Sunwepra - instructions for use, dose, side effects, contraindications

Active substanceAsunaprevirAsunaprevir

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Sunwapra ™

capsules inwards

Bristol-Myers Squibb Company USA

Dosage form: & nbspcapsules are soft

Composition:

Each capsule contains:

Active substance: Asunaprevir 100.0 mg.

Excipients: medium chain triglycerides 150.0 mg, glyceromonokaprilokaproate (type I) 150.0 mg, polysorbate 80 99.5 mg, butylhydrocitroxoluene 0.5 mg;

shell: gelatin 168.0 mg, sorbitol and sorbitan solution 60.4 mg, glycerol 50.4 mg, titanium dioxide 2.0 mg, ink Opacode® Monogramming Ink, black * q.s.

* - Ink composition: ethanol / ethyl acetate (SDA 35A alcohol) **, propylene glycol, iron oxide black, polyvinyl acetate phthalate, purified water, isopropyl alcohol, polyethylene glycol, ammonium hydroxide.

** - ethanol, denatured with ethyl acetate.

Description:

Soft gelatin capsules of oval form, opaque, from white to light yellow color, with marking "BMS" black on the first line and marked "711" in black on the second line (under "BMS"); contents of capsules - light yellow Pmortar mortar.

Pharmacotherapeutic group:Antiviral agent

ATX: & nbsp

J.05.A.E.15 Asunaprevir

Pharmacodynamics:

Asunaprevir is a highly specific direct action agent 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 protein complex NS3/4A HCV. Enzyme complex of proteins NS3/4A is responsible for the processing of the HCV polyprotein to obtain mature viral proteins required for viral replication.

Based on the data obtained in vitro, shown, that asunaprevir most active against isoforms of protease complexes NS3/4A, representing the genotype 1 BHS (IC50 [concentration at which 50% inhibition is achieved] for 1a is 0.7-1.8 nM; 1b: IC50 = 0.3 nM) and shows a decreased activity with respect to isoforms characteristic for genotype 2 (2a: IC50 = 15 nM, 2b: IC50 = 78 nM) and 3 (3a: IC50 = 320 nM). The activity with respect to the genotype isoforms 4a, 5a and 6a was 1.6, 1.7 and 0.9 nM, respectively. In experiments on the replication of HCV in cells asunaprevir suppressed the replication of HCV genotypes 1a, 1b and 2a at effective concentrations (50% reduction, EC50) 4, 1.2 and 230 nM, respectively. Against hybrid replicas that encode a protease domain NS3, which corresponds to the genotype 4a of the HCV, the EC50 was 1.8 to 7.6 nM.

Asunaprevir demonstrated an additive and / or synergistic interaction with interferon alpha, daklatasvir, inhibitors interacting with the active site NS5B HCV, or allosteric inhibitors interacting with sites I or II NS5B HCV, and ribavirin in studies using a two- or three-component combination on the HCV cell model of replication. 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 the protease NS3 the basis of the corresponding replicon. In the HCV-resistant genotype 1a, resistant to asunaprevir, the main substitutions were detected in amino acids R155K, D168G and I170T. Recombinant replicons containing replacement data have confirmed their role in resistance to asunaprevir (decreased sensitivity to asunaprevir 5-21 times). In asunaprevir-resistant replicas of HCV genotype 1b the main substitutions were detected in the amino acid D168A/G/H/V/Y. Recombinant replicons containing replacement data confirmed their role in resistance to asunaprevir (a decrease in sensitivity to asunaprevir in 16-280 times). Replicas of HCV with replacements that cause resistance to asunaprevir retained sensitivity to interferon alpha and ribavirin,as well as other antiviral agents of direct action with various mechanisms of action, for example, inhibitors NS5A complex of replication and NS5B polymerase of HCV. It was shown that amino acid substitutions in NS3 in positions V36 and T54, found in patients treated with telaprevir and boceprevir and who did not achieve a stable virologic response (SVR), did not affect the antiviral activity of asunaprevir and did not affect the success of therapy. In contrast, amino acid substitutions R155K, V36M + R155K and A156T/V, which were also found in patients treated with telaprevir and boceprevir and who did not achieve SVR, showed a decreased sensitivity to asunaprevir (a 6-55 decrease in sensitivity) and other protease inhibitors NS3.

Studies have been carried out on the relationship between naturally occurring amino acid substitutions NS3 at the initial level (polymorphisms) and the outcome of the treatment. The effectiveness of combination therapy daklataswir + asunaprevir was reduced in patients with chronic hepatitis C genotype 1b with replacement NS3-D168E at the initial level. The incidence of this change was 0.7% (6 of 905 patients) and was initially present in 2% (3 of 138) of patients who had failed therapy.

Combination therapy daklataswir, peginterferon alfa and ribavirin: from 379 patients with available initial genotyping NS3 4 had substitutions in position R155 (R155K/T) and / or D168 (D168E/N), associated with resistance to asunaprevir. Of the 4 patients, three patients were ineffective (all 3 were infected with HCV genotype 1a).

The resulting resistance during treatment the patients who did not reach SVR

Most of the Nazis with chronic hepatitis C genotype 1b, treated with a combination daklataswir and asunaprevir, with failure of treatment, had substitutions related to resistance to asunaprevir and daklatasvir; replacements NS5A-L31, NS5A-Y93H and NS3- D168 often (79%) were observed together.

Substitutions NS5A-Q30 and NS3-R155 were most often observed together with ineffective therapy with a combination of drugs daklataswir, peginterferon alfa and ribavirin (61%) in patients with chronic hepatitis C with genotype 1a, whereas NS5A-L31I/M-Y93M and NS3-D168V were observed in a single patient with HCV with genotype 1b with ineffectiveness of therapy.

Pharmacokinetics:

The pharmacokinetic properties of asunaprevir were evaluated in adult healthy volunteers and in patients with chronic hepatitis C.After repeated oral administration of asunaprevir at a dose of 100 mg twice daily in combination with daklatasvir, the mean (variability factor,%) of the maximum concentration (C_m_Oh) of asunaprevir was 572 (75) ng / ml, the area under the concentration-time curve was from 0 to 12 h (AUC_0-12h) was 1887 (77) ng · h / ml and the minimum concentration (C_min) was 47.6 (105) ng / ml.

Absorption and bioavailability

Absorption fast. FROM_max Asunaprevir is observed through 1-4 hours after ingestion. AUC, FROM_m_Oh, FROM_minare dose-dependent, a stable concentration of asunaprevir in the blood plasma is observed after 7 days of application of the drug when taken orally 2 times a day. Research in vitro, conducted with human cells of the Caco-2 line, showed that asunaprevir is a substrate for P-glycoprotein (P-gp). 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 (about 1000 Kcal with a fat content of about 50%) increased the degree of absorption with respect to the fasting state, but did not have a clinically significant effect on the overall bioavailability of asunaprevir, increasing C_m_Oh and AUC by 34% and 20%, respectively. The time to reach the maximum concentration (T_m_Oh) Asunaprevir, when taken with food, was observed after 1.5 hours, whereas when taken on an empty stomach it was about 2.5 hours.

Distribution

Research in vitro, carried out on HEK-293 cells, showed that asunaprevir is the carrier substrate of the hepatic capture system of the AATR 1B1 and 2B1. In those receiving 100 mg of asunaprevir in soft gelatin capsules, followed by intravenous injection of 100 μg of asunaprevir labeled with radioactive carbon C14 ([¹⁴C] -asunaprevir), the volume of distribution (V_ss) is 194 liters. 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%.

Metabolism

Research in vitro showed that asunaprevir is exposed to oxidative metabolism mainly through isoenzyme CYP3A.

Excretion

Given that the 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 administration by healthy volunteers of single doses [¹⁴C] - asunaprevir, 84% of all radioactivity was excreted through the intestine (mainly in the form of metabolites, unchanged asunaprevir 7.5% dose), and less than 1 % was excreted by the kidneys (mainly in the form of metabolites). how asunaprevir, and heo metabolites were determined in the bile of a person.

After repeated intake of asunaprevir with healthy volunteers, the half-life of asunaprevir ranged from 17 to 23 hours. In patients who took asunaprevir in soft capsules 100 mg followed by intravenous injection of 100 μg [¹⁴C] - asunaprevir, the total clearance was 49.5 l / h.

Patients with impaired renal function

The pharmacokinetic properties of asunaprevir were studied in patients without HCV infection suffering from end-stage kidney disease (PTCA) and on dialysis after using 100 mg of asunaprevir twice a day for 7 days. Average value of the indicator AUC Asunaprevir was 10% lower and C_max was 29% higher in patients with PTCA compared with those with normal renal function.

Population pharmacokinetic analysis of patients with chronic hepatitis C with mild or moderate renal insufficiency showed that creatinine clearance did not affect the pharmacokinetic parameters of asunaprevir in a clinically significant manner.

Patients with impaired hepatic function

The pharmacokinetic properties of asunaprevir were studied in patients without HCV infection with mild (class A), medium (class B), and severe (class C) liver function impairment (Child-Pugh scale) compared to patients without hepatic impairment. The values of C_m_Oh, AUC and C_min Asunaprevir was significantly increased (in 5.0, 9.8 and 32.9 times, respectively) in patients with moderate hepatic insufficiency and in 22.9, 32.1 and 76.5 times, respectively, in patients with severe impairment liver function but compared with the values of these indicators in healthy volunteers.

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.

Floor

Population pharmacokinetic analysis of the results of clinical studies has revealed the effect of sex on the apparent volume of distribution of asunaprevir, but the degree of this effect is not clinically significant.

Indications:

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

- with the drug daklataswir for patients with hepatitis C virus of genotype Ib;

- with preparations daklataswir, peginterferon alfa and ribavirin for patients with hepatitis C virus of genotype 1.

Contraindications:

- The drug should not be used in the form of monotherapy;

- Hypersensitivity to asunaprevir and / or any of the auxiliary components of the drug;

- In patients with moderate to severe hepatic insufficiency (grade B and C in Child-Pugh, 7 or more) and decompensated liver disease;

- Simultaneous reception with medicines:

- the clearance of which is highly dependent on isoenzyme 2D6 (CYP2D6) cytochrome P450 and in which elevated plasma concentrations are associated with serious and / or life-threatening events (narrow therapeutic index): flecainide, propafenone, thioridazine;

- which to a significant or moderate extent induce isoenzyme 3A (CYP3A) cytochrome P450 and, thus, can lead to a decrease in the concentration and loss of efficacy of asunaprevir: phenytoin, carbamazepine, phenobarbital, rifampicin, rifabutin, rifapentin, nafcillin, bosentan, dexamethasone, preparations of St. John's wort perfumed (Hypericum perforatum), efavirenz, etravirine, modafinil, nevirapine;

- which to a large or moderate extent suppress the isoenzyme CYP3A and, thus, can lead to an increase in the concentration and increase of toxicity of asunaprevir: ketoconazole, itraconazole, voriconazole, fluconazole, phosphluconazole, miconazole, clarithromycin, erythromycin, diltiazem, verapamil, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, darunavir, fosamprenavir;

- which largely suppress transport polypeptides (OATP) 1B1 or 2B1 organic anions and, thus, can lead to a decrease in the concentration in the liver and loss of efficacy of asunaprevir such as: rifampicin, ciclosporin, sirolimus, gemfibrozil.

- In the presence of contraindications to the use of drugs combined scheme (daklataswir and / or peginterferon alfa + ribavirin) - see instructions for the use of appropriate drugs;

- pregnancy and lactation;

- Age under 18 years (effectiveness and safety not studied).

Carefully:

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

Joint use of Sunvepra with other drugs can lead to a change in the concentration of both asunaprevir and other drugs (see section "Interaction with other drugs").

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), the reproductive toxicity of the drug was not revealed. Applying a combination Daklataswir + asunaprevir when 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 the asunaprevir in breast milk. Asunaprevir penetrated into breast milk in animal studies, so if you need to use the drug Sunvepra during lactation should stop breastfeeding.

Daklatasvir + Asunaprevir + Peginterferon alfa + ribavirin

The use of ribavirin can cause fetal malformations, fetal death and abortion, so careful care should be taken when using a therapy regimen that includes 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.

Dosing and Administration:

Recommended dosing regimen

The recommended dose of Sunvepra is 100 mg twice daily, regardless of food intake. The drug should be used in combination with other medicines (see Table 1). and already at the beginning of therapy, drugs asunaprevir and daklataswir always apply simultaneously. Recommendations for doses of other drug regimens are given in the relevant instructions for medical use. Therapy is recommended both for patients who have not previously received treatment for chronic hepatitis C, and for patients with previous ineffectiveness of therapy.

Table 1. Recommended schemes for the therapy of the drug Sunvepr when used at a dose of 100 mg twice a day as part of a combination therapy

Genotype of HCV	Treatment	Duration
Genotype 1b	daklatasvir + asunaprevir	24 weeks
Genotype 1	daklatasvir + asunaprevir + peginterferon alfa and ribavirin	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, use of the drug Sunvepra in the form of monotherapy should not be used.

During treatment, it is necessary to monitor the viral load (the amount of HCV RNA 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. Termination of treatment is recommended in patients with a virologic breakthrough - an increase in the level PHK HCV on more than 1 log₁₀ from the previous level.

Dose skip

In case of missed receipt of another dose of the drug Sunvepra for up to 8 hours, the patient should take the drug as soon as possible and then adhere to the original therapy. If, when a dose is missed, more than 8 hours have elapsed 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.

Patients with renal insufficiency

Dose changes in patients with renal failure of any degree are not required.

Patients with hepatic insufficiency

Dose changes in patients with mild liver failure (class A on the Child-Pugh scale) are not required. Therapy with patients with moderate to severe hepatic insufficiency (class B and C on the Child-Pugh scale) and decompensated liver disease is contraindicated.

Side effects:

The drug Sunvepra is used only as part of combined therapy. It is necessary to get acquainted with the side effect of the medications included in the treatment regimen before the initiation of therapy. Unwanted drug reactions (NLR) associated with the use of daklatasvira, peginterferon alfa and ribavirin are described in the instructions for the medical use of these drugs.

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

The safety of daklataswir in combination with asunaprevir was evaluated in 4 studies with an average duration of 24 weeks. The most common (frequency of 10% and higher) of NLR observed in clinical trials using a therapy regimen Daklataswir + Asunaprevir, there was a headache (15%) and increased fatigue (12%). Most HLP were mild and moderate in severity. In 6% of patients, serious adverse events (SNR) were registered, 3% of patients discontinued treatment due to the occurrence of NLR. In this case, the most common The adverse events (AEs) leading to discontinuation of treatment were an increase in the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (ACT). In a clinical study of drug therapy Daklataswir + Asunaprevir during the first 12 weeks of treatment, the frequency of reported HLR was similar between patients receiving placebo and patients receiving this therapy.

Undesirable reactions that occurred in ≥5% of patients with chronic hepatitis C when combined Daklataswir + Asunaprevir, are presented below.

Frequency of occurrence of NLR according to the scale: very often (≥1 / 10), often (≥1 / 100 and <1/10)

Table 2.
	Undesirable reactions^a
Disturbances from the nervous system
Often	Headache (15%)
Disorders from the gastrointestinal tract
Often	Diarrhea (9%), nausea (8%)
General disorders
Often	Fatigue (12%)
Laboratory and instrumental data
Often	Increase in ALT (7%), increase ACT (5%)

^a - undesirable reactions, the relationship of which with the use of the drug is at least possible.

Combined data from several studies.

Undesirable reactions that occur in less than 5% of patients with chronic hepatitis C when combined Daklataswir + Asunaprevir: skin rash, itchy skin, alopecia; eosinophilia, thrombocytopenia, anemia; fever, malaise, chills; insomnia; decreased appetite, abdominal discomfort, constipation, upper abdominal pain, stomatitis, bloating, vomiting; increased blood pressure; pain in the joints, stiff muscles; nasopharyngitis, pain in the oropharynx; increased activity of gamma globulin transferase, alkaline phosphatase, lipase, and hypoalbuminemia.

Asunaprevir in combination with daklatasvir, peginterferon alfa and ribavirin The safety of the use of asunaprevir in combination with daklatasvir, peginterferon alfa and ribavirin was evaluated in a clinical study HALLMARK QUAD with an average duration of 24 weeks. The most common NLRs (frequency 15% and higher), observed in clinical studies using a therapy regimen Daklatasvandp + AsunaPauditor Pegandnterferon alfa + Ribavirin were: fatigue (39%), headache (28%), pruritus (25%), asthenia (23%), flu-like condition (22%), insomnia (21%), anemia (19%), rash (18 %), alopecia (16%), irritability (16%) and nausea (15%). Additional side effects occurred in patients with chronic hepatitis C when using a therapy regimen Daklataswir + Asunaprevir + Peginterferon alfa + Ribavirin were dry skin (15%), decreased appetite (12%), muscle pain (14%), fever (15%), cough (13%), dyspnea (11%), neutropenia (14%), lymphopenia 1%), diarrhea (14%), joint pain (9%). Most NLDs were mild and moderate in severity. In 6% of patients, SNAP was registered. 5% of patients discontinued treatment due to AE, the most common AEs leading to discontinuation of treatment were rash, malaise, dizziness and neutropenia.

In a clinical study of therapy Daklataswir + Asunaprevir + Peginterferon alfa + Ribavirin the frequency 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 HLR were the only ones that occurred at a minimum rate of 5% higher than among patients receiving a placebo.

Laboratory results

The abnormal deviations of the laboratory parameters from the norm of 3-4 degrees, observed among patients with chronic hepatitis C who received combined treatment with the drug Sunvepra, are presented in the table.

Table 3. Pathological deviations of laboratory indicators from the norm of 3-4 degrees, observed in clinical trials

Parameter^a	Asunaprevir in combination with daklatasvir n= 918	Asunaprevir in combination with daklatasvir, peginterferon alfa, ribavirin n= 398
Increased activity of ALT (> 5.1 x VGN^b)	4%	3 %
Increased activity ACT (> 5.1 x VGN)	3 %	3%
Increase in the concentration of total bilirubin (> 2.6 VGN)	1 %	1 %

^a- The results of laboratory studies were classified by the system DAIDS

for the classification of severity of adverse events in adults and children, version 1.0.

^b- upper limit of the norm

If any of the specified in the NLR instruction is aggravated or you notice any other side effects not indicated in the instructions, inform the doctor about it.

Overdose:

Symptoms of overdose are not described.

In Phase I clinical trials, when the drug was used in healthy volunteers, doses of up to 300 mg of asunaprevir twice a day for a period of up to 10 days did not cause unforeseen side effects. In clinical studies, the intake of doses of asunaprevir exceeding the recommended levels was associated with an increase in the activity of liver enzymes. Antidote to the drug Sunvipra is absent. Treatment of drug overdose should include general supportive measures, including monitoring of vital signs and monitoring the clinical state of the patient. Due to the high binding of asunaprevir to plasma proteins, dialysis is not recommended for overdose.

Interaction:

In view of the fact that Sunwapra is used as a part of combined treatment regimens,should be aware of the possible interactions with each of the drugs scheme.

In the elimination of asunaprevir isoenzyme participates CYP3A. Therefore, moderate and strong isoenzyme inducers CYP3A can reduce the concentration of asunaprevir in plasma, and moderate and strong inhibitors of isoenzyme CYP3A can increase the concentration of asunaprevir in plasma. Asunaprevir is also a substrate for transport P-glycoprotein (P-gp), but the joint use of tools that affect only the properties P-gp (without simultaneous effect on the isoenzyme CYP3A) is not sufficient to obtain a clinically significant effect on the concentration of plasma asunaprevir. OATR 1B1 and 2B1 are involved in the distribution of asunaprevir in the liver, so strong inhibitors of OATP-mediated transport can increase the concentration of plasma asunaprevir and may reduce the therapeutic effect.

Asunaprevir is a moderate isoenzyme inhibitor CYP2D6, a weak inhibitor of OATP 1B1/1B3/2B1 mediated transport and P-gp, and a weak isoenzyme inducer CYP3A. Caution should be exercised when using Sunvisra with the substrates of these isoenzymes or transport mechanisms with careful clinical monitoring of both the desired therapeutic effects,and undesirable phenomena. Asunaprevir in vitro did not suppress isoenzymes CYPIA2, CYP2C9 or CYP2C19.

Preparations, the use of which is contraindicated in conjunction with asunaprevir, are listed in Table 4 (see also the section "Contraindications"):

Table 4. Drugs, the use of which together with asunaprevir is contraindicated

The mechanism of interaction	Result interactions	Medicines that are contraindicated for use with asunaprevir
Inhibition of isoenzyme CYP2D6 asunaprevir	Increased plasma levels of the drug may lead to cardiac arrhythmias	Antiarrhythmics Flecainide, propafenop Antipsychotic agent Thioridazine
Strong or moderate induction of isoenzyme CYP3A from the side of the jointly used medicinal product	May result in no virologic response to asunaprevir	Antiepileptic facilities Phenytoin, carbamazepine, phenobarbital Antibacterial agents Rifampicin^b, Rifabutin, rifapentin, nafcillin The receptor antagonist endothelin Boszentan System glucocorticosteroids Dexamethasone
		Herbal products Preparations of St. John's wort perfumed (Hypericum perforatum) Non-nucleoside reverse transcriptase inhibitors Efavirenz, etravirine, nevirapine Analeptics Modafinil
Significant or moderate inhibition of isoenzyme CYP3A from the side of the medication used together, in some cases (for example ketoconazole, itraconazole, clarithromycin, erythromycin, diltiazem, lopinavir / ritonavir, verapamil) in combination with inhibition P-gp	An increase in the concentration of asunaprevir may increase the likelihood and severity of adverse reactions from the hepatobiliary system	Antifungal means 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
Significant inhibition of the OATP 1B1 or 2B1	May result in no virologic response to asunaprevir	Antibacterial agents Rifampicin^b, Immunosuppressive drugs Cyclosporine, sirolimus Lipid-lowering drugs Gemfibrozil

^b- Rifampicin has both an inducing action on CYP3A, and inhibiting on the OATP 1B1 and 2B1.

Table 5 below provides information on drug interactions of Sunvepra and clinical recommendations for established and potentially significant drug interactions. Clinically significant increase in concentration is shown as "↑", clinically significant decrease in concentration - as "↓" and absence of clinically significant changes - as "↔".

Table 5. Information on the drug interaction of the drug Sunvepra and other drugs

Drugs for therapeutic areas	Interaction	Recommendations for joint application
Antiviral drugs, HCV
Daklatasvir 30 mg once daily	↔ asunaprevir ↔ daklutasvir	Correction of the dose of asunaprevir is not required
Peginterferon alfa 180 μg once a week and ribavirin 500 mg or 600 mg twice daily	↔ asunaprevir ↔ peginterferon alfa ↔ ribavirin	Correction of the dose of asunaprevir, peginterferon alfa or ribavirin is not required
DRUGS SUPPRESSING ACID FORMATION
Proton Pump Inhibitors
Omeprazole 40 mg once	↔ omeprazole	Correction of the dose of omeprazole or other isoenzyme substrates CYP2CI9 is not required. The use of this combination does not affect the kinetics of asunaprevir.
ANTI-DEPRESSANTS
Selective serotonin reuptake inhibitors
Escitalopram 10 mg once daily	↔ asunaprevir ↔ escitalopram	Correction of the dose of Sunvepr's and escitalopram not required
Sertraline 50 mg once daily	↔ asunaprevir ↔ sertraline	Correction of the dose of Sunvepr's and sertraline not required.
ANTIHYPERTENSIVE MEANS
Losartan 25 mg once	↔ losartan	Correction of dose of losartan or other isoenzyme substrates CYP2C9 is not required. With the combined use of angiotensin-2 receptor blockers and asunaprevir, a clinically significant change in the kinetics of asunaprevir is not expected.
MISCELLANEOUS AGENTS
Dextromethorphan 30 mg once	↑ dextromethorphan Suppression of isoenzyme CYP2D6 from the side of asunaprevir.	A thorough clinical monitoring is required when combined use of dextromethorphan or other isoenzyme substrates CYP2D6 with the drug Sunvepra.It is recommended to consider a decrease in the dose of sensitive substrates of the isoenzyme CYP2D6.
CARDIOVASCULAR RESOURCES
Antiarrhythmics
Digoxin 0.5 mg once	↑ digoxin Suppression P-gp from the side of asunaprevir	Digoxin and other substrates P-gp with a narrow therapeutic range should be used with caution when used in conjunction with asunaprevir. The lowest dose of digoxin should be administered and the digoxin concentration in the blood plasma should be monitored. To achieve the desired therapeutic effect, dose titration should be used.
HORMONAL CONTRAINDICATIONS
Ethinylestradiol 35 μg once a day + norgestimate 0.180 / 0.215 / 0.250 mg once and day for 7/7/7 days	↓ ethinylestradiol ↓ noregestromine Ethinyl estradiol: induction of isoenzyme CYP3A Noregestromine: the mechanism is unknown.	For patients who use oral contraceptives. recommended the use of high-dose oral preparations containing at least 30 μg of ethinylestradiol in combination with norethindrone acetate / norethindrone when used in conjunction with asunaprevir.Simultaneous administration does not have a clinically significant effect on the pharmacokinetics of asunaprevir.
Ethinylestradiol 30 μg once daily / norethindrone acetate 1.5 mg once daily (high-dose contraceptive)⁵⁵ (asunaprevir 100 mg twice a day and daklataswir 60 mg once and day)	↔ ethinylestradiol * ↔ norethindrone * ↑ ethinylestradiol * ↑ norethindrone * * Pharmacokinetics ethinylestradiol / norethindrone in a joint application of high doses oral contraceptives with asunaprevir and daklataswir compared with pharmacokinetics ethinyl estradiol / norethindrone when used alone low doses of oral contraceptives (ethinylestradiol 20 μg once a day / norethindrone 1 mg once daily).
HYPOLIPIDEMIC MEANS
Inhibitors of reductase HMG-CoA (statins)
Rosuvastatin 10 mg once	↑ rosuvastatin Suppression of the 1B1 / 1B3 OATP from the side of asunaprevir.	Treatment with rosuvastatin and other substrates of OATP 1Bl/1B3 can be started with the recommended doses when combined with the drug Sunvepra, with careful monitoring of side effects and the therapeutic effect of rosuvastatin.
OPIOIDS
Methadone, stable maintenance application 40-120 mg	↔ total methadone ↔ R-methanone	Correction of methadone dose when combined with Asunaprevir is not required
ESSENTIAL MEANS
Benzodiazepines
Midazolam 5 mg once	↓ midazolam Induction of isoenzyme CYP3A from the side of asunaprevir	Combination with asunaprevir should be used with caution because of a decrease in midazolam in the blood plasma and a decrease in its therapeutic effect. Similarly for other drugs group, the elimination of which depends on the isoenzyme CYP3A.
STIMULATORS
Caffeine 200 mg once	↔ caffeine	Correction of the dose of caffeine or other substances metabolized by the isoenzyme CYP1A2, is not required.

Special instructions:

Asunaprevir therapy 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 increased activity of alanine aminotransferase (ALT) and aspartate aminotransferase (ACT) At least 5 times higher than the upper limit of the norm (VLN) was 3 to 4%.and the frequency of increasing bilirubin concentration by at least 2.6 times was I%. When applying the combination asunaprevir + daklataswir increased 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 efficacy of combined therapy with Sunwepr in patients with decompensated liver disease, with transplanted liver and other transplanted organs has not been 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.

Effect on the ability to drive transp. cf. and fur:

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 the patient has AEs that may affect the ability to concentrate, he should refrain from driving and working with machinery.

Form release / dosage:

Capsules soft 100 mg.

Packaging:

14 capsules per perforated PVC / Aklar blister^® and aluminum foil with a paper coating on the outside.

By 4 perforated blisters together with instructions for use in a cardboard bundle.

Storage conditions:

At a temperature of no higher than 25 ° C in a dark place.

KEEP OUT OF THE REACH OF CHILDREN.

Shelf life:

2 years.

Do not use the product after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003022

Date of registration:03.06.2015

The owner of the registration certificate:Bristol-Myers Squibb CompanyBristol-Myers Squibb Company USA

Manufacturer: & nbsp

Representation: & nbspBRISTOL-Majers SKVIBB, LLCBRISTOL-Majers SKVIBB, LLCRussia

Information update date: & nbsp09.03.2016

Illustrated instructions

Instructions

Sunwapra ™ (Sunvepra ™)