsequent miscarriage was observed in rabbits when using glecaprevir, which precluded the possibility of further studies. As a precautionary measure, this combination is not recommended during pregnancy.

It is unknown whether Glecaprevir or Pibrentasvir is excreted in human breast milk. Available data from pharmacokinetic studies in animals have shown excretion of glecaprevir and pibrentasvir in milk, so a risk to newborns and infants cannot be excluded. A decision should be made either to discontinue breastfeeding or to discontinue or refrain 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 the 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 in accordance with current guidelines.

Effect on ability to drive vehicles and mechanisms

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 an increase in the plasma concentration 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.

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

During treatment with this combination, changes in liver function may occur, 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 the plasma concentration of glecaprevir and pibrentasvir, leading to a reduction in the therapeutic effect of this combination and loss of virological response. The use of such drugs concomitantly with this combination is contraindicated.

The use of this combination concomitantly with drugs that are moderate inducers of P-glycoprotein and CYP3A may cause a decrease in the plasma concentration 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. The 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 the 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.