Maviret 100 mg+40 mg, 84 pcs.

Maviret is a combination of two pangenotypic direct-acting, fixed-dose antivirals, glecaprevir (NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor), which target different stages of the hepatitis C virus life cycle.

Glecaprevir

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

Pibrentasvir

Pibrentasvir is a pangenotype inhibitor of the hepatitis C virus NS5A protein, which is essential for viral RNA replication and virion assembly. The mechanism of action of pibrentasvir has been studied in studies of antiviral activity on cell cultures and in studies to determine the nature of drug resistance.

Antiviral activity

The EU5o values of glecapsvir and pibrentasvir against full-length or hybrid replicons. encoding NS3 or NS5A from laboratory strains.

The evaluation of the combination of glecaprsvir and pibrentasvir on HCV genotype 1 replicon cell cultures showed no evidence of antagonistic antiviral activity. Resistance

In cell culture

A phenotypic analysis of amino acid substitutions in NS3 or NS5A proteins. isolated in cell culture or significant for the inhibitor class was performed for replicons.

The substitutions significant for the HCV protease inhibitor class at positions 36, 43, 54. 55, 56, 155, 166 or 170 in the NS3 protein have no effect on the activity of glecapsvir. For genotype 2, amino acid substitutions in NS3 at position 168 have no effect, while some substitutions at position 168 cause a decrease in sensitivity to glecaprevir by up to 55-fold (genotypes 1, 3, 4) or a decrease in sensitivity by more than 100-fold (genotype 6). Some substitutions at position 156 cause a decrease in sensitivity to glecaprevir by more than 100 times (genotypes 1-4). Amino acid substitutions at position 80 do not decrease sensitivity to glecaprevir except for the Q80R substitution in genotype Z, which decreases sensitivity to glecaprevir 21-fold.

Single substitutions important for the NS5A protease inhibitor class at positions 24, 28, 30, 31, 58. 92 or 93 in NS5A in genotypes 1-6 have no effect on the activity of pibrentasvir. For example, in genotype Z, substitutions in amino acids A30K or Y93H have no effect on piBrentasvir activity. Some combinations of substitutions in genotypes 1a and Za (including A30K+Y93H in genotype Za) show reduced sensitivity to pibrentasvir. Use in children

There are no data on the use of the drug in children.

The use in elderly patients

The clinical trials of Maviret included 328 patients aged 65 years and older (13.8% of the total number of patients). The frequency of achieving a virologic response in the group of patients aged > 65 years was similar to that in patients aged < 65 years.

Indications

Active ingredient

Composition

Active ingredients: glecaprevir 100.0 mg, pibrentasvir 40.0 mg

Excipients: copovidone K 28, D-alpha-tocopherol macrogoal succinate, colloidal silicon dioxide, croscarmellose sodium. Sodium stearyl fumarate, propylene glycol monocaprylate type II; film coating Opadryu II pink (Opadryu II 32F240023)’. hypromellose 2910. lactose monohydrate, titanium dioxide, macrogol 3350, iron oxide red.

How to take, the dosage

To be taken orally.

The tablets should be swallowed whole with meals and should not be chewed, crushed or broken. Maviret® should be prescribed by a healthcare professional and under the care of a healthcare professional who has experience treating patients with chronic hepatitis C.

Doses

The recommended dose of Maviret is 300 mg/120 mg (three 100 mg/40 mg tablets) once daily with meals.

If you miss a dose of Maviret, it can be taken within 18 hours of the scheduled dosing time. If more than 18 hours have elapsed since your scheduled time of taking Maviret, do not take the missed dose and take the next dose at your regular scheduled time. Do not take a double dose of Maviret.

If vomiting occurs within 3 hours of taking Maviret, an additional dose of the drug should be taken. If vomiting occurred later than 3 hours after administration of Maviret, an additional dose of the drug is not required.

Use in elderly patients

In elderly patients, no dose adjustment of Maviret is required.

Patients with impaired renal function

In patients with renal impairment, including patients on dialysis, dosage adjustment of Maviret is not required.

Patients with impaired hepatic function

In patients with mild hepatic impairment (Child-Pugh class A), no dose adjustment of Maviret is required. Maviret is not recommended for patients with moderate hepatic impairment (Child-Pugh class B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh class C).

Children

There are no data on the safety and effectiveness of Maviret in children and adolescents under 18 years of age.

Patients after liver transplantation

Maviret must be used for at least 12 weeks in patients after liver transplantation.

An extension of therapy (for 16 weeks) should be considered in patients with genotype 3 who have previously received peg-IFN + ribavirin therapy (with or without sofosbuvir) or sofosbuvir + ribavirin.

Patients with HCV/HIV-1 co-infection

The recommendations in Table 1 and 2 should be followed. Dosing recommendations for Maviret when used together with HIV-1 therapy drugs.

Interaction

Possible effects of Maviret on other medications

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

Concomitant use with Maviret may increase plasma concentrations of drugs that are substrates of P-glycoprotein (dabigatran etexilate, digoxin), BCRP (rosuvastatin) or OATP1B1/3 (atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin). For other P-glycoprotein substrates. BCRP and OATP1B1/3 a dose adjustment may be required.

Glecaprevir and pibrentasvir are weak inhibitors of the cytochrome P450 CYP3A and uridine glucuronosyltransferase (UGT) 1A1 system isoenzymes in vivo. There was no clinically significant increase in systemic exposure for sensitive CYP3A substrates (midazolam, felodipine) and UGT1AI (ralgegravir) when concomitantly administered with Maviret.

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

Lack of clinically significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6 substrates is not expected. UGT1A6, UGT1A9. UGT1A4, UGT2B7, OCTI, OCT2, OAT1, OATZ, MATE1 and MATE2K.

Patients receiving vitamin K antagonists

Liver function may be altered during treatment with Maviret, so close monitoring of the international normalized ratio (INR) is recommended. Potential effects of other medicinal products on Maviret

Combination with strong P-glycoprotein inducers/SURZA

Potential effects of other medicinal products on Maviret

Combination with strong P-glycoprotein inducers Drugs that are strong inducers of P-glycoprotein and CYP3A (rifampicin, carbamazepine, Hypericum perforatum, phenobarbital, phenytoin and primidone) may cause a significant decrease in plasma concentrations of glecapsvir and pibrentasvir and lead to a decrease in therapeutic effect of Maviret and loss of virologic response. The use of such drugs concomitantly with Maviret is contraindicated.

The use of Maviret concomitantly with drugs that are moderate inducers of P-glycoprotein and CYP3A may decrease the plasma concentrations of glecapsvir and pibrentasvir (oxcarbazepine. eslicarbazepine, lumacaftor. crizotinib). Concomitant use with moderate inducers is not recommended.

Glecaprevir and pibrentasvir are substrates of P-glycoprotein and/or BCRP efflux transporters. Glecaprevir is also a substrate of the hepatic uptake transporters OATP1B1/3. Administration of Maviret concomitantly with drugs that are inhibitors of P-glycoprotein and BCRP (cyclosporine, cobicistat, dronedarone, itraconazole, ketoconazole, ritonavir) may slow the excretion of glecapsvir and pibrentasvir and may cause increased exposure of antiviral drugs in blood plasma. Drugs that are inhibitors of OATP1B1/3 (elvitegravir. cyclosporine, darunavir. loinavir) may cause increased systemic concentration of glecapsvir.

Special Instructions

Hepatitis B reactivation

Hepatitis B virus reactivation, in some cases fatal, has been reported during treatment with direct-acting antiviral drugs. All patients should be screened for HBV before starting therapy. Patients with HBV/HCV coinfection are at risk for HBV reactivation.

Patients after liver transplantation

The safety and effectiveness of Maviret in liver transplant patients has not been evaluated. Treatment with Maviret according to the recommended route of administration and doses should be based on an assessment of the potential benefits and risks for each individual patient.

Hepatic impairment

Maviret is not recommended for patients with moderate hepatic impairment (Child-Pugh class B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh class C). The likelihood of developing resistance to glecaprevir/pibrentasvir in patients infected with genotype 1 virus and a limited number of patients infected with genotype 4 virus who had not responded to a prior therapy regimen was studied. As expected, the risk of therapy failure was higher in patients with prior therapy including both classes of drugs (NS5A and NS3/4A inhibitors). A methodology for predicting therapy failure based on baseline data on resistance to therapy has not been defined. The development of resistance to both classes of drugs was a major finding in patients who did not respond to glecaprevir/pibrentasvir therapy. There are no data on re-treatment of patients infected with genotypes 2, 3, 5 and 6. The use of Maviret is not recommended for re-treatment of patients previously treated with NS3/4A and/or NS5A inhibitors.

Influence on driving and operating machinery

Maviret has no or negligible effect on the ability to drive vehicles and operate machinery.

Contraindications

– Hypersensitivity to any active ingredient of the drug or to any of the excipients.

– Patients with severe hepatic impairment (Child-Pugh class C), see

sections “How to use” and “How to use”.

The sections on Administration and Doses and Pharmacokinetics.

– Co-administration with the following drugs: atazanavir. atorvastatin,

simvastatin, dabigatran etexilate, drugs containing estradiol, strong inducers of P-glycoprotein and CYP3A such as rifampicin, carbamazepine, preparations of Hypericum perjoratum, phenobarbital, phenytoin, primidone, (see “Interaction with other drugs. section “Interaction with other medicinal products”).

– Childhood under 18 years of age.

– Lactase deficiency, lactose deficiency, glucose-galactose malabsorption.

WARNING

Maviret is not recommended for use with omeprazole (40 mg), darunavir/ritonavir, efavirenz, lopinavir/ritonavir, lovastatin, cyclosporine (>100 mg daily).

Maviret should be used with caution with the following drugs: digoxin, pravastatin, rosuvastatin, fluvastatin, pitavastatin, tacrolimus.

Side effects

Safety Profile Summary

The safety of Maviret in patients with compensated liver function (with or without cirrhosis) was evaluated from phase 2 and 3 studies involving approximately 2,300 patients infected with HCV genotypes 1, 2, 3, 4, 5, or 6. receiving Maviret for 8, 12, or 16 weeks.

The most common adverse reactions (incidence > 10%) were headaches and fatigue. Less than 0.1% of patients treated with Maviret developed serious adverse reactions (transient ischemic attack). The proportion of patients who permanently discontinued Maviret because of adverse reactions was 0.1%. The type and severity of adverse reactions in patients with cirrhosis were comparable to those in patients without cirrhosis.

Table of adverse reactions

The following adverse reactions have been reported in patients treated with Maviret. Below is a list of adverse reactions, grouped according to organ system class and frequency of occurrence. The frequency of occurrence is defined as follows: very common (> 1/10), common (>1/100 to < 1/10), infrequent (> 1/1,000 to < 1/100), rare (>1/10,000 to < 1/1,000) and very rare (< 1/10,000).

Indesirable reactions observed when taking Maviret:

Description of individual adverse reactions

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Indesirable reactions in patients with severe renal impairment, including dialysis patients

The safety of Maviret in patients with chronic kidney disease (stage 4 or stage 5, including patients on dialysis) and chronic infection caused by hepatitis C virus genotypes 1, 2, 3, 4, 5, or 6 with compensated liver failure (with or without cirrhosis) was evaluated in 104 patients. The most common adverse reactions in patients with severe renal impairment were skin itching (17%) and fatigue (12%).

Safety evaluation in patients with HCV/HIV-1 co-infection

The overall safety profile of patients with HCV/HIV-1 co-infection was comparable to that of patients with HCV mono-infection.

Elevated serum bilirubin levels

In 1.3% of patients, there was an increase in total bilirubin levels of at least 2 times the upper limit of normal, which was associated with glecaprevir-mediated inhibition of bilirubin carrier proteins and bilirubin metabolism. The increase in bilirubin levels was asymptomatic, transient, and usually occurred early in treatment. Increases in bilirubin levels occurred predominantly due to the indirect fraction and were not associated with increases in ALT levels. Direct hyperbilirubinemia was observed in 0.3% of patients.

Overdose