Asunaprevir - instructions for use, analogs, reviews and release forms (soft capsules 100 mg) drugs for the treatment of chronic hepatitis C in adults, children and pregnancy. Composition

In this article, you can read the instructions for using the drug Asunaprevir. Comments of visitors of the site - consumers of this medication, as well as opinions of doctors of specialists on the use of Asunaprevir in their practice are presented. A big request is to actively add their feedback on the drug: the medicine helped or did not help get rid of the disease, which were observed complications and side effects, possibly not declared by the manufacturer in the annotation. Analogues of Asunaprevir in the presence of existing structural analogues. Use for the treatment of chronic viral hepatitis C in adults, children, as well as in pregnancy and lactation. Composition of the preparation.

Asunaprevir - a highly specific direct action against hepatitis C virus (HCV) and does not have a pronounced activity against other RNA and DNA containing viruses, including human immunodeficiency virus (HIV). Asunaprevir is an inhibitor of the serine protease complex of HCV NS3 / 4A proteins responsible for viral replication.

Based on in vitro data, It was shown that asunaprevir is most active with respect to isoforms of protease complexes of NS3 / 4A, which represent genotype 1 of the virus and shows a decreased activity with respect to isoforms characteristic for genotype 2.

Asunaprevir demonstrated an additive and / or synergistic interaction with Interferon alpha, daklatasvir, inhibitors interacting with the active HCV NS5B center, or allosteric inhibitors interacting with HCV NS5B sites 1 or 2 and Ribavirin in studies using a two- or three-component combination on a cell model replication of HCV. Antagonism in the manifestation of antiviral activity was not observed.

Resistance

Resistance to asunaprevir in cell culture was assessed by introducing the resulting replacements in NS3 protease into the basis of the corresponding replicon.In the HCV-resistant genotype 1a, resistant to asunaprevir, the main substitutions were detected in the amino acids R155K, D168G and I170T. They confirmed their role in resistance to asunaprevir (decreased sensitivity to asunaprevir 5-21 times). In the HCV-resistant genotype 1b resistant to asunaprevir, the main substitutions were detected in amino acid D168A / G / H / V / Y. They confirmed their role in resistance to asunaprevir (decreased sensitivity to asunaprevir in 16-280 times).

HCV replicas with substitutions that are resistant to asunaprevir retained sensitivity to interferon alpha and ribavirin, as well as other antiviral agents, such as NS5A inhibitors of the replication complex and NS5B polymerase. It was shown that amino acid substitutions in NS3 at positions V36 and T54 found in patients treated with telaprevir and boceprevir and not achieving a stable virologic response (SVR) do not affect the antiviral activity of asunaprevir and do not influence the success of therapy. In contrast, the amino acid substitutions of R155K, V36M + R155K and A156T / V, which were also found in patients treated with telaprevir and bocetrevir and not reached the SVR, showed a decreased sensitivity to asunaprevir (a 6-55 decrease in sensitivity) and other NS3 protease inhibitors .

Studies have been conducted on the relationship between naturally occurring amino acid substitutions of NS3 at baseline (polymorphisms) and the outcome of treatment. Efficacy daklatasvir combination therapy asunaprevir + was reduced in patients with chronic hepatitis C genotype 1b with replacement of NS3-D168K at baseline. The frequency of this substitution was 0.7% (6 of 905 patients) and it was initially present in 2% (3 of 138) of patients who had ineffective therapy.

Daklatasvir therapy combination preparations peginterferon alfa and ribavirin: from 379 patients with available starting from 4 NS3 genotyping were substitutions at position R155 (R155K / T) and / or D168 (D168E / N), associated with resistance to asunapreviru. Of 4 patients, three patients were ineffective (all 3 were infected with HCV genotype 1a).

The stability in the course of treatment in patients who did not achieve a stable virologic response (SVR)

Most patients with chronic genotype 1b hepatitis C, treated with a combination daklatasvir asunaprevir and, if unsuccessful treatment had substitutions associated with resistance to asunapreviru and daklatasviru; substitutions of NS5A-L31, NS5A-Y93H and NS3-D168 were often (79%) observed together.

Substitutions NS5A-Q30 and NS3-R155 were most frequently observed together with ineffective therapy with a combination of daklatasvir, peginterferon alfa and ribavirin (61%) in patients with chronic hepatitis C with genotype 1a, whereas NS5A-L31I / M-Y93H and NS3-D168V were observed in a single patient with HCV with genotype 1b with ineffective therapy.

Composition

Asunaprevir + auxiliary substances.

Pharmacokinetics

Absorption is fast. Maximum concentration Asunaprevir occurs 1-4 hours after ingestion. A stable concentration of asunaprevir in the blood plasma is observed after 7 days of the drug application for ingestion twice a day. Absolute bioavailability of the drug is 9.3%.

In studies on healthy volunteers, it was found that a single dose of 100 mg asunaprevir together with a high-fat meal increased the degree of absorption in relation to the fasting state, but did not have a clinically significant effect on the overall bioavailability of asunaprevir. The time to reach the maximum concentration of asunaprevir when taken with food was observed after 1.5 hours, whereas when taken on an empty stomach it was about 2.5 hours.

The connection with plasma proteins is not dose-dependent (the range studied is from 200 mg to 600 mg when taken twice a day) and is more than 99%.

While unchanged asunaprevir is the main substance in the blood plasma after repeated administration of the drug, metabolism is the main way of excreting asunaprevir. After oral intake of healthy volunteers with single doses of asunaprevir, 84% was excreted through the intestine (mainly in the form of metabolites) and less than 1% was excreted by the kidneys (mainly in the form of metabolites). Both asunaprevir and its metabolites were determined in human bile.

Indications

Treatment of chronic hepatitis C in patients with compensated liver disease (including cirrhosis) in the following combinations of asunaprevir:

• with daklatasvir for patients with hepatitis C virus of genotype 1b;
• with preparations of daklatasvir, pegitferon alfa and ribavirin for patients with hepatitis C virus of genotype 1.

Forms of release

Capsules soft 100 mg in a blister (trade name - Sunvepra).

Instructions for use and dosing regimen

The recommended dose of Asunaprevir is 100 mg 2 times a day, regardless of food intake.The drug should be used in combination with other medicines, and at the beginning of therapy, the drugs asunaprevir and daklatasvir are always used simultaneously. Therapy is recommended both for patients who have not previously received treatment for chronic hepatitis C, and for patients with previous ineffectiveness of therapy.

In viral hepatitis C, caused by genotype 1b of the virus, Asunaprevir is combined with daklatasvir and taken within 24 weeks. In viral hepatitis C, caused by genotype 1 of the virus, Asunaprevir is combined with daklatasvir, Peginterferon alfa and ribavirin, and is also taken within 24 weeks.

Dose change and suspension of therapy

After the start of therapy, a change in the dose of Asunaprevir and Daklataswir is not recommended. To change the dose of other drugs of the regimen, it is necessary to familiarize yourself with the relevant instructions for medical use. Interruption of treatment should be avoided; However, in the event that the interruption of treatment with any preparation of the scheme is necessary because of the adverse reactions that have arisen, Asunaprevir should not be used as monotherapy.

During treatment, it is necessary to monitor the viral load (the amount of PNK HCV in the patient's blood). Patients with an inadequate virologic response during treatment with a low degree of probability will achieve a sustained virologic response (SVR), and this group also has the potential for developing resistance. Discontinuation of treatment is recommended in patients with a virologic breakthrough - an increase in the level of HCV RNA.

Dose skip

If you miss a regular dose of Asunaprevir for up to 8 hours, the patient should take the drug as soon as possible and then adhere to the original therapy regimen. If a dose is missed more than 8 hours from the planned time of taking the drug, the patient should skip this dose, the next dose of the drug should be taken in accordance with the initial therapy regimen.

Side effect

The safety of asunaprevir was evaluated in 5 clinical trials in patients with chronic hepatitis C who received 100 mg of the drug Sunvepra 2 times a day in combination with daklatasvir and / or peginterferon alfa and ribavirin. The safety data are presented below for treatment regimens.

Daklatasvir + Asunaprevir

• headache (15% of subjects);
• increased fatigue (12%);
• diarrhea (9%);
• nausea (8%);
• increase in ALT (alanine aminotransferase) - 7%;
• increase of AST (aspartate aminotransferase) - 5%
• skin rash;
• itching;
• alopecia;
• increased body temperature;
• malaise, chills;
• insomnia;
• decreased appetite;
• stomatitis;
• vomiting;
• discomfort in the abdomen;
• pain in the upper abdomen;
• bloating;
• constipation;
• increased blood pressure;
• joint pain;
• Stiffness of muscles (increase of tone);
• nasopharyngitis (inflammation of the nasopharynx);
• pain in the oropharynx;
• eosinophilia (increase in the number of eosinophils in the blood);
• thrombocytopenia (decrease in the number of platelets in the blood);
• anemia (decrease in the concentration of hemoglobin in the blood);
• increased activity of gamma globulin transferase;
• increased alkaline phosphatase;
• increased lipase;
• hypoalbuminemia (decrease of serum albumin);
• increase in total bilirubin.

In 6% of patients, serious adverse events (SNR) were registered, 3% of patients discontinued treatment because of their occurrence.

Asunaprevir in combination with daklatasvir, peginterferon alfa and ribavirin

• increased fatigue (39%);
• headache (28%);
• itching (25%);
• asthenia (23%);
• influenza-like state (22%);
• insomnia (21%);
• anemia (19%);
• rash (18%);
• alopecia (16%);
• irritability (16%);
• nausea (15%);
• dry skin (15%);
• diarrhea (14%);
• decreased appetite (12%);
• muscle pain (14%);
• fever (15%);
• cough (13%);
• dyspnea (11%);
• pain in the joints (9%);
• neutropenia (decrease in the number of neutrophils in the blood) - 14%;
• lymphopenia (decrease in the number of lymphocytes in the blood) - 1%;
• increase in total bilirubin.

In 6% of patients serious adverse events were registered. 5% of patients discontinued treatment for their reasons.

In the clinical study of therapy, daklutasvir + asunaprevir + peginterferon alfa + ribavirin, the incidence of reported adverse reactions was similar between patients receiving placebo and patients receiving this therapy, with the exception of 2 adverse reactions, asthenia and influenza-like conditions. These HLPs were the only ones that occurred at a minimum of 5% higher than among the patients receiving the placebo.

Contraindications

• the drug should not be used as a monotherapy;
• hypersensitivity to asunaprevir and / or any of the auxiliary components of the drug;
• in patients with moderate and severe hepatic impairment (Child-Pugh grade B and C, 7 or more points) and decompensated liver disease;
• simultaneous administration with drugs whose elevated plasma concentrations are associated with serious and / or life-threatening events (narrow therapeutic index): flecainide, propafenone, thioridazine;
• simultaneous administration with drugs that can lead to a decrease in the concentration and loss of efficacy of asunaprevir: phenytoin, carbamazepine, phenobarbital, rifampicin, rifabutin, rifapentin, nafcillin, bosentan, dexamethasone, Hypericum perforalum preparations, efavirenz, etravirine, modafinil, nevirapine;
• simultaneous with drugs that may lead to increased concentrations and increased toxicity asunaprevira: ketoconazole, itraconazole, voriconazole, fluconazole, fosfluconazole, miconazole, clarithromycin, erythromycin, diltiazem, verapamil, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, darunavir, fosamprenavir;
• simultaneous administration with drugs that can lead to a decrease in the concentration in the liver and loss of efficacy of asunaprevir: rifampicin, cyclosporin, sirolimus, gemfibrozil.
• in the presence of contraindications to the use of drugs combined scheme (daklatasvir and / or peginterferon alfa + ribavirin;
• pregnancy and lactation;
• age to 18 years (efficacy and safety not studied).

Carefully

Because the drug is used as a combined regimen, combination therapy should be used with caution under the conditions described in the instructions for each drug included in the scheme (daklataswir and / or peginterferon alfa and ribavirin).

Joint use of the drug Asunaprevir with other drugs can lead to a change in the concentration of both asunaprevir and the active substances of other drugs.

Application in pregnancy and lactation

Daklatasvir + Asunaprevir

There are no adequate and well-controlled studies involving pregnant women. In studies on animals using doses exceeding therapeutic (in 472 times in mice, 1.2 times in rabbits), no reproductive toxicity of the drug was detected. The use of combination daklatasvir + asunaprevir in pregnancy is contraindicated.During the period of treatment with this combination, it is recommended to use adequate methods of contraception.

It is not known whether asunaprevir penetrates into breast milk. Asunaprevir penetrated into breast milk in animal studies, so if you need to use the drug during lactation you should stop breastfeeding.

Daklatasvir + Asunaprevir + Peginterferon alfa + Ribavirin

The use of Ribavirin can cause fetal malformations, fetal death and abortion, so care should be taken when applying a therapy regimen including ribavirin. It is necessary to prevent the onset of pregnancy both in the patients themselves and in women whose sexual partners receive this therapy. Ribavirin therapy should not begin until patients capable of childbearing and their male sexual partners will not use at least 2 effective methods of contraception, which is necessary both throughout the therapy and for at least 6 months after it completion. During this period, it is necessary to perform standard pregnancy tests.When using oral contraceptives as one of the ways to prevent pregnancy, it is recommended to use high doses of oral contraceptives (containing at least 30 micrograms of ethinylestradiol in combination with norethindrone acetate / norethindrone).

Investigation of interferons in animal experiments was associated with abortive effects, the possibility of development of which in humans can not be ruled out. Therefore, when using therapy, both patients and their partners should use adequate contraception.

Use in children

The use of the drug for children and adolescents under the age of 18 years is contraindicated (efficacy and safety not studied).

Application in elderly patients

In elderly patients, there was a change in clearance with oral administration of asunaprevir, but there was no clinical effect of this change on the efficacy of the drug.

special instructions

Therapy Asunaprevir should be administered only to patients for whom taking the drug is assessed as necessary, under the supervision of a doctor with experience in the treatment of viral liver diseases.

In clinical studies, the frequency of increase in ALT and ACT activity was at least 5-fold higher than the upper limit of normal (IV), from 3 to 4%, and the frequency of increase in bilirubin concentration was at least 2.6 times 1%. With the use of the combination of asunaprevir + daklatasvir, the increase in ALT / AST activity tended to develop during the first 13 weeks of treatment (range: 4 to 24 weeks), then in most cases the activity of liver enzymes returned to normal despite continued medication. Data on the increase in hepatic enzyme activity were reversible in patients who stopped treatment prematurely. Of the 19 patients who discontinued the study because of the increased activity of transaminases, 16 patients noted the achievement of SVR.

It is necessary to monitor the activity of liver enzymes during drug therapy. Evaluation of liver function should be performed at least once every 2 weeks in the first 12 weeks of treatment, and every 4 weeks thereafter. If there is a worsening of liver function, evaluation of liver function should be performed more often with the adoption of appropriate measures, until the cessation of treatment.If the activity of hepatic enzymes is increased by 10 or more times compared with the upper limit of the norm, treatment should be immediately stopped and not restarted.

In patients with chronic hepatitis C and compensated liver cirrhosis (class A), differences in safety and efficacy with patients without cirrhosis were not observed.

The safety and effectiveness of combination therapy with Asunaprevir in patients with decompensated liver disease, with transplanted liver and other transplanted organs is not established. The use of the drug for the treatment of patients with chronic hepatitis C with concomitant infection of the hepatitis B virus or human immunodeficiency virus has not been studied.

Influence on ability to drive vehicles, mechanisms

Studies of the possible effects of the use of the drug on the ability to drive vehicles and work with mechanisms have not been carried out. If a patient develops undesirable phenomena that may affect his ability to concentrate, he should refrain from driving and working with machinery.

Drug Interactions

Drugs, the use of which together with asunaprevir is contraindicated:

• antiarrhythmics (Flecainide, Propafenone);
• antipsychotic agent Thioridazine;
• anti-epileptic drugs (phenytoin, carbamazepine, phenobarbital);
• antibacterial agents (Rifampicin, Rifabutin, Rifapentin, Nafcillin);
• antagonist of endothelin prescriptions (Bosentan);
• systemic glucocorticoids (dexamethasone);
• plant remedies (preparations of St. John's wort perfumed);
• non-nucleoside reverse transcriptase inhibitors (Efavirenz, etravirine, Nevirapine);
• analeptics (Modafilil);
• antifungal agents (ketoconazole, Itraconazole, Voriconazole, Fluconazole, Phosphluconazole, Miconazole);
• antibacterial agents (Clarithromycin, Erythromycin);
• calcium channel blockers (Diltiazem, Verapamil);
• HIV protease inhibitors (Atazanavir, Indinavir, Lopinavir, Nelfinavir, Ritonavir, Saquinavir, Darunavir, Fosamprenavir);
• immunosuppressants (Cyclosporine, Sirolimus);
• lipid-lowering drugs (gemfibrozil).

Clinical recommendations for established and potentially significant drug interactions

When combined with Dextromethorphan (antitussive), careful clinical monitoring is required, it is recommended that dose reduction be considered.

Caution should be exercised when taking Digoxin together. It should be prescribed the smallest dose of Digoxin and monitor its concentration in the blood plasma. To achieve the desired therapeutic effect, dose titration should be used.

With the simultaneous use of hormonal contraceptives, the use of high-dose oral preparations containing at least 30 μg of ethinyl estradiol in combination with norethindrone acetate / norethindrone is recommended. Simultaneous administration does not have a clinically significant effect on the pharmacokinetics of Asunaprevir.

With simultaneous treatment with Rosuvastatin (lipid-lowering agent), you can start with the recommended doses when combined with the drug Sunvisra, with careful monitoring of side effects and the therapeutic effect of rosuvastatin.

When combined with Midazolam (sedative), care should be taken in view of the decrease in the content of midazolam in the blood plasma and reduce its therapeutic effect.

Analogues of the drug Asunaprevir

Structural analogs for the active substance:

• Sunvepra.

Analogues on the curative effect (agents for the treatment of chronic viral hepatitis C):

• Algeron;
• Altevir;
• Alfaron;
• Vero-Ribavirin;
• Ingaron;
• Intron A;
• Layfferon;
• Milife + selenium;
• Milife + amber;
• Milife;
• Moliksan;
• Neovir;
• Pegasys;
• PegIntron;
• Realdiron;
• EU Reaferon;
• Rebetol;
• Ribavirin Meduna;
• Rimbamidil;
• Roferon-A;
• Sovriad;
• Ferrovir
• Cycloferon.

Doctor's Feedbackinfectious disease

According to the experience of treatment of hepatitis C, the drug Sunvepra (active substance Asunaprevir) in combination with other antiviral direct action (Daklinsa, Sofosbuvir) shows high efficacy (a stable virologic response in more than 90% of patients). But, unfortunately, for most of the infected, their cost is too expensive, and they at best receive a standard out-of-date scheme of peginterferon + ribavirin or are costed by hepatoprotectors. Interferon treatment brings a temporary result, but is accompanied by a number of side effects. Those patients who find the right amount for a modern therapy scheme, face difficulties in buying because of problems with registration.In such cases, they buy cheaper, but illegal generics from China and India. Those patients who were lucky enough to buy original drugs, as a rule, completely eliminate the virus (virus RNA is not determined in the analysis after six months or more after the completion of the admission). Therapy is tolerated normally, not including some weakness.

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