Viqueira Pak (Viekira Pak)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceDasabuvir; Ombitasvir + Paritateapyr + RitonavirDasabuvir; Ombitasvir + Paritateapyr + Ritonavir
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  • Viqueira Pak
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    EbbVi Ltd.     Russia
    • Dosage form: & nbsp

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    Composition:

    1 mabldasabuvirara (film coated tablets, 250 mg) contains:

    Active substance: dasabuvir sodium monohydrate (in terms of dasabuvir) - 270.26 mg (250 mg).

    Excipients: microcrystalline cellulose (type Avicel® PH 101) - 103.04 mg, microcrystalline cellulose (of the type Avicel® PH 102) 104.72 mg, lactose monohydrate 47.10 mg, copovidone 101.35 mg, croscarmellose sodium 33.78 mg, silicon colloidal dioxide 4.05 mg, magnesium stearate 11.15 mg, film (Opadry II Beige) - 21.00 mg (polyvinyl alcohol (40.00%), titanium dioxide (21.55%), macrogol 3350 (20.20%), talc (14.80%) , iron oxide yellow (3.00%), iron oxide red (0.35%), iron oxide black (0.10%)).

    1 tablet of ombitasvir + parapravir + ritonavir (tablets, film-coated, 12.5 mg + 75 mg + 50 mg) contains:

    Asubstances: ombitasvir hydrate (1: 4.5) (in terms of ombinsavir) - 13.6 mg (12.5 mg); paritrapepril dihydrate (in terms of paritrapeprir) - 78.5 mg (75.0 mg); ritonavir 50.0 mg.

    Excipients: copovidone - 849.2 mg, D-alpha-tocopherol macrogol succinate - 42.5 mg, silicon colloidal dioxide -10.8 mg, propylene glycol monolaurate-10.0 mg, sorbitan laurate-33.3 mg, film coating, Opadrai II pink (Opadry II Pink) - 32.5 mg (polyvinyl alcohol (46.94%), macrogol 3350 (23.70%), talc (17.36%), titanium dioxide (11.90%), iron oxide red (0.10% )).

    Description:

    Dasabuvir - oval tablets covered with a film shell of light brown color with engraving "AV2" on one side.

    Ombitasvir + Paritateapyr + Ritonavir - oblong biconvex tablets covered with a pink film shell with an engraving "AV1" on one side.

    Pharmacotherapeutic group:Antiviral agent
    ATX: & nbsp

    J.05.A.X.66   Dasabuvir, ombitasvir, paritrapepril and ritonavir

    Pharmacodynamics:

    Mechanism of action

    The Vikaira Pak drug combines three direct antiviral agents for the treatment of viral hepatitis C (HCV) with various mechanisms of action and with non-overlapping resistance profiles, which makes it possible to fight the hepatitis C virus at various stages of its life cycle, and ritonavir.

    Dasabuvir

    Dasabuvir is a non-nucleoside inhibitor of the RNA-dependent RNA polymerase of the virus encoded by the gene NS5B, which is necessary for the replication of the viral genome. According to biochemical studies, dasabuvir inhibits polymerase activity NS5B enzymes of the recombinant genotype 1a and 1b HCV with values IFROM50 2.8 and 10.7 nM, respectively.

    Ombitaswir

    Ombitaswir is an inhibitor of HCV NS5A protein required for viral replication. In studies on replicon cell cultures, the EU values50 for ombitasvir were 14.1 and 5.0 pM for HCV genotypes 1a and 1b, respectively.

    Paritaprevir

    Paritaprevir is an inhibitor of HCV protease NS3/4A, which is necessary for proteolytic cleavage of the encoded polyprotein of HCV (into mature forms of proteins NS3, NS4A, NS4B, NS5A and NS5B) and is important for the replication of the virus. According to biochemical analysis, paritrapevir inhibits the proteolytic activity of the protease NS3/4A recombinant genotype of HCV 1a and 1b with values IC50 0.18 and 0.43 nM, respectively.

    Ritonavir

    Ritonavir does not have antiviral activity against HCV. Ritonavir acts as a pharmacokinetic enhancer that increases the peak concentration of paritaprevir in the blood plasma and the concentration of paritapovir, measured immediately before taking its next dose, and increases the overall exposure of the drug (i.e.area under the curve "concentration-time").

    Pharmacokinetics:

    The pharmacokinetic properties of the combined use of ombitaswir / paritaprevir / ritonavir and dasabuwir were evaluated in healthy adults and in patients with chronic hepatitis C.

    Table 1 shows the average values ​​of Cmax (maximum concentration) and AUC (area under the pharmacokinetic concentration-time curve) of ombitasvir / paritrapevir / ritonavir 25/150/100 mg once daily with dasabuwir 250 mg twice daily from healthy volunteers after taking multiple doses with food.

    Table 1. The average geometric Cmax, AUC several doses of ombitolcvira / parinaprevir / ritonavir 25/150/100 mg once a day in combination with dasabuwir 250 mg twice daily during the intake of healthy volunteers

    FROMmax (ng / ml),

    (the coefficient of variation, %)

    AUC (ng * h / ml)

    (the coefficient of variation, %)

    Yescabuvir

    1030 (31)

    6840 (32)

    Ombitaswir

    127 (31)

    1420 (36)

    Paritaprevir

    1470 (87)

    6990 (96)

    Ritonavir

    1600 (40)

    9470 (41)

    AUC24 - value for ombitasvir, paritrapeprivir and ritonavir; AUC12 - a value for dasabuvir.

    Suction

    Ombitasvir / paritrapeprir / ritonavir and dasabuvir are absorbed after oral administration at an average Tmax (the time of maximum concentration) from 4 to 5 hours. The exposure of ombitasvira and dasabuvir increases in proportion to the dose, while the exposure of paritaprevir and ritonavir increases more than proportionally to the dose. The cumulation coefficient of ombitasvir and dasabuvir is minimal, while for ritonavir and paritrapevir it is 1.5 to 2. The pharmacokinetic equilibrium concentration for the combination is achieved after about 12 days of use.

    The absolute bioavailability of ombitasvira, paritrapeprivir and dasabuvir was approximately 50% when a combination of ombitasvir + paritrapepriv + ritonavir. The absolute bioavailability of dasabuvir was approximately 70%.

    Effect of food on absorption

    Ombitasvir / paritaprevir / ritonavir and dasabuvir should be taken with food. In all clinical studies, ombitasvir / paritaprevir / ritonavir and dasabuvir were taken during meals.

    Reception with food increases exposure (AUC) of ombitasvira / paritaprevir / ritonavir and dasabuvir by almost 82%, 211%, 49% and 30%, respectively, with respect to fasting.The increase in exposure was the same regardless of the type of food (for example, a meal with a high fat content compared to a moderately fatty meal) or caloric content (approximately 600 kcal compared to 1000 kcal). In order to maximize bioavailability, Vikaira Pak should be taken with meals, regardless of the fat content or calorie content of the food.

    Distribution

    Ombitasvir / paritrapeprir / ritonavir and dasabuvir actively bind to blood plasma proteins. Binding to blood plasma proteins is virtually unchanged in patients with renal or hepatic insufficiency. The ratio of concentrations in the blood and blood plasma in humans is 0.49; 0.7; 0.6 and 0.7 for ombitasvir + pariteprevir + ritonavir, indicating that paritrapeprir, ombitasvir and dasabuvir are predominantly distributed in the blood plasma.

    Paritaprevir approximately 97-98.6% binds to human plasma proteins at a concentration range of 0.08 μg / ml to 8 μg / ml.

    Ritonavir more than 99% binds to human plasma proteins at concentrations ranging from 0.007 μg / ml to 22 μg / ml.

    Ombitaswir approximately 99.5% binds to human plasma proteins at a concentration range of 0.09 μg / ml to 9 μg / ml.

    Dasabuvir more than 99.9% binds to human plasma proteins at concentrations ranging from 0.15 μg / ml to 5 μg / ml.

    In animal studies, the concentration of paraprepivir in the liver was significantly higher than the concentration in the blood plasma (for example, the ratio in the liver and in blood plasma of more than 300: 1 in mice). Research data in vitro indicate that paritrapepril is a substrate for hepatic transporters OATP1B1 and OATP1B3.

    Metabolism and excretion

    Metabolism and excretion of the drug Viqueira Pak were studied with the help of paritrapevir, ombitasvir, ritonavir and dasabuvir, labeled with carbon isotope C14.

    The methods of radioisotope diagnostics are based on the detection, recording and measurement of radiation from radioactive isotopes. These methods allow you to explore the absorption, movement in the body, accumulation in individual tissues, biochemical transformations and the isolation of the substances from the body.

    Dasabuvir

    Dasabuvir is mainly metabolized by isoenzyme CYP2C8 and to a lesser extent - isoenzyme CYP3A. After taking 400 mg of dasabuvir (carbon-labeled C14) in humans dasabuvir in its unaltered form was the main component (approximately 60%); In the blood plasma, seven dasabuwir metabolites were found.The most common metabolite in plasma was M1, which was 21% of AUC and in vitro showed the same properties (with regard to binding to blood plasma proteins) for HCV genotype 1, which is the original drug.

    Ombitaswir

    Ombitasvir is metabolized by amide hydrolysis followed by oxidative metabolism. After taking a single dose of 25 mg of ombitasvir (labeled with carbon isotope C14) without taking other medications, the initial drug, which did not undergo changes, accounted for 8.9% of the total volume in the blood plasma; in total, 13 metabolites in plasma were detected. These metabolites do not possess antiviral or any other pharmacological activity.

    Paritaprevir

    Paritaprevir is metabolized predominantly by isoenzyme CYP3A4 and to a lesser extent isoenzyme CYP3A5. After receiving a single oral dose of 200/100 mg of paritrapevir (carbon-labeled C14) / ritonavir, the initial drug was the main circulating component, amounting to approximately 90% in the blood plasma. Plasma detected at least 5 minor metabolites of paritrapevir, which corresponds to approximately 10%.These metabolites do not have antiviral activity.

    Ritonavir

    Ritonavir is predominantly metabolized by isoenzyme CYP3A and at less isoenzyme CYP2D6. Almost the whole radioactivity of blood plasma after a single dose of oral solution of 600 mg of ritonavir (labeled with carbon isotope C14) in the human body was associated with unchanged ritonavir.

    Excretion

    Dasabuvir

    After taking dasabuwir with ombitasvir / paritrapevir / ritonavir, the average half-life of dasabuvir was about 5.5-6 hours. After taking 400 mg of dasabuvir (carbon-labeled C14), about 94.4% of the isotopes were found in the stool and a small amount (about 2%) in the urine.

    26% of the isotopes of unaltered dasabuwir were found in feces and 0.03% in urine.

    Ombytaswir

    After taking ombitasvir / pariteprevir / ritonavir with dasabuvir or without it, the average half-life of ombitasvir was about 21-25 hours. After taking 25 mg of ombitasvir (labeled with carbon isotope C14), about 90.2% of the isotopes were found in the stool and a small amount (1.91%) in the urine. 87.8% of the isotopes of unmodified ombitasvir were found in feces and 0.03% in urine.

    Paritaprevir

    After taking ombitasvir / paritapovir / ritonavir with or without dasabuvir, the average half-life of paritaprevir from the blood plasma was about 5.5 hours. After the joint application of 200 mg of paritaprevir (isotope-labeled carbon C14) with 100 mg of ritonavir, about 88% of the isotopes were detected in the stool and a small amount (8.8%) in the urine.

    1.1% of the isotopes of unchanged paraprepivir were found in stool and 0.05% - at urine.

    Ritonavir

    After taking ombitasvir / paritaprevir / ritonavir, the average half-life of ritonavir from the plasma was about 4 hours. After taking 600 mg of ritonavir (carbon-labeled C14) in the form of a solution for oral administration - 86,4% isotopes were found in feces and 11.3% from the dose in the urine.

    Special patient groups

    Age

    Elderly patients

    There is no need to adjust the dose of Viqueira Pak in elderly patients.

    Children

    The pharmacokinetics of the drug Viqueira Pak in patients of childhood is not investigated.

    Sex and weight

    There is no need to adjust the dose of the Viqueira Pak drug depending on sex or body weight.

    Race and ethnic belonging

    There is no need to adjust the dose of the Viqueira Pak drug depending on race and ethnicity

    Impaired liver function

    The pharmacokinetics of the combination of 200 mg of paritaprevir, 100 mg of ritonavir, 25 mg of ombitasvir and 400 mg of dasabuir were evaluated in patients with mild (class A on the Child-Pugh scale), medium (class B on the Child-Pugh scale) and severe (class C on the Child scale -Pew) degree of hepatic insufficiency.

    Compared with patients with normal liver function in patients with mild hepatic impairment FROMmax and AUC paritrapeprivir, ritonavir and ombitasvir decreased by 29-48%, 34-40% and up to 8% respectively, the average values ​​of Cmax and AUC for dasabuvir were 17-24% higher.

    In comparison with patients with normal liver function in patients with moderate hepatic impairment, the mean Cmax and AUC for paritrapepril were increased by 26-62%, for ombitasvir and ritonavir, the mean and AUC decreased by 29-30% and 30-33% respectively; mean Cmax and AUC dasabuvir were reduced by 16-39%.

    Compared with patients with normal liver function in patients with severe hepatic impairment, the mean Cmax and AUC paritrapeprivir and dasabuvir increased by 3.2-9.5 times and 0.3-3.3 times, respectively, the mean values Cmax ritonavir were 35% lower, a AUC 13% higher, the value of Cmax and AUC ombitasvira decreased by 68% and 54% respectively. Viqueira Pak can not be used for moderate to severe hepatic insufficiency (classes B and C on the Child-Pugh scale).

    Impaired renal function

    The change in the exposure of paritrapeprir, ombitasvira, dasabuvir and ritonavir in patients with mild, moderate and severe renal insufficiency is clinically insignificant, therefore, a change in the dose of Viqueira Pak is not required for hepatitis C-infected patients with mild, moderate or severe renal insufficiency.

    The pharmacokinetics of a combination of 25 mg of ombitasvir, 150 mg of parapravir and 100 mg of ritonavir with or without 400 mg of dasabuvir was evaluated in patients with mild (creatinine clearance from 60 to 89 ml / min), mean (creatinine clearance from 30 to 59 ml / min) and severe (creatinine clearance from 15 to 29 ml / min) degree of renal failure.

    Compared with subjects with normal renal function in patients with mild renal failure, the Cmax and AUC for paritrapeprira were comparable (up to 19% higher), mean values Cmax and AUC for ombitasvir were comparable (up to 7% lower), the average values ​​of Cmax and AUC for ritonavir were higher by 26-42%, and for dasabuvir, the average Cmax and AUC higher by 5-21%.

    In comparison with subjects with normal renal function in patients with an average degree of renal failure, the values ​​of Cmax were comparable (an increase of less than 1%), and the values AUC were 33% higher, the average values ​​of Cmax and AUC for ombitasvir were comparable (up to 12% lower), for ritonavir the mean values FROMmax and AUC were higher by 48-80%, for dasabwir the average value of Cmax and AUC were higher and in 9-37%.

    Compared with subjects with normal renal function in patients with severe renal failure, the mean Cmax for paritrapepril were comparable (increase less than 1%) and values AUC were 45% higher, for ombitaswir the average values ​​of Cmax and AUC were comparable (up to 15% lower), for ritonavir the average values ​​of Cmax and AUC were 66-114% higher, and also for dasabwir the average values ​​of Cmax and AUC were higher by 12-50%.

    Indications:

    Chronic hepatitis C of genotype 1, including patients with compensated cirrhosis of the liver in combination with or without ribavirin.

    Contraindications:

    - Hypersensitivity to ombitasvir, paritrapevir, ritonavir, dasabvir or any excipients of the drug, (eg, toxic epidermal necrolysis or Stevens-Johnson syndrome).

    - The average and severe degree of hepatic insufficiency (classes B and C on the Child-Pugh scale).

    - Contraindications to the use of ribavirin (with the combined use of the drug Viqueira Pak and ribavirin). For information about the contraindications to the use of ribavirin, you should read its instructions for use.

    - The use of ribavirin in women during pregnancy, as well as in men whose partners are pregnant.

    - Simultaneous use of drugs, increasing the concentration of which in the blood plasma can lead to serious adverse reactions and the clearance of which significantly depends on the metabolism by isoenzyme CYP3A.

    - Simultaneous use of drugs that are potent inhibitors CYP2C8 (as this may lead to a significant increase in the concentration of dasabwir in the blood plasma and the risk of lengthening the interval QT).

    - Simultaneous use of drugs - powerful and moderate isoenzyme inducers CYP3A (can significantly reduce the concentrations of paritrapevir, ombitasvir and dasabuvir in blood plasma).

    - Simultaneous use of drugs, which are powerful inducers of isoenzyme CYP2C8 (as this can lead to a significant reduction in the concentration of dasabvir in the blood plasma).

    - Simultaneous use with drugs containing ethinyl estradiol (eg, combined oral contraceptives)

    - Simultaneous use with drugs:

    Substrates of the isoenzyme CYP3A4:

    • alfuzosin;
    • amiodarone;
    • astemizole, terfenadine;
    • colchicine (in patients with renal and / or liver failure);
    • ergot alkaloids (ergotamine, dihydroergotamine, ergometrine, methylergomethrin);
    • fusidic acid;
    • lovastatin, simvastatin, atorvastatin;
    • midazolam and triazolam (in medicinal forms for oral administration);
    • pimozide;
    • quetiapine;
    • quinidine;
    • salmeterol;
    • sildenafil (when used to treat pulmonary arterial hypertension);
    • ticagrelor;
    • cisapride.

    Inductors of isoenzyme CYP3A4:

    • carbamazepine, phenytoin, phenobarbital;
    • efavirenz;
    • nevirapine;
    • etravirine;
    • enzalutamide;
    • mitotane;
    • rifampicin;
    • preparations of St. John's wort (St. John's Wort, Hypericum perforatum).

    Inhibitor inhibitors CYP3A4:

    Inhibitor inhibitors CYP2C8:

    • gemfibrozil.

    Preparations metabolized by isoenzyme CYP3A4:

    • rilpivirin;

    HIV treatment day drugs, protease inhibitors

    • darunavir/ritonavir;
    • atazanavir / ritonavir in a fixed combination.

    - Children under 18 years.

    - Deficiency of lactase, intolerance to galactose, glucose-galactoseaI am malabsorption.

    Carefully:

    Joint use of the drug Viqueira Pak and fluticasone, or other glucocorticosteroids, which are metabolized with the participation of isoenzyme CYP3A4.

    Joint use with antiarrhythmic drugs.

    And also with the following drugs: bepridil, disopyramid, flecainide, lidocaine (systemic administration), mexiletine, propafenone, erythromycin, dabigatran, diltiazem, fluvastatin, repaglinide, sulfasalazine, trazodone, fexofenadine, deferazirox, teriflunomide.

    Pregnancy and lactation:

    Pregnancy

    The results of qualitative and well-controlled studies on the use of Viqueur Pak in pregnant women are not available.

    In animal studies using ombitasvir / paritrapevir / ritonavir and its basic inactivemetabolites in humans (M29, M36), as well as dasabuvir, there was no effect on the development of the embryo and fetus. In the tests using paritaprevir / ritonavir, the maximum doses corresponding to the 98-fold (in mice) or the 8-fold (in rats) recommended clinical dose in humans were used. In tests using ombitasvira, maximum doses corresponding to a 28-fold (in mice) or a 4-fold (in rabbits) recommended clinical dose in humans were used. The highest doses of the main inactive human metabolites in the study in mice gave exposures 26 times higher than in the human body using the recommended clinical doses. In trials using dasabvir, the maximum doses corresponding to 24-fold (in rats) or 6-fold (in rabbits) of the recommended clinical dose in humans were used.

    Due to the fact that it is impossible to draw conclusions on the use of the drug in pregnant women, based on the data obtained on animals, the drug Viqueira Pak should be used during pregnancy only in case of emergency, justified by the clinical situation.

    Co-administration with ribavirin

    The simultaneous administration of the drug Viqueira Pak with ribavirin is contraindicated in pregnant women, as well as in men whose partners are pregnant. Ribavirin may cause developmental and / or fetal death. Female patients and partners of male patients should take the best possible measures to avoid pregnancy, as in animal studies in all species exposed to ribavirin, a pronounced teratogenic effect and / or embryocidal effect was confirmed. Do not use a ribavirin treatment regimen until a negative pregnancy test result is obtained immediately before the start of therapy. For the period of treatment and for at least 7 months after the end, women of childbearing age and their partners, as well as male patients and their partners, are recommended to use at least two effective methods of contraception. During the entire treatment with ribavirin, scheduled pregnancy tests should be performed monthly

    Contraindicated simultaneous reception with Viqueira Pak combined contraceptives containing ethinyl estradiol.

    Before starting therapy, you should carefully read the instructions for use of ribavirin.

    Breastfeeding period

    No information on the penetration of ombitasvipa, paritrapeprivir, ritonavir or dasabuvir and their metabolites into breast milk in women.

    Paritaprevir and the product of its hydrolysis M13, ombitasvir and dasabuvir in unchanged form were the predominant components found in the milk of lactating rats without affecting the feeding young.

    Due to the possibility of adverse reactions due to the effect of the drug on infants, a decision must be made to stop breastfeeding or discontinue treatment with Wikeyra Pak taking into account the importance of therapy for the mother.

    Patients receiving ribavirin, please read its instruction manual.

    Dosing and Administration:

    Inside. The drug Viqueira Pak should be taken with meals, regardless of fat content or calorie content of food.

    Before starting therapy with Vikayr Pak, it is necessary to exclude decompensation of liver function on the basis of laboratory and clinical signs

    The recommended dose of Viqueira Pak includes two ombitasvir / paritrapevir / ritonavir 12.5 / 75/50 mg once a day (morning) and one dasabuwir 250 mg twice daily (morning and evening). In some groups of patients, the Vickeira Pak preparation is used in combination with ribavirin (see Table 2).

    Table 2 shows the recommended treatment regimens and the duration of therapy, depending on the patient group.

    Table 2. Scheme of treatment and its duration for different groups of patients (first-time treatment or after therapy with interferon)

    Patient group

    Medications*

    Duration

    Genotype 1a, without cirrhosis

    Viqueira Pak + ribavirin

    12 weeks

    Genotype 1a, with cirrhosis

    Viqueira Pak + ribavirin

    24 weeks**

    Genotype 1b, without cirrhosis

    Viqueira Pak

    12 weeks

    Genotype 1b c cirrhosis

    Viqueira Pak + ribavirin

    12 weeks

    Notes:

    * It is recommended to follow the dosing regimen for genotype 1a in patients with unknown subtype of genotype 1 or genotype 1 of mixed type.

    ** Scheme of application of Viqueira Pak in combination with ribavirin for 12 weeks can be considered for some patients on the basis of previous therapy.

    When used with Viqueira Pak, the recommended dose of ribavirin is based on the body weight of the patient: 1000 mg per day for patients weighing ≤75 kg and 1200 mg / day for patients with a body weight> 75 kg divided into 2 divided meals a day. If it is necessary to correct the dose of ribavirin, it is recommended that you read its instructions for use.

    The drug Viqueira Pak should be taken in accordance with the duration recommended in the instructions for its use, without interrupting or changing the dose of the drug.

    If the drug Viqueira Pak is used in conjunction with ribavirin, then ribavirin should be appointed for the same period as the drug Viqueira Pak.

    Skipping the drug

    If you miss a pill containing ombitasvir + paritaprevir + ritonavir, the prescribed dose can be taken within 12 hours after the scheduled time.

    If a tablet containing dasabuvir is missed, the prescribed dose can be taken within 6 hours after the scheduled time.

    In the event that more than 12 hours have elapsed from the scheduled time of taking a tablet containing ombitasvir + paritrapeprir + ritonavir or more than 6 hours after the scheduled time of taking a tablet containing dasabuvir, missed doses are not taken and the patient should take the next dose according to the usual schedule of drug intake.

    Special patient groups

    Patients after liver transplantation

    The recommended duration of treatment for patients with normal liver function and fibrosis stage on a scale Metavir - 2 or less after liver transplantation with the use of the drug Viqueira Pak in combination with ribavirin is 24 weeks, regardless of the genotype of HCV 1 subtype.

    When using the drug Viqueira Pak with calcineurin inhibitors, a correction of the dose of calcineurin inhibitors is necessary.

    In clinical studies in patients after liver transplantation, ribavirin doses ranging from 600 mg to 800 mg per day were individually selected.

    Have patients with HCV / HIV-1 co-infection

    The recommendations in the Table should be followed 2. Recommendations for concomitant antiviral therapy for HIV-1 are presented in the section "Interaction with other drugs".

    Liver failure

    In patients with mild hepatic insufficiency (class A on the Child-Pugh scale), no adjustment of the dose of Viqueira Pak is required.Viqueira Pak is contraindicated in patients with moderate to severe hepatic insufficiency (class B and C on the Child-Pugh scale).

    Gel function tests should be monitored for the first 4 weeks of therapy (see section "Special instructions").

    Side effects:

    Clinical research experience

    If the drug Viqueira Pak is used with ribavirin: for information on the adverse reactions of ribavirin, you should read its instructions for use.

    The safety assessment is based on the combined data of phase 2 and 3 clinical trials in more than 2,600 patients who received Vikayr Pak with or without ribavirin.

    The drug Viqueira Pak in combination with ribavirinom (including in patients with cirrhosis)

    In patients receiving Viqueira Pak in combination with ribavirin, the most frequent adverse reactions observed (more than in 20% patients) were tired and nauseous. The number of patients who completely discontinued treatment due to adverse reactions was 1.2% (25/2044). 1.3% (27/2044) of patients were interrupted (with the possibility of further resumption) treatment due to side effects.7.7% (158/2044) patients required a lower dose of ribavirin due to adverse reactions.

    The safety profile of Viqueira Pak and ribavirin in patients with cirrhosis was similar to that in patients without cirrhosis.

    Use of Viqueira Pak without ribavirin

    Patients at clinical study, who received the drug Viqueira Pak without ribavirin, the only recorded adverse reaction was itching. The number of patients who completely discontinued treatment due to adverse reactions was 0.3% (2/588). 0.5% (3/588) of patients took breaks in treatment because of adverse reactions.

    Table 3 lists the adverse events associated with or unrelated to the use of Viqueira Pak, documented in two randomized, placebo-controlled trials (SAPPHIRE I and SAPPHIRE II), which were observed with a frequency of at least 5% higher than in patients receiving Viqueira Pak in combination with ribavirin, compared with patients receiving placebo.

    In addition, Table 3 includes a list of these adverse reactions in three studies in which patients received Viqueira Pak with or without ribavirinPEARL II, PEARL III and PEARL IV), and an analysis of these adverse reactions in studies in patients with cirrhosis who received Viqueira Pak in combination with ribavirin for 12 or 24 weeks (TURQUOISE II).

    Table 3. Summary table of frequencies of adverse events identified in Phase 3 of clinical trials1,2

    SAPPHIRE I and II studies

    Studies of PEARL II, III and IV

    Study TURQUOISE II (patients with cirrhosis)

    Adverse Reactions

    Viqueira Pak + ribavirin

    12 weeks

    N = 770

    n (%)

    Placebo

    12 weeks

    N = 255

    n (%)

    Viqueira Pak + ribavirin

    12 weeks

    N = 401

    n (%)

    Viqueira Pak

    12 weeks

    N = 509

    n (%)

    Viqueira Pak + ribavirin

    12 or 24 weeks

    N = 380

    n (%)

    Fatigue

    263 (34)

    67 (26,3)

    120 (29,9)

    135 (26,5)

    148 (38,9)

    Nausea

    172 (22,3)

    38 (14,9)

    63(15,7)

    43 (8,4)

    72 (18,9)

    Itching3

    121 (15,7)

    11 (4,3)

    48 (12,0)

    31 (6,1)

    71 (18,7)

    Other manifestations of the skin4

    (16)

    (9)

    Insomnia

    108 (14,0)

    19 (7,5)

    49 (12,2)

    26 (5,1)

    63 (16,6)

    Weakness

    104 (13,5)

    17 (6,7)

    36 (9,0)

    20 (3,9)

    51 (13,4)

    Anemia

    41 (5,3)

    0

    30 (7,5)

    1 (0,2)

    34 (8,9)

    1 - listed adverse reactions occurred with a frequency of more than 5% among patients who received the preparation Viqueira Pak in combination with ribavirin compared to patients receiving placebo in SAPPHIRE I and II.

    2 - the layout of the table graph is provided to simplify the presentation; Direct comparisons should not be conducted for research results that differ in design.

    3 - the grouping term "pruritus" includes the preferred term "pruritus" and "generalized pruritus."

    4 - The group term includes a rash,erythema, eczema, maculopapular rash, macular rash, dermatitis, including allergic and contact, papular rash, exfoliative phenomena, rash, itching, erythematous rash, generalized rash, photosensitivity reactions, psoriasis, skin reactions, ulceration, urticaria.

    Most adverse reactions in phase 3 clinical trials were mild (grade 1).

    The safety profile of the Viqueira Pak preparation when combined with ribavirin is consistent with the existing safety profile of ribavirin.

    Adverse events in organs and systems according to frequency of occurrence

    Frequency of occurrence is defined as follows: very often (≥ 1/10), often (≥ 1/100 to <1/10), rarely (≥ 1/1000 to <1/100), rarely (≥ 1/10000 <1 / 1000) or very rarely (<1/10000).

    The following are undesirable reactions that occurred with a frequency of at least greater than 5% in patients taking the drug Viqueira Pak with ribavirin or without ribavirin compared to patients receiving a placebo.

    Frequency inart.speecheadverse reactions in patients taking the drug Viqueira Pak with ribavirin (N = 2044). The data include s all patientsof the genestype 1 in phase II and III, including patientin cirrosom

    Disturbances from the hematopoietic and lymphatic system

    Often: anemia.

    Disorders from the psyche

    Often: insomnia.

    Disorders from the gastrointestinal tract

    Often: nausea.

    Disturbances from the skin and subcutaneous tissues

    Often: pruritus

    General disorders and disorders at the site of administration

    Often: weakness, fatigue.

    Frequency inart.speecheadverse reactions in patients taking the drug Viqueira Pak with ribavirin (N = 588)

    Disturbances from the skin and subcutaneous tissues

    Often: itching.

    Skin Reactions

    In studies PEARL-II, - III and-IV, 7% of patients treated with Viqueira Pak as monotherapy and 10% of patients treated with Viqueira Pak in combination with ribavirin had rash dermatitis. In studies SAPPHIRE-I and II, 16% of patients receiving Viqueira Pak with ribavirin, and 9% of patients receiving placebo, had undesirable skin effects.

    In the study TURQUOISE-II in 18% and 24% of patients who received the drug Viqueira Pak in combination with ribavirin for 12 or 24 weeks were observedundesirable phenomena from the skin. The severity of most phenomena is classified as light. Not Registered serious phenomena and severe skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, dermatitis, allergic associated with taking drugs (with eosinophilia and systemic symptoms).

    Deviations from the norm of laboratory indicators

    Changes in individual laboratory indicators are given in Table 4.

    Table 4. Selected deviations in laboratory indicators that occurred during treatment2

    Laboratory indicators

    SAPPHIRE I and II studies

    Studies of PEARL II, III and IV

    Study TURQUOISE II (patients with cirrhosis)

    Viqueira Pak + ribavirin

    12 weeks

    N = 770

    n (%)

    Placebo

    12 weeks

    N = 255

    n (%)

    Viqueira Pak + ribavirin

    12 weeks

    N = 401

    n (%)

    Viqueira Pak

    12 weeks

    N 509

    n (%)

    Viqueira Pak + ribavirin

    12 or 24 weeks

    N = 380

    n (%)

    ALT (alanine aminotransferase)

    > 5-20 х upper limit of the norm1

    (3rd degree)

    6/765

    (0,8%)

    10/254

    (3,9%)

    3/401

    (0,7 %)

    1/509

    (0,2%)

    4/380

    (1,1%)

    > 20 x the upper limit of the norm

    (4th degree)

    3/765

    (0,4%)

    0

    0

    0

    2/380

    (0,5 %)

    Hemoglobin

    <10-8 g / dL

    (2nd degree)

    41/765

    (5,4%)

    0

    23/401 (5,7 %)

    0

    30/380

    (7,9%)

    <8-6.5 g / dL

    (3rd degree)

    1/765

    (0,1%)

    0

    2/401

    (0,5%)

    0

    3/380

    (0,8%)

    <6.5 g / dL

    (4th degree)

    0

    0

    0

    0

    1/380

    (0,3%)

    Total bilirubin

    > 3-10 x upper limit of the norm (grade 3)

    19/765

    (2,5%)

    0

    23/401

    (5,7%)

    2/509

    (0,4%)

    37/380

    (9,7%)

    > 10 x upper limit of the norm (4 degree)

    1/765

    (0,1%)

    0

    0

    0

    0

    1 - the upper limit of the norm in accordance with laboratory data

    2 - the layout of the table graph is provided to simplify the presentation; Direct comparisons should not be conducted for research results that differ in design.

    Increased activity of ALT in serum

    In clinical trials with Vikayr Pak with and without ribavirin, approximately 1% of patients had a temporary increase in ALT activity more than 5 times the upper limit of the norm after initiation of treatment.

    At women on a background of concomitant use of the preparations containing ethinyl estradiol, the incidence of increased ALT activity increased to 25% (4/16). The incidence of clinically significant increases in ALT activity among women receiving other estrogens other than ethinylestradiol (eg, estradiol and conjugated estrogens) as hormone replacement therapy was 3% (2/59) (see the section "Contraindications"),

    As a rule, this phenomenon was asymptomatic, manifested during the first 4 weeks of treatment and was resolved as the therapy continued. Increased ALT activity, as a rule, is not associated with an increase in bilirubin concentration. Cirrhosis was not a risk factor for increasing ALT activity.

    Anemia / Reduction of hemoglobin

    In all phase 3 studies, the mean deviation from the initial hemoglobin concentration in patients taking Viqueira Pak in combination with ribavirin was 2.4 g / dl and the mean change in patients taking Viqueira Pak without ribavirin was 0.5 g / dl.

    Reduction of hemoglobin occurred at the beginning of treatment (1-2 weeks) with further decrease during 3 weeks of therapy. The concentration of hemoglobin remained low during the remainder of the treatment and returned to baseline values ​​at week 4 after the end of therapy.

    Less than 1% of patients treated with Viqueira Pak with ribavirin showed a decrease in hemoglobin concentration of less than 8.0 g / dl during therapy. In 7% of patients treated with Viqueira Pak in combination with ribavirin, a dose reduction of ribavirin was required due to a decrease in hemoglobin. 3 patients required a blood transfusion and 5 patients received erythropoietin. One patient discontinued therapy because of anemia. The cases of a decrease in hemoglobin concentration of less than 10 g / dl during therapy with Viqueira Pak without ribavirin were not observed.

    Increased bilirubin concentration

    A temporary increase in the concentration of bilirubin (predominantly indirect) was observed in patients receiving the drug Viqueira Pak in combination with ribavirin, which is associated with the inhibition of parapretavir by bilirubin transporters OATP1B1/1B3 and due to hemolysis caused by the use of ribavirin.

    The increase in bilirubin concentration occurred after the start of treatment, peaked at week 1 of the study, and was completely resolved as therapy continued. An increase in the concentration of bilirubin was not associated with an increase in the concentration of aminotransferases. The incidence of increased indirect bilirubin was lower among patients who did not receive ribavirin.

    PrimitiveEnlargement of Viqueira Pak the patients with co-infection of HCV / HIV-1

    The use of Viqueira Pak in combination with ribavirin was evaluated in 63 patients with co-infection with HCV / HIV-1 who received antiretroviral therapy on a stable basis.

    The most common adverse events recorded in at least 10% of patients are: weakness (48%), insomnia (19%), nausea (17%), headache (16%), itching (13%), cough (11%), irritability (10%), icteric sclera (10%).

    The overall safety profile in patients with co-infection with HCV genotype 1 and HIV-1 was similar to the safety profile in patients with HCV genotype 1 without concomitant HIV-1 infection.

    Short-term increases in total bilirubin> 3 x VGN (mainly indirect) occurred in 17 (27.0%) patients; 15 of these patients received atazanavir. None of the patients with hyperbilirubinemia had a concomitant increase in aminotransferases.

    In patients with hyperbilirubinemia, there was no concomitant increase in aminotransferase activity.

    In 7 patients (11%), at least one case of a decrease in hemoglobin concentration below 10 g / dL was recorded; in 6 of them, a dose adjustment of ribavirin was carried out. In these cases, blood transfusions and the administration of erythropoietin were not required.

    At the end of 12 and 24 weeks of therapy, there was a decrease in the average number Cd4+ T cells to a concentration of 47 cells / mm3 and 62 cells / mm3 respectively; in most cases after the completion of the course of therapy, the indicators returned to the baseline. In 2 patients, a reduction in the number of Cd4+ T cells to a concentration of less than 200 cells / mm3 without lowering Cd4+. No cases of AIDS-associated opportunistic infections have been reported.

    The use of Viqueira Pak in liver transplant recipients

    The use of Viqueira Pak in combination with ribavirin was evaluated in 34 patients who underwent liver transplantation with relapse of HCV. Adverse events recorded in more than 20% of patients: weakness (50%), headache (44.1%), cough (32.4%), diarrhea (26.5%), insomnia (26.5%), asthenia (23.5%), nausea (23.5%), anemia 20.6%, muscle spasms (20.6%), rashes (20.6%). In 10 patients (29.4%), at least one case of a decrease in hemoglobin concentration to a concentration of less than 10 g / dL was noted. In 10 of 34 patients (29.4%), a dose adjustment of ribavirin was carried out due to a decrease in the hemoglobin concentration; In 2,9% (1/34) patients the course of ribavirin therapy was interrupted. A change in the dose of ribavirin did not affect the sustained virologic response. 5 patients received erythropoietin, in all these patients the initial dose of ribavirin was 1000-1200 mg per day. Blood transfusions were not performed.

    Post-business undesirable phenomena

    The following undesirable reactions were detected during the post-marketing use of the drug Vicair Park.Due to the fact that reports of these reactions are received voluntarily from a population of undetermined size, it is not always possible to reliably estimate their frequency or establish a causal relationship with the effect of the drug

    Infringements from immuneth system: hypersensitivity reactions (including angioedema).

    Disorders from the hepatobiliary system: dCompensation of liver function, hepatic insufficiency.

    Overdose:

    The highest documented single doses given to healthy volunteers were 400 mg for paritrapevir (100 mg of ritonavir), 200 mg for ritonavir (100 mg of paritrapevir), 350 mg for ombitasvir, and 2000 mg for dasabuwir. In case of an overdose, it is recommended to monitor the appearance of any signs or symptoms of adverse reactions and, if necessary, immediately carry out appropriate symptomatic therapy.

    Interaction:

    Ritonavir is a potent inhibitor of isoenzyme CYP3A. Joint use of ombitasvir / paritrapevir/ritonavir and dasabuwir with preparations predominantly metabolizing with the CYP3A isoenzyme may lead to an increase in the concentration of these drugs in the plasma.Contraindicated joint use with drugs, the clearance of which is largely dependent on the activity of the isoenzyme CYP3A, and an increase in plasma concentrations which can cause serious adverse events (see the section "Contraindications").

    Paritaprevir is an inhibitor of the hepatic carrier proteins OATP1B1 and OATP2B3, and paritrapepriv and ritonavir - OATP2B1.

    Paritaprevir, ritonavir and dasabuvir are inhibitors of the breast cancer resistance protein (BCRP) in vivo. The combined use of ombitasvir / paritrapevir / ritonavir and dasabuwir with preparations that are substrates of OATP1B1, OATP1B3, OATP2B1 or BCRP can increase the plasma concentrations of these transport protein substrates, and potentially cause the need for dose changes or clinical control.

    Although paritrapeprir, ritonavir and dasabuvir are inhibitors of glycoprotein-P in vitro, there were no significant changes in the exposure of the glycoprotein-P substrate, digoxin, when taken concomitantly with ombitasvir / paritaprevir / ritonavir and dasabuvir. Together with that, joint ingestion of digoxin withombitasvir / paritaprevir / ritonavir and dasabuvir can lead to an increase in the concentration of digoxin in the plasma.

    Ombitasvir, paritrapepril and dasabuvir are inhibitors of the enzyme UGT1A1. There was a minimal (≤22%) increase of substrate exposure UGT1A1 raltegravir when taken with an ombitasvir / paritrapevir / ritonavir preparation. However, the combined use of ombitasvir / paritaprevir / ritonavir and dasabuvir with raltegravir resulted in an approximately twofold increase in the concentration of the latter.

    It is believed that ombitasvir, paritrapevir, ritonavir and dasabuvir do not inhibit UGT1A4, UGT1A6, UCT1A9 and UGT2B7 at clinically significant concentrations.

    Joint reception of ombitasvira / paritrapeprir / ritonavir and dasabuvir with drugs that undergo metabolism CYP2C19, may reduce their exposure, which may require dose adjustment and clinical observation.

    The intake of ombitasvir / paritrapeprir / ritonavir and dasabuvir does not affect the exposure of warfarin, the isoenzyme substrate CYP2C9, or duloxetine, a substrate of isoenzymes CYP2D6/CYP1A2. It is not necessary to correct the dose of the substrates of the isoenzymes CYP2C9, CYP2D6 or the isozyme CYP1A2 when taken in combination with ombitasvir / paritrapevir / ritonavir and dasabuvir.

    Ombitasvir, paritrapeprivir and ritonavir do not inhibit the carrier of organic anions (OAT1) in vivo, which is shown by the lack of interaction with tenofovir (substrate OAT1).

    Research in vitro showed that ombitasvir, paritrapevir and ritonavir at clinically significant concentrations, do not inhibit carriers of organic cations (OST1 and OST2), carriers of organic anions (OAT3) or proteins that displace various drugs and toxins (MATE1 and MATE2K). Therefore, it is believed that ombitasvir / paritrapeprir / ritonavir and dasabuvir do not affect the drugs that are mainly excreted through the kidneys by these carriers.

    The effect of other drugs on the preparation of Viqueira Pak

    Combined use of Viqueira Pak with powerful isoenzyme inhibitors CYP3A can increase the concentration of paritrapevir up to 2 times.

    Joint use of the drug Viqueira Pak with drugs that induce isoenzyme CYP3A, leads to the expected decrease in the concentration of dasabvir, paritrapevir, ombitasvir and ritonavir in blood plasma and reduce their therapeutic effect.

    Joint use of the drug Viqueira Pak with drugs that inhibit the isoenzyme CYP2C8, can increase the concentration of dasabwir in blood plasma.

    Joint use of the drug Viqueira Pak with drugs that induce isoenzyme CYP2C8, is expected to lead to a decrease in the concentration of dasabvir in blood plasma and reduces its therapeutic effect.

    Change in exposure (Cmax and AUC) paritrapeprivir, ombitasvir and yescAbuvir from 0.5 to 2.0 times is not considered clinically significant and does not require dose adjustment of the drug Vicaira Pak.

    Viqueira Pak can be administered together with drugs that are inhibitors of the isoenzyme CYP3A, at the same time it is contraindicated to combine the administration of the drug Viqueira Pak with potent inhibitors of the isoenzyme CYP2C8 or isoenzyme inducers CYP3A/2C8.

    Parataprevir, dasabuvir and ritonavir are substrates of P-glycoprotein. Paritaprevir and dasabuvir are substrates of BCRP. Ombitaswir is a substrate of P-glycoprotein and / or BCRP. Paritaprevir is the substrate of OATP1B1 and OATP1B3. However, it is unlikely that inhibition of the P-glycoprotein, BCRP, OATP1B1 or OATP1B3 will result in a clinically significant increase in the exposure of the Vicair Pak preparation.

    Established and other potential drug interactions

    The interaction profile of drugs used in conjunction with the Vicera Pak preparation was developed for a number of the most commonly prescribed drugs for joint use (Table 5).

    If the patient is currently taking medication (s) that probably have the potential for drug interaction, or has begun to take them during therapy with Wikeyra Pak, it is recommended to consider the need for dose adjustment of the concomitant drug (s) or necessary clinical monitoring.

    If at the time of treatment with the drug Vichera Pak, the correction of the doses of the joint drugs was carried out, after the treatment with the drug Viqueira Pak they should be corrected.

    Table 5 provides information on the effects of the combined use of Viqueira Pak on the concentration of the drugs used together. When appointing the drugs used in combination, listed in Table 5, the dose adjustment of the Viqueira Pak preparation is not required.

    Table 5. Established drug interaction based on data from studies on drug drug interactions

    Class of concomitant drug / drug name

    Effect on concentration

    Comments

    Antiarrhythmic drugs

    Digoxin

    ↔ digoxin

    In spite of the fact that with a single admission of 0.5 mg of digoxin, correction of the dota is not required, it is recommended to monitor serum concentrations of digoxin

    Bepridil, disopyramid, flecainide, lidocaine (systemic administration), mexiletine, propafenone

    ↑ antiarrhythmic drugs

    Apply with caution, it is recommended to monitor (if possible) the therapeutic concentration antiarrhythmic drugs on the background of a joint application with Viqueira Pak.

    Amiodarone, quinidine

    Not studied, presumably ↑ amiodarone

    ↑ quinidine

    Joint use is contraindicated.

    Antibiotics (systemic administration)

    Clarithromycin,

    Not studied, presumably

    ↑ clarithromycin

    Joint use is contraindicated.

    Telithromycin

    ↑ telithromycin

    ↑ parapravir

    ↑ dasabuvir

    Erythromycin

    Not studied, presumably

    ↑ erythromycin

    ↑ parapravir

    ↑ dasabuvir

    It should be used with caution, as a joint application can lead to an increase in the concentrations of erythromycin and paritrapevir

    Fusidic acid

    Not studied, presumably

    ↑ fusidic acid

    Joint use is contraindicated

    Antineoplastic agents

    Enzalutamide

    Not studied, presumably

    ↓ ombitaswir

    Joint use is contraindicated.

    Mitotan

    ↓ pariteppevir

    ↓ dasabuvir

    Imatinib

    Not studied, presumably

    ↑ imatinib

    Clinical monitoring and reduced doses of imatinib have been recommended.

    Anticoagulants

    Warfarin

    ↔ warfarin

    Despite the fact that with a single dose of 5 mg warfarin dose adjustment is not required, it is recommended to monitor the international normalized relationship (INR).

    Dabigatran

    Not studied, presumably

    ↑ dabigatran

    It should be used with caution, as co-administration can lead to increased concentrations of dabigatran.

    Antifungal drugs

    Ketoconazole

    ↑ ketoconazole

    Joint use is contraindicated.

    Voriconazole

    ↓ voriconazole

    Joint use is contraindicated

    Itraconazole

    Not studied, presumably

    ↑ itraconazole

    Joint use is contraindicated.

    Posaconazole

    ↑ Posaconazole

    ↑ parapravir

    ↑ dasabuvir

    Joint use is contraindicated

    Blocks of "slow" calcium channels

    Amlodipine 5 mg once

    ↑ amlodipine

    It is recommended to reduce the dose of amlodipine by 50% and conduct clinical monitoring of patients

    Diltiazem

    Not studied, presumably ↑diltiazem, verapamil

    Use with caution because of a presumed increase in the concentration of paritaprevir. It is recommended to reduce the dose of blockers of "slow" calcium channels and conduct clinical monitoring.

    Verapamil

    ↑ parapravir

    ↑ / ↔ dasabuvir

    Nifedipine

    Not studied, presumably

    ↑ nifedipine

    It is recommended to reduce the dose of blockers of "slow" calcium channels and conduct clinical monitoring

    Glucocorticosteroids (inhaled / nasal)

    Fluticasone

    ↑ fluticasone

    The combined use of Viqueira Pak with inhaled or nasal fluticasone may decrease the concentration of cortisol in the serum. Consider the possibility of using other glucocorticosteroids, especially in the case of long courses of therapy.

    Oral contraceptives

    Ethinyl estradiol / norgestimate

    ↔ ethinyl estradiol

    Contraindicated use with the drug Vikeira Pak.

    Ethinyl estradiol / norethindrone

    Metabolites of norgestimate:

    ↑ norgestrel

    ↑ noregestromine

    Diuretics

    Furosemide

    ↑furosemide (Cmax)

    Clinical observation of patients is recommended. The reduction of the vine is allowed up to 50%, depending on the clinical response. Changing the dose of Viqueira Pak is not required.

    Antiviral (HIV) means

    Atazanavir

    ↑ parapravir

    Viqueira Pak and Atazanavir 300 mg once a day, taken concomitantly, should be used together without the addition of ritonavir. Ritonavir contained in the tablet of ombitasvir + paritrapepril + ritonavir, is a pharmacokinetic enhancer of atazanavir. Changing the dose of Viqueira Pak is not required.

    Also, with the combined use of the drug Viqueira Pak and atazanavir, the concentration of bilirubin in the blood can increase, especially when the hepatitis C therapy regimen is included ribavirin.

    Atazanavir / ritonavir

    ↑ parapravir

    The combination atazanavir + ritonavir it is contraindicated to apply together with the drug Vichera Pak.

    Darunavir

    800 mg once a day (taken simultaneously with the drug Viqueira Pak)

    ↓ darunavir (Ctrough)

    Viqueira Pak and darunavir should be used together without the additional administration of ritonavir.

    Ritonavir contained in the tablet of ombitasvir + paritrapepril + ritonavir, is a pharmacokinetic enhancer of darunavir.

    Darunavir / ritonavir

    ↓ darunavir (Ctrough)

    Contraindicated use with the drug Vikeira Pak.

    Lopinavir / ritonavir

    ↑ parapravir

    Lopinavir / ritonavir 400/100 mg twice a day and 800/200 mg once a day (in the evening) increases the concentration of paritapovir. The combined use of lopinavir / ritonavir and Viqueira Pak is contraindicated.

    Indinavir

    Saquinavir

    Tipranavir

    Not studied, presumably

    ↑ parapravir

    Joint use is contraindicated.

    Rilpivirine

    ↑ Rilpivirine

    The simultaneous administration of Viqueira Pak with rilpivirin is contraindicated once a day due to the possibility of prolonging the QT interval with a higher exposure to rilpivirin.

    Efavirenz

    ↑ ALT

    Joint use is contraindicated.

    Nevirapine

    Not studied, presumably

    ↓ ombitaswir

    Joint use is contraindicated.

    Etravirine

    ↓ pariteppevir

    ↓ dasabuvir

    Raltegravir

    400 mg twice daily

    There were no changes in the concentrations of dasabuwir, paritrapevir, ombitaswir

    It is not required to change the dose of the drug Viqueira Pak.

    Emtricitabine / tenofovir

    ↔ Emtricitabine

    ↔ tenofovir

    ↔ ombitaswir

    ↓ pariteppevir

    ↔ dasabwir

    It is not required to change the dose of the drug Viqueira Pak

    Antiviral (HIV) agents, pharmacokinetic enhancers

    Co-therapy with cobicystate

    Not studied, presumably ↑ ombitaswir

    ↑ parapravir

    ↑ dasabuvir

    Joint use is contraindicated

    Inhibitors of hydroxymethylglutaryl coenzyme A-reductase (HMG-CoA)

    Rosuvastatin

    ↑ rosuvastatin

    The dose of rosuvastatin should not exceed 5 mg per day. It is not required to change the dose of the drug Viqueira Pak.

    Pravastatin

    ↑ pravastatin

    It is necessary to reduce the dose of pravastatin by 50%. Changing the dose of Viqueira Pak is not required.

    Fluvastatin

    Not studied, presumably

    ↑ fluvastatin

    Joint use is not recommended.

    It is recommended temporary suspension of fluvastatin therapy for the time of treatment with the drug Viqueira Pak.

    If treatment with statins is necessary during the entire treatment period, then it is necessary to reduce the dose of fluvastatin.

    Lovastatin

    Simvastatin

    Atorvastatin

    Not studied, presumably

    ↑ lovastatin

    ↑ simvastatin

    ↑ atorvastatin

    Joint use is contraindicated

    Immunosuppressive drugs

    Cyclosporin

    ↑ cyclosporine

    At the beginning of the scheme of joint application with the drug Viqueira Pak, it is necessary to appoint 20% of the total daily dose of cyclosporine once a day. It is necessary to monitor the concentration of cyclosporine and adjust the dose and / or frequency of application as needed.

    Tacrolimus

    ↑ Tacrolimus

    In the case of co-administration of tacrolimus with Viqueira Pak, 0.5 mg of Tacrolimus should be used once a week. It is necessary to monitor the concentration of tacrolimus and adjust the dose and / or frequency of application if necessary. It is not required to change the dose of the drug Viqueira Pak.

    Long-acting beta-adrenergic agonists

    Salmeterol

    ↑ salmeterol

    The combined use of Viqueira Pak and salmeterol is contraindicated.

    Combined use may increase the risk of cardiovascular adverse events associated with the use of salmeterol, including increased QT interval, palpitations and sinus tachycardia

    Hypoglycemic agents

    Repaglinide

    Not studied, presumably

    ↑ repaglinide

    Use with caution, you may need to reduce the dose of repaglinide

    Narcotic analgesics

    Buprenorphine / naloxone

    ↑ buprenorphine

    ↑ Norbuprenorphine

    Against the background of a joint application with Viqueira Pak, no correction of buprenorphine / naloxone doses is required. It is recommended to monitor the degree of sedation and cognitive phenomena.

    Methadone

    ↔ paritrapeprir / ombitasvir / dasabuvir

    It is not required to change the dose of methadone and the drug Viqueira Pak

    Proton Pump Inhibitors

    Omeprazole

    ↓ omeprazole

    Monitoring of patients to detect a decrease in the effectiveness of omeprazole. It is recommended to increase the dose of omeprazole in patients whose symptoms are not adequately controlled; avoid using more than 40 mg per day of omeprazole. Changing the dose of Viqueira Pak is not required.

    Esomeprazole

    lansoprazole

    Not studied, presumably ↓ esomeprazole

    ↓ lansoprazole

    You may need an increase in the dose of esomeprazole / lansoprazole.

    Sedatives / hypnotics

    Alprazolam

    ↑ alprazolam

    Clinical observation of patients is recommended.It is possible to reduce the dose of alprazolam depending on the clinical response. Changing the dose of Viqueira Pak is not required.

    Midazolam in a dosage form for ingestion.

    Triazolam in the oral dosage form

    Not studied, presumably ↑midazolam or triazolam

    Joint use is contraindicated

    Zolpidem

    ↔ Zolpidem

    ↔ ombitaswir

    ↓ pariteppevir

    ↔ dasabwir

    It is not required to change the dose of zolpidem and the preparation of Viqueira Pak.

    Antipsychotics

    Quetiapine

    Pimozide

    ↑ Quetiapine

    ↑ pimozide

    Joint use is contraindicated

    Alpha1-adrenoceptor blockers

    Alfuzosin

    Not studied, presumably

    ↑ Alfuzosin

    Joint use is contraindicated.

    Aminosalicylates

    Sulfasalazine

    Not studied, presumably

    ↑ sulfasalazine

    Care should be taken when using together.

    Angiotensin II receptor antagonists

    Valsartan

    Not studied, presumably

    ↑ valsartan

    It is recommended to carry out clinical monitoring and reduce the dose of valsartan

    Antiepileptic agents

    Carbamazepine with a dosage regimen of 200 mg 2 times a day, followed by administration of 200 mg once a day

    ↔ carbamazepine

    ↓ ombitaswir

    ↓ pariteppevir

    ↓ dasabuvir

    Joint use is contraindicated

    Phenobarbital

    Not studied, presumably

    ↓ ombitaswir

    ↓ pariteppevir

    ↓ dasabuvir

    Joint use is contraindicated

    Phenytoin

    Not studied, presumably

    ↓ ombitaswir

    ↓ pariteppevir

    ↓ dasabuvir

    Joint use is contraindicated

    Mephenytoin

    Not studied, presumably

    ↓ mephenytoin

    It is recommended to conduct clinical monitoring and possibly reduce the dose of mephenitoin.

    Antidepressants

    Escitalopram

    10 mg once

    ↔ escitalopram

    ↑ S-desmethyl citalopram

    ↔ ombitaswir

    ↔ dasabwir

    There is no need for a dose change for escitalopram and Viqueira Pak.

    Duloxetine

    ↓ duloxetine

    ↔ ombitaswir

    ↓ pariteppevir

    ↔ dasabwir

    No dose change is required for duloxetine and Vicair's Pak preparation.

    Trazodone

    Not studied, presumably

    ↑ trazodone

    It should be used with caution trazodone. It may be necessary to reduce the dose of trazodone.

    Antidiuretic hormone

    Konivaptan

    Not studied, presumably

    ↑ konywaptan

    ↑ parapravir

    ↑ dasabuvir

    Joint use is contraindicated.

    Means that affect the exchange of uric acid

    Colchicine

    Not studied, presumably

    ↑ colchicine

    Joint use is contraindicated in patients with renal and / or liver failure.

    In patients with normal renal or hepatic function, if Vickeir Pak is required, a dose reduction of colchicine or interruption -circulation with colchicine is recommended.

    Antihistamines

    Astemizole

    Terfenadine

    Not studied, presumably

    ↑ astemizole / terfenadine

    Joint use is contraindicated

    Fexofenadine

    Not studied, presumably

    ↑ fexofenadine

    Use with caution.

    Lipid-lowering drugs

    Gemfibrozil

    600 mg 2 times a day

    ↑ parapravir

    ↑ dasabuvir

    Joint use is contraindicated.

    Anti-TB drugs

    Rifampicin

    Not studied, presumably

    ↓ ombitaswir

    ↓ pariteppevir

    ↓ dasabuvir

    Joint use is contraindicated.

    Antiaggregants

    Tikagrelor

    Not studied, presumably

    ↑ ticagrelor

    Joint use is contraindicated

    Alkaloids of ergot

    ergotamine, dihydroergotamine, ergometrine, methylergometrine

    Not studied, presumably

    ↑ ergot alkaloids

    Joint use is contraindicated

    Motility stimulators GIT

    Cisapride

    Not studied, presumably

    ↑ cisapride

    Joint use is contraindicated

    Herbal medicines

    St. John's Wort, Hypericum perforatum

    Not studied, presumably

    ↓ dasabuvir

    ↓ ombitaswir

    ↓ pariteppevir

    Joint use is contraindicated

    Complexing agents

    Deferazirox

    Not studied, presumably

    ↑ dasabuvir

    Use with caution.

    Medicines used for multiple sclerosis

    Teriflunomide

    Not studied, presumably

    ↑ dasabuvir

    Use with caution.

    Inhibitors of phosphodiesterase 5 (PDE-5)

    Sildenafil (in the treatment of pulmonary hypertension)

    Not studied, presumably

    ↑ sildenafil

    Joint use is contraindicated

    Thyroid drugs

    Levothyroxine

    Not studied, presumably

    ↑ levothyroxine

    Clinical monitoring and dose modification of levothyroxine may be required.

    The direction of the arrow indicates the direction of exposure change (Cmax and AUC) (↑ = increase by more than 20%, ↓ = decrease by more than 20%, ↔ = no change or change less than 20%).

    The list of drugs, the combined use of which with the drug Viqueira Pak contraindicated. also presented in the section "Contraindications."

    Special instructions:

    Increased ALT activity

    In clinical studies, the drug ribavirin Vikeyra Pak with or without ribavirin for about 1% of the observed transient, asymptomatic increase in ALT activity by more than 5 times the upper limit of normal (see. The section "Side effect").

    Increased ALT activity observed much more frequently in women taking ethinylestradiol preparations based on, for example, combined oral contraceptives, contraceptive patches, and vaginal contraceptive ring (see. The section "Contraindications"). Increased ALT activity is typically observed during the 4 weeks of treatment and decreased within 2-8 weeks from the start of increase of ALT activity with continued therapy with ribavirin Vikeyra Pak with or without ribavirin. You should stop taking medications containing ethinyl estradiol before the use of the drug Viqueira Pak. During the course of therapy with Vikeyra Pack is recommended to use alternative methods of contraception (eg, oral contraceptives, progestin-based or non-hormonal contraceptives). Renewal of medication containing ethinyl estradiol, it is recommended to begin approximately 2 weeks after the termination of the course of therapy with the drug Viqueira Pak.

    Women who received no ethinyl estradiol, and other estrogens (for example, estradiol and conjugated estrogens) as hormone replacement therapy, ALT activity indicators corresponded to those recorded in patients who did not receive estrogens. Nevertheless, since the number of patients receiving other estrogens is limited, they should be used with caution in combination with Viqueira Pak.

    Biochemical parameters of the liver should be measured during the first 4 weeks of therapy and if the serum ALT activity exceeds the upper limit of the norm, then it is necessary to re-conduct the study and further monitor the activity of ALT of such patients, and also:

    - patients should be informed of the need for consultation with the attending physician immediately if they experience fatigue, weakness, loss of appetite, nausea and vomiting, jaundice or discoloration of stool;

    - consider stopping the use of Vicair Pak if the serum ALT activity is above the upper limit of 10time.

    Risk of decompensation of liver function and liver failure in patients with cirrhosis of the liver

    In the postmarketing period, there have been cases of decompensation of liver function and liver failure, including liver transplantation or death, in patients who received the drug Viqueira Pak. Most patients with these severe outcomes had signs of advanced stages of liver cirrhosis before initiating therapy with Vicair Pak.

    Registered cases usually occurred within one to four weeks after the initiation of therapy and were characterized by a sharp increase in the concentration of direct bilirubin in the serum without increasing the activity of ALT along with clinical signs of liver decompensation. Due to the fact that reports of these events are received voluntarily from a population of undetermined size, it is not always possible to reliably estimate their frequency or establish a causal relationship with the effect of the drug.

    Viqueira Pak is contraindicated in patients with moderate and severe liver function disorders (class B and C on the Child-Pugh scale).

    For patients with cirrhosis of the liver it is necessary:

    - monitor the appearance of clinical signs of decompensation of liver function (eg, ascites, hepatic encephalopathy, bleeding from varicose veins);

    - laboratory indicators of liver function, including the concentration of direct bilirubin, should be evaluated before the initiation of therapy and within the first 4 weeks after initiation of treatment, as well as in the presence of clinical indications;

    - to cancel the drug Viqueira Pak in patients with signs of decompensation of liver function.

    Risks associated with concomitant use of ribavirin

    In the case of combined use of Viqueira Pak with ribavirin, the warnings and precautions applicable to ribavirin, in particular the unwantedness of pregnancy, should be considered. A complete list of warnings and precautions against the use of ribavirin is provided in the instructions for its use.

    Risks associated with side effects or a decrease in the effect of therapy due to simultaneous prescription with other drugs

    The combined use of a number of drugs can lead to known, or potentially significant, drug interactions, resulting in:

    - Loss of therapeutic effectiveness, possibly - with the development of resistance;

    - Clinically significant adverse reactions associated with an increase in exposure to drugs that are used in conjunction with the drug Viqueira Pak, or with the excipients of the drug.

    Table 5 (section "Interaction with other drugs") indicates measures to correct possible and known significant drug interactions, including recommendations for dosing of drugs. The possibility of developing drug interactions should be assessed prior to the use of Vicair Pak and during the course of therapy; recommended monitoring of adverse reactions associated with the use of drugs used in conjunction with active and auxiliary substances of the drug Viqueira Pak.

    Use with fluticasone

    Fluticasone is a glucocorticosteroid metabolized by isoenzyme CYP3A. Caution should be exercised when using the combination of Viqueira Pak and fluticasoma or other glucocorticosteroids that are metabolized with the participation of the CYP3A4 isoenzyme.

    The combined use of inhaled glucocorticosteroids metabolized by the CYP3A isoenzyme may increase the systemic effect of glucocorticosteroids; Cushing's syndrome and subsequent suppression of adrenal function with drugs containing ritonavir. The combined use of the drug Viqueira Pak and glucocorticosteroids, in particular for long-term therapy, should be started only if the potential benefit of treatment outweighs the risk of systemic effects of glucocorticosteroids.

    Simultaneous use with other antiviral drugs, direct action against the hepatitis C virus

    The safety and efficacy of Viqueira Pak with ribavirin or without ribavirin have been established. The simultaneous use of the drug Viqueira Pak with other direct antiviral drugs for the treatment of chronic hepatitis C has not been studied and therefore can not be recommended.

    Simultaneous use with colchicine

    The interaction between the preparation of Viqueira Pak and colchicine has not been studied.It is recommended to reduce the dose of colchicine or to temporarily discontinue treatment with colchicine in patients with normal renal or hepatic function if treatment with Viqueira Pak is required. In patients with renal or hepatic insufficiency, concomitant use of colchicine with the preparation of Viqueira Pak is contraindicated.

    Simultaneous use with statins

    Simvastatin, lovastatin and atorvastatin are contraindicated.

    Rosuvastatin

    With the joint application of the drug Viqueira Pak with rosuvastatin, the exposure of rosuvastatin may be increased more than 3-fold. If rosuvastatin is required during treatment with Viqueira Pak, the maximum daily dose of rosuvastatin should be 5 mg.

    Pitavastatin and fluvastatin

    Investigations of the interaction of fluvastatin, Pitavastatin and Viqueira Pak have not been conducted. Theoretically, it is possible to increase the exposure of fluvastatin and Pitavastatin when combined with Vicair Pack. It is recommended to temporarily stop the use of Pitavastatin and fluvastatin for the duration of treatment with Vicera Pak.If treatment with statins is necessary during the entire period of treatment with Vikaira Pak, a reduced dose should be used pravastatin / rosuvastatin

    Treatment of patients with co-infection of VGC/ HIV-1

    Low doses of ritonavir in the Vickeyr Pak preparation may lead to the appearance of viral strains with resistance to HIV protease inhibitors in patients with HIV / HCG co-infection who are not receiving continuous antiretroviral therapy. HIV-infected patients who do not receive antiretroviral therapy should not take the drug.

    When co-infection with HIV, drug interactions should be considered.

    Atazanavir can be used in combination with Vikaira Pak. It should be noted that atazanavir must be taken without ritonavir, since ritonavir in a dose of 100 mg once a day is included in the drug Viqueira Pak. This combination is characterized by an increased risk of developing hyperbilirubinemia (including yellowing of the sclera), in particular, when ribavirin is part of the hepatitis C treatment regimen.

    Darunavir 800 mg once a day with simultaneous admission with the drug Viqueira Pak can be used in the absence of pronounced resistance to HIV protease inhibitors(reduced effect of darunavir).

    HIV protease inhibitors, with the exception of atazanavir and darunavir (eg, indinavir, saquinavir, tipranavir, lopinavir, ritonavir), are contraindicated.

    When combined with the preparation Viqueira Pak and raltegravir, the exposure of raltegravir is significantly increased (2-fold). The use of this combination was not associated with any specific safety problems in a limited population of patients during therapy for 12-24 weeks.

    Exposure of rilpivirin significantly increases (3-fold) in the appointment of rilpivirin in combination with the preparation of Viqueira Pak; As a result, the possibility of extending the interval QT. If a HIV protease inhibitor is added (atazanavir, darunavir), exposure to rilpivirin may be further increased, and therefore this combination is contraindicated.

    Other NNRTIs (non-nucleoside reverse transcriptase inhibitors) efavirenz, etravirine and nevirapine are contraindicated.

    Liver failure

    In patients with mild hepatic insufficiency (class A on the Child-Pugh scale), a correction of the proportion of Vickeyr Pak is not required.Viqueira Pak is contraindicated in patients with moderate to severe hepatic insufficiency (class B and C on the Child-Pugh scale).

    Renal insufficiency

    It is not necessary to adjust the dose of Viqueira Pak in patients with mild, moderate and severe renal failure.

    Patients after liver transplantation

    The safety and efficacy of the use of Vickeyr Pak in combination with ribavirin was studied in 34 patients with HCV genotype 1 after liver transplantation (at least 12 months after liver transplantation). The main objectives of this study were to assess safety and determine the proportion of patients who achieved a sustained virologic response 12 weeks after the end of treatmentSVR12) and after 24 weeks of treatment with Viqueira Pak in combination with ribavirin. The initial dose of ribavirin ranged from 600 mg to 800 mg per day as the most commonly used at the beginning and at the end of treatment with Vicair Pak.

    Thirty-four participants who did not receive treatment for HCV after liver transplantation and who had a fibrosis score on a scale Metavir - 2 or less (29 with HCV genotype 1a and 5 with HCV genotype 1b) were included in clinical studies.Thirty-one of 32 patients for whom data were obtained at a time point SVR12 (96.9%) achieve SVR12 (96.3% in patients with genotype 1a). One patient with a genotype of HCV 1a had a relapse after treatment.

    The overall safety profile of the Vickeyr Pak preparation in combination with ribavirin in HCV-infected patients after liver transplantation was the same as in patients treated with Wikeyra Pak in combination with ribavirin in phase 3 clinical trials, with the exception of anemia. Ten patients (29.4%) had at least one hemoglobin value (after the initial) less than 10 g / dL. In 55.9% (19/34) of patients, the dose of ribavirin was reduced and 2.9% (1/34) of ribavirin was withdrawn. Dose change ribavirin did not affect the frequency of achieving a stable virologic response. Five patients required the use of erythropoietin (in all five patients, ribavirin in an initial dose of 1000 mg to 1200 mg. No patient required a blood transfusion).

    Other genotypes of HCV

    For patients infected with other genotypes of HCV, with the exception of genotype 1, the safety and efficacy of the Vickeyr Pak drug has not been established.

    Effect on ECG

    Effect of the combined use of ombitasvir / paritrapeprir / ritonavir and dasabuwir on the interval QTc were evaluated in a randomized double-blind study with placebo and active control (moxifloxacin 400 mg), 4-way cross, careful monitoring QT in 60 healthy subjects who received ombitasvir / paritaprevir / ritonavir and dasabuvir. In a study with the ability to detect small effects in doses exceeding therapeutic - paritrapevin 350 mg, ritonavir 150 mg, ombitasvir 50 mg and dasabuvir 500 mg - did not show a clinically significant prolongation of the interval QT. The above doses provide a concentration of 6, 1.8 and 2 times higher than the therapeutic concentrations of paritrapeprir, ombitasvir and dasabuvir.

    Children

    There is no data on the efficacy and safety of the drug in children under 18 years of age.

    Elderly patients

    Do not require dose adjustment in elderly patients.

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

    Patients should be informed that the unwanted fatigue was observed with the use of Viqueira Pak in combination with ribavirin.

    Form release / dosage:

    Tablets set containing:

    Dasabuvir - tablets coated with a film coating, 250 mg;

    Ombitasvir + Paritateapir + Ritonavir - film-coated tablets, 12.5 mg + 75 mg + 50 mg.

    Packaging:

    2 tablets of dasabwir coated with a film coat and 2 tablets of ombitasvir + paritrapepril + ritonavir coated with a film sheath in a blister of polyvinyl chloride / polyethylene / polychlorotrifluoroethylene and aluminum foil.

    For 7 blisters in a pack of cardboard, 4 packs of cardboard along with instructions for use in a pack of cardboard.

    Storage conditions:

    Store at a temperature not exceeding 25 FROM.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002965
    Date of registration:21.04.2015 / 13.12.2016
    Expiration Date:21.04.2020
    The owner of the registration certificate:EbbVi Ltd.EbbVi Ltd. Russia
    Manufacturer: & nbsp
    Representation: & nbspEbbVi Ltd.EbbVi Ltd.Russia
    Information update date: & nbsp11.03.2017
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