Viqueira Pak set tablets 250 mg (12.5 mg+75 mg+50 mg) N102 ➤ instructions for use
Inside. Viqueira Pak should be taken with meals, regardless of the fat or calorie content of the food. Before starting therapy with Vikeira Pak, it is necessary to exclude decompensation of liver function based on laboratory and clinical signs. The recommended dose of Vikeira Pak includes 2 tablets. ombitasvir/paritaprevir/ritonavir 12.5/75/50 mg 1 time/day (morning) and 1 tablet. dasabuvir 250 mg 2 times / day (morning and evening). When used with Vikeyra Pak, the recommended dose of ribavirin is based on the patient’s body weight: 1000 mg / day for patients with body weight ≤75 kg and 1200 mg / day for patients with weight body >75 kg, divided into 2 doses per day with food. If it is necessary to adjust the dose of ribavirin, it is recommended to read its instructions for use. Viqueira Pak should be taken in accordance with the recommended duration and instructions for its use, without interruption or change in the dose of the drug. If Vikeira Pak is used in conjunction with ribavirin, then ribavirin should be prescribed for the same period as Vikeira Pak. Skipping a dose If you miss a dose of a tablet containing ombitasvir + paritaprevir + ritonavir, the prescribed dose can be taken within 12 hours after the scheduled dose time. In case of missing a tablet containing dasabuvir, the prescribed dose can be taken within 6 hours after the scheduled time. In case more than 12 hours have passed since the scheduled time of taking the tablet containing ombitasvir + paritaprevir + ritonavir or more than 6 hours after the scheduled time to take a tablet containing dasabuvir, missed doses are not taken and the patient should take the next dose according to the usual dosing schedule. Special groups of patients Recommended duration of treatment for patients with normal liver function and fibrosis stage on the Metavir-2 scale or less after liver transplantation using Viqueira Pak in combination with ribavirin is 24 weeks, regardless of the genotype of HCV subtype 1. When using Vikeyra Pak with calcineurin inhibitors, a dose adjustment of the calcineurin inhibitors is necessary. In clinical studies in patients after liver transplantation, doses of ribavirin were individually selected, which ranged from 600 mg to 800 mg per day. Recommendations for concomitant antiviral therapy for HIV-1 are presented in the section Drug interactions. In patients with mild hepatic impairment (class A according to Child-Pugh scale) no dose adjustment of Viqueira Pak is required. Viqueira Pak is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh class B and C). Liver function tests should be monitored during the first 4 weeks of therapy. In patients with mild, moderate, severe renal failure, as well as in patients with end-stage renal failure (grade 4–5) on dialysis, no dose adjustment is required . If it is necessary to include ribavirin in the regimen, you should read the instructions for use of ribavirin. There are no data on efficacy and safety in children under 18 years of age. Dose adjustment in elderly patients is not required. Phase III clinical trials of genotype 1 included only one patient over 65 years of age. There were no differences in the effectiveness and safety of therapy in young patients and elderly patients.
Viqueira Pak
In vitro studies have shown that ritonavir inhibits some cytochrome P450 isoenzymes, but the drug at clinically significant concentrations does not have a significant effect on the CYP2C9 and CYP2C19 isoenzymes.
Paritaprevir, ritonavir and dasabuvir are P-gp inhibitors in vitro, but no significant changes were observed when the drug interacted with digoxin, a sensitive P-gp substrate.
Paritaprevir is an inhibitor of organic anion transport polypeptide 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 glucuronyl transferase isoform 1A1 (UGT1A1), and ritonavir is an inhibitor of the cytochrome CYP3A4 isoenzyme. Concomitant use with drugs that are primarily metabolized by CYP3A or are substrates for UGT1A1, BCRP, OATP1B1, or OATP1B3 may result in increased plasma concentrations of such drugs.
Paritaprevir, ombitasvir, ritonavir and dasabuvir do not inhibit the organic anion transporter (OAT1) in vivo, nor are they likely to inhibit the organic cation transporters (OCT1 and OCT2), organic anion transporters (OAT3) or multidrug resistance and toxin clearance proteins (MATE1 and MATE2K) in clinically significant concentrations; thus, the drug does not affect these renal excretion routes.
The effect of other drugs on Viqueira Pak
Concomitant use of potent inhibitors of the CYP3A isoenzyme can increase the concentration of paritaprevir up to 2 times. Co-administration with drugs that induce the CYP3A isoenzyme leads to an expected decrease in the plasma concentrations of dasabuvir, paritaprevir, ombitasvir and ritonavir and reduces their therapeutic effect. Co-administration with drugs that inhibit CYP2C8 may increase plasma concentrations of dasabuvir. Co-administration with drugs that induce the CYP2C8 isoenzyme expectedly leads to a decrease in the concentration of dasabuvir in the blood plasma and reduces its therapeutic effect.
A change in exposure (Cmax and AUC) of paritaprevir, ombitasvir and dasabuvir from 0.5 to 2.0 times is not considered clinically significant and does not require dose adjustment.
The drug Vikeyra Pak can be prescribed together with drugs that are inhibitors of the CYP3A isoenzyme, while at the same time it is contraindicated to combine the drug with potent inhibitors of the CYP2C8 isoenzyme or inducers of the CYP3A/2C8 isoenzyme.
Paritaprevir, dasabuvir and ritonavir are P-gp substrates. Paritaprevir and dasabuvir are BCRP substrates. Ombitasvir is a substrate of P-glycoprotein and/or BCRP. Paritaprevir is a substrate of OATP1B1 and OATP1B3. However, it is unlikely that inhibition of P-glycoprotein. BCRP, OATP1B1 or OATP1B3 will result in a clinically significant increase in drug exposure.
Established and other potential drug interactions
A co-drug interaction profile has been developed for a number of the most commonly prescribed co-administered drugs.
If the patient is currently taking drug(s) that may have the potential for drug interactions, or has begun taking them while on drug therapy, it is recommended that dosage adjustments of the concomitant drug(s) or appropriate clinical monitoring be considered.
If during treatment with the drug the doses of concomitantly used drugs were adjusted, they should be adjusted at the end of therapy.
Viqueira Pak tablets set pack cont cell/pack cards x112
ATX code: J05A (Direct-acting antiviral drugs) Dosage form VIKEIRA PAK set of tablets: blisters, tablets, coated. film coating, 250 mg 2 pcs., tab., coated. film coating, 12.5 mg+75 mg+50 mg 2 pcs., 28 blisters in a pack of reg. No.: LP-002965 dated 04/21/15 - Valid Release form, composition and packaging Light brown, oval, film-coated tablets, with “AV2” engraved on one side.
1 tab. dasabuvir sodium monohydrate 270.26 mg, which corresponds to the content of dasabuvir 250 mg
Excipients: microcrystalline cellulose PH101 - 103.04 mg, microcrystalline cellulose PH102 - 104.72 mg, lactose monohydrate - 47.3 mg, copovidone - 101.35 mg, croscarmellose sodium - 33.78 mg, colloidal silicon dioxide - 4.05 mg, magnesium stearate - 11 .15 mg.
Film shell composition: Opadry 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%, black iron oxide - 0.1%.
The tablets are pink, oblong, biconvex, film-coated, with “AV1” engraved on one side.
1 tab. ombitasvir hydrate 13.6 mg, which corresponds to the content of ombitasvir 12.5 mg, paritaprevir dihydrate 78.5 mg, which corresponds to the content of paritaprevir 75 mg, ritonavir 50 mg
Excipients: copovidone - 849.2 mg, D-alpha-tocopherol macrogol succinate - 42.5 mg, colloidal silicon dioxide - 10.8 mg, propylene glycol monolaurate - 10 mg, sorbitan laurate - 33.3 mg.
Film shell composition: Opadry II pink - 32.5 mg, including polyvinyl alcohol - 46.94%, macrogol 3350 - 23.7%, talc - 17.36%, titanium dioxide - 11.9%, red iron oxide - 0.1%.
4 things. (2 tablets + 2 tablets) - blisters (7) - cardboard packs (4) - cardboard packs.
Clinical-pharmacological group: Antiviral drug active against hepatitis C virus Pharmaco-therapeutic group: Antiviral drug Pharmacological action Mechanism of action
Viqueira Pak combines three direct-acting antiviral agents for the treatment of hepatitis C virus (HCV) with different mechanisms of action and non-overlapping resistance profiles, which allows the fight against the hepatitis C virus at different stages of its life cycle, and ritonavir.
Dasabuvir
Dasabuvir is a non-nucleoside inhibitor of the viral RNA-dependent RNA polymerase encoded by the NS5B gene, which is required for viral genome replication. According to biochemical studies, dasabuvir inhibits the polymeric activity of NS5B enzymes of recombinant genotype Ia and Ib of HCV with IC30 values of 2.8 and 10.7 nM, respectively.
Ombitasvir
Ombitasvir is an inhibitor of the HCV NS5A protein, which is necessary for viral replication. In replicon cell culture studies, 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 NS3/4A protease, which is required for the proteolytic cleavage of the encoded HCV polyprotein (to the mature forms of the NS3, NS4A, NS4B, NS5A and NS5B proteins) and is essential for viral replication. According to biochemical analysis, paritaprevir inhibits the proteolytic activity of NS3/4A protease of recombinant HCV genotypes Ia and Ib with IC50 values of 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 plasma concentration of paritaprevir and the concentration of paritaprevir measured immediately before the next dose, and increases the total exposure of the drug (i.e., the area under the drug interaction curve).
Liver failure
In patients with mild hepatic impairment (Child-Pugh class A), no dose adjustment of Vikeyra Pak is required. The safety and effectiveness of Vikeyra Pak in patients infected with hepatitis C with moderate hepatic impairment (Child-Pugh class B) has not been established; the use of Vikeyra Pak is not recommended in patients with moderate hepatic impairment. Viqueira Pak is contraindicated in patients with severe hepatic impairment (Child-Pyotr class C).
Liver function indicators should be monitored before starting therapy and during the course.
Side effects Clinical trial experience
If Vikeira Pak is used with ribavirin: for information about adverse reactions of ribavirin, you should read its instructions for use.
The safety assessment is based on pooled data from phase 2 and 3 clinical trials in more than 2,600 patients treated with Viqueira Pak with or without ribavirin.
Viqueira Pak in combination with ribavirin (including in patients with cirrhosis)
In patients receiving Viqueira Pak in combination with ribavirin, the most common adverse reactions observed (in more than 20% of patients) were fatigue and tiredness. The number of patients who completely discontinued treatment due to adverse reactions was 1.2% (25/2044), 1.3% (27/2044) of patients interrupted (with the possibility of further resumption) treatment due to side effects. 7.7% (158/2044) of patients required a dose reduction of ribavirin due to adverse reactions.
The safety profile of Viqueira Pak and ribavirin in patients with cirrhosis was the same as in patients without cirrhosis.
Using Viqueira Pak without ribavirin
In patients in a clinical study receiving Viqueira Pak without ribavirin, the only reported 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 due to adverse reactions.
Table 2 lists adverse events, related or not related to the use of Vikeyra Pak, recorded in two randomized plano-controlled trials (SAPPHIRE I and SAPPHIRE II), which were observed at an incidence of at least 5% higher than in patients receiving Viqueira Pak in combination with ribavirin compared with patients receiving placebo. In addition, Table 2 includes a list of these adverse reactions in three studies in which patients received Viqueira Pak with or without ribavirin (PEARL II, PEARL III and PEARL IV), and an analysis of these adverse reactions in studies in patients with cirrhosis livers receiving Viqueira Pak 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 trials1'2.
SAPPHIRE I and II studies PEARL II, III and IV studies TURQUOISE II study (patients with cirrhosis) Adverse reaction 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 with sides 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 - the listed adverse reactions occurred with an incidence of more than 5% among patients receiving Viqueira Pak in combination with ribavirin compared with patients receiving placebo in SAPPHIRE I and II. 2 - The layout of the table columns is provided to simplify the presentation; direct comparisons should not be made for the results of studies that differ in design. 3—The grouping term “itch” includes the preferred term “itch” and “generalized itch.” 4 - grouping term includes: rash, erythema, eczema, maculopapular rash, dermatitis, incl. allergic and contact, papular rash, exfoliative phenomena, rash accompanied by itching, erythematous rash, generalized rash, photosensitivity reactions, psoriasis, skin reactions, ulcerations, urticaria. The majority of adverse reactions in phase 3 clinical trials were mild (grade 1). The safety profile of Viqueira Pak when used in combination with ribavirin is consistent with the existing safety profile of ribavirin.
Skin reactions
In the PEARL-II, -III and -IV studies, 7% of patients receiving Vikeira Pak monotherapy and 10% of patients receiving Vikeira Pak in combination with ribavirin experienced dermatitis in the form of rash. In the SAPPHIRE-I and II studies, 16% of patients receiving Viqueira Pak with ribavirin and 9% of patients receiving placebo experienced skin adverse events. In the TURQUOISE II study, 18% and 24% of patients receiving Viqueira Pak in combination with ribavirin for 12 or 24 weeks experienced skin adverse events. The severity of most events is classified as mild. No serious events or severe skin reactions have been reported, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, drug-associated allergic dermatitis (with eosinophilia and systemic symptoms).
Deviations from normal laboratory parameters
Changes in selected laboratory parameters are shown in Table 3.
Table 3. Selected laboratory abnormalities that occurred during treatment2.
Laboratory parameters SAPPHIRE studies I and II PEARL studies II, III and IV TURQUOISE II study (patients with cirrol) 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 (alannaminotransferase) >5-20×upper limit of normal1 (grade 3) 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 (grade 4) 3/765 (0.4 %) 0 0 0 2/380 (0.5%) Hemoglobin Total bilirubin >3-10×upper limit of normal (grade 3) 19/765 (2.5%) 0 23/401 (5.7%) 2/509 (0.4%) 37 /380 (9.7%) > 10×upper limit of normal (grade 4) 1/765 (0.1%) 0 0 0 0 1 - upper limit of normal according to laboratory data. 2 - the layout of the table columns is provided to simplify the presentation; direct comparisons should not be made for the results of studies that differ in design. Increased ALT activity in blood serum
In clinical studies using Viqueira Pak with and without ribavirin, less than 1% of patients not using estrogen-containing drugs experienced a transient increase in ALT levels greater than 5 times the upper limit of normal after initiation of treatment.
In women, with concomitant use of drugs containing ethinyl estradiol, the incidence of increased ALT activity increased to 25% (4/16). The incidence of clinically significant increases in ALT among women receiving estrogens other than ethinyl estradiol (e.g., estradiol and conjugated estrogens) for hormone replacement therapy was 3% (2/59).
As a rule, this phenomenon was asymptomatic, appeared during the first 4 weeks of treatment and resolved as therapy continued. An increase in ALT activity is usually not associated with an increase in bilirubin concentration. Cirrhosis was not a risk factor for elevated ALT levels. For most patients, no special monitoring of liver biochemical parameters is required.
Increased bilirubin concentration
A temporary increase in bilirubin concentrations (mainly indirect) was observed in patients receiving Viqueira Pak in combination with ribavirin, which is associated with inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir and due to hemolysis caused by the use of ribavirin. Increases in bilirubin concentrations occurred after initiation of treatment, peaked in week I of the study, and resolved completely as therapy continued. The increase in bilirubin concentration was not associated with an increase in aminotransferase concentrations. The incidence of increased indirect bilirubin was lower among patients who did not receive ribavirin.
Use of Vikeyra Pak in patients with HCV/HIV-1 co-infection
Viqueira Pak in combination with ribavirin was evaluated in 63 patients with HCV/HIV-1 co-infection who were receiving antiretroviral therapy on a stable basis. The most common adverse events reported in at least 10% of patients: weakness (48%), insomnia (19%), nausea (17%). headache (16%), itching (13%). cough (11%), irritability (10%), scleral icterus (10%).
An increase in the concentration of total bilirubin by 2 or more times relative to the upper limit of normal (more often due to indirect bilirubin) was recorded in 34 patients (54%). 15 of them took atazanavir during the period of increased bilirubin concentration; 9 patients also had scleral icterus, jaundice or hyperbilirubinemia. In patients with hyperbilirubinemia, there was no concomitant increase in aminotransferase activity. There were no cases of grade 3 increases in ALT 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 performed. In these cases, blood transfusion and erythropoietin administration were not required.
At the end of 12 and 24 weeks of therapy, there was a decrease in the average number of CD4+ T cells to a concentration of 47 cells/mm3 and 62 cells/mm3, respectively; in most cases, after completion of the course of therapy, the indicators returned to the original values. In 2 patients, during the course of therapy, a decrease in the number of CD4+ T cells to a concentration of less than 200 cells/mm3 without a decrease in CD4+ was recorded. There were no cases of AIDS-associated opportunistic infections reported.
Use of Viqueira Pak in liver transplant recipients
Viqueira Pak in combination with ribavirin was evaluated in 34 liver transplant patients with relapsed HCV. 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%). In 10 patients (29%) there was at least one case of decrease in hemoglobin concentration to a concentration of less than 10 g/dL. In 10 patients, the dose of ribavirin was adjusted due to a decrease in hemoglobin concentration; in 3% (1/34) of patients, the course of 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.
Contraindications for use: hypersensitivity to ombitasvir, paritaprevir, ritonavir, dasabuvir or any excipients of the drug,
- known hypersensitivity to ritonavir (for example, toxic epdermal necrolysis or Stevens-Johnson syndrome),
- severe liver failure (Child-Pugh class C),
— contraindications to the use of ribavirin (when using Vikeyra Pak and ribavirin together). To obtain information about contraindications to the use of ribavirin, you should read its instructions for use,
- use of ribavirin in women during pregnancy, as well as in men whose partners are pregnant,
- simultaneous use of drugs, an increase in the concentration of which in the blood plasma can lead to serious adverse reactions and the clearance of which significantly depends on metabolism through the CYP3A isoenzyme,
- simultaneous use of drugs that are potent inhibitors of CYP2C8 (as this can lead to a significant increase in the concentration of dasabuvir in the blood plasma and the risk of prolongation of the QT interval),
- simultaneous use of drugs that are powerful inducers of the CYP3A isoenzyme (can significantly reduce the concentrations of paritaprevir, ombitasvir and dasabuvir in the blood plasma),
- simultaneous use of drugs that are powerful inducers of the CYP2C8 isoenzyme (as this can lead to a significant decrease in the concentration of dasabuvir in the blood plasma),
- simultaneous use with drugs: alfuzosin, carbamazepine, phenytoin, phenobarbital, efavirenz, ergot alkaloids (ergotamine, dihydroergotamine, zrgometrine, methylergometrine), gemfibrozil, lovastatin, simvastatin, midazolam and triazolam (in dosage forms for oral administration), pimozide, rifampicin, salmeterol, St. John's wort preparations (St. John's wort, Hypericum perforatum), sildenafil (when used to treat pulmonary arterial hypertension): rilpivirine, lopinavir/ritonavir, darunavir/ritonavir, drugs containing ethinyl estradiol (for example, combined oral contraceptives), atazanavir/ritonavir in fixed dose combinations,
- children under 18 years of age,
- lactase deficiency, galactose intolerance, glucose-galactose malabsorption.
Carefully
Combined use of Vikeyra Pak and fluticasone. or other glucocorticosteroids that are metabolized with the participation of the CYP3A4 isoenzyme. Combined use with antiarrhythmic drugs. Liver failure of moderate severity.
Use during pregnancy and lactation Pregnancy
There are no results from high-quality and well-controlled studies regarding the use of Viqueira Pak in pregnant women.
In animal studies using ombitasvir/paritaprevir/ritonavir and its main inactive metabolites in humans (M29, M36), as well as dasabuvir, no effect on the development of the embryo and fetus was noted. Trials with paritaprevir/ritonavir used maximum doses corresponding to 98 times (in mice) or 8 times (in rats) the recommended clinical dose in humans. Trials with ombitasvir used maximum doses corresponding to 28 times (in mice) or 4 times (in rabbits) the recommended clinical dose in humans. The highest doses of major inactive human metabolites were given in a mouse study, with exposures 26 times higher than in humans using recommended clinical doses. Trials using dasabuvir used maximum doses corresponding to 48 times (in rats) or 12 times (in rabbits) the recommended clinical dose in humans.
Due to the fact that it is impossible to draw conclusions about the use of the drug in pregnant women based on data obtained in animals, Vikeyra Pak should be used during pregnancy only if absolutely necessary, justified by the clinical situation.
Combined use with ribavirin
Ribavirin may cause birth defects and/or fetal death. Female patients and partners of male patients should take maximum precautions to avoid pregnancy as significant teratogenicity and/or embryocidal effects have been demonstrated in animal studies in all species exposed to ribavirin. A treatment regimen containing ribavirin should not be started until a negative pregnancy test result is obtained immediately before starting therapy. On peri
