Zepatier^® (Tablets) Instructions for Use

Marketing Authorization Holder

MSD Pharmaceuticals, LLC (Russia)

Manufactured By

MSD International, GmbH (Ireland)

Labeled By

SCHERING-PLOUGH LABO, N.V. (Belgium)

Packaging and Quality Control Release

SCHERING-PLOUGH LABO, N.V. (Belgium)

Or

AKRIKHIN Chemical and Pharmaceutical Plant, JSC (Russia)

ATC Code

J05AP54 (Elbasvir and Grazoprevir)

Active Substances

Grazoprevir (Rec.INN registered by WHO)

Elbasvir (Rec.INN registered by WHO)

Dosage Form

Zepatier®

Film-coated tablets, 100 mg+50 mg: 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light brown in color, oblong, biconvex, engraved with “770” on one side, smooth on the other side.

Excipients: sodium lauryl sulfate, copovidone, mannitol, croscarmellose sodium, sodium chloride, colloidal silicon dioxide, magnesium stearate, hypromellose 2910, vitamin E polyethylene glycol succinate, microcrystalline cellulose, lactose monohydrate.

Film coating composition Opadry II Beige 39K170006, carnauba wax.

Composition of Opadry II Beige 39K170006 lactose monohydrate, hypromellose 2910, titanium dioxide, triacetin, iron oxide yellow dye, iron oxide red dye, iron oxide black dye.

7 pcs. – sealed blisters (2) – cardboard covers (2) – cardboard packs^×.

^× to control first opening, stickers are applied to the cardboard pack.

Clinical-Pharmacological Group

Antiviral drug active against hepatitis C virus

Pharmacotherapeutic Group

Antiviral agent

Pharmacological Action

Combined antiviral agent. It combines two direct-acting antiviral drugs with different mechanisms and non-overlapping resistance profiles to act on the hepatitis C virus (HCV) at various stages of the viral life cycle.

Elbasvir is an inhibitor of the HCV NS5A protein, which is necessary for viral RNA replication and virion assembly.

Grazoprevir is an inhibitor of the HCV NS3/4A protease, which is necessary for the proteolytic cleavage of the encoded HCV polyprotein (into mature forms of NS3, NS4A, NS4B, NS5A, and NS5B proteins) and for viral replication. In a biochemical study, Grazoprevir inhibited the proteolytic activity of recombinant HCV NS3/4A protease enzymes of genotypes 1a, 1b, 2, 3, and 4a with IC50 values ranging from 4 to 690 pmol/L.

Pharmacokinetics

After oral administration of this combination to HCV patients, the average time to reach C_max of elbasvir in plasma was 3 hours (range 3 to 6 hours), and for grazoprevir – 2 hours (range 30 minutes to 3 hours). The absolute bioavailability of elbasvir was estimated to be 32% and of grazoprevir from 10% to 40%. The binding of elbasvir and grazoprevir to plasma proteins is >99.9% and 98.8%, respectively. Elbasvir and Grazoprevir bind to serum albumin and alpha1-acid glycoprotein. Elbasvir and Grazoprevir are partially metabolized by oxidation, primarily via CYP3A isoenzymes. No other circulating metabolites of elbasvir and grazoprevir were detected in human plasma. The apparent terminal T_1/2 is approximately 24 hours (24%) for 50 mg of elbasvir and approximately 31 hours (34%) for 100 mg of grazoprevir in HCV-infected patients. Elbasvir and Grazoprevir are primarily eliminated via the intestine.

The pharmacokinetics of elbasvir are close to dose-dependent when taken in the range of 5 to 100 mg once daily.

The pharmacokinetic parameters of grazoprevir increased more significantly when taken in the range of 10 to 800 mg once daily by HCV-infected patients than with a dose-dependent increase.

Indications

Treatment of chronic hepatitis C genotypes 1, 3, or 4 in adult patients.

ICD codes

Dosage Regimen

Take one tablet orally once daily, with or without food.

Swallow the tablet whole; do not crush or chew.

The treatment duration is 12 or 16 weeks, depending on HCV genotype, prior treatment history, and presence of baseline NS5A resistance-associated substitutions.

For treatment-naïve and treatment-experienced patients with genotype 1a, determine the presence of NS5A polymorphisms prior to initiating therapy.

For genotype 1a without baseline NS5A polymorphisms, administer for 12 weeks.

For genotype 1a with baseline NS5A polymorphisms, administer with ribavirin for 16 weeks.

For genotype 1b, administer for 12 weeks.

For genotype 4, administer for 12 weeks.

For genotype 3, administer with sofosbuvir for 12 weeks; this regimen is not recommended in patients with prior treatment failure.

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

If a dose is missed and it is within 16 hours of the usual time, take the missed dose immediately.

If it is more than 16 hours since the usual time, skip the missed dose and resume the normal schedule; do not double the dose.

Adverse Reactions

Metabolism and nutrition disorders common – decreased appetite.

Psychiatric disorders common – insomnia, anxiety, depression.

Nervous system disorders very common – headache; common – dizziness.

Gastrointestinal disorders common – nausea, diarrhea, constipation, upper abdominal pain, abdominal pain, dry mouth, vomiting.

Skin and subcutaneous tissue disorders common – pruritus, alopecia.

Musculoskeletal and connective tissue disorders common – arthralgia, myalgia.

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

Contraindications

Hypersensitivity to elbasvir, grazoprevir; moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment; concomitant use with inhibitors of the organic anion transporting polypeptide 1B1 (OATP1B1), such as rifampicin, atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cobicistat or cyclosporine; concomitant use with the drugs atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir, elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate; concomitant use with inducers of the CYP3A isoenzyme or P-glycoprotein, such as efavirenz, phenytoin, carbamazepine, bosentan, etravirine, modafinil and St. John’s wort preparations; age under 18 years.

With caution

Patients with HCV and HBV (hepatitis B virus) co-infection; not recommended for concomitant use with strong CYP3A inhibitors, such as ketoconazole; concomitantly with the following drugs: dabigatran etexilate, vitamin K antagonists, atorvastatin, rosuvastatin, fluvastatin, lovastatin, simvastatin, tacrolimus, sunitinib.

Use in Pregnancy and Lactation

There are no sufficient data and strictly controlled studies on the use of this combination during pregnancy. Use during pregnancy is possible only if the expected benefit of therapy for the mother outweighs the potential risk to the fetus.

It is unknown whether the components of this combination are excreted in human breast milk. Elbasvir and Grazoprevir are excreted in the milk of lactating rats. The benefits of breastfeeding should be weighed against the mother’s need for treatment and possible adverse events in the infant associated with the mother’s treatment with this combination and the mother’s underlying disease.

Use in Hepatic Impairment

Contraindicated in patients with moderate and severe hepatic impairment (Child-Pugh classes B and C).

Use in Renal Impairment

The drug is approved for use in renal impairment.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

The drug is approved for use in elderly patients.

Special Precautions

The rate of late elevation of ALT activity during treatment is directly related to the plasma exposure of grazoprevir.

Laboratory tests to monitor liver status should be performed before starting therapy, at week 8 of therapy, and as clinically indicated. For patients receiving therapy for 16 weeks, additional laboratory testing should be performed at week 12 of therapy.

Patients should be informed of the need for immediate consultation with their doctor in case of an episode of fatigue, weakness, loss of appetite, nausea and vomiting, jaundice, or discoloration of stool.

Discontinuation of this combination should be considered if ALT activity exceeds the upper limit of normal by more than 10 times.

This combination should be discontinued if the increase in ALT activity is accompanied by signs or symptoms of liver inflammation or an increase in conjugated bilirubin concentration, alkaline phosphatase activity, or INR value.

The efficacy of this combination has not been established in patients with HCV genotypes 2, 5, and 6; it is not recommended for use in patients infected with these HCV genotypes.

Cases of HBV reactivation, some fatal, have been reported during or after treatment with direct-acting antiviral drugs. Screening for HBV should be performed in all patients before starting treatment. In HCV/HBV co-infected patients, there is a risk of HBV reactivation, and their condition should be monitored and managed according to current clinical guidelines.

If this combination is used together with ribavirin or with sofosbuvir, the contraindications and precautions for taking ribavirin, including special measures to prevent pregnancy in female patients, must be taken into account. The instructions for medical use of the medicinal products included in the antiviral therapy regimens with this combination should be carefully studied.

Effect on ability to drive vehicles and operate machinery

Patients should be informed that increased fatigue has been reported during therapy with this combination.

Drug Interactions

Grazoprevir is a substrate of the OATP1B1 drug transporter. Concomitant use of this combination and OATP1B1 inhibitors, which may lead to a significant increase in the plasma concentration of grazoprevir, is contraindicated. Elbasvir and Grazoprevir are substrates of CYP3A and Pgp. Concomitant use of this combination with inducers of CYP3A or Pgp is contraindicated, as it may reduce the plasma concentrations of grazoprevir and elbasvir, leading to a reduction in the therapeutic effect of this combination.

Concomitant use of this combination with strong CYP3A inhibitors increases the plasma concentrations of elbasvir and grazoprevir, and their concomitant use is not recommended.

Concomitant use of this combination with Pgp inhibitors is expected to have a minimal effect on the plasma concentrations of grazoprevir and elbasvir.

The potential for grazoprevir to be a substrate of the breast cancer resistance protein (BCRP) cannot be ruled out. Elbasvir and Grazoprevir are inhibitors of the BCRP drug transporter at the intestinal level in humans and may increase the plasma concentrations of concomitantly administered BCRP substrates.

In patients receiving therapy with vitamin K antagonists, careful monitoring of INR values is recommended because liver function may change during treatment.

When used concomitantly with dabigatran etexilate, an increase in the concentration of dabigatran etexilate is expected, which increases the risk of bleeding. Clinical and laboratory monitoring is recommended.

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.