Viekira Pak (Tablet kit) Instructions for Use

Marketing Authorization Holder

AbbVie, LLC (Russia)

Manufactured By

AbbVie Ireland NL, B.V. (Ireland)

Or

Fournier Laboratories Ireland, Limited (Ireland)

Labeled By

AbbVie, Inc. (USA)

Packaging and Quality Control Release

AbbVie, Inc. (USA)

Or

ORTAT, JSC (Russia)

ATC Code

J05AP52 (Dasabuvir, ombitasvir, paritaprevir and ritonavir)

Dosage Form

Viekira Pak

Tablet kit (film-coated tablets, 250 mg: 2 pcs., film-coated tablets, 12.5 mg+75 mg+50 mg: 2 pcs.): 112 pcs.

Dosage Form, Packaging, and Composition

Tablet kit.

Film-coated tablets light brown, oval, engraved with “AV2” on one side (2 pcs. in a blister).

Excipients: microcrystalline cellulose (type Avicel^® PH101) – 103.04 mg, microcrystalline cellulose (type Avicel^® 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 coating composition Opadry II Beige – 21 mg (polyvinyl alcohol – 40%, titanium dioxide – 21.55%, macrogol 3350 – 20.2%, talc – 14.8%, yellow iron oxide – 3%, red iron oxide – 0.35%, black iron oxide – 0.1%).

Film-coated tablets pink, oblong, biconvex, engraved with “AV1” on one side (2 pcs. in a blister).

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 coating composition Opadry II Pink – 32.5 mg (polyvinyl alcohol – 46.94%, macrogol 3350 – 23.7%, talc – 17.36%, titanium dioxide – 11.9%, red iron oxide – 0.1%).

4 pcs. (2+2) – blisters (7) – cardboard packs (4) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug active against hepatitis C virus

Pharmacotherapeutic Group

Antiviral agent

Pharmacological Action

Pharmacodynamics

Mechanism of action

Viekira Pak combines three direct-acting antiviral substances for the treatment of viral hepatitis C (HCV) with different mechanisms of action and non-overlapping resistance profiles, which allows targeting the hepatitis C virus at different stages of its life cycle, and ritonavir.

Dasabuvir

Dasabuvir is a non-nucleoside inhibitor of the virus-encoded NS5B RNA-dependent RNA polymerase, which is essential for replication of the viral genome. According to biochemical studies, dasabuvir inhibits the polymerase activity of recombinant HCV genotype 1a and 1b NS5B enzymes with IC₅₀ values of 2.8 and 10.7 nM, respectively.

Ombitasvir

Ombitasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication. In replicon cell culture studies, EC₅₀ values for ombitasvir were 14.1 and 5.0 nM for HCV genotypes 1a and 1b, respectively.

Paritaprevir

Paritaprevir is an inhibitor of the HCV NS3/4A protease, which is required for proteolytic cleavage of the encoded HCV polyprotein (into mature forms of NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. According to biochemical analysis, paritaprevir inhibits the proteolytic activity of recombinant HCV genotype 1a and 1b NS3/4A protease 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 C_max of paritaprevir in plasma and the concentration of paritaprevir measured just before the next dose, and increases the overall drug exposure (i.e., AUC).

Resistance

In cell culture

Genotype 1

Resistance to paritaprevir and ombitasvir is controlled by NS3 and NS5A genes, respectively, identified in cell culture or identified in phase IIb and III clinical trials. These variants were phenotypically characterized for the corresponding genotype 1a or 1b replicons.

In genotype 1a, substitutions F43L, R155K, A156T, and D168A/F/H/V/Y in HCV NS3 reduce susceptibility to paritaprevir. In the genotype 1a replicon, paritaprevir activity was reduced 20-, 37-, and 17-fold by F43L, R155K, and A156T substitutions, respectively. Paritaprevir activity was reduced 96-fold by the D168V substitution and from 50- to 219-fold by each of the other D168 substitutions. Paritaprevir activity against HCV genotype 1a was not significantly altered (change was less than or equal to 3-fold) by single substitutions V36A/M, V55I, Y56H, Q80K, or E357K. Double variants, including combinations of V36L/M, F43L, Y56H, Q80K, or E357K with R155K or with a D168 substitution, further reduced paritaprevir activity by 2- to 3-fold compared to the single R155K or D168 substitution. In the genotype 1b replicon, paritaprevir activity was reduced 76-, 159-, and 337-fold by the D168A, D168H, D168V, and D168Y substitutions, respectively. It was not possible to evaluate the isolated Y56H substitution due to poor replication capacity; however, the combination of Y56H and D168A/V/Y reduced paritaprevir activity from 700- to 4118-fold.

In genotype 1a, substitutions M28T/V, Q30E/R, L31V, H58D, Y93C/H/N, and M28V + Q30R in HCV NS5A reduce susceptibility to ombitasvir. In the genotype 1a replicon, ombitasvir activity was reduced 896-, 58-, and 243-fold by M28T/V and H58D substitutions, respectively, and 1326-, 800-, 155-fold and from 1675- to 66740-fold by Q30E/R, L31V, and Y93C/H/N substitutions, respectively. Y93H, Y93N, or M28V in combination with Q30R reduced ombitasvir activity by more than 42802-fold. In genotype 1b, substitutions L28T, L31F/V, and Y93H alone or in combination with L28M, R30Q, L31F/M/V, or P58S in HCV NS5A reduced susceptibility to ombitasvir. In the genotype 1b replicon, ombitasvir activity was reduced less than 10-fold by amino acid variations at positions 30 and 31. Ombitasvir activity was reduced 661-, 77-, 284-, and 142-fold compared to genotype 1b by the L28T, Y93H, R30Q in combination with Y93H, and L31M in combination with Y93H substitutions, respectively. All other double Y93H substitutions in combination with substitutions at positions 28, 31, or 58 reduced ombitasvir activity by more than 400-fold.

Genotype 4

In genotype 4a, resistance to paritaprevir or ombitasvir was phenotypically characterized by variants in NS3 or NS5A, respectively (determination in cell culture). Substitutions R155C, A156T/V, and D168H/V in HCV NS3 reduced susceptibility to paritaprevir by 40- to 332-fold. The L28V substitution in HCV NS5A reduced susceptibility to ombitasvir by 21-fold.

Cross-resistance

Cross-resistance may be observed among NS5A inhibitors, NS3/4A protease inhibitors, and non-nucleoside NS5B inhibitors by class. The effect of prior treatment experience with ombitasvir, paritaprevir, or dasabuvir on the efficacy of other NS5A inhibitors, NS3/4A protease inhibitors, or NS5B inhibitors has not been studied.

Pharmacokinetics

The pharmacokinetic properties of the combined use of ombitasvir/paritaprevir/ritonavir and dasabuvir have been evaluated in healthy adults and in patients with chronic hepatitis C. Table 1 shows the mean C_max and AUC values for ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily in combination with dasabuvir 250 mg twice daily, obtained in healthy volunteers after multiple doses with food.

Table 1. Geometric mean C_max, AUC of multiple doses of ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily in combination with dasabuvir 250 mg twice daily, with food in healthy volunteers

AUC₂₄ – value for ombitasvir, paritaprevir, and ritonavir; AUC₁₂ – value for dasabuvir.

Absorption

Ombitasvir/paritaprevir/ritonavir and dasabuvir are absorbed after oral administration with a mean T_max of 4 to 5 h. Exposure to ombitasvir and dasabuvir increases proportionally with dose, while exposure to paritaprevir and ritonavir increases more than proportionally with dose. The accumulation factor for ombitasvir and dasabuvir is minimal, while for ritonavir and paritaprevir it is from 1.5 to 2. Pharmacokinetic steady-state for the combination is reached after approximately 12 days of use.

The absolute bioavailability of ombitasvir and paritaprevir when co-administered with ritonavir was 48% and 53%, respectively. 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 with food. Taking with food increases the exposure (AUC) of ombitasvir/paritaprevir/ritonavir and dasabuvir by approximately 82%, 211%, 49%, and 30%, respectively, relative to fasting. The increase in exposure was the same regardless of the type of food (e.g., high-fat meal compared to moderate-fat meal) or calorie content (approximately 600 kcal compared to 1000 kcal). To maximize bioavailability, Viekira Pak should be taken with a meal, regardless of fat or calorie content.

Distribution

Ombitasvir/paritaprevir/ritonavir and dasabuvir are highly bound to plasma proteins. Plasma protein binding is virtually unchanged in patients with renal or hepatic impairment. The blood-to-plasma concentration ratio in humans is 0.49, 0.7, 0.6, and 0.7 for ombitasvir + paritaprevir + ritonavir and dasabuvir, indicating that paritaprevir, ritonavir, ombitasvir, and dasabuvir are predominantly distributed in plasma. Paritaprevir is approximately 97-98.6% bound to human plasma proteins at concentrations ranging from 0.08 µg/ml to 8 µg/ml. Ritonavir is more than 99% bound to human plasma proteins at concentrations ranging from 0.007 µg/ml to 22 µg/ml. Ombitasvir is approximately 99.5% bound to human plasma proteins at concentrations ranging from 0.09 µg/ml to 9 µg/ml. Dasabuvir is more than 99.9% bound to human plasma proteins at concentrations ranging from 0.15 µg/ml to 5 µg/ml.

In animal studies, paritaprevir concentrations in the liver were significantly higher than in plasma (e.g., liver-to-plasma ratio greater than 300:1 in mice). In vitro data indicate that paritaprevir is a substrate for hepatic transporters OATP1B1 and OATP1B3.

Metabolism and excretion

The metabolism and excretion of Viekira Pak were studied using carbon-14 ¹⁴C-labeled paritaprevir, ombitasvir, ritonavir, and dasabuvir.

Radioisotope diagnostic methods are based on the detection, recording, and measurement of radiation from radioactive isotopes. These methods allow the study of absorption, movement in the body, accumulation in individual tissues, biochemical transformations, and excretion from the body of the studied substances.

Dasabuvir is primarily metabolized by the CYP2C8 isoenzyme and to a lesser extent by the CYP3A isoenzyme. After administration of 400 mg of dasabuvir (carbon-14 ¹⁴C-labeled) to humans, unchanged dasabuvir was the main component (approximately 60%); seven metabolites of dasabuvir were detected in plasma. The most common metabolite in plasma was M1, which accounted for 21% of the AUC and in vitro exhibited the same properties (taking into account plasma protein binding) against HCV genotype 1 as the parent drug.

Ombitasvir is metabolized via amide hydrolysis followed by oxidative metabolism. After a single 25 mg dose of ombitasvir (carbon-14 ¹⁴C-labeled) without other drugs, the unchanged parent drug accounted for 8.9% of the total in plasma; a total of 13 metabolites were detected in plasma. These metabolites have no antiviral or any other pharmacological activity.

Paritaprevir is metabolized primarily by the CYP3A4 isoenzyme and to a lesser extent by the CYP3A5 isoenzyme. After a single oral dose of 200/100 mg of paritaprevir (carbon-14 ¹⁴C-labeled)/ritonavir, the parent drug was the major circulating component, accounting for approximately 90% in plasma. At least 5 minor metabolites of paritaprevir were identified in plasma, accounting for approximately 10%. These metabolites have no antiviral activity.

Ritonavir is primarily metabolized by the CYP3A isoenzyme and to a lesser extent by the CYP2D6 isoenzyme. Almost all plasma radioactivity after a single 600 mg oral solution dose of ritonavir (carbon-14 ¹⁴C-labeled) in humans was associated with unchanged ritonavir.

Excretion

Dasabuvir. After administration of dasabuvir with ombitasvir/paritaprevir/ritonavir, the mean T_1/2 of dasabuvir was about 5.5-6 h. After administration of 400 mg of dasabuvir (carbon-14 ¹⁴C-labeled), approximately 94.4% of the isotopes were found in feces and a negligible amount (about 2%) in urine. 26% of the isotope of unchanged dasabuvir was found in feces and 0.03% in urine.

Ombitasvir. After administration of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, the mean T_1/2 of ombitasvir was about 21-25 h. After administration of 25 mg of ombitasvir (carbon-14 ¹⁴C-labeled), approximately 90.2% of the isotopes were found in feces and a negligible amount (1.91%) in urine. 87.8% of the isotopes of unchanged ombitasvir were found in feces and 0.03% in urine.

Paritaprevir. After administration of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, the mean plasma T_1/2 of paritaprevir was about 5.5 h. After co-administration of 200 mg of paritaprevir (carbon-14 ¹⁴C-labeled) with 100 mg of ritonavir, approximately 88% of the isotopes were found in feces and a negligible amount (8.8%) in urine. 1.1% of the isotopes of unchanged paritaprevir were found in feces and 0.05% in urine.

Ritonavir. After administration of ombitasvir/paritaprevir/ritonavir, the mean plasma T_1/2 of ritonavir was about 4 h. After administration of 600 mg of ritonavir (carbon-14 ¹⁴C-labeled) as an oral solution – 86.4% of the isotopes were found in feces and 11.3% of the dose in urine.

Special patient groups

Age. No dose adjustment of Viekira Pak is required in elderly patients. The pharmacokinetics of Viekira Pak have not been studied in pediatric patients.

Gender and body weight. No dose adjustment of Viekira Pak is required based on gender or body weight.

Race and ethnicity. No dose adjustment of Viekira Pak is required based on race and ethnicity.

Hepatic impairment. The pharmacokinetics of a single dose of ombitasvir, paritaprevir, ritonavir, and dasabuvir were evaluated in non-HCV patients with mild hepatic impairment (Child-Pugh class A; score 5-6), moderate hepatic impairment (Child-Pugh class B; score 7-9), and severe hepatic impairment (Child-Pugh class C; score 10-15).

Compared to patients with normal liver function, in patients with mild hepatic impairment, the AUC values of ombitasvir, paritaprevir, and ritonavir were decreased by 8%, 29%, and 34%, respectively, while the dasabuvir AUC value was increased by 17%.

Compared to patients with normal liver function, in patients with moderate hepatic impairment, the AUC values of ombitasvir, ritonavir, and dasabuvir were decreased by 30%, 30%, and 16%, respectively, while the paritaprevir AUC value was increased by 62%.

Compared to patients with normal liver function, in patients with severe hepatic impairment, the AUC values of paritaprevir, ritonavir, and dasabuvir were increased by 945%, 13%, and 325%, respectively, while the ombitasvir AUC value was decreased by 54%.

Renal impairment. The pharmacokinetics of a single dose of ombitasvir, paritaprevir, ritonavir, and dasabuvir were evaluated in non-HCV patients with mild (CrCl 60-89 ml/min), moderate (CrCl 30-59 ml/min), and severe (CrCl 15-29 ml/min) renal impairment.

Overall, changes in exposure to ombitasvir, paritaprevir, ritonavir, and dasabuvir in non-HCV patients with mild, moderate, and severe renal impairment are not clinically significant. Pharmacokinetic data for Viekira Pak in non-HCV patients with end-stage renal disease are not available.

Compared to patients with normal renal function, in patients with mild renal impairment, the AUC values of paritaprevir, ritonavir, and dasabuvir were increased by 19%, 42%, and 21%, respectively, while the ombitasvir AUC value remained unchanged.

Compared to patients with normal renal function, in patients with moderate renal impairment, the AUC values of paritaprevir, ritonavir, and dasabuvir were increased by 33, 80, and 37%, respectively, while the ombitasvir AUC value remained unchanged.

Compared to patients with normal renal function, in patients with severe renal impairment, the AUC values of paritaprevir, ritonavir, and dasabuvir were increased by 45%, 114%, and 50%, respectively, while the ombitasvir AUC value remained unchanged.

Indications

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

ICD codes

Dosage Regimen

Orally. Viekira Pak should be taken with food, regardless of the fat content or caloric value of the meal. Do not break, chew, or dissolve the tablets.

Before starting therapy with Viekira Pak, liver function decompensation must be ruled out based on laboratory and clinical signs.

The recommended dose of Viekira Pak includes 2 tablets of ombitasvir/paritaprevir/ritonavir 12.5/75/50 mg once daily (in the morning) and 1 tablet of dasabuvir 250 mg twice daily (in the morning and evening). In some patient groups, Viekira Pak is used in combination with ribavirin (see Table 2).

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

Table 2. Treatment regimen and its duration for different patient groups (treatment-naive or after interferon therapy)

When used with Viekira Pak, the recommended dose of ribavirin is based on the patient’s body weight: 1000 mg/day for patients with a body weight <75 kg and 1200 mg/day for patients with a body weight ≥75 kg, divided into two daily doses with food. If ribavirin dose adjustment is necessary, it is recommended to refer to its prescribing information.

Viekira Pak should be taken for the duration recommended in its prescribing information, without interruption or dose modification. If Viekira Pak is used with ribavirin, ribavirin should be prescribed for the same duration as Viekira Pak.

Missed Dose

If a dose of the tablet containing ombitasvir + paritaprevir + ritonavir is missed, the prescribed dose can be taken within 12 hours of the scheduled time.

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

If more than 12 hours have passed since the scheduled time for taking the tablet containing ombitasvir + paritaprevir + ritonavir or more than 6 hours have passed since the scheduled time for taking the tablet containing dasabuvir, the missed doses should not be taken, and the patient should take the next dose according to the regular dosing schedule.

Special Patient Groups

Patients after liver transplantation

The recommended duration of treatment for patients with normal liver function and Metavir fibrosis stage F2 or less after liver transplantation using Viekira Pak in combination with ribavirin is 24 weeks, regardless of HCV genotype 1 subtype. When using Viekira Pak with calcineurin inhibitors, dose adjustment of the calcineurin inhibitors is necessary. In clinical studies in post-liver transplant patients, ribavirin doses were individually tailored, ranging from 600 mg to 800 mg per day.

Patients with HCV/HIV-1 co-infection

The recommendations specified in Table 2 should be followed. Recommendations for concomitant antiretroviral therapy for HIV-1 are provided in the “Drug Interactions” section.

Hepatic impairment

In patients with mild hepatic impairment (Child-Pugh class A), no dose adjustment of Viekira Pak is required. Viekira Pak is contraindicated in patients with moderate and severe hepatic impairment (Child-Pugh class B and C). Liver function tests should be monitored during the first 4 weeks of therapy (see the “Special Instructions” section).

Renal impairment

In patients with mild, moderate, severe renal impairment, as well as in patients with end-stage renal disease (stage 4-5) on dialysis, no dose adjustment is required. If ribavirin needs to be included in the regimen, refer to the ribavirin prescribing information.

Children

Data on efficacy and safety in children under 18 years of age are not available.

Elderly patients

No dose adjustment is required in elderly patients. Phase III clinical trials for genotype 1 included patients over 65 years of age. No differences in efficacy and safety of therapy were observed between young and elderly patients. However, increased sensitivity in elderly individuals cannot be ruled out.

Adverse Reactions

The safety assessment is based on pooled data from phase 2 and 3 clinical trials in more than 2600 patients who received Viekira Pak with or without ribavirin.

Viekira Pak in combination with ribavirin

In patients receiving Viekira Pak in combination with ribavirin, the most frequently observed adverse reactions (in more than 20% of patients) were fatigue and nausea. The number of patients who completely discontinued treatment due to adverse reactions was 0.2% (5/2044). 4.8% (99/2044) of patients required a reduction in the ribavirin dose due to the occurrence of adverse reactions.

Use of Viekira Pak without ribavirin

In patients receiving Viekira Pak without ribavirin, adverse reactions typically associated with ribavirin intake (e.g., nausea, insomnia, anemia) were observed less frequently. No patients (0/588) who completely discontinued treatment due to adverse reactions were identified.

The safety profile of Viekira Pak in patients without cirrhosis was the same as in patients with compensated cirrhosis, except for transient hyperbilirubinemia when co-administered with ribavirin.

Table 3 lists adverse reactions for which a causal relationship with the use of Viekira Pak in combination with or without ribavirin cannot be excluded. Most of the adverse reactions presented in Table 3 were mild (grade 1).

Adverse reactions are listed below by system organ class and frequency of occurrence. Frequency is defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), or very rare (<1/10000).

Table 3. Adverse reactions identified during the use of Viekira Pak in combination with or without ribavirin

Increased serum ALT activity

In clinical trials using Viekira Pak with and without ribavirin, 1% of patients had a transient increase in ALT activity of more than 5 times the ULN after starting treatment.

In women on concomitant use of drugs containing ethinyl estradiol, the frequency of increased ALT activity increased to 26%. The use of Viekira Pak with these drugs is contraindicated (see the “Contraindications” section). No increase in the frequency of clinically significant increases in ALT activity was observed among women receiving other estrogens (e.g., estradiol and conjugated estrogens) as hormone replacement therapy. Typically, this phenomenon was asymptomatic, generally occurred within the first 4 weeks of treatment (average 20 days, range 8-57 days), and resolved with continued therapy. 2 patients discontinued Viekira Pak due to elevated ALT levels; 1 of these patients was taking ethinyl estradiol. 3 patients temporarily discontinued Viekira Pak for 1-7 days; 1 of these patients was taking ethinyl estradiol. Most cases of increased ALT activity were transient and resolved spontaneously with continued therapy. Increased ALT activity was generally not associated with increased bilirubin concentration. Cirrhosis was not a risk factor for increased ALT activity.

Increased bilirubin concentration

A transient increase in bilirubin concentration (predominantly indirect) was observed in patients receiving Viekira Pak in combination with ribavirin, which is associated with inhibition of bilirubin transporters OATP1B1/1B3 by paritaprevir and due to hemolysis caused by ribavirin use. The increase in bilirubin concentration occurred after the start of treatment, peaked in the first week of the study, and completely resolved with continued therapy. The increase in bilirubin concentration was not associated with an increase in aminotransferase concentrations. The frequency of increased indirect bilirubin was lower among patients who did not receive ribavirin.

Use of Viekira Pak in patients with HCV/HIV-1 co-infection

The use of Viekira Pak 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%), pruritus (13%), cough (11%), irritability (10%), and scleral icterus (10%).

The overall safety profile in patients co-infected with chronic hepatitis C genotype 1 and HIV-1 was similar to the safety profile in patients with HCV genotype 1 without concomitant HIV-1 infection. Transient increases in total bilirubin >3×ULN (mainly indirect) occurred in 17 (27.0%) patients; 15 of these patients were receiving atazanavir. None of the patients with hyperbilirubinemia had a concomitant increase in aminotransferase.

Patients with hyperbilirubinemia did not experience a concomitant increase in aminotransferase activity.

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

At the end of 12 and 24 weeks of therapy, a decrease in the mean CD4⁺ T-cell count to 47 cells/mm³ and 62 cells/mm³, respectively, was noted; in most cases, the levels returned to baseline after completion of the treatment course. In 2 patients during the treatment course, a decrease in CD4⁺ T-cell count to less than 200 cells/mm³ was recorded without a decrease in the CD4⁺ percentage. No AIDS-associated opportunistic infections were reported.

Use of Viekira Pak without ribavirin in patients with HCV genotype 1b with compensated liver cirrhosis

In the TURQUOISE-III clinical trial involving 60 patients with hepatitis C genotype 1b with compensated liver cirrhosis who took Viekira Pak without ribavirin for 12 weeks, the most common adverse events (20% or more) were fatigue and diarrhea.

One patient (2%) had a decrease (grade 2) in blood hemoglobin concentration.

An increase (grade 2) in total bilirubin was observed in 12 patients (20%).

There were no cases of hemoglobin decrease of grade 3 or more from baseline or increase in total bilirubin of grade 3 or more from baseline. One patient (2%) had a grade 3 increase in ALT activity. One patient (2%) experienced a serious adverse event. One patient (2%) temporarily interrupted therapy due to an adverse event. No patient completely discontinued therapy due to adverse events.

Use of Viekira Pak in liver transplant recipients

The overall safety profile in HCV-infected liver transplant recipients who took Viekira Pak in combination with ribavirin (in addition to immunosuppressants) was similar to the safety profile in patients taking Viekira Pak in combination with ribavirin in phase 3 clinical trials, although the frequency of some adverse reactions increased. In 10 patients (29.4%), at least one case of hemoglobin concentration decrease to less than 10 g/dL was noted. In 10 out of 34 patients (29.4%), the ribavirin dose was adjusted due to decreased hemoglobin concentration; in 2.9% (1/34) of patients, the ribavirin course was interrupted. Changing the ribavirin dose did not affect the sustained virological response. 5 patients received erythropoietin; all these patients had an initial ribavirin dose of 1000-1200 mg/day. Blood transfusions were not performed.

Use of Viekira Pak in patients with HCV genotype 1 with or without liver cirrhosis with end-stage renal disease on dialysis

In the RUBY-I clinical trial involving 68 patients with hepatitis C genotype 1 with or without liver cirrhosis and end-stage renal disease on dialysis, no differences in the efficacy and safety profile were observed compared to the previous phase III trial without patients with severe renal impairment, except for patients who discontinued therapy due to adverse reactions associated with ribavirin (decreased hemoglobin concentration). The mean baseline hemoglobin level was 12.1 g/dL, and the mean decrease in hemoglobin level by the end of treatment for patients taking ribavirin was 1.2 g/dL. In 39 out of 50 cases of using Viekira Pak in combination with ribavirin, temporary discontinuation of ribavirin was required, and in 11 out of 50 cases, erythropoietin therapy was administered. 4 patients had a hemoglobin level decrease <8 g/dL. 2 patients required blood transfusion. In 18 patients with hepatitis C genotype 1b who did not take ribavirin, anemia was not observed.

In 18 patients with hepatitis C genotypes 1a and 4 not taking ribavirin, no cases of anemia were observed.

Post-marketing adverse events

The following adverse reactions have been identified during post-marketing use of Viekira Pak in combination with or without ribavirin.

Adverse events are listed by system organ class. Frequency is unknown.

Immune system disorders anaphylactic reactions.

Hepatobiliary disorders hepatic decompensation, liver failure.

Skin and subcutaneous tissue disorders erythema multiforme.

Children

The safety profile of Viekira Pak in children under 18 years of age cannot be established due to the lack of relevant data.

Contraindications

• Hypersensitivity to ombitasvir, paritaprevir, ritonavir, dasabuvir, or any excipients of the drug (e.g., toxic epidermal necrolysis or Stevens-Johnson syndrome);
• Moderate and severe hepatic impairment (Child-Pugh classes B and C);
• Contraindications to the use of ribavirin (when Viekira Pak and ribavirin are used concomitantly). For information on contraindications to ribavirin, refer to its prescribing information;
• Use of ribavirin in women who are pregnant, and in men whose partners are pregnant;
• Concomitant use of drugs for which an increase in plasma concentration may lead to serious adverse reactions and whose clearance is significantly dependent on metabolism via the CYP3A isoenzyme;
• Concomitant use of drugs that are potent inhibitors of CYP2C8 (as this may lead to a significant increase in dasabuvir plasma concentration and risk of QT interval prolongation);
• Concomitant use of drugs that are potent and moderate inducers of the CYP3A isoenzyme (may significantly reduce plasma concentrations of paritaprevir, ombitasvir, and dasabuvir);
• Concomitant use of drugs that are potent inducers of the CYP2C8 isoenzyme (as this may lead to a significant decrease in dasabuvir plasma concentration);
• Concomitant use with drugs containing ethinyl estradiol (e.g., combined oral contraceptives);
• Concomitant use with the following drugs:
  • substrates of the CYP3A4 isoenzyme – alfuzosin; ranolazine; dronedarone; amiodarone; astemizole, terfenadine; colchicine (in patients with renal and/or hepatic impairment); disopyramide; ergot alkaloids (ergotamine, dihydroergotamine, ergometrine, methylergometrine); fusidic acid; lovastatin, simvastatin, atorvastatin; midazolam and triazolam (in oral formulations); lurasidone; pimozide; quetiapine; quinidine; salmeterol; sildenafil (when used for pulmonary arterial hypertension); ticagrelor, cisapride;
  • inducers of the CYP3A4 isoenzyme – carbamazepine, phenytoin, phenobarbital; efavirenz; nevirapine; etravirine; enzalutamide; mitotane; rifampicin; preparations of St. John’s wort (Hypericum perforatum);
  • inhibitors of the CYP3A4 isoenzyme – cobicistat; indinavir, lopinavir/ritonavir; saquinavir; tipranavir; itraconazole, ketoconazole, posaconazole, voriconazole; clarithromycin, telithromycin; conivaptan;
  • inhibitors of the CYP2C8 isoenzyme – gemfibrozil;
  • inhibitor of the microsomal triglyceride transfer protein – lomitapide;
  • antineoplastic agents – apalutamide;
• Children under 18 years of age;
• Lactase deficiency, galactose intolerance, glucose-galactose malabsorption.

With caution

• Concomitant use of Viekira Pak and fluticasone or other corticosteroids that are metabolized by the CYP3A4 isoenzyme;
• Concomitant use with antiarrhythmic drugs;
• Concomitant use is not recommended with the following drugs (see section “Drug Interactions”): darunavir (in patients with protease inhibitor resistance); fluvastatin; pitavastatin; everolimus; sirolimus (except when the benefit outweighs the risk); tacrolimus (except when the benefit outweighs the risk);
• Should be used with caution with the following drugs (see section “Drug Interactions”): repaglinide; sulfasalazine; erythromycin; trazodone; fexofenadine; diltiazem; verapamil.

Use in Pregnancy and Lactation

Pregnancy

There are no results of qualitative and well-controlled studies on the use of Viekira Pak in pregnant women.

In animal studies using ombitasvir/paritaprevir/ritonavir and its major inactive human metabolites (M29, M36), as well as dasabuvir, no effects on embryo-fetal development were observed. In studies using paritaprevir/ritonavir, maximum doses corresponding to 98 times (in mice) or 8 times (in rats) the recommended human clinical dose were used. In studies using ombitasvir, maximum doses corresponding to 28 times (in mice) or 4 times (in rabbits) the recommended human clinical dose were used. The highest doses of the major inactive human metabolites in a mouse study resulted in exposures 26 times higher than in humans at the recommended clinical doses. In studies using dasabuvir, maximum doses corresponding to 24 times (in rats) or 6 times (in rabbits) the recommended human clinical dose were used.

Since conclusions cannot be drawn regarding the use of the drug in pregnant women based on animal data, Viekira Pak should be used during pregnancy only in case of extreme necessity, justified by the clinical situation.

Concomitant use with ribavirin

Concomitant use of Viekira Pak with ribavirin is contraindicated in pregnant women and in men whose partners are pregnant. Ribavirin can cause fetal malformations and/or death. Female patients and partners of male patients should take maximum possible measures to avoid pregnancy, as animal studies in all species exposed to ribavirin have confirmed a significant teratogenic effect and/or embryocidal effect. A treatment regimen containing ribavirin should not be used until a negative pregnancy test result is obtained immediately before starting therapy. During treatment and for at least 7 months after its completion, women of childbearing potential and their partners, as well as male patients and their partners, are recommended to use at least two effective methods of contraception. Throughout the entire treatment period with ribavirin, scheduled pregnancy tests should be performed monthly.

Concomitant use of combined contraceptives containing ethinyl estradiol with Viekira Pak is contraindicated.

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

Breastfeeding period

There is no information on the penetration of ombitasvir, paritaprevir, ritonavir, or dasabuvir and their metabolites into breast milk in women.

Paritaprevir and its hydrolysis product M13, ombitasvir, and dasabuvir in unchanged form were the predominant components found in the milk of lactating rats without affecting the nursing pups. Due to the possibility of adverse reactions due to the drug’s effect on breastfed infants, a decision should be made to discontinue breastfeeding or discontinue Viekira Pak treatment, taking into account the importance of therapy for the mother. Patients receiving ribavirin should read its instructions for use.

Use in Hepatic Impairment

In patients with mild hepatic impairment (Child-Pugh class A), no dose adjustment of Viekira Pak is required.

Viekira Pak is contraindicated in patients with moderate and severe hepatic impairment (Child-Pugh class B and C).

Use in Renal Impairment

In patients with mild, moderate, severe renal impairment, as well as in patients with end-stage renal disease (stage 4-5) on dialysis, no dose adjustment is required.

Pediatric Use

The use of the drug in children and adolescents under 18 years of age is contraindicated.

Geriatric Use

No dose adjustment is required in elderly patients.

Special Precautions

Elevation of ALT activity

In clinical studies of Viekira Pak with or without ribavirin, transient, asymptomatic elevation of ALT activity more than 5 times the upper limit of normal (ULN) was observed in approximately 1% of cases (see section “Adverse Reactions”).

Increased ALT activity was significantly more common in women taking drugs based on ethinyl estradiol, such as combined oral contraceptives, contraceptive patches, and contraceptive vaginal rings (see section “Contraindications”). Elevation of ALT activity was usually observed within the first 4 weeks of therapy and decreased within 2-8 weeks from the onset of ALT elevation while continuing therapy with Viekira Pak with or without ribavirin. Drugs containing ethinyl estradiol should be discontinued before starting Viekira Pak. During the course of therapy with Viekira Pak, alternative methods of contraception (e.g., progestin-only oral contraceptives or non-hormonal contraceptives) are recommended. Resumption of drugs containing ethinyl estradiol is recommended to begin approximately 2 weeks after the end of the course of therapy with Viekira Pak.

In women receiving other estrogens (e.g., estradiol and conjugated estrogens) as hormone replacement therapy instead of ethinyl estradiol, ALT activity levels corresponded to those recorded in patients not receiving estrogens. However, since the number of patients receiving other estrogens is limited, they should be used in combination with Viekira Pak with caution.

Liver biochemical parameters should be measured during the first 4 weeks of therapy, and if serum ALT levels exceed the ULN, the test should be repeated and ALT activity in such patients should be monitored further, and

• Patients should be informed of the need to consult their doctor immediately if they experience fatigue, weakness, loss of appetite, nausea and vomiting, jaundice, or light-colored stools;
• Consider discontinuing Viekira Pak if serum ALT levels exceed 10 times the ULN.

Routine monitoring of liver enzyme activity is not necessary in patients without cirrhosis.

Risk of hepatitis B virus (HBV) reactivation

Cases of HBV reactivation have been observed during treatment with direct-acting antiviral drugs for hepatitis C virus in patients co-infected with HBV/HCV, some of which led to liver failure and death. HBV reactivation is characterized by a sudden increase in HBV replication, manifested by an increase in serum HBV DNA. In patients who have previously undergone successful treatment for HBV infection (HBsAg-negative and anti-HBc-positive), reappearance of HBsAg is possible. HBV reactivation is often accompanied by abnormalities in liver function tests, such as increased aminotransferase activity and/or bilirubin concentration.

All patients should be screened for HBV before starting treatment. Patients with HBV/HCV co-infection, including those with a history of HBV infection, are at risk of HBV reactivation; therefore, they should be monitored and treated according to current clinical guidelines.

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

Post-marketing cases of liver function decompensation and liver failure, including liver transplantation or fatal outcomes, have been reported in patients receiving Viekira Pak. Most patients with these severe outcomes had signs of advanced liver cirrhosis before starting therapy with Viekira Pak. The reported cases generally occurred within 1-4 weeks after starting therapy and were characterized by an acute increase in serum direct bilirubin concentration without an increase in ALT activity, along with clinical signs of liver decompensation. Since reports of these events are voluntarily provided from a population of uncertain size, it is not always possible to reliably assess their frequency or establish a causal relationship with drug exposure.

Viekira Pak is contraindicated in patients with moderate and severe liver impairment (Child-Pugh class B and C).

For patients with liver cirrhosis, it is necessary

• To monitor for the appearance of clinical signs of liver decompensation (e.g., ascites, hepatic encephalopathy, variceal bleeding);
• Laboratory parameters of liver function, including direct bilirubin concentration, should be assessed before starting therapy and during the first 4 weeks after starting treatment, as well as when clinically indicated;
• Discontinue Viekira Pak in patients with signs of liver decompensation.

Risk associated with concomitant use of ribavirin

In case of combined use of Viekira Pak with ribavirin, the warnings and precautions applicable to ribavirin should be taken into account, in particular, the undesirability of pregnancy. The complete list of warnings and precautions for ribavirin use is presented in its instructions for use.

Risk associated with adverse effects or reduced therapeutic effect due to concomitant administration with other drugs

Combined use of a number of drugs can lead to known or potentially significant drug interactions, which may result in

• Loss of therapeutic efficacy, possibly with the development of resistance;
• Clinically significant adverse reactions associated with increased exposure to drugs used in combination with Viekira Pak or with the excipients of the drug.

Table 5 (section “Drug Interactions”) indicates measures to correct possible and known significant drug interactions, including recommendations for drug dosing. The possibility of drug interactions should be assessed before starting Viekira Pak and during the course of therapy; monitoring of adverse reactions associated with drugs used concomitantly with the active and excipient substances of Viekira Pak is recommended.

Concomitant use with tacrolimus, sirolimus, and everolimus

When Viekira Pak is used concomitantly with systemic tacrolimus, sirolimus, and everolimus, the concentration of tacrolimus, sirolimus, and everolimus increases through inhibition of the CYP3A isoenzyme. Serious and/or life-threatening events have been observed with concomitant use of Viekira Pak and systemic tacrolimus, sirolimus, and everolimus.

Concomitant use of tacrolimus or sirolimus with Viekira Pak should be avoided except when the benefit outweighs the risk. If tacrolimus or sirolimus and Viekira Pak are used concomitantly, caution should be exercised (for dosing regimen, see section “Drug Interactions”). Everolimus should not be used due to the lack of a suitable dose.

Monitoring of blood concentrations of tacrolimus or sirolimus should be performed at the start of concomitant use with Viekira Pak and throughout the entire period of concomitant use with Viekira Pak. The dose and/or frequency of administration should be adjusted as necessary. Regular monitoring of changes in renal function and adverse events associated with the use of tacrolimus or sirolimus should be performed. Refer to the instructions for use of tacrolimus or sirolimus for additional information on doses and monitoring instructions.

Concomitant use with fluticasone

Fluticasone is a corticosteroid metabolized by the CYP3A isoenzyme. Caution should be exercised when using Viekira Pak concomitantly with fluticasone or other corticosteroids that are metabolized by the CYP3A4 isoenzyme. Concomitant use of inhaled corticosteroids metabolized by the CYP3A isoenzyme may increase systemic exposure to corticosteroids; cases of Cushing’s syndrome and subsequent adrenal suppression have been reported with drugs containing ritonavir. Concomitant use of Viekira Pak and corticosteroids, particularly for long-term therapy, should be initiated only if the potential benefit of treatment outweighs the risk of systemic corticosteroid effects.

Concomitant use with other direct-acting antiviral drugs for hepatitis C virus

The safety and efficacy of Viekira Pak with or without ribavirin have been established. Concomitant use of Viekira Pak with other direct-acting antiviral drugs for the treatment of chronic hepatitis C has not been studied and therefore cannot be recommended.

Concomitant use with colchicine

The interaction between Viekira Pak and colchicine has not been studied. A reduction in the dose of colchicine or temporary discontinuation of colchicine treatment is recommended in patients with normal renal or hepatic function if treatment with Viekira Pak is required. In patients with renal or hepatic impairment, concomitant use of colchicine with Viekira Pak is contraindicated.

Concomitant use with statins

Simvastatin, lovastatin, and atorvastatin are contraindicated.

Rosuvastatin. When Viekira Pak is used concomitantly with rosuvastatin, an increase in rosuvastatin exposure of more than 3 times is possible. If rosuvastatin use is required during treatment with Viekira Pak, the maximum daily dose of rosuvastatin should be 5 mg.

Pitavastatin and fluvastatin. Interaction studies of fluvastatin, pitavastatin, and Viekira Pak have not been conducted. Theoretically, an increase in the exposure of fluvastatin and pitavastatin is possible when used concomitantly with Viekira Pak. Temporary discontinuation of pitavastatin and fluvastatin during treatment with Viekira Pak is recommended. If statin therapy is necessary throughout the entire period of Viekira Pak treatment, a reduced dose of pravastatin/rosuvastatin should be used.

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

Low doses of ritonavir as part of Viekira Pak may lead to the emergence of viral strains resistant to HIV protease inhibitors in patients with HIV/HCV co-infection who are not receiving continuous antiretroviral therapy. HIV-infected patients not receiving antiretroviral therapy should not take the drug.

In case of HIV co-infection, drug interactions must be taken into account.

Atazanavir can be used in combination with Viekira Pak. It should be noted that atazanavir must be taken without ritonavir, since ritonavir at a dose of 100 mg once daily is part of Viekira Pak. This combination is characterized by an increased risk of hyperbilirubinemia (including scleral icterus), particularly when ribavirin is part of the hepatitis C treatment regimen.

Darunavir at a dose of 800 mg once daily when taken concomitantly with Viekira Pak can be used in the absence of significant resistance to HIV protease inhibitors (reduced exposure to darunavir).

HIV protease inhibitors, except for atazanavir and darunavir (e.g., indinavir, saquinavir, tipranavir, lopinavir/ritonavir), are contraindicated.

When used concomitantly with Viekira Pak and raltegravir, the exposure of raltegravir significantly increases (2 times). The use of this combination has not been associated with any specific safety problems in a limited patient population during therapy for 12-24 weeks.

The exposure of rilpivirine significantly increases (3 times) when rilpivirine is prescribed in combination with Viekira Pak; as a result, the possibility of QT interval prolongation increases. If an HIV protease inhibitor (atazanavir, darunavir) is added, the exposure of rilpivirine may further increase, and therefore such a combination is contraindicated.

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

Hepatic impairment

In patients with mild hepatic impairment (Child-Pugh class A), no dose adjustment of Viekira Pak is required. Viekira Pak is contraindicated in patients with moderate and severe hepatic impairment (Child-Pugh class B and C).

Patients after liver transplantation

The safety and efficacy of Viekira Pak in combination with ribavirin were 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 safety and determine the proportion of patients who achieved sustained virological response 12 weeks after the end of treatment (SVR12) after 24 weeks of treatment with Viekira Pak in combination with ribavirin. The initial dose of ribavirin ranged from 600 mg to 800 mg/day, as most commonly used at the beginning and end of treatment with Viekira Pak.

34 participants who had not received treatment for HCV after liver transplantation and had a Metavir fibrosis score of 2 or less (29 with HCV genotype 1a and 5 with HCV genotype 1b) were included in clinical studies. 31 out of 32 patients for whom data were available at the SVR12 time point (96.9%) achieved SVR12 (96.3% in patients with genotype 1a). One patient with HCV genotype 1a had a relapse after treatment.

The overall safety profile of Viekira Pak in combination with ribavirin in HCV-infected patients after liver transplantation was the same as in patients receiving Viekira Pak in combination with ribavirin in phase 3 clinical studies, except for the occurrence of anemia. Ten patients (29.4%) had at least one hemoglobin value (post-baseline) of less than 10 g/dL. In 55.9% (19/34) of patients, the ribavirin dose was reduced, and in 2.9% (1/34), ribavirin use was discontinued. The ribavirin dose modification did not affect the rate of sustained virologic response achievement. Five patients required the use of erythropoietin (all 5 patients received daily ribavirin at an initial dose ranging from 1000 mg to 1200 mg. No patient required a blood transfusion).

Other HCV Genotypes

For patients infected with other HCV genotypes, except for genotype 1, the safety and efficacy of Viekira Pak have not been established.

Potential Effects of Direct-Acting Antiviral (DAA) Drugs for HCV Treatment

In patients with diabetes mellitus, the use of direct-acting antiviral drugs for HCV treatment may lead to improved glucose levels due to symptomatic hypoglycemia.

In patients with diabetes mellitus who are starting therapy with direct-acting antiviral drugs, glucose levels should be carefully monitored, especially during the first 3 months of treatment. If necessary, the diabetes treatment regimen should be adjusted. The physician responsible for the patient’s diabetes treatment should be informed that the patient has started therapy with direct-acting antiviral drugs.

Effect on ECG

The effect of the combined use of ombitasvir/paritaprevir/ritonavir and dasabuvir on the QTc interval was evaluated in a randomized, double-blind, placebo- and active-controlled (moxifloxacin 400 mg), 4-period crossover, thorough QT study in 60 healthy subjects receiving ombitasvir/paritaprevir/ritonavir and dasabuvir. In a study capable of detecting small effects at doses exceeding therapeutic doses – paritaprevir 350 mg, ritonavir 150 mg, ombitasvir 50 mg, and dasabuvir 500 mg – no clinically significant prolongation of the QT interval was observed. The aforementioned doses provide concentrations 6, 1.8, and 2 times higher than the therapeutic concentrations of paritaprevir, ombitasvir, and dasabuvir, respectively.

Depression or Psychiatric Illness

Cases of depression, and less frequently, suicidal thoughts and suicide attempts, have been reported, mostly during the use of Viekira Pak in combination with ribavirin. Although some cases had a history of depression, psychiatric illness, and/or substance abuse, a causal relationship with Viekira Pak cannot be excluded. Caution should be exercised when using Viekira Pak in patients with a history of depression or psychiatric illness. Patients and caregivers should be informed of the need to notify the treating physician of any changes in behavior or mood or the emergence of suicidal thoughts.

Effect on Ability to Drive and Use Machines

Viekira Pak has no or negligible influence on the ability to drive and use machines. Patients should be informed that fatigue, an adverse event, has been observed during the use of Viekira Pak in combination with ribavirin.

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.

Treatment in case of overdose is recommended to monitor for the appearance of any signs or symptoms of adverse reactions and, if necessary, immediately initiate appropriate symptomatic therapy.

Drug Interactions

Drugs Metabolized by CYP3A4 Isoenzyme

Ritonavir is a strong inhibitor of the CYP3A isoenzyme. Coadministration of ombitasvir/paritaprevir/ritonavir and dasabuvir with drugs primarily metabolized by the CYP3A isoenzyme may lead to increased plasma concentrations of these drugs. Coadministration is contraindicated with drugs for which clearance is highly dependent on CYP3A activity, and an increase in their plasma concentration may cause serious adverse events (see section “Contraindications”).

Substrates of the CYP3A isoenzyme that were evaluated in drug interaction studies and that may require dose adjustment and/or monitoring of clinical parameters include cyclosporine, sirolimus, tacrolimus, amlodipine, rilpivirine, and alprazolam (see Table 5). Examples of other CYP3A4 substrates that may require dose adjustment and/or monitoring of clinical parameters include calcium channel blockers (e.g., nifedipine) and trazodone. Although buprenorphine and zolpidem are also metabolized by the CYP3A isoenzyme, drug interaction studies have shown that no dose adjustment is required when coadministered with ombitasvir/paritaprevir/ritonavir and dasabuvir (see Table 5).

Drugs Transported by OATP and OCT1 Transport Proteins

Paritaprevir is an inhibitor of the hepatic transporter proteins OATP1B1 and OATP1B3, and paritaprevir and ritonavir are inhibitors of OATP2B1. Ritonavir is an inhibitor of OCT1 in vitro, but the clinical significance of this is unknown. Coadministration of ombitasvir/paritaprevir/ritonavir and dasabuvir with drugs that are substrates of OATP1B1, OATP1B3, OATP2B1, or OCT1 may increase the plasma concentrations of these transporter substrates and potentially necessitate dose adjustments of the drugs or clinical monitoring. Such drugs include certain statins (see Table 5), fexofenadine, repaglinide, and angiotensin II receptor antagonists (e.g., valsartan).

Substrates of OATP1B1/3 included pravastatin and rosuvastatin, which were evaluated in drug interaction studies (see Table 5).

Drugs Transported by BCRP Proteins

Paritaprevir, ritonavir, and dasabuvir are inhibitors of the breast cancer resistance protein (BCRP) in vivo. Coadministration of ombitasvir/paritaprevir/ritonavir and dasabuvir with drugs that are substrates of BCRP may increase the plasma concentrations of these transporter substrates and potentially necessitate changes in drug doses or clinical monitoring. Such drugs include sulfasalazine, imatinib, and certain statins (see Table 5).

A substrate of BCRP was rosuvastatin, which was evaluated in drug interaction studies (see Table 5).

Drugs Transported by Intestinal P-gp

Although paritaprevir, ritonavir, and dasabuvir are inhibitors of P-glycoprotein in vitro, no significant changes in the exposure of the P-glycoprotein substrate digoxin were observed when coadministered with ombitasvir/paritaprevir/ritonavir and dasabuvir.

Drugs Metabolized by Glucuronidation (UGT1A1)

Ombitasvir, paritaprevir, and dasabuvir are inhibitors of the UGT1A1 enzyme. Concurrent use of ombitasvir/paritaprevir/ritonavir and dasabuvir with drugs primarily metabolized by the UGT1A1 enzyme leads to an increase in their plasma concentration. For drugs with a narrow therapeutic index (e.g., levothyroxine), routine monitoring of clinical parameters is recommended. Specific instructions for the use of raltegravir and buprenorphine, which were evaluated in drug interaction studies, are also provided in Table 5.

Drugs Metabolized by CYP2C19 Isoenzyme

Coadministration of Viekira Pak with drugs (e.g., lansoprazole, esomeprazole, s-mephenytoin) that undergo CYP2C19 metabolism may reduce their exposure, which may require dose adjustment and clinical observation.

Substrates of the CYP2C19 isoenzyme included omeprazole and escitalopram, which were evaluated in drug interaction studies (see Table 5).

Drugs Metabolized by CYP2C9 Isoenzyme

Administration of Viekira Pak does not affect the exposure of warfarin, a substrate of the CYP2C9 isoenzyme. For other substrates of the CYP2C9 isoenzyme (NSAIDs, e.g., ibuprofen; antidiabetic drugs, e.g., glimepiride, glipizide), dose adjustment is generally not required.

Drugs Metabolized by CYP2D6 or CYP1A2 Isoenzymes

Administration of Viekira Pak did not affect the exposure of duloxetine, a substrate of the CYP2D6/CYP1A2 isoenzyme. The exposure of cyclobenzaprine, a substrate of the CYP1A2 isoenzyme, was decreased. For other substrates of the CYP1A2 isoenzyme (e.g., ciprofloxacin, cyclobenzaprine, theophylline, and caffeine), dose adjustment or monitoring of clinical parameters may be required. For substrates of the CYP2D6 isoenzyme (e.g., desipramine, metoprolol, and dextromethorphan), dose adjustment is generally not required.

Drugs Eliminated by the Kidneys via Transport Proteins

Ombitasvir, paritaprevir, dasabuvir, and ritonavir do not inhibit the organic anion transporter (OAT1) in vivo, as demonstrated by the lack of interaction with tenofovir (an OAT1 substrate). In vitro studies have shown that ombitasvir, paritaprevir, dasabuvir, and ritonavir at clinically relevant concentrations do not inhibit organic cation transporters (OCT2), organic anion transporters (OAT3), or multidrug and toxin extrusion proteins (MATE1 and MATE2K). Therefore, ombitasvir/paritaprevir/ritonavir and dasabuvir are not considered to affect drugs that are primarily eliminated by the kidneys via these transporters.

Drugs Inhibiting CYP3A4 Isoenzyme

Coadministration of Viekira Pak with strong inhibitors of the CYP3A isoenzyme may lead to increased plasma concentrations of paritaprevir (see Table 5).

Enzyme Inducers

Coadministration of Viekira Pak 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.

Enzyme inducers for which concomitant use is contraindicated are listed in Table 5.

Drugs Inhibiting CYP3A4 Isoenzyme and Transport Proteins

Paritaprevir is eliminated via CYP3A4-mediated metabolism and through bile (a substrate of hepatic transporter proteins OATP1B1, P-gp, and BCRP). Caution should be exercised when using Viekira Pak with drugs that are both moderate inhibitors of CYP3A4 and inhibitors of multiple transporter proteins (P-gp, BCRP, and/or OATP1B1/OATP1B3). These drugs may lead to a clinically significant increase in paritaprevir exposure (e.g., ritonavir with atazanavir, erythromycin, diltiazem, or verapamil).

Drugs Inhibiting Transport Proteins

Strong inhibitors of P-gp, BCRP, OATP1B1, and/or OATP1B3 may potentially increase paritaprevir concentrations. Clinically significant increases in the plasma concentrations of ombitasvir and dasabuvir are not expected with the inhibition of these transport proteins.

Patients Taking Vitamin K Antagonists

If Viekira Pak is used concomitantly with a vitamin K antagonist, careful monitoring of INR is recommended. This is due to possible changes in liver function during treatment with Viekira Pak.

Table 5 provides recommendations for the coadministration of Viekira Pak with some other drugs.

If a patient is already taking medication(s) or starts a medication while taking Viekira Pak and a drug interaction is expected, the possibility of dose adjustment of the concomitant medication(s) or appropriate monitoring of clinical parameters should be considered (Table 5).

If a dose adjustment of concomitant medications has been made during treatment with Viekira Pak, their doses should be re-evaluated after completion of Viekira Pak therapy.

Table 5 shows the ratio of least squares geometric means (90% confidence interval) of the effect of Viekira Pak on the concentration of co-administered drugs.

The direction of the arrow indicates the direction of the change in plasma concentration (C_max and AUC) of paritaprevir, ombitasvir, dasabuvir, and the co-administered drug (↑ = increase (more than 20%), ↓ = decrease (more than 20%), ↔ = no change or change less than 20%). The list is not exhaustive.

Table 5. Established Drug Interactions Based on Drug Interaction Study Data

¹ Lopinavir/ritonavir 800/200 mg once daily (evening dose) was also used with Viekira Pak. The effect on C_max and AUC of the direct-acting agents was identical to the effect observed with lopinavir/ritonavir 400/100 mg twice daily used with Viekira Pak.

² In two other groups of this study, rilpivirine was also taken in the evening with food and at night 4 hours after a meal, concomitantly with Viekira Pak. The effect on rilpivirine plasma concentration was identical to the effect observed when taken in the morning with food, concomitantly with Viekira Pak (see table above).

³ Cyclosporine at a dose of 100 mg was taken alone, and at a dose of 30 mg was taken concomitantly with Viekira Pak. The dose-normalized ratio of cyclosporine during interaction with ombitasvir paritaprevir/ritonavir with or without dasabuvir is shown.

⁴ C₁₂: = concentration 12 hours after a single dose of everolimus.

⁵ Sirolimus at a dose of 2 mg was taken alone, and at a dose of 0.5 mg was taken concomitantly with Viekira Pak. A dose-normalized ratio of sirolimus during interaction with Viekira Pak was observed.

⁶ C₂₄: = concentration over 24 hours after a single dose of cyclosporine, tacrolimus, or sirolimus.

⁷ Tacrolimus at a dose of 2 mg was taken alone, and at a dose of 2 mg was taken concomitantly with Viekira Pak. A dose-normalized ratio of tacrolimus during interaction with ombitasvir/paritaprevir/ritonavir with or without dasabuvir was observed.

⁸ Dose-normalized parameters were recorded for methadone, buprenorphine, and naloxone.

Note The doses of Viekira Pak used: ombitasvir 25 mg, paritaprevir 150 mg, ritonavir 100 mg once daily and dasabuvir 400 mg twice daily or 250 mg twice daily. The plasma concentration of dasabuvir after administration of 400 mg and 250 mg doses is the same. In drug interaction studies, except for studies of interaction with carbamazepine, gemfibrozil, ketoconazole, and sulfamethoxazole/trimethoprim, Viekira Pak was used repeatedly.

The list of drugs for which concomitant use with Viekira Pak is contraindicated is also presented in the “Contraindications” section.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.