Viqueira Pac, tablets set 250 mg+(12, 5 mg+75 mg+50 mg) 112 pcs

The drug Viqueira Pac combines three direct-acting antiviral agents for the treatment of hepatitis C virus (HCV) with different mechanisms of action and non-overlapping resistance profiles to fight the hepatitis C virus at different stages of its life cycle, and ritonavir.

The antiviral drug active against hepatitis C virus.

Dasabuvir

Dasabuvir is a non-nucleoside inhibitor of the viral RNA-dependent RNA polymerase encoded by the NS5B gene, which is necessary for replication of the viral genome. According to biochemical studies, dasabuvir inhibits the NS5B polymerase activity of HCV recombinant genotype Ia and Ib enzymes with IC30 values of 2.8 and 10.7 nM, respectively.

Ombitasvir

Ombitasvir is an inhibitor of the HCV NS5A protein, which is essential for viral replication. In studies on replicon cell cultures, the EC50 values for ombitasvir were 14.1 and 5.0 nM for HCV genotypes Ia and Ib, respectively.

Paritaprevir

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

Ritonavir

Ritonavir has no antiviral activity against HCV. Ritonavir acts as a pharmacokinetic enhancer that increases the peak plasma concentration of paritaprevir and the paritaprevir concentration measured immediately before the next dose is taken and increases the total drug exposure (i.e., the area under the concentration-time curve).

Indications

Cronic hepatitis C virus genotype 1, including patients with compensated cirrhosis, with or without ribavirin.

Active ingredient

Composition

2. film-coated tablets are pink, oblong, biconvex, engraved “AV1” on one side.

1 tablet contains:

Associates:

copovidone – 849.2 mg,

D-alpha-tocopherol macrogoal succinate – 42.5 mg,

silicon dioxide colloid – 10.8 mg,

propylene glycol monolaurate – 10 mg,

sorbitan laurate – 33.3 mg.

Content of film coating:

Papadray II pink – 32.5 mg, incl. Polyvinyl alcohol – 46.94%, macrogol 3350 – 23.7%, talc – 17.36%, titanium dioxide – 11.9%, iron oxide red – 0.1%.

The complex antiviral drug Viqueira Pac contains two types of tablets.

1. The film-coated tablets are light brown, oval, engraved “AV2” on one side.

1 tablet contains dasabuvir sodium monohydrate 270.26 mg, which corresponds to dasabuvir 250 mg.

Auxiliary substances:

Microcrystalline cellulose PH101 – 103.04 mg,

Ph102 microcrystalline cellulose – 104.72 mg,

Lactose monohydrate – 47.3 mg,

copovidone – 101.35 mg,

croscarmellose sodium – 33.78 mg,

colloidal silica – 4.05 mg,

magnesium stearate – 11.15 mg.

Composition of the film coating:

Opadray II beige – 21 mg, including polyvinyl alcohol – 40%, titanium dioxide – 21.55%, macrogol 3350 – 20.2%, talc – 14.8%, iron oxide yellow – 3%, iron oxide red – 0.35%, iron oxide black – 0.1%.

How to take, the dosage

Ingestion. Viqueira Pac should be taken with food, regardless of the fat or caloric content of the food.

The recommended dose of Viqueira Pac includes:

Viqueira Pac is used in combination with ribavirin in some patient groups (see Table 1).

Table 1 shows the recommended treatment regimens and duration of therapy depending on the patient group.

Table 1. Treatment regimen and duration for different groups of patients (first-time or post-interferon therapy.

. Patient groupDrugs*DurationTreatment durationGenotype Ia, without cirrhosisViqueira Pac+ribavirin12 weeksGenotype Ia, with cirrhosisViqueira Pac+ribavirin24 weeks**Genotype Ib, without cirrhosisViqueira Pac12 weeksGenotype Ib, with cirrhosisViqueira Pac+ribavirin12 weeksNotes:
*People with unknown genotype I subtype or mixed genotype I are recommended to follow the dosing regimen for genotype Ia.
**Viqueira Pac in combination with ribavirin for 12 weeks may be considered for some patients based on previous therapy.

When used with Viqueira Pac, the recommended dose of ribavirin is based on the patient’s body weight: 1000 mg/day for patients with a body weight of 75 kg, divided into 2 doses daily with meals. If it is necessary to adjust the dose of ribavirin, it is recommended to read its instructions for use.

Viqueira Pac should be taken according to the duration recommended in the instructions for use without interruption. If Viqueira Pac is used together with ribavirin, ribavirin should be prescribed for the same duration as Viqueira Pac.

Patients after liver transplantation

The recommended duration of treatment (with Viqueira Pac in combination with ribavirin) in patients with normal liver function and Metavir fibrosis stage ≤ 2 is 24 weeks, regardless of HCV genotype 1 subtype.

When using Viqueira Pac with calcineurin inhibitors, correction of the dose of calcineurin inhibitors is necessary. In clinical studies in patients after liver transplantation the doses of ribavirin were individually adjusted from 600 mg to 800 mg per day.

In patients with HCV/HIV-1 co-infection

The recommendations in Table 1 should be followed. Recommendations for concomitant HIV-1 antiviral therapy are presented in “Interactions with other medications.

Hepatic impairment

In patients with mild hepatic impairment (Child-Pugh class A), no dose adjustment of Viqueira Pac is required. The safety and efficacy of Viqueira Pac in patients infected with hepatitis C with moderate hepatic insufficiency (Child-Pugh class B) has not been established; use of Viqueira Pacne is recommended in patients with moderate hepatic insufficiency. Viqueira Pacne is contraindicated in patients with severe hepatic impairment (Child-Pugh class C).

Liver function parameters should be monitored before and during therapy.

Interaction

Paritaprevir, ombitasvir, ritonavir and dasabuvir do not inhibit organic anion transporter (OAT1) in vivo, nor are they likely to inhibit organic cation transporters (OAT1 and OAT2), organic anion transporters (OAT3) or multiple resistance and toxin elimination proteins {MATE1 and MATE2K) at clinically relevant concentrations; thus, Viqueira Pac has no effect on these renal excretion pathways.

In in vitro studies it has been observed that ritonavir inhibits some cytochrome P450 isoenzymes, but Viqueira Pac at clinically relevant concentrations has no significant effect on the CYP2C9 and CYP2C19 isoenzymes.

Paritaprevir, ritonavir and dasabuvir, are in vilro P-glycoprotein inhibitors, but no significant changes were noted in the interaction of Viqueira Pac with digoxin, a sensitive P-glycoprotein substrate.

Paritaprevir is an inhibitor of the transport polypeptide of organic anions 1B1 and 1B3 (OATP1B1 and OATP1B3). Paritaprevir, ritonavir and dasabuvir are inhibitors of Breast Cancer Resistance Protein (BCRP).

Paritaprevir, ombitasvir and dasabuvir are inhibitors of uridine diphosphate glucuronyltransferase isoform 1A1 (UGT1A1) and ritonavir is an inhibitor of the cytochrome CYP3A4 enzyme. Co-administration of Viqueira Pac with drugs that are primarily metabolized through CYP3A isoenzyme or are substrates for UGT1A1, BCRP, OATP1B1 or OATP1B3 may lead to increased plasma concentration of such drugs.

Special Instructions

Elevated ALT activity was significantly more frequently observed in women taking ethypielestradiol-based medications such as combined oral contraceptives, contraceptive patches and contraceptive vaginal rings (see section “Contraindications”).

In clinical trials of Viqueira Pac with or without ribavirin, a transient, asymptomatic increase in ALT activity greater than 5 times the upper limit of normal was observed in approximately 1% of cases (see section “Side effects”).

The increase in ALT activity was usually observed within 4 weeks of therapy and decreased within 2-8 weeks of the onset of the ALT increase when continuing therapy with Viqueira Pac with or without ribavirin.

The administration of drugs containing ethinylestradiol should be discontinued prior to initiation of Viqueira Pac. During therapy with Viqueira Pac, the use of alternative methods of contraception (e.g., progestin-based oral contraceptives or non-hormonal contraceptives) is recommended.

Resumption of therapy with drugs containing ethinylestradiol is recommended about 2 weeks after completion of therapy with Viqueira Pac.

In women who received estrogens other than ethinylestradiol (e.g., estradiol and conjugated estrogens) as hormone replacement therapy, ALT activity values were consistent with those reported in patients not receiving estrogens. However, because the number of patients treated with other estrogens is limited, caution should be exercised when using them in combination with Viqueira Pac.

The liver biochemical parameters should be measured during the first 4 weeks of therapy and if serum ALT activity exceeds the upper limit of normal, the study should be repeated and further ALT activity should be monitored in these patients as well:

Risks associated with concomitant use of ribavirin

Warnings and precautions applicable to ribavirin should be considered when combining Viqueira Pac with ribavirin, often including the undesirability of pregnancy. For a complete list of warnings and precautions for ribavirin, refer to the instructions for use.

Risks of side effects or reduced effect of therapy due to concomitant administration with other drugs

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

Table 4 (section “Interactions with other medicinal products”) shows measures to correct possible and known significant drug interactions, including recommendations for drug dosing. The possibility of drug interactions should be assessed before starting the use of Viqueira Pac and during the course of therapy; monitoring of adverse reactions associated with the use of drugs used together with the active and excipients of Viqueira Pac is recommended.

The use with fluticasone

Fluticasone is a glucocorticosteroid that is metabolized by the CYP3A isoenzyme.

Caution should be exercised when co-administering Viqueira Pac and fluticasone or other glucocorticosteroids that are metabolized with participation of CYP3A4 isoenzyme. Co-administration of inhaled glucocorticosteroids metabolized by the CYP3A isoenzyme may increase the systemic effects of glucocorticosteroids; cases of Cushing’s syndrome and subsequent suppression of adrenal function by drugs containing ritonavir have been reported. Co-administration of Viqueira Pac and glucocorticosteroids, particularly for long-term therapy, should be initiated only if the potential benefit of treatment outweighs the risk of systemic effects of glucocorticosteroids.

Hepatic impairment

In patients with mild hepatic impairment (Chapld-Pugh class A) no dose adjustment of Viqueira Pac is required. The safety and efficacy of Viqueira Pac in patients infected with hepatitis C with moderate hepatic impairment (Child-Pugh class B) has not been established; Viqueira Pac is not recommended for use in patients with moderate hepatic impairment. The drug Viqueira Pac is contraindicated in patients with severe hepatic failure (Child-Pugh class C). The drug Viqueira Pac is not recommended for use in patients with decompensated liver disease.

The risk of developing resistance to HIV-1 protease inhibitors in patients with HCV/HIV-1 co-infection

Ritonavir, which is part of Viqueira Pac, is an HIV-1 protease inhibitor and may contribute to the selection of amino acid substitutions associated with resistance to HIV-1 protease inhibitors. Patients with HCV/HIV-1 co-infection who receive Viqueira Pac therapy should also receive antiretroviral therapy to reduce the risk of developing resistance to HIV-1 protease inhibitors.

Patients after liver transplantation

The safety and efficacy of Viqueira Pac 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 evaluate the safety and determine the proportion of patients who achieved a sustained virologic response after 12 weeks of treatment (SVR12) and after 24 weeks of treatment with Viqueira Pac in combination with ribavirin. The starting dose of ribavirin ranged from 600 mg to 800 mg per day as the most commonly used at the beginning and end of treatment with Viqueira Pac.

Thirty-four participants who had not received HCV treatment after liver transplantation and had a Metavir fibrosis score ≤ 2 (29 with HCV genotype 1a and 5 with HCV genotype 1b) were included in the clinical trials. Thirty-one of the 32 patients for whom SVR12 (96.9%) time point data were available achieved SVR12 (96.3% in patients with genotype 1a). One patient with HCV genotype 1a had relapse after treatment.

The overall safety profile of Viqueira Pac in combination with ribavirin in HCV-infected patients after liver transplantation was the same as in patients treated with Viqueira Pac in combination with ribavirin in a phase 3 clinical trial, except for the occurrence of anemia. Ten patients (29.4%) had at least one hemoglobin value (after baseline) less than 10 g/dL. In 55.9% (19/34) of patients, the dose of ribavirin was reduced and in 2.9% (1/34) the use of ribavirin was discontinued.

Changing the dose of ribavirin had no effect on the rate of achieving a sustained virologic response. Erythropoietin was required in five patients (all five patients had daily ribavirin at a starting dose of 1,000 mg to 1,200 mg. No patient required a blood transfusion).

Other HCV genotypes

The safety, and effectiveness, of Viqueira Pac has not been established in patients infected with HCV genotypes other than genotype 1.

The effect on ECG

. The effect of combined ombitasvir/paritaprevir/ritonavir and dasabuvir on the QTc interval was evaluated in a randomized, double-blind, placebo and active control (moxifloxacin 400 mg), 4-band cross-over, close QT monitoring study in 60 healthy subjects receiving ombitasvir/paritaprevir/ritonavir and dasabuvir.

In a study with detectable small effects at doses higher than therapeutic – paritaprevir 350 mg, ritonavir 150 mg, ombitasvir 50 mg and dasabuvir 500 mg – showed no clinically significant QT interval prolongation.

Contraindications

Side effects

Viqueira Pac in combination with ribavirin (including in patients with cirrhosis) Safety evaluations are based on pooled data from phase 2 and 3 clinical trials in more than 2,600 patients treated with or without Viqueira Pac.

If Viqueira Pac is used with ribavirin: Read the instructions for use for information about adverse reactions to ribavirin.

In patients receiving Viqueira Pac in combination with ribavirin, the most common adverse reactions observed (in more than 20% of patients) were fatigue and nausea. The number of patients who discontinued .treatment completely because of adverse reactions was 1.2% (25/2044), 1.3% (27/2044) of patients interrupted (with the possibility of further resumption) treatment because of adverse effects. 7.7% (158/2044) of patients required a dose reduction of ribavirin due to adverse reactions.
The safety profile of Viqueira Pac and ribavirin in patients with cirrhosis was the same as in patients without cirrhosis.

The use of Viqueira Pac without ribavirin

In patients in the clinical trial who received Viqueira Pac without ribavirin, the only reported adverse reaction was pruritus. The number of patients who discontinued treatment completely because of adverse reactions was 0.3% (2/588). 0.5% (3/588) of patients discontinued treatment because of adverse reactions.

Table 2 lists adverse events associated or unrelated to Viqueira Pac reported in two randomized, placebo-controlled trials (SAPPHIRE I and SAPPHIRE II) that occurred at a rate at least 5% higher in patients receiving Viqueira Pac in combination with ribavirin compared to patients receiving placebo. In addition, Table 2 includes a list of these adverse reactions in three studies in which patients received Viqueira Pac with or without ribavirin (PEARL II, PEARL III, and PEARL IV) and an analysis of these adverse reactions in studies in patients with cirrhosis who received Viqueira Pac in combination with ribavirin for 12 or 24 weeks (TURQUOISE II).

Table 2. Summary table of frequencies of adverse events identified in Phase 3 clinical trials 1,2

. SAPPHIRE studies I and IIThe PEARL studies II, III and IVTURQUOISE Study II (cirrhotic patients)Adverse reactionViqueira Pac+ribavirin 12 weeks N=770 n (%)Placebo 12 weeks N=255 n (%)Viqueira Pac+ribavirin 12 weeks N=401 n (%)Viqueira Pac 12 weeks N=509 n (%)Viqueira Pac+ribavirin 12 or 24 weeks N=380 n (%)Fatigue263 (34)67 (26.3)120 (29.9)135 (26.5)148 (38.9)Nausea172(22.3)38 (14.9)63 (15.7)43 (8.4)72 (18.9)Itching3121 (15.7)11 (4.3)48 (12.0)31 (6.1)71 (18.7)Other skin manifestations4(16)(9)

Insomnia108 (14.0)19 (7.5)49 (12.2)26 (5.1)63 (16.6)Weakness104 (13.5)17 (6.7)36 (9.0)20 (3.9)51 (13.4)Anemia41 (5.3)030 (7.5)1 (0.2)34 (8.9)1 – The listed adverse reactions occurred at a frequency of more than 5% among patients who received Viqueira Pac in combination with ribavirin compared with patients who received placebo in SAPPHIRE I and II.
2 – The column arrangement of the table is provided for ease of presentation; direct comparisons should not be made for results of studies that differ in design.
3 – The grouping term “pruritus” includes the preferred term “pruritus” and “generalized pruritus.”
4 – The grouping term includes: rash, erythema, eczema, maculopapular rash, dermatitis including. allergic and contact, papular rash, exfoliative phenomena, rash accompanied by itching, erythematous rash, generalized rash, photosensitivity reactions, psoriasis, skin reactions, ulceration, urticaria.

Most adverse reactions in phase 3 clinical trials were mild in severity (grade 1). The safety profile of Viqueira Pac when coadministered with ribavirin is consistent with the available safety profile of ribavirin.

Skin reactions

In the PEARL-II, -III and -IV studies, 7% of patients treated with Viqueira Pac as monotherapy and 10% of patients treated with Viqueira Pac in combination with ribavirin experienced dermatitis in the form of rash.

In studies of SAPPHIRE-I and II, 16% of patients receiving Viqueira Pac with ribavirin and 9% of patients receiving placebo showed adverse events of skin.

In the TURQUOISE II trial, 18% and 24% of patients who received Viqueira Pac in combination with ribavirin for 12 or 24 weeks had adverse events in the skin.

The severity of most events was classified as mild. No serious events or severe skin reactions have been reported, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and drug-associated allergic dermatitis (with eosinophilia and systemic symptoms).

Table 3 summarizes the changes in individual laboratory parameters.

Table 3: Selected laboratory deviations that occurred during treatment 2.

Laboratory indicatorsSAPPHIRE studies I and IIThe PEARL studies II, III and IVTURQUOISE Study II (cirrol patients)Viqueira Pac+ribavirin 12 weeks N=770 n (%)Placebo 12 weeks N=255 n (%)Viqueira Pac+ribavirin 12 weeks N=401 n (%)Viqueira Pac 12 weeks N=509 n (%)Viqueira Pac+ribavirin 12 or 24 weeks N=380 n (%)ALT (alannaminotransferase)>5-20× upper limit of normal1 (3rd degree)6/765 (0.8%)10/254 (3.9%)3/401 (0.7%)1/509 (0.2%)4/380(1.1%)>20× upper limit of normal (4th degree)3/765 (0.4%)0002/380 (0.5%)Hemoglobin41/765 (5.4%)023/401 (5.7%)030/380 (7.9%)1/765 (0.1%)02/401 (0.5%)03/380 (0.8%)00001/380 (0.3%)Total bilirubin>3-10× upper limit of normal (3rd degree)19/765 (2.5%)023/401 (5.7%)2/509 (0.4%)37/380 (9.7%)>10× upper limit of normal (4th degree)1/765 (0.1%)00001 is the upper limit of normal according to the laboratory data.
2 – The arrangement of the table columns is provided for ease of presentation; direct comparisons should not be made for results of studies that differ in design.

Elevated serum ALT activity

In clinical trials using Viqueira Pac with and without ribavirin, less than 1% of patients who did not use estrogen-containing medications showed a temporary increase in ALT activity of more than 5 times the upper limit of normal after initiation of treatment.

In women with concomitant use of drugs containing ethinylestradiol, the incidence of increased ALT activity increased to 25% (4/16). The incidence of clinically significant increases in ALT activity among women who received estrogens other than ethinylestradiol (e.g., estradiol and conjugated estrogens) as hormone replacement therapy was 3% (2/59).
Generally, this phenomenon was asymptomatic, manifested within the first 4 weeks of treatment and resolved as therapy continued.

The increase in ALT activity was not usually associated with an increase in bilirubin concentrations.

Cirrhosis was not a risk factor for increased ALT activity.

For most patients, no special monitoring of liver biochemical parameters is required.

Elevated bilirubin concentrations

Transient increases in bilirubin concentrations (predominantly indirect) were observed in patients receiving Viqueira Pac in combination with ribavirin, which is associated with inhibition of bilirubin transporters OATP1B1/1BZ by paritaprevir and due to hemolysis induced by ribavirin use. The increase in bilirubin concentrations occurred after initiation of treatment, peaked at week I of the trial, and resolved completely as therapy continued.

The increase in bilirubin concentration was not associated with an increase in aminotransferase concentration.

The incidence of increased indirect bilirubin was lower among patients who did not receive ribavirin.

The use of Viqueira Pac in patients with HCV/HIV-1 co-infection

The use of Viqueira Pac in combination with ribavirin was evaluated in 63 patients with HCV/HIV-1 co-infection who were receiving stable antiretroviral therapy. The most common adverse events reported in at least 10% of patients were: weakness (48%), insomnia (19%), nausea (17%). headache (16%), itching (13%). cough (11%), irritability (10%), and sclera icterica (10%).

Elevation of total bilirubin concentration by 2 or more times in relation to the upper limit of norm (more often – at the expense of indirect bilirubin) was registered in 34 patients (54%). Fifteen of them took atazanavir during the period of increased bilirubin concentration, and 9 patients also had acidity of sclerae, jaundice or hyperbilirubinemia.

In patients with hyperbilirubinemia, there was no concomitant increase in aminotransferase activity. No cases of an increase in ALT grade 3 activity have been reported.

In 7 patients (11%) at least one case of a decrease in hemoglobin concentration below 10 g/dL was registered; in 6 of them the dose of ribavirin was corrected. No blood transfusions or erythropoietin prescriptions were required in these cases.

At the end of 12 and 24 weeks of therapy, there was a decrease in the mean CD4+ T-cell count to a concentration of 47 cells/mm3 and 62 cells/mm3, respectively; in most cases the numbers returned to baseline after completion of therapy.

Two patients showed a decrease in the CD4+ T-cell count to less than 200 cells/mm3 without a decrease in CD4+ cells during the course of therapy.

There were no cases of AIDS-associated opportunistic infections.

The use of Viqueira Pac in liver transplant recipients

The use of Viqueira Pac in combination with ribavirin was evaluated in 34 liver transplant patients with HCV recurrence. Adverse events reported in more than 20% of patients: weakness (50%). headache (44%), cough (32%), diarrhea (26%), insomnia (26%), asthenia (24%), nausea (24%), muscle cramps (21%), rash (21%). Ten patients (29%) had at least one case of decrease in hemoglobin concentration to less than 10 g/dL. In 10 patients the dose of ribavirin was corrected because of decrease in hemoglobin concentration; in 3% (1/34) patients the ribavirin therapy was interrupted. 5 patients received erythropoietin; in all these patients the initial dose of ribavirin was 1000-1200 mg per day. No blood transfusions were performed.

Overdose

The highest documented single doses administered to healthy volunteers were 400 mg for paritaprevir (+100 mg ritonavir), 200 mg for ritonavir (+100 mg paritaprevir), 350 mg for ombitasvir, and 2000 mg for dasabuvir.

In case of overdose, it is recommended that any signs or symptoms of adverse reactions be monitored and, if necessary, appropriate symptomatic therapy be initiated immediately.