Viekira XR

Serious side effects have been reported with Viekira XR. See the “Viekira XR Precautions” section.

Common side effects of Viekira XR include:

• feeling tired
• itching
• feeling weak or lacking energy
• nausea
• trouble sleeping

This is not a complete list of Viekira XR side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Vikekira XR crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using Viekira XR.

There is a risk of hepatitis B virus (HBV) becoming an active infection in those who have a current or previous infection with HBV and is treated with a certain antiviral medication (a direct-acting antiviral) to treat hepatitis C virus. Your healthcare provider will screen and monitor for HBV in those taking a direct-acting antiviral. Tell your healthcare provider if you have a history of hepatitis B infection or other liver problems before you are treated for hepatitis C. 

Do not use this medicine together with ribavirin if you are pregnant, or if you are a man and your sexual partner is pregnant.

Before you start taking Viekira, you must stop using certain birth control pills or hormone replacement medicines. Ask your doctor about using non-hormonal birth control to prevent pregnancy.

If you have ever had hepatitis B, Viekira can cause this condition to come back or get worse. You will need frequent blood tests to check your liver function.

If you miss a dose of the pink tablets, take the missed dose with a meal as soon as you remember. If you are more than 12 hours late, skip the missed dose and take your next dose at the usual time with a meal.

If you forget to take the beige tablet, take it with a meal as soon as you remember. If you are more than 6 hours late in taking the beige tablet, skip the missed dose and take your next dose at the usual time with a meal.

Do not take extra medicine to make up a missed dose.

In the U.S.

• Viekira XR

Available Dosage Forms:

• Tablet, Extended Release

Therapeutic Class: Antiviral

Pharmacologic Class: Hepatitis C Virus NS5A Inhibitor

Dasabuvir, ombitasvir, paritaprevir, and ritonavir combination is used with or without ribavirin to treat chronic hepatitis C infection, including patients with compensated cirrhosis.

This medicine is available only with your doctor's prescription.

• If you have an allergy to Viekira XR or any part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have liver problems other than hepatitis C.
• If you have had a severe skin reaction after taking ritonavir.
• If you are taking a drug that contains ethinyl estradiol, like certain birth control pills. Do not take a drug that contains ethinyl estradiol while taking Viekira XR and for some time after stopping this medicine. Your doctor will tell you when you can start taking a drug that contains ethinyl estradiol again after stopping Viekira XR.
• If you take any drugs (prescription or OTC, natural products, vitamins) that must not be taken with this medicine, like certain drugs that are used for high cholesterol, HIV, or seizures. There are many drugs that must not be taken with Viekira XR.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Viekira XR with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Mechanism of Action

Viekira XR combines three direct-acting hepatitis C virus antiviral agents with distinct mechanisms of action [see Microbiology (12.4)].

Ritonavir is not active against HCV. Ritonavir is a potent CYP3A inhibitor that increases peak and trough plasma drug concentrations of paritaprevir and overall drug exposure (i.e., area under the curve).

Pharmacodynamics

Cardiac Electrophysiology

The effect of a combination of ombitasvir, paritaprevir, ritonavir, and dasabuvir on QTc interval was evaluated in a randomized, double blind, placebo and active-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT study in 60 healthy subjects. At concentrations approximately 6, 1.8 and 2 times the therapeutic concentrations of paritaprevir, ombitasvir, and dasabuvir, the combination did not prolong QTc to any clinically relevant extent.

Pharmacokinetics

Dasabuvir, ombitasvir, paritaprevir, and ritonavir film-coated bilayer tablets consist of an extended-release (ER) layer of dasabuvir and an immediate-release (IR) layer of ombitasvir, paritaprevir and ritonavir.

The pharmacokinetic properties of the components of Viekira XR are provided in Table 6.

Specific Populations

There are no clinically relevant changes in the pharmacokinetics of the components of Viekira XR in relation to sex, race/ethnicity, or geriatric age [see Use in Specific Populations (8.5)]. The pharmacokinetics of Viekira XR in pediatric patients less than 18 years of age have not been established [see Use in Specific Populations (8.4)].

Hepatic Impairment

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

Relative to subjects with normal hepatic function, dasabuvir AUC values increased by 17%, and ombitasvir, paritaprevir and ritonavir AUC values decreased by 8%, 29% and 34%, respectively, in subjects with mild hepatic impairment.

Relative to subjects with normal hepatic function, dasabuvir, ombitasvir, and ritonavir AUC values decreased by 16%, 30%, and 30% respectively, and paritaprevir AUC values increased by 62% in subjects with moderate hepatic impairment.

Relative to subjects with normal hepatic function, dasabuvir, paritaprevir, and ritonavir AUC values increased by 325%, 945%, and 13%, respectively, and ombitasvir AUC values decreased by 54% in subjects with severe hepatic impairment.

Renal Impairment

The single dose pharmacokinetics of the combination of dasabuvir, ombitasvir, paritaprevir, and ritonavir were evaluated in non-HCV infected subjects with mild (CLcr: 60 to 89 mL/min), moderate (CLcr: 30 to 59 mL/min), and severe (CLcr: 15 to 29 mL/min) renal impairment.

Pharmacokinetic data are not available on the use of Viekira XR in non-HCV infected subjects with End Stage Renal Disease (ESRD).

Relative to subjects with normal renal function, dasabuvir, paritaprevir, and ritonavir AUC values increased by 21%, 19%, and 42% respectively, while ombitasvir AUC values were unchanged in subjects with mild renal impairment.

Relative to subjects with normal renal function, dasabuvir, paritaprevir, and ritonavir AUC values increased by 37%, 33%, and 80% respectively, while ombitasvir AUC values were unchanged in subjects with moderate renal impairment.

Relative to subjects with normal renal function, dasabuvir, paritaprevir, and ritonavir AUC values increased by 50%, 45%, and 114% respectively, while ombitasvir AUC values were unchanged in subjects with severe renal impairment [see Use in Specific Populations (8.7)].

Drug Interaction Studies

See also Contraindications (4), Warnings and Precautions (5.5), Drug Interactions (7)

All drug-drug interaction trials were conducted with VIEKIRA PAK. The effects of some drugs discussed in Table 5 on the exposures of dasabuvir, ombitasvir, paritaprevir, and ritonavir are shown in Table 7. For information regarding clinical recommendations, see Drug Interactions (7).

Table 8 summarizes the effects of dasabuvir, ombitasvir, paritaprevir, and ritonavir on the pharmacokinetics of co-administered drugs which showed clinically relevant changes. For information regarding clinical recommendations, see Drug Interactions (7).

Microbiology

Mechanism of Action

Viekira XR combines three direct-acting antiviral agents with distinct mechanisms of action and non-overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle.

Dasabuvir

Dasabuvir is a non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase encoded by the NS5B gene, which is essential for replication of the viral genome. In a biochemical assay, dasabuvir inhibited a panel of genotype 1a and 1b NS5B polymerases with median IC50 values of 2.8 nM (range 2.4 nM to 4.2 nM; n = 3) and 3.7 nM (range 2.2 nM to 10.7 nM; n = 4), respectively. Based on drug resistance mapping studies of HCV genotypes 1a and 1b, dasabuvir targets the palm domain of the NS5B polymerase, and is therefore referred to as a non-nucleoside NS5B-palm polymerase inhibitor.

Ombitasvir

Ombitasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. The mechanism of action of ombitasvir has been characterized based on cell culture antiviral activity and drug resistance mapping studies.

Paritaprevir

Paritaprevir is an inhibitor of the HCV NS3/4A protease which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. In a biochemical assay, paritaprevir inhibited the proteolytic activity of recombinant HCV genotype 1a and 1b NS3/4A protease enzymes with IC50 values of 0.18 nM and 0.43 nM, respectively.

Antiviral Activity

Dasabuvir

The EC50 values of dasabuvir against genotype 1a-H77 and 1b-Con1 strains in HCV replicon cell culture assays were 7.7 nM and 1.8 nM, respectively. The median EC50 values of dasabuvir against HCV replicons containing NS5B genes from a panel of genotype 1a and 1b isolates from treatment-naïve subjects were 0.6 nM (range 0.4 nM to 2.1 nM; n = 11) and 0.3 nM (range 0.2 nM to 2 nM; n = 10), respectively.

Ombitasvir

The EC50 values of ombitasvir against genotype 1a-H77 and 1b-Con1 strains in HCV replicon cell culture assays were 14.1 pM and 5 pM, respectively. The median EC50 values of ombitasvir against HCV replicons containing NS5A genes from a panel of genotype 1a and 1b isolates from treatment-naïve subjects were 0.68 pM (range 0.35 to 0.88 pM; n = 11) and 0.94 pM (range 0.74 to 1.5 pM; n = 11), respectively.

Paritaprevir

The EC50 values of paritaprevir against genotype 1a-H77 and 1b-Con1 strains in the HCV replicon cell culture assay were 1.0 nM and 0.21 nM, respectively. The median EC50 values of paritaprevir against HCV replicons containing NS3 genes from a panel of genotype 1a and 1b isolates from treatment-naïve subjects were 0.68 nM (range 0.43 nM to 1.87 nM; n = 11) and 0.06 nM (range 0.03 nM to 0.09 nM; n = 9), respectively.

Ritonavir

In HCV replicon cell culture assays, ritonavir did not exhibit a direct antiviral effect and the presence of ritonavir did not affect the antiviral activity of paritaprevir.

Combination Antiviral Activity

Evaluation of pairwise combinations of ombitasvir, paritaprevir, dasabuvir and ribavirin in HCV genotype 1 replicon cell culture assays showed no evidence of antagonism in antiviral activity.

Resistance

In Cell Culture

Exposure of HCV genotype 1a and 1b replicons to ombitasvir, paritaprevir or dasabuvir resulted in the emergence of drug resistant replicons carrying amino acid substitutions in NS5A, NS3, or NS5B, respectively. Amino acid substitutions in NS5A, NS3, or NS5B selected in cell culture or identified in Phase 2b and 3 clinical trials were phenotypically characterized in genotype 1a or 1b replicons.

For dasabuvir, in HCV genotype 1a replicons single NS5B substitutions C316Y, M414I/T, E446K/Q, Y448C/H, A553T, G554S, S556G/R, and Y561H reduced dasabuvir antiviral activity by 8- to 1,472-fold. In genotype 1b replicons, single NS5B substitutions C316H/N/Y, S368T, N411S, M414I/T, Y448C/H, A553V, S556G and D559G reduced dasabuvir antiviral activity by 5- to 1,569-fold.

For ombitasvir, in HCV genotype 1a replicons single NS5A substitutions M28T/V, Q30E/R, L31V, H58D, and Y93C/H/L/N reduced ombitasvir antiviral activity by 58- to 67,000-fold. In genotype 1b replicons, single NS5A substitutions L28T, L31F/V, and Y93H reduced ombitasvir antiviral activity by 8- to 661-fold. In general, combinations of ombitasvir resistance-associated substitutions in HCV genotype 1a or 1b replicons further reduced ombitasvir antiviral activity.

For paritaprevir, in HCV genotype 1a replicons single NS3 substitutions F43L, R155G/K/S, A156T, and D168A/E/F/H/N/V/Y reduced paritaprevir antiviral activity by 7- to 219-fold. An NS3 Q80K substitution in a genotype 1a replicon reduced paritaprevir antiviral activity by 3-fold. Combinations of V36M, Y56H, or E357K with R155K or D168 substitutions reduced the activity of paritaprevir by an additional 2- to 7-fold relative to the single R155K or D168 substitutions in genotype 1a replicons. In genotype 1b replicons single NS3 substitutions A156T and D168A/H/V reduced paritaprevir antiviral activity by 7- to 159-fold. The combination of Y56H with D168 substitutions reduced the activity of paritaprevir by an additional 16- to 26-fold relative to the single D168 substitutions in genotype 1b replicons.

In Clinical Studies

In a pooled analysis of subjects treated with regimens containing dasabuvir, ombitasvir, paritaprevir, and ritonavir with or without ribavirin (for 12 or 24 weeks) in Phase 2b and Phase 3 clinical trials, resistance analyses were conducted for 64 subjects who experienced virologic failure (20 with on-treatment virologic failure, 44 with post-treatment relapse). Treatment-emergent substitutions observed in the viral populations of these subjects are shown in Table 9. Treatment-emergent substitutions were detected in all 3 HCV drug targets in 30/57 (53%) HCV genotype 1a infected subjects, and 1/6 (17%) HCV genotype 1b infected subjects.

Persistence of Resistance-Associated Substitutions

The persistence of dasabuvir, ombitasvir, and paritaprevir treatment-emergent amino acid substitutions in NS5B, NS5A, and NS3, respectively, was assessed in HCV genotype 1a-infected subjects in Phase 2 trials whose virus had at least 1 treatment-emergent resistance-associated substitution in the drug target, and with available data through at least 24 weeks post-treatment. Population and clonal nucleotide sequence analyses (assay sensitivity approximately 5-10%) were conducted to detect the persistence of viral populations with treatment-emergent substitutions.

For dasabuvir, viral populations with 1 or more treatment-emergent substitutions in NS5B persisted at detectable levels through at least Post-Treatment Week 24 in 11/16 (69%) subjects, and through Post-Treatment Week 48 in 8/15 (53%) subjects with available data. Treatment-emergent S556G persisted through Post-Treatment Week 48 in 6/9 (67%) subjects.

For ombitasvir, viral populations with 1 or more resistance-associated treatment-emergent substitutions in NS5A persisted at detectable levels through at least Post-Treatment Week 24 in 24/24 (100%) subjects, and through Post-Treatment Week 48 in 18/18 (100%) subjects with available data.

For paritaprevir, viral populations with 1 or more treatment-emergent substitutions in NS3 persisted at detectable levels through at least Post-Treatment Week 24 in 17/29 (59%) subjects, and through Post-Treatment Week 48 in 5/22 (23%) subjects with available data. Resistance-associated variant R155K remained detectable in 5/8 (63%) subjects through Post-Treatment Week 24, and in 1/5 (20%) subjects through Post-Treatment Week 48. Resistance-associated D168 substitutions remained detectable in 6/22 (27%) subjects through Post-Treatment Week 24, and were no longer detectable through Post-Treatment Week 48.

Among HCV genotype 1b infected subjects who experienced virologic failure with a regimen including ombitasvir and paritaprevir, a treatment-emergent NS5A Y93H substitution persisted through at least Post-Treatment Week 48 in 2/2 subjects, and a NS3 D168V treatment-emergent substitution persisted through Post-Treatment Week 24 in 2/4 subjects, but was no longer detectable through Post-Treatment Week 48 (0/4 subjects).

The lack of detection of virus containing a resistance-associated substitution does not indicate that the resistant virus is no longer present at clinically significant levels. The long-term clinical impact of the emergence or persistence of virus containing Viekira XR-resistance-associated substitutions is unknown.

Effect of Baseline HCV Polymorphisms on Treatment Response

A pooled analysis of subjects in the Phase 3 clinical trials of dasabuvir, ombitasvir, and paritaprevir with or without ribavirin was conducted to explore the association between baseline HCV NS5B, NS5A, or NS3 resistance-associated polymorphisms and treatment outcome. Baseline samples from HCV genotype 1a infected subjects who experienced virologic failure (n=47), as well as samples from a subset of demographically matched subjects who achieved SVR (n=94), were analyzed to compare the frequencies of resistance-associated polymorphisms in these two populations. The NS3 Q80K polymorphism was detected in approximately 38% of subjects in this analysis and was enriched approximately 2-fold in virologic failure subjects compared to SVR-achieving subjects. Ombitasvir resistance-associated polymorphisms in NS5A (pooling data from all resistance-associated amino acid positions) were detected in approximately 22% of subjects in this analysis and similarly were enriched approximately 2-fold in virologic failure subjects. Dasabuvir resistance-associated polymorphisms in NS5B were detected in approximately 5% of subjects in this analysis and were not enriched in virologic failure subjects.

In contrast to the Phase 3 subset analysis, no association of NS3 or NS5A polymorphisms and treatment outcome was seen in an analysis of noncirrhotic HCV genotype 1a-infected subjects (n=174 for NS3 and n=183 for NS5A) who received dasabuvir, ombitasvir, and paritaprevir with or without ribavirin (for 12 or 24 weeks) in a Phase 2b trial.

Baseline HCV polymorphisms are not expected to have a substantial impact on the likelihood of achieving SVR when Viekira XR is used as recommended for HCV genotype 1a and 1b infected patients, based on the low virologic failure rates observed in clinical trials.

Cross-resistance

Cross-resistance is expected among NS5A inhibitors, NS3/4A protease inhibitors, and non-nucleoside NS5B-palm inhibitors by class. Dasabuvir retained full activity against HCV replicons containing a single NS5B L159F, S282T, or V321A substitution, which are associated with resistance or prior exposure to nucleot(s)ide analogue NS5B polymerase inhibitors. In clinical trials of the components of Viekira XR, no subjects who experienced virologic failure had treatment-emergent substitutions potentially associated with resistance to nucleot(s)ide analogue NS5B polymerase inhibitors.

The impact of prior dasabuvir, ombitasvir, or paritaprevir treatment experience on the efficacy of other NS5B inhibitors, NS5A inhibitors, or NS3/4A protease inhibitors has not been studied. Similarly, the efficacy of Viekira XR has not been studied in subjects who have failed prior treatment with another NS5B inhibitor, NS5A inhibitor, or NS3/4A protease inhibitor.