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VIEKIRA PAK includes ombitasvir, a hepatitis C virus NS5A inhibitor, paritaprevir, a hepatitis C virus NS3/4A protease inhibitor, ritonavir, a CYP3A inhibitor and dasabuvir, a hepatitis C virus non-nucleoside NS5B palm polymerase inhibitor.
VIEKIRA PAK is not recommended for use in patients with decompensated liver disease.
VIEKIRA PAKs efficacy was evaluated in six clinical trials enrolling 2,308 participants with chronic HCV infection with and without cirrhosis.
DOSAGE AND ADMINISTRATION
Recommended Dosage in Adults
VIEKIRA PAK is ombitasvir, paritaprevir, ritonavir fixed dose combination tablets copackaged with dasabuvir tablets.
The recommended oral dosage of VIEKIRA PAK is two ombitasvir, paritaprevir, ritonavir tablets once daily (in the morning) and one dasabuvir tablet twice daily (morning and evening). Take VIEKIRA PAK with a meal without regard to fat or calorie content
VIEKIRA PAK is used in combination with ribavirin (RBV) in certain patient populations (see Table 1). When administered with VIEKIRA PAK, the recommended dosage of RBV is based on weight: 1000 mg for subjects ≤75 kg and 1200 mg/day for those more than 75 kg, divided and administered twice-daily with food. For ribavirin dosage modifications, refer to the ribavirin prescribing information.
For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in Table 1. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs.
Monitor liver chemistry tests before initiating and during therapy
Table 1 shows the recommended VIEKIRA PAK treatment regimen and duration based on patient population.
Table 1. Treatment Regimen and Duration by Patient Population (Treatment-Naïve or Interferon-Experienced)
2.3 Hepatic Impairment No dosage adjustment of VIEKIRA PAK is required in patients with mild hepatic impairment (Child-Pugh A). VIEKIRA PAK is not recommended in patients with moderate hepatic impairment (Child-Pugh B). VIEKIRA PAK is contraindicated in patients with severe hepatic impairment (Child-Pugh C).
CONTRAINDICATIONS
Table 2. Drugs that are Contraindicated with VIEKIRA PAK
VIEKIRA PAK is contraindicated in patients with known hypersensitivity (e.g. toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome) to ritonavir.
WARNINGS AND PRECAUTIONS
Increased Risk of ALT Elevations
During clinical trials with VIEKIRA PAK with or without ribavirin, elevations of ALT to greater than 5 times the upper limit of normal (ULN) occurred in approximately 1% of all. ALT elevations were typically asymptomatic, occurred during the first 4 weeks of treatment, and declined within two to eight weeks of onset with continued dosing of VIEKIRA PAK with or without ribavirin.
These ALT elevations were significantly more frequent in female subjects who were using ethinyl estradiol-containing medications such as combined oral contraceptives, contraceptive patches or contraceptive vaginal rings. Ethinyl estradiol-containing medications must be discontinued prior to starting therapy with VIEKIRA PAK. Alternative methods of contraception (e.g, progestin only contraception or non-hormonal methods) are recommended during VIEKIRA PAK therapy. Ethinyl estradiol-containing medications can be restarted approximately 2 weeks following completion of treatment with VIEKIRA PAK.
Women using estrogens other than ethinyl estradiol, such as estradiol and conjugated estrogens used in hormone replacement therapy had a rate of ALT elevation similar to those not receiving any estrogens; however, due to the limited number of subjects taking these other estrogens, caution is warranted for co-administration with VIEKIRA PAK.
Hepatic laboratory testing should be performed during the first 4 weeks of starting treatment and as clinically indicated thereafter. If ALT is found to be elevated above baseline levels, it should be repeated and monitored closely:
Risks Associated With Ribavirin Combination Treatment
If VIEKIRA PAK is administered with ribavirin, the warnings and precautions for ribavirin, in particular the pregnancy avoidance warning, apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of the warnings and precautions for ribavirin.
Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions
The concomitant use of VIEKIRA PAK and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to:
Risk of HIV-1 Protease Inhibitor Drug Resistance in HCV/HIV-1 Co-infected Patients
The ritonavir component of VIEKIRA PAK is also an HIV-1 protease inhibitor and can select for HIV-1 protease inhibitor resistance-associated substitutions. Any HCV/HIV-1 co-infected patients treated with VIEKIRA PAK should also be on a suppressive antiretroviral drug regimen to reduce the risk of HIV-1 protease inhibitor drug resistance.
ADVERSE REACTIONS
If VIEKIRA PAK is administered with ribavirin (RBV), refer to the prescribing information for ribavirin for a list of ribavirin-associated adverse reactions.
The following adverse reaction is described below and elsewhere in the labeling:
The safety assessment was based on data from six Phase 3 clinical trials in more than 2,000 subjects who received VIEKIRA PAK with or without ribavirin for 12 or 24 weeks.
VIEKIRA PAK with Ribavirin in Placebo-Controlled Trials
The safety of VIEKIRA PAK in combination with ribavirin was assessed in 770 subjects with chronic HCV infection in two placebo-controlled trials (SAPPHIRE-I and -II). Adverse reactions that occurred more often in subjects treated with VIEKIRA PAK in combination with ribavirin compared to placebo were fatigue, nausea, pruritus, other skin reactions, insomnia, and asthenia (see Table 3). The majority of the adverse reactions were mild in severity. Two percent of subjects experienced a serious adverse event (SAE). The proportion of subjects who permanently discontinued treatment due to adverse reactions was less than 1%.
Table 3. Adverse Reactions with more than 5% Greater Frequency Reported in Subjects with Chronic HCV GT1 Infection Treated with VIEKIRA PAK in Combination with Ribavirin Compared to Placebo for 12 Weeks
VIEKIRA PAK with and without Ribavirin in Regimen-Controlled Trials
VIEKIRA PAK with and without ribavirin was assessed in 401 and 509 subjects with chronic HCV infection, respectively, in three clinical trials (PEARL-II, PEARL-III and PEARL-IV). Pruritus, nausea, insomnia, and asthenia were identified as adverse events occurring more often in subjects treated with VIEKIRA PAK in combination with ribavirin (see Table 4). The majority of adverse events were mild to moderate in severity. The proportion of subjects who permanently discontinued treatment due to adverse events was less than 1% for both VIEKIRA PAK in combination with ribavirin and VIEKIRA PAK alone.
Table 4. Adverse Events with ≥5% Greater Frequency Reported in Subjects with Chronic HCV GT1 Infection Treated with VIEKIRA PAK in Combination with Ribavirin Compared to VIEKIRA PAK for 12 Weeks
VIEKIRA PAK with Ribavirin in Subjects with Compensated Cirrhosis
VIEKIRA PAK with ribavirin was assessed in 380 subjects with compensated cirrhosis who were treated for 12 (n=208) or 24 (n=172) weeks duration (TURQUOISE-II).The type and severity of adverse events in subjects with compensated cirrhosis was comparable to non-cirrhotic subjects in other phase 3 trials. Fatigue, skin reactions and dyspnea occurred at least 5% more often in subjects treated for 24 weeks. The majority of adverse events occurred during the first 12 weeks of dosing in both treatment arms. Most of the adverse events were mild to moderate in severity. The proportion of subjects treated with VIEKIRA PAK for 12 and 24 weeks with SAEs was 6% and 5%, respectively and 2% of subjects permanently discontinued treatment due to adverse events in each treatment arm.
Skin Reactions
In PEARL-II, -III and -IV, 7% of subjects receiving VIEKIRA PAK alone and 10% of subjects receiving VIEKIRA PAK with ribavirin reported rash-related events. In SAPPHIRE-I and -II 16% of subjects receiving VIEKIRA PAK with ribavirin and 9% of subjects receiving placebo reported skin reactions. In TURQUOISE-II, 18% and 24% of subjects receiving VIEKIRA PAK with ribavirin for 12 or 24 weeks reported skin reactions. The majority of events were graded as mild in severity. There were no serious events or severe cutaneous reactions, such as Stevens Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), erythema multiforme (EM) or drug rash with eosinophilia and systemic symptoms (DRESS).
Laboratory Abnormalities
Serum ALT Elevations
Approximately 1% of subjects treated with VIEKIRA PAK experienced post-baseline serum ALT levels greater than 5 times the upper limit of normal (ULN) after starting treatment. The incidence increased to 25% (4/16) among women taking a concomitant ethinyl estradiol containing medication. The incidence of clinically relevant ALT elevations among women using estrogens other than ethinyl estradiol, such as estradiol and conjugated estrogens used in hormone replacement therapy was 3% (2/59).
ALT elevations were typically asymptomatic, generally occurred during the first 4 weeks of treatment (mean time 20 days, range 8-57 days) and most resolved with ongoing therapy. The majority of these ALT elevations were assessed as drug-related liver injury. Elevations in ALT were generally not associated with bilirubin elevations. Cirrhosis was not a risk factor for elevated ALT.
Serum Bilirubin Elevations
Post-baseline elevations in bilirubin at least 2 x ULN were observed in 15% of subjects receiving VIEKIRA PAK with ribavirin compared to 2% in those receiving VIEKIRA PAK alone. These bilirubin increases were predominately indirect and related to the inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir and ribavirin-induced hemolysis. Bilirubin elevations occurred after initiation of treatment, peaked by study Week 1, and generally resolved with ongoing therapy. Bilirubin elevations were not associated with serum ALT elevations.
Anemia/Decreased Hemoglobin
Across all Phase 3 studies, the mean change from baseline in hemoglobin levels in subjects treated with VIEKIRA PAK in combination with ribavirin was -2.4 g/dL and the mean change in subjects treated with VIEKIRA PAK alone was -0.5 g/dL. Decreases in hemoglobin levels occurred early in treatment (Week 1-2) with further reductions through Week 3. Hemoglobin values remained low during the remainder of treatment and returned towards baseline levels by post-treatment Week 4. Less than 1% of subjects treated with VIEKIRA PAK with ribavirin had hemoglobin levels decrease to less than 8.0 g/dL during treatment. Seven percent of subjects treated with VIEKIRA PAK in combination with ribavirin underwent a ribavirin dose reduction due to a decrease in hemoglobin levels; three subjects received a blood transfusion and five required erythropoietin. One patient discontinued therapy due to anemia. No subjects treated with VIEKIRA PAK alone had a hemoglobin level less than 10 g/dL.
Elevations in total bilirubin greater than 2 x ULN (mostly indirect) occurred in 34 (54%) subjects. Fifteen of these subjects were also receiving atazanavir at the time of bilirubin elevation and nine also had adverse events of ocular icterus, jaundice or hyperbilirubinemia. None of the subjects with hyperbilirubinemia had concomitant elevations of aminotransferases. No subject experienced a grade 3 ALT elevation.
Seven subjects (11%) had at least one post-baseline hemoglobin value of less than 10 g/dL, and six of these subjects had a ribavirin dose modification; no subject in this small cohort required a blood transfusion or erythropoietin.
Median declines in CD4+ T-cell counts of 47 cells/mm3 and 62 cells/mm3 were observed at the end of 12 and 24 weeks of treatment, respectively, and most returned to baseline levels post-treatment. Two subjects had CD4+ T-cell counts decrease to less than 200 cells/mm3 during treatment without a decrease in CD4%. No subject experienced an AIDS-related opportunistic infection.
Potential for VIEKIRA PAK to Affect Other Drugs
Ombitasvir, paritaprevir, and dasabuvir are inhibitors of UGT1A1, and ritonavir is an inhibitor of CYP3A4. Paritaprevir is an inhibitor of OATP1B1 and OATP1B3 and paritaprevir, ritonavir and dasabuvir are inhibitors of BCRP. Co-administration of VIEKIRA PAK with drugs that are substrates of CYP3A, UGT1A1, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs.
Potential for Other Drugs to Affect One or More Components of VIEKIRA PAK
Paritaprevir and ritonavir are primarily metabolized by CYP3A enzymes. Co-administration of VIEKIRA PAK with strong inhibitors of CYP3A may increase paritaprevir and ritonavir concentrations. Dasabuvir is primarily metabolized by CYP2C8 enzymes. Co-administration of VIEKIRA PAK with drugs that inhibit CYP2C8 may increase dasabuvir plasma concentrations. Ombitasvir is primarily metabolized via amide hydrolysis while CYP enzymes play a minor role in its metabolism. Ombitasvir, paritaprevir, dasabuvir and ritonavir are substrates of P-gp. Ombitasvir, paritaprevir and dasabuvir are substrates of BCRP. Paritaprevir is a substrate of OATP1B1 and OATP1B3. Inhibition of P-gp, BCRP, OATP1B1 or OATP1B3 may increase the plasma concentrations of the various components of VIEKIRA PAK.
Established and Other Potential Drug Interactions
If dose adjustments of concomitant medications are made due to treatment with VIEKIRA PAK, doses should be re-adjusted after administration of VIEKIRA PAK is completed. Dose adjustment is not required for VIEKIRA PAK.
Table 5 provides the effect of co-administration of VIEKIRA PAK on concentrations of concomitant drugs and the effect of concomitant drugs on the various components of VIEKIRA PAK. See Contraindications for drugs that are contraindicated with VIEKIRA PAK. Refer to the ritonavir prescribing information for other potentially significant drug interactions with ritonavir.
Table 5. Established Drug Interactions Based on Drug Interaction Trials
Drugs without Clinically Significant Interactions with VIEKIRA PAK
No dose adjustments are recommended when VIEKIRA PAK is co-administered with the following medications: digoxin, duloxetine, emtricitabine/tenofovir disoproxil fumarate, escitalopram, methadone, progestin only contraceptives, raltegravir, warfarin and zolpidem.
CLINICAL STUDIES
Description of Clinical Trials
The efficacy and safety of VIEKIRA PAK was evaluated in six randomized, multicenter, clinical trials in 2,308 subjects with genotype 1 (GT1) chronic hepatitis C virus (HCV) infection, including one trial exclusively in subjects with cirrhosis with mild hepatic impairment (Child-Pugh A), as summarized in Table 9.
Table 9. Randomized, Multicenter Trials Conducted with VIEKIRA PAK With or Without Ribavirin (RBV) in Subjects with Chronic HCV GT1 Infection
VIEKIRA PAK with RBV was also evaluated in the following two studies:
Clinical Trial Results in Adults with Chronic HCV Genotype 1a and 1b Infection without Cirrhosis
Subjects with Chronic HCV GT1a Infection without Cirrhosis
Subjects with HCV GT1a infection without cirrhosis treated with VIEKIRA PAK with RBV for 12 weeks in SAPPHIRE-I and -II and in PEARL-IV had a median age of 53 years (range: 18 to 70); 63% of the subjects were male; 90% were White; 7% were Black/African American; 8% were Hispanic or Latino; 19% had a body mass index of at least 30 kg per m2; 55% of patients were enrolled in US sites; 72% had IL28B non-CC genotype; 85% had baseline HCV RNA levels of at least 800,000 IU per mL.
Table 10 presents treatment outcomes for HCV GT1a treatment-naïve and treatment-experienced subjects treated with VIEKIRA PAK with RBV for 12 weeks in SAPPHIRE-I, PEARL-IV and SAPPHIRE-II.
Treatment-naïve, HCV GT1a-infected subjects without cirrhosis treated with VIEKIRA PAK in combination with RBV for 12 weeks in PEARL-IV had a significantly higher SVR12 rate than subjects treated with VIEKIRA PAK alone (97% and 90% respectively; difference +7% with 95% confidence interval, +1% to +12%). VIEKIRA PAK alone was not studied in treatment-experienced subjects with GT1a infection.
In SAPPHIRE-I and SAPPHIRE-II, no placebo subject achieved a HCV RNA <25 IU/mL during treatment.
Table 10. SVR12 for HCV Genotype 1a-Infected Subjects without Cirrhosis Who Were Treatment-Naïve or Previously Treated with PegIFN/RBV
Subjects with Chronic HCV GT1b Infection without Cirrhosis
Subjects with HCV GT1b infection without cirrhosis were treated with VIEKIRA PAK with or without RBV for 12 weeks in PEARL-II and -III. Subjects had a median age of 52 years (range: 22 to 70); 47% of the subjects were male; 93% were White; 5% were Black/African American; 2% were Hispanic or Latino; 21% had a body mass index of at least 30 kg per m2; 21% of patients were enrolled in US sites; 83% had IL28B non-CC genotype; 77% had baseline HCV RNA levels of at least 800,000 IU per mL.
The SVR rate for HCV GT1b-infected subjects without cirrhosis treated with VIEKIRA PAK without RBV for 12 weeks in PEARL-II (treatment-experienced: null responder, n=32; partial responder, n=26; relapser, n=33) and PEARL-III (treatment-naïve, n=209) was 100%.
Clinical Trial Results in Adults with Chronic HCV Genotype 1a and 1b Infection and Compensated Cirrhosis
TURQUOISE-II was an open-label trial that enrolled 380 HCV GT1a and 1b-infected subjects with cirrhosis and mild hepatic impairment (Child-Pugh A) who were either treatment-naïve or did not achieve SVR with prior treatment with pegIFN/RBV. Subjects were randomized to receive VIEKIRA PAK in combination with RBV for either 12 or 24 weeks of treatment.
Treated subjects had a median age of 58 years (range: 21 to 71); 70% of the subjects were male; 95% were White; 3% were Black/African American; 12% were Hispanic or Latino; 28% had a body mass index of at least 30 kg per m2; 43% of patients were enrolled in US sites; 82% had IL28B non‑CC genotype; 86% had baseline HCV RNA levels of at least 800,000 IU per mL; 69% had HCV GT1a infection, 31% had HCV GT1b infection; 42% were treatment-naïve, 36% were prior pegIFN/RBV null responders; 8% were prior pegIFN/RBV partial responders, 14% were prior pegIFN/RBV relapsers; 15% had platelet counts of less than 90 x 109 per L; 50% had albumin less than 4.0 mg per dL.
Table 11 presents treatment outcomes for GT1 treatment-naïve and treatment-experienced subjects with cirrhosis treated with VIEKIRA PAK with RBV for 12 or 24 weeks in TURQUOISE-II. In GT1a infected subjects, the overall SVR12 rate difference between 24 and 12 weeks of treatment with VIEKIRA PAK with RBV was +6% with 95% confidence interval, -0.1% to +13% with differences varying by pretreatment history.
Table 11. TURQUOISE-II: SVR12 for Chronic HCV Genotype 1-Infected Subjects with Cirrhosis Who Were Treatment-Naïve or Previously Treated with pegIFN/RBV
Effect of Ribavirin Dose Reductions on SVR12
Seven percent of subjects (101/1551) treated with VIEKIRA PAK with RBV had a RBV dose adjustment due to a decrease in hemoglobin level; of these, 98% (98/100) achieved an SVR12.
Clinical Trial of Selected Liver Transplant Recipients (CORAL-I)
VIEKIRA PAK with RBV was administered for 24 weeks to 34 HCV GT1-infected liver transplant recipients who were at least 12 months post transplantation at enrollment with normal hepatic function and mild fibrosis (Metavir fibrosis score F2 or lower). The initial dose of RBV was left to the discretion of the investigator with 600 to 800 mg per day being the most frequently selected dose range at initiation of VIEKIRA PAK and at the end of treatment.
Of the 34 subjects (29 with HCV GT1a infection and 5 with HCV GT1b infection) enrolled, (97%) achieved SVR12 (97% in subjects with GT1a infection and 100% of subjects with GT1b infection). One subject with HCV GT1a infection relapsed post-treatment.
Clinical Trial in Subjects with HCV/HIV-1 Co-infection (TURQUOISE-I)
In an open-label clinical trial 63 subjects with HCV GT1 infection co-infected with HIV-1 were treated for 12 or 24 weeks with VIEKIRA PAK in combination with RBV. Subjects were on a stable HIV-1 antiretroviral therapy (ART) regimen that included tenofovir disoproxil fumarate plus emtricitabine or lamivudine, administered with ritonavir boosted atazanavir or raltegravir. Subjects on atazanavir stopped the ritonavir component of their HIV-1 ART regimen upon initiating treatment with VIEKIRA PAK in combination with RBV. Atazanavir was taken with the morning dose of VIEKIRA PAK. The ritonavir component of the HIV-1 ART regimen was restarted after completion of treatment with VIEKIRA PAK and RBV.
Treated subjects had a median age of 51 years (range: 31 to 69); 24% of subjects were black; 81% of subjects had IL28B non-CC genotype; 19% of subjects had compensated cirrhosis; 67% of subjects were HCV treatment-naïve; 33% of subjects had failed prior treatment with pegIFN/RBV; 89% of subjects had HCV genotype 1a infection.
The SVR12 rates were 91% (51/56) for subjects with HCV GT1a infection and 100% (7/7) for those with HCV GT1b infection. Of the 5 subjects who were non-responders, 1 experienced virologic breakthrough, 1 discontinued treatment, 1 experienced relapse and 2 subjects had evidence of HCV re-infection post-treatment.
One subject had confirmed HIV-1 RNA >400 copies/mL during the post-treatment period. This subject had no evidence of resistance to the ART regimen. No subjects switched their ART regimen due to loss of plasma HIV-1 RNA suppression.
Durability of Response
In an open-label clinical trial, 92% of subjects (526/571) who received various combinations of the direct acting antivirals included in VIEKIRA PAK with or without RBV achieved SVR12, and 99% of those who achieved SVR12 maintained their response through 48 weeks post-treatment (SVR48).
Viekira Pak is marketed by AbbVie Inc., based in North Chicago, Illinois. Olysio is marketed by Raritan, New Jersey-based Janssen Pharmaceuticals. Sovaldi and Harvoni are marketed by Gilead Sciences, based in Foster City, California.
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
HOW SUPPLIED/STORAGE AND HANDLING
VIEKIRA PAK is dispensed in a monthly carton for a total of 28 days of therapy. Each monthly
carton contains four weekly cartons. Each weekly carton contains seven daily dose packs.
Each child resistant daily dose pack contains four tablets: two 12.5/75/50 mg ombitasvir,
paritaprevir, ritonavir tablets and two 250 mg dasabuvir tablets, and indicates which tablets need
to be taken in the morning and evening. The NDC number is NDC 0074-3093-28.
Ombitasvir, paritaprevir, ritonavir 12.5/75/50 mg tablets are pink-colored, film-coated, oblong
biconvex shaped, debossed with “AV1” on one side. Dasabuvir 250 mg tablets are beige-colored,
film-coated, oval-shaped, debossed with “AV2” on one side.
Store at or below 30°C (86°F).
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients to review the Medication Guide for ribavirin [see Warnings and Precautions
(5.2)].
Risk of ALT Elevations
Inform patients to watch for early warning signs of liver inflammation, such as fatigue,
weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice and
discolored feces, and to consult their health care professional without delay if such symptoms
occur [see Warnings and Precautions (5.1) and Adverse Reactions (6)].
Pregnancy Advise patients to avoid pregnancy during treatment with VIEKIRA PAK with ribavirin. Inform
patients to notify their health care provider immediately in the event of a pregnancy. Inform
pregnant patients that there is an Antiretroviral Pregnancy Registry that monitors pregnancy
outcomes in women who are HCV/HIV-1 co-infected and taking concomitant antiretrovirals [see
Use in Specific Populations (8.1)].
Drug Interactions
Inform patients that VIEKIRA PAK may interact with some drugs; therefore, patients should be
advised to report to their healthcare provider the use of any prescription, non-prescription
medication or herbal products [see Contraindications (4), Warnings and Precautions (5.3) and
Drug Interactions (7)].
Inform patients that contraceptives containing ethinyl estradiol are contraindicated with
VIEKIRA PAK [see Contraindications (4) and Warnings and Precautions (5.1)].
Hepatitis C Virus Transmission
Inform patients that the effect of treatment of hepatitis C virus infection on transmission is not
known, and that appropriate precautions to prevent transmission of the hepatitis C virus during
treatment should be taken.
Missed Dose
Inform patients that in case a dose of ombitasvir, paritaprevir, ritonavir is missed, the prescribed
dose can be taken within 12 hours.
In case a dose of dasabuvir is missed, the prescribed dose can be taken within 6 hours.
If more than 12 hours has passed since ombitasvir, paritaprevir, ritonavir is usually taken or more
than 6 hours has passed since dasabuvir is usually taken, the missed dose should NOT be taken
and the patient should take the next dose as per the usual dosing schedule.
Instruct patients not to take more than their prescribed dose of VIEKIRA PAK to make up for a
missed dose.
Also see FDA Press Release
VIEKIRA PAK includes ombitasvir, a hepatitis C virus NS5A inhibitor, paritaprevir, a hepatitis C virus NS3/4A protease inhibitor, ritonavir, a CYP3A inhibitor and dasabuvir, a hepatitis C virus non-nucleoside NS5B palm polymerase inhibitor.
VIEKIRA PAK is not recommended for use in patients with decompensated liver disease.
VIEKIRA PAKs efficacy was evaluated in six clinical trials enrolling 2,308 participants with chronic HCV infection with and without cirrhosis.
DOSAGE AND ADMINISTRATION
Recommended Dosage in Adults
VIEKIRA PAK is ombitasvir, paritaprevir, ritonavir fixed dose combination tablets copackaged with dasabuvir tablets.
The recommended oral dosage of VIEKIRA PAK is two ombitasvir, paritaprevir, ritonavir tablets once daily (in the morning) and one dasabuvir tablet twice daily (morning and evening). Take VIEKIRA PAK with a meal without regard to fat or calorie content
VIEKIRA PAK is used in combination with ribavirin (RBV) in certain patient populations (see Table 1). When administered with VIEKIRA PAK, the recommended dosage of RBV is based on weight: 1000 mg for subjects ≤75 kg and 1200 mg/day for those more than 75 kg, divided and administered twice-daily with food. For ribavirin dosage modifications, refer to the ribavirin prescribing information.
For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in Table 1. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs.
Monitor liver chemistry tests before initiating and during therapy
Table 1 shows the recommended VIEKIRA PAK treatment regimen and duration based on patient population.
Table 1. Treatment Regimen and Duration by Patient Population (Treatment-Naïve or Interferon-Experienced)
Patient Population | Treatment* | Duration |
|---|---|---|
| Genotype 1a, without cirrhosis | VIEKIRA PAK + ribavirin | 12 weeks |
| Genotype 1a, with cirrhosis | VIEKIRA PAK + ribavirin | 24 weeks** |
| Genotype 1b, without cirrhosis | VIEKIRA PAK | 12 weeks |
| Genotype 1b, with cirrhosis | VIEKIRA PAK + ribavirin | 12 weeks |
*Note: Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection. | ||
2.2 Use in Liver Transplant Recipients
In liver transplant recipients with normal hepatic function and mild fibrosis (Metavir fibrosis score 2 or lower), the recommended duration of VIEKIRA PAK with ribavirin is 24 weeks, irrespective of HCV genotype 1 subtype. When VIEKIRA PAK is administered with calcineurin inhibitors in liver transplant recipients, dosage adjustment of calcineurin inhibitors is needed.
In liver transplant recipients with normal hepatic function and mild fibrosis (Metavir fibrosis score 2 or lower), the recommended duration of VIEKIRA PAK with ribavirin is 24 weeks, irrespective of HCV genotype 1 subtype. When VIEKIRA PAK is administered with calcineurin inhibitors in liver transplant recipients, dosage adjustment of calcineurin inhibitors is needed.
2.3 Hepatic Impairment No dosage adjustment of VIEKIRA PAK is required in patients with mild hepatic impairment (Child-Pugh A). VIEKIRA PAK is not recommended in patients with moderate hepatic impairment (Child-Pugh B). VIEKIRA PAK is contraindicated in patients with severe hepatic impairment (Child-Pugh C).
- If VIEKIRA PAK is administered with ribavirin, the contraindications to ribavirin also apply to this combination regimen. Refer to the ribavirin prescribing information for a list of contraindications for ribavirin.
- VIEKIRA PAK is contraindicated in patients with severe hepatic impairment due to risk of potential toxicity. VIEKIRA PAK is contraindicated with:
- Drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events.
- Drugs that are strong inducers of CYP3A and CYP2C8 and may lead to reduced efficacy of VIEKIRA PAK.Drugs that are strong inhibitors of CYP2C8 and may increase dasabuvir plasma concentrations and the risk of QT prolongation.
Table 2. Drugs that are Contraindicated with VIEKIRA PAK
Drug Class | Drug(s) within Class that are Contraindicated | Clinical Comments |
|---|---|---|
| Alpha1-adrenoreceptor antagonist | Alfuzosin HCL | Potential for hypotension. |
| Anticonvulsants | Carbamazepine, phenytoin, phenobarbital | Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of VIEKIRA PAK. |
| Antihyperlipidemic agent | Gemfibrozil | Increase in dasabuvir exposures by 10-fold which may increase the risk of QT prolongation. |
| Antimycobacterial | Rifampin | Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of VIEKIRA PAK. |
| Ergot derivatives | Ergotamine, dihydroergotamine, ergonovine, methylergonovine | Acute ergot toxicity characterized by vasospasm and tissue ischemia has been associated with co-administration of ritonavir and ergonovine, ergotamine, dihydroergotamine, or methylergonovine. |
| Ethinyl estradiol-containing products | Ethinyl estradiol-containing medications such as combined oral contraceptives | Potential for ALT elevations |
| Herbal Product | St. John’s Wort (Hypericum perforatum) | Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of VIEKIRA PAK. |
| HMG-CoA Reductase Inhibitors | Lovastatin, simvastatin | Potential for myopathy including rhabdomyolysis. |
| Neuroleptics | Pimozide | Potential for cardiac arrhythmias. |
| Non-nucleoside reverse transcriptase inhibitor | Efavirenz | Co-administration of efavirenz based regimens with paritaprevir, ritonavir plus dasabuvir was poorly tolerated and resulted in liver enzyme elevations. |
| Phosphodiesterase-5 (PDE5) inhibitor | Sildenafil when dosed as REVATIO for the treatment of pulmonary arterial hypertension (PAH) | There is increased potential for sildenafil-associated adverse events such as visual disturbances, hypotension, priapism, and syncope. |
| Sedatives/hypnotics | Triazolam Orally administered midazolam | Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam or orally administered midazolam with VIEKIRA PAK may cause large increases in the concentration of these benzodiazepines. The potential exists for serious and/or life threatening events such as prolonged or increased sedation or respiratory depression. |
WARNINGS AND PRECAUTIONS
Increased Risk of ALT Elevations
During clinical trials with VIEKIRA PAK with or without ribavirin, elevations of ALT to greater than 5 times the upper limit of normal (ULN) occurred in approximately 1% of all. ALT elevations were typically asymptomatic, occurred during the first 4 weeks of treatment, and declined within two to eight weeks of onset with continued dosing of VIEKIRA PAK with or without ribavirin.
These ALT elevations were significantly more frequent in female subjects who were using ethinyl estradiol-containing medications such as combined oral contraceptives, contraceptive patches or contraceptive vaginal rings. Ethinyl estradiol-containing medications must be discontinued prior to starting therapy with VIEKIRA PAK. Alternative methods of contraception (e.g, progestin only contraception or non-hormonal methods) are recommended during VIEKIRA PAK therapy. Ethinyl estradiol-containing medications can be restarted approximately 2 weeks following completion of treatment with VIEKIRA PAK.
Women using estrogens other than ethinyl estradiol, such as estradiol and conjugated estrogens used in hormone replacement therapy had a rate of ALT elevation similar to those not receiving any estrogens; however, due to the limited number of subjects taking these other estrogens, caution is warranted for co-administration with VIEKIRA PAK.
Hepatic laboratory testing should be performed during the first 4 weeks of starting treatment and as clinically indicated thereafter. If ALT is found to be elevated above baseline levels, it should be repeated and monitored closely:
- Patients should be instructed to consult their health care professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces.
- Consider discontinuing VIEKIRA PAK if ALT levels remain persistently greater than 10 times the ULN.
- Discontinue VIEKIRA PAK if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR.
Risks Associated With Ribavirin Combination Treatment
If VIEKIRA PAK is administered with ribavirin, the warnings and precautions for ribavirin, in particular the pregnancy avoidance warning, apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of the warnings and precautions for ribavirin.
Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions
The concomitant use of VIEKIRA PAK and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to:
- Loss of therapeutic effect of VIEKIRA PAK and possible development of resistance
- Possible clinically significant adverse reactions from greater exposures of concomitant drugs or components of VIEKIRA PAK
Risk of HIV-1 Protease Inhibitor Drug Resistance in HCV/HIV-1 Co-infected Patients
The ritonavir component of VIEKIRA PAK is also an HIV-1 protease inhibitor and can select for HIV-1 protease inhibitor resistance-associated substitutions. Any HCV/HIV-1 co-infected patients treated with VIEKIRA PAK should also be on a suppressive antiretroviral drug regimen to reduce the risk of HIV-1 protease inhibitor drug resistance.
ADVERSE REACTIONS
If VIEKIRA PAK is administered with ribavirin (RBV), refer to the prescribing information for ribavirin for a list of ribavirin-associated adverse reactions.
The following adverse reaction is described below and elsewhere in the labeling:
- Increased Risk of ALT Elevations
The safety assessment was based on data from six Phase 3 clinical trials in more than 2,000 subjects who received VIEKIRA PAK with or without ribavirin for 12 or 24 weeks.
VIEKIRA PAK with Ribavirin in Placebo-Controlled Trials
The safety of VIEKIRA PAK in combination with ribavirin was assessed in 770 subjects with chronic HCV infection in two placebo-controlled trials (SAPPHIRE-I and -II). Adverse reactions that occurred more often in subjects treated with VIEKIRA PAK in combination with ribavirin compared to placebo were fatigue, nausea, pruritus, other skin reactions, insomnia, and asthenia (see Table 3). The majority of the adverse reactions were mild in severity. Two percent of subjects experienced a serious adverse event (SAE). The proportion of subjects who permanently discontinued treatment due to adverse reactions was less than 1%.
Table 3. Adverse Reactions with more than 5% Greater Frequency Reported in Subjects with Chronic HCV GT1 Infection Treated with VIEKIRA PAK in Combination with Ribavirin Compared to Placebo for 12 Weeks
| SAPPHIRE-I and -II | ||
|---|---|---|
| VIEKIRA PAK + RBV 12 Weeks N = 770 % | Placebo 12 Weeks N = 255 % | |
| Fatigue | 34 | 26 |
| Nausea | 22 | 15 |
| Pruritus* | 18 | 7 |
| Skin reactions** | 16 | 9 |
| Insomnia | 14 | 8 |
| Asthenia | 14 | 7 |
| *Grouped term pruritus included the preferred terms pruritus and pruritus generalized. **Grouped terms: rash, erythema, eczema, rash maculo-papular, rash macular, dermatitis, rash papular, skin exfoliation, rash pruritic, rash erythematous, rash generalized, dermatitis allergic, dermatitis contact, exfoliative rash, dermatitis, photosensitivity reaction, psoriasis, skin reaction, ulcer, urticaria. | ||
VIEKIRA PAK with and without Ribavirin in Regimen-Controlled Trials
VIEKIRA PAK with and without ribavirin was assessed in 401 and 509 subjects with chronic HCV infection, respectively, in three clinical trials (PEARL-II, PEARL-III and PEARL-IV). Pruritus, nausea, insomnia, and asthenia were identified as adverse events occurring more often in subjects treated with VIEKIRA PAK in combination with ribavirin (see Table 4). The majority of adverse events were mild to moderate in severity. The proportion of subjects who permanently discontinued treatment due to adverse events was less than 1% for both VIEKIRA PAK in combination with ribavirin and VIEKIRA PAK alone.
Table 4. Adverse Events with ≥5% Greater Frequency Reported in Subjects with Chronic HCV GT1 Infection Treated with VIEKIRA PAK in Combination with Ribavirin Compared to VIEKIRA PAK for 12 Weeks
| PEARL-II, -III and -IV | ||
|---|---|---|
| VIEKIRA PAK + RBV 12 Weeks N = 401 % | VIEKIRA PAK 12 Weeks N = 509 % | |
| Nausea | 16 | 8 |
| Pruritus* | 13 | 7 |
| Insomnia | 12 | 5 |
| Asthenia | 9 | 4 |
| *Grouped term pruritus included the preferred terms pruritus and pruritus generalized. | ||
VIEKIRA PAK with Ribavirin in Subjects with Compensated Cirrhosis
VIEKIRA PAK with ribavirin was assessed in 380 subjects with compensated cirrhosis who were treated for 12 (n=208) or 24 (n=172) weeks duration (TURQUOISE-II).The type and severity of adverse events in subjects with compensated cirrhosis was comparable to non-cirrhotic subjects in other phase 3 trials. Fatigue, skin reactions and dyspnea occurred at least 5% more often in subjects treated for 24 weeks. The majority of adverse events occurred during the first 12 weeks of dosing in both treatment arms. Most of the adverse events were mild to moderate in severity. The proportion of subjects treated with VIEKIRA PAK for 12 and 24 weeks with SAEs was 6% and 5%, respectively and 2% of subjects permanently discontinued treatment due to adverse events in each treatment arm.
Skin Reactions
In PEARL-II, -III and -IV, 7% of subjects receiving VIEKIRA PAK alone and 10% of subjects receiving VIEKIRA PAK with ribavirin reported rash-related events. In SAPPHIRE-I and -II 16% of subjects receiving VIEKIRA PAK with ribavirin and 9% of subjects receiving placebo reported skin reactions. In TURQUOISE-II, 18% and 24% of subjects receiving VIEKIRA PAK with ribavirin for 12 or 24 weeks reported skin reactions. The majority of events were graded as mild in severity. There were no serious events or severe cutaneous reactions, such as Stevens Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), erythema multiforme (EM) or drug rash with eosinophilia and systemic symptoms (DRESS).
Laboratory Abnormalities
Serum ALT Elevations
Approximately 1% of subjects treated with VIEKIRA PAK experienced post-baseline serum ALT levels greater than 5 times the upper limit of normal (ULN) after starting treatment. The incidence increased to 25% (4/16) among women taking a concomitant ethinyl estradiol containing medication. The incidence of clinically relevant ALT elevations among women using estrogens other than ethinyl estradiol, such as estradiol and conjugated estrogens used in hormone replacement therapy was 3% (2/59).
ALT elevations were typically asymptomatic, generally occurred during the first 4 weeks of treatment (mean time 20 days, range 8-57 days) and most resolved with ongoing therapy. The majority of these ALT elevations were assessed as drug-related liver injury. Elevations in ALT were generally not associated with bilirubin elevations. Cirrhosis was not a risk factor for elevated ALT.
Serum Bilirubin Elevations
Post-baseline elevations in bilirubin at least 2 x ULN were observed in 15% of subjects receiving VIEKIRA PAK with ribavirin compared to 2% in those receiving VIEKIRA PAK alone. These bilirubin increases were predominately indirect and related to the inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir and ribavirin-induced hemolysis. Bilirubin elevations occurred after initiation of treatment, peaked by study Week 1, and generally resolved with ongoing therapy. Bilirubin elevations were not associated with serum ALT elevations.
Anemia/Decreased Hemoglobin
Across all Phase 3 studies, the mean change from baseline in hemoglobin levels in subjects treated with VIEKIRA PAK in combination with ribavirin was -2.4 g/dL and the mean change in subjects treated with VIEKIRA PAK alone was -0.5 g/dL. Decreases in hemoglobin levels occurred early in treatment (Week 1-2) with further reductions through Week 3. Hemoglobin values remained low during the remainder of treatment and returned towards baseline levels by post-treatment Week 4. Less than 1% of subjects treated with VIEKIRA PAK with ribavirin had hemoglobin levels decrease to less than 8.0 g/dL during treatment. Seven percent of subjects treated with VIEKIRA PAK in combination with ribavirin underwent a ribavirin dose reduction due to a decrease in hemoglobin levels; three subjects received a blood transfusion and five required erythropoietin. One patient discontinued therapy due to anemia. No subjects treated with VIEKIRA PAK alone had a hemoglobin level less than 10 g/dL.
- VIEKIRA PAK in HCV/HIV-1 Co-infected Subjects
Elevations in total bilirubin greater than 2 x ULN (mostly indirect) occurred in 34 (54%) subjects. Fifteen of these subjects were also receiving atazanavir at the time of bilirubin elevation and nine also had adverse events of ocular icterus, jaundice or hyperbilirubinemia. None of the subjects with hyperbilirubinemia had concomitant elevations of aminotransferases. No subject experienced a grade 3 ALT elevation.
Seven subjects (11%) had at least one post-baseline hemoglobin value of less than 10 g/dL, and six of these subjects had a ribavirin dose modification; no subject in this small cohort required a blood transfusion or erythropoietin.
Median declines in CD4+ T-cell counts of 47 cells/mm3 and 62 cells/mm3 were observed at the end of 12 and 24 weeks of treatment, respectively, and most returned to baseline levels post-treatment. Two subjects had CD4+ T-cell counts decrease to less than 200 cells/mm3 during treatment without a decrease in CD4%. No subject experienced an AIDS-related opportunistic infection.
- VIEKIRA PAK in Selected Liver Transplant Recipients
- VIEKIRA PAK with ribavirin was assessed in 34 post-liver transplant subjects with recurrent HCV infection. Adverse events occurring in more than 20% of subjects included fatigue 50%, headache 44%, cough 32%, diarrhea 26%, insomnia 26%, asthenia 24%, nausea 24%, muscle spasms 21% and rash 21%. Ten subjects (29%) had at least one post-baseline hemoglobin value of less than 10 g/dL. Ten subjects underwent a ribavirin dose modification due to decrease in hemoglobin and 3% (1/34) had an interruption of ribavirin. Five subjects received erythropoietin, all of whom initiated ribavirin at the starting dose of 1000 to 1200 mg daily. No subject received a blood transfusion .
Potential for VIEKIRA PAK to Affect Other Drugs
Ombitasvir, paritaprevir, and dasabuvir are inhibitors of UGT1A1, and ritonavir is an inhibitor of CYP3A4. Paritaprevir is an inhibitor of OATP1B1 and OATP1B3 and paritaprevir, ritonavir and dasabuvir are inhibitors of BCRP. Co-administration of VIEKIRA PAK with drugs that are substrates of CYP3A, UGT1A1, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs.
Potential for Other Drugs to Affect One or More Components of VIEKIRA PAK
Paritaprevir and ritonavir are primarily metabolized by CYP3A enzymes. Co-administration of VIEKIRA PAK with strong inhibitors of CYP3A may increase paritaprevir and ritonavir concentrations. Dasabuvir is primarily metabolized by CYP2C8 enzymes. Co-administration of VIEKIRA PAK with drugs that inhibit CYP2C8 may increase dasabuvir plasma concentrations. Ombitasvir is primarily metabolized via amide hydrolysis while CYP enzymes play a minor role in its metabolism. Ombitasvir, paritaprevir, dasabuvir and ritonavir are substrates of P-gp. Ombitasvir, paritaprevir and dasabuvir are substrates of BCRP. Paritaprevir is a substrate of OATP1B1 and OATP1B3. Inhibition of P-gp, BCRP, OATP1B1 or OATP1B3 may increase the plasma concentrations of the various components of VIEKIRA PAK.
Established and Other Potential Drug Interactions
If dose adjustments of concomitant medications are made due to treatment with VIEKIRA PAK, doses should be re-adjusted after administration of VIEKIRA PAK is completed. Dose adjustment is not required for VIEKIRA PAK.
Table 5 provides the effect of co-administration of VIEKIRA PAK on concentrations of concomitant drugs and the effect of concomitant drugs on the various components of VIEKIRA PAK. See Contraindications for drugs that are contraindicated with VIEKIRA PAK. Refer to the ritonavir prescribing information for other potentially significant drug interactions with ritonavir.
Table 5. Established Drug Interactions Based on Drug Interaction Trials
Concomitant Drug Class: Drug Name | Effect on Concentration | Clinical Comments |
|---|---|---|
| ANTIARRHYTHMICS | ||
| amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine |  | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with VIEKIRA PAK. |
| ANTIFUNGALS | ||
| ketoconazole | ketoconazole | When VIEKIRA PAK is co-administered with ketoconazole, the maximum daily dose of ketoconazole should be limited to 200 mg per day. |
| voriconazole | ↓ voriconazole | Co-administration of VIEKIRA PAK with voriconazole is not recommended unless an assessment of the benefit-to-risk ratio justifies the use of voriconazole. |
| CALCIUM CHANNEL BLOCKERS | ||
| amlodipine | amlodipine | Consider dose reduction for amlodipine. Clinical monitoring is recommended. |
| CORTICOSTEROIDS (INHALED/NASAL) | ||
| fluticasone | fluticasone | Concomitant use of VIEKIRA PAK with inhaled or nasal fluticasone may reduce serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use. |
| DIURETICS | ||
| furosemide | furosemide (Cmax) | Clinical monitoring of patients is recommended and therapy should be individualized based on patient’s response. |
| HIV-ANTIVIRAL AGENTS | ||
| atazanavir/ritonavir once daily | paritaprevir | When coadministered with VIEKIRA PAK, atazanavir 300 mg (without ritonavir) should only be given in the morning. |
| darunavir/ritonavir | ↓ darunavir (Ctrough) | Co-administration of VIEKIRA PAK with darunavir/ritonavir is not recommended. |
| lopinavir/ritonavir | paritaprevir | Co-administration of VIEKIRA PAK with lopinavir/ritonavir is not recommended. |
| rilpivirine | rilpivirine | Co-administration of VIEKIRA PAK with rilpivirine once daily is not recommended due to potential for QT interval prolongation with higher concentrations of rilpivirine. |
| HMG CoA REDUCTASE INHIBITORS | ||
| rosuvastatin | rosuvastatin | When VIEKIRA PAK is co-administered with rosuvastatin, the dose of rosuvastatin should not exceed 10 mg per day. |
| pravastatin | pravastatin | When VIEKIRA PAK is co-administered with pravastatin, the dose of pravastatin should not exceed 40 mg per day. |
| IMMUNOSUPPRESSANTS | ||
| cyclosporine tacrolimus | cyclosporinetacrolimus | When initiating therapy with VIEKIRA PAK, reduce cyclosporine dose to 1/5th of the patient’s current cyclosporine dose. Measure cyclosporine blood concentrations to determine subsequent dose modifications. Upon completion of VIEKIRA PAK therapy, the appropriate time to resume pre-VIEKIRA PAK dose of cyclosporine should be guided by assessment of cyclosporine blood concentrations. Frequent assessment of renal function and cyclosporine-related side effects is recommended. When initiating therapy with VIEKIRA PAK, the dose of tacrolimus needs to be reduced. Do not administer tacrolimus on the day VIEKIRA PAK is initiated. Beginning the day after VIEKIRA PAK is initiated; reinitiate tacrolimus at a reduced dose based on tacrolimus blood concentrations. Typical tacrolimus dosing is 0.5 mg every 7 days. Measure tacrolimus blood concentrations and adjust dose or dosing frequency to determine subsequent dose modifications. Upon completion of VIEKIRA PAK therapy, the appropriate time to resume pre-VIEKIRA PAK dose of tacrolimus should be guided by assessment of tacrolimus blood concentrations. Frequent assessment of renal function and tacrolimus related side effects is recommended. |
| LONG ACTING BETA-ADRENOCEPTOR AGONIST | ||
| salmeterol | salmeterol | Concurrent administration of VIEKIRA PAK and salmeterol is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| NARCOTIC ANALGESICS | ||
| buprenorphine/naloxone | buprenorphinenorbuprenorphine | No dose adjustment of buprenorphine/naloxone is required upon co-administration with VIEKIRA PAK. Patients should be closely monitored for sedation and cognitive effects. |
| PROTON PUMP INHIBITORS | ||
| omeprazole | ↓ omeprazole | Monitor patients for decreased efficacy of omeprazole. Consider increasing the omeprazole dose in patients whose symptoms are not well controlled; avoid use of more than 40 mg per day of omeprazole. |
| SEDATIVES/HYPNOTICS | ||
| alprazolam | alprazolam | Clinical monitoring of patients is recommended. A decrease in alprazolam dose can be considered based on clinical response. |
| ||
No dose adjustments are recommended when VIEKIRA PAK is co-administered with the following medications: digoxin, duloxetine, emtricitabine/tenofovir disoproxil fumarate, escitalopram, methadone, progestin only contraceptives, raltegravir, warfarin and zolpidem.
CLINICAL STUDIES
Description of Clinical Trials
The efficacy and safety of VIEKIRA PAK was evaluated in six randomized, multicenter, clinical trials in 2,308 subjects with genotype 1 (GT1) chronic hepatitis C virus (HCV) infection, including one trial exclusively in subjects with cirrhosis with mild hepatic impairment (Child-Pugh A), as summarized in Table 9.
Table 9. Randomized, Multicenter Trials Conducted with VIEKIRA PAK With or Without Ribavirin (RBV) in Subjects with Chronic HCV GT1 Infection
Trial | Population | Study Arms (Number of Subjects Treated) |
|---|---|---|
| SAPPHIRE-I (double-blind) | GT1 (a and b) TNa without cirrhosis |
|
| SAPPHIRE-II (double-blind) | GT1 (a and b) TEb without cirrhosis |
|
| PEARL-II (open-label) | GT1b TE without cirrhosis |
|
| PEARL-III (double-blind) | GT1b TN without cirrhosis |
|
| PEARL-IV (double-blind) | GT1a TN without cirrhosis |
|
| TURQUOISE-II (open-label) | GT1 (a and b) TN & TE with cirrhosis |
|
| ||
- In SAPPHIRE-I and -II, subjects without cirrhosis were randomized to VIEKIRA PAK in combination with ribavirin for 12 weeks or to placebo. Subjects in the placebo arm received placebo for 12 weeks, after which they received open-label VIEKIRA PAK in combination with RBV for 12 weeks.
- In PEARL-II, -III and -IV, subjects without cirrhosis were randomized to receive VIEKIRA PAK with or without RBV for 12 weeks of treatment.
- In the open-label TURQUOISE-II trial, subjects with compensated cirrhosis (Child-Pugh A) who were either treatment-naïve or pegylated interferon/RBV (pegIFN/RBV) treatment-experienced were randomized to receive VIEKIRA PAK in combination with RBV for either 12 or 24 weeks of treatment. Subjects who previously failed therapy with a treatment regimen that included VIEKIRA PAK or other direct-acting antiviral agents were excluded.
VIEKIRA PAK with RBV was also evaluated in the following two studies:
- HCV GT1-infected liver transplant recipients (CORAL-I).
- Subjects with HCV GT1 co-infected with HIV-1 (TURQUOISE-I).
Clinical Trial Results in Adults with Chronic HCV Genotype 1a and 1b Infection without Cirrhosis
Subjects with Chronic HCV GT1a Infection without Cirrhosis
Subjects with HCV GT1a infection without cirrhosis treated with VIEKIRA PAK with RBV for 12 weeks in SAPPHIRE-I and -II and in PEARL-IV had a median age of 53 years (range: 18 to 70); 63% of the subjects were male; 90% were White; 7% were Black/African American; 8% were Hispanic or Latino; 19% had a body mass index of at least 30 kg per m2; 55% of patients were enrolled in US sites; 72% had IL28B non-CC genotype; 85% had baseline HCV RNA levels of at least 800,000 IU per mL.
Table 10 presents treatment outcomes for HCV GT1a treatment-naïve and treatment-experienced subjects treated with VIEKIRA PAK with RBV for 12 weeks in SAPPHIRE-I, PEARL-IV and SAPPHIRE-II.
Treatment-naïve, HCV GT1a-infected subjects without cirrhosis treated with VIEKIRA PAK in combination with RBV for 12 weeks in PEARL-IV had a significantly higher SVR12 rate than subjects treated with VIEKIRA PAK alone (97% and 90% respectively; difference +7% with 95% confidence interval, +1% to +12%). VIEKIRA PAK alone was not studied in treatment-experienced subjects with GT1a infection.
In SAPPHIRE-I and SAPPHIRE-II, no placebo subject achieved a HCV RNA <25 IU/mL during treatment.
Table 10. SVR12 for HCV Genotype 1a-Infected Subjects without Cirrhosis Who Were Treatment-Naïve or Previously Treated with PegIFN/RBV
| VIEKIRA PAK with RBV for 12 Weeks % (n/N) | |
|---|---|
| GT1a treatment-naïve | |
| SAPPHIRE-I SVR12 Outcome for subjects without SVR12 On-treatment VF Relapse Other | 96% (308/322) <1% (1/322) 2% (6/314) 2% (7/322) |
| PEARL-IV SVR12 Outcome for subjects without SVR12 On-treatment VF Relapse Other | 97% (97/100) 1% (1/100) 1% (1/98) 1% (1/100) |
| GT1a treatment-experienced | |
| SAPPHIRE-II SVR12 Outcome for subjects without SVR12 On-treatment VF Relapse Other | 96% (166/173) 0% (0/173) 3% (5/172) 1% (2/173) |
| SVR12 by Prior pegIFN Experience Null Responder Partial Responder Relapser | 95% (83/87) 100% (36/36) 94% (47/50) |
Subjects with Chronic HCV GT1b Infection without Cirrhosis
Subjects with HCV GT1b infection without cirrhosis were treated with VIEKIRA PAK with or without RBV for 12 weeks in PEARL-II and -III. Subjects had a median age of 52 years (range: 22 to 70); 47% of the subjects were male; 93% were White; 5% were Black/African American; 2% were Hispanic or Latino; 21% had a body mass index of at least 30 kg per m2; 21% of patients were enrolled in US sites; 83% had IL28B non-CC genotype; 77% had baseline HCV RNA levels of at least 800,000 IU per mL.
The SVR rate for HCV GT1b-infected subjects without cirrhosis treated with VIEKIRA PAK without RBV for 12 weeks in PEARL-II (treatment-experienced: null responder, n=32; partial responder, n=26; relapser, n=33) and PEARL-III (treatment-naïve, n=209) was 100%.
Clinical Trial Results in Adults with Chronic HCV Genotype 1a and 1b Infection and Compensated Cirrhosis
TURQUOISE-II was an open-label trial that enrolled 380 HCV GT1a and 1b-infected subjects with cirrhosis and mild hepatic impairment (Child-Pugh A) who were either treatment-naïve or did not achieve SVR with prior treatment with pegIFN/RBV. Subjects were randomized to receive VIEKIRA PAK in combination with RBV for either 12 or 24 weeks of treatment.
Treated subjects had a median age of 58 years (range: 21 to 71); 70% of the subjects were male; 95% were White; 3% were Black/African American; 12% were Hispanic or Latino; 28% had a body mass index of at least 30 kg per m2; 43% of patients were enrolled in US sites; 82% had IL28B non‑CC genotype; 86% had baseline HCV RNA levels of at least 800,000 IU per mL; 69% had HCV GT1a infection, 31% had HCV GT1b infection; 42% were treatment-naïve, 36% were prior pegIFN/RBV null responders; 8% were prior pegIFN/RBV partial responders, 14% were prior pegIFN/RBV relapsers; 15% had platelet counts of less than 90 x 109 per L; 50% had albumin less than 4.0 mg per dL.
Table 11 presents treatment outcomes for GT1 treatment-naïve and treatment-experienced subjects with cirrhosis treated with VIEKIRA PAK with RBV for 12 or 24 weeks in TURQUOISE-II. In GT1a infected subjects, the overall SVR12 rate difference between 24 and 12 weeks of treatment with VIEKIRA PAK with RBV was +6% with 95% confidence interval, -0.1% to +13% with differences varying by pretreatment history.
Table 11. TURQUOISE-II: SVR12 for Chronic HCV Genotype 1-Infected Subjects with Cirrhosis Who Were Treatment-Naïve or Previously Treated with pegIFN/RBV
| GT1a | GT1b | ||
|---|---|---|---|
| VIEKIRA PAK with RBV for 24 Weeks % (n/N) | VIEKIRA PAK with RBV for 12 Weeks % (n/N) | VIEKIRA PAK with RBV for 12 Weeks % (n/N) | |
| SVR12 Outcome for subjects without SVR12 On-treatment VF Relapse Other | 95% (115/121) 2% (3/121) 1% (1/116) 2% (2/121) | 89% (124/140) <1% (1/140) 8% (11/135) 3% (4/140) | 99% (67/68) 0% (0/68) 1% (1/68) 0% (0/68) |
| SVR12 for Naïve SVR12 by Prior pegIFN Experience Null Responder Partial Responder Relapser | 95% (53/56) 93% (39/42) 100% (10/10) 100% (13/13) | 92% (59/64) 80% (40/50) 100% (11/11) 93% (14/15) | 100% (22/22) 100% (25/25) 86% (6/7) 100% (14/14) |
Effect of Ribavirin Dose Reductions on SVR12
Seven percent of subjects (101/1551) treated with VIEKIRA PAK with RBV had a RBV dose adjustment due to a decrease in hemoglobin level; of these, 98% (98/100) achieved an SVR12.
Clinical Trial of Selected Liver Transplant Recipients (CORAL-I)
VIEKIRA PAK with RBV was administered for 24 weeks to 34 HCV GT1-infected liver transplant recipients who were at least 12 months post transplantation at enrollment with normal hepatic function and mild fibrosis (Metavir fibrosis score F2 or lower). The initial dose of RBV was left to the discretion of the investigator with 600 to 800 mg per day being the most frequently selected dose range at initiation of VIEKIRA PAK and at the end of treatment.
Of the 34 subjects (29 with HCV GT1a infection and 5 with HCV GT1b infection) enrolled, (97%) achieved SVR12 (97% in subjects with GT1a infection and 100% of subjects with GT1b infection). One subject with HCV GT1a infection relapsed post-treatment.
Clinical Trial in Subjects with HCV/HIV-1 Co-infection (TURQUOISE-I)
In an open-label clinical trial 63 subjects with HCV GT1 infection co-infected with HIV-1 were treated for 12 or 24 weeks with VIEKIRA PAK in combination with RBV. Subjects were on a stable HIV-1 antiretroviral therapy (ART) regimen that included tenofovir disoproxil fumarate plus emtricitabine or lamivudine, administered with ritonavir boosted atazanavir or raltegravir. Subjects on atazanavir stopped the ritonavir component of their HIV-1 ART regimen upon initiating treatment with VIEKIRA PAK in combination with RBV. Atazanavir was taken with the morning dose of VIEKIRA PAK. The ritonavir component of the HIV-1 ART regimen was restarted after completion of treatment with VIEKIRA PAK and RBV.
Treated subjects had a median age of 51 years (range: 31 to 69); 24% of subjects were black; 81% of subjects had IL28B non-CC genotype; 19% of subjects had compensated cirrhosis; 67% of subjects were HCV treatment-naïve; 33% of subjects had failed prior treatment with pegIFN/RBV; 89% of subjects had HCV genotype 1a infection.
The SVR12 rates were 91% (51/56) for subjects with HCV GT1a infection and 100% (7/7) for those with HCV GT1b infection. Of the 5 subjects who were non-responders, 1 experienced virologic breakthrough, 1 discontinued treatment, 1 experienced relapse and 2 subjects had evidence of HCV re-infection post-treatment.
One subject had confirmed HIV-1 RNA >400 copies/mL during the post-treatment period. This subject had no evidence of resistance to the ART regimen. No subjects switched their ART regimen due to loss of plasma HIV-1 RNA suppression.
Durability of Response
In an open-label clinical trial, 92% of subjects (526/571) who received various combinations of the direct acting antivirals included in VIEKIRA PAK with or without RBV achieved SVR12, and 99% of those who achieved SVR12 maintained their response through 48 weeks post-treatment (SVR48).
Viekira Pak is marketed by AbbVie Inc., based in North Chicago, Illinois. Olysio is marketed by Raritan, New Jersey-based Janssen Pharmaceuticals. Sovaldi and Harvoni are marketed by Gilead Sciences, based in Foster City, California.
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
HOW SUPPLIED/STORAGE AND HANDLING
VIEKIRA PAK is dispensed in a monthly carton for a total of 28 days of therapy. Each monthly
carton contains four weekly cartons. Each weekly carton contains seven daily dose packs.
Each child resistant daily dose pack contains four tablets: two 12.5/75/50 mg ombitasvir,
paritaprevir, ritonavir tablets and two 250 mg dasabuvir tablets, and indicates which tablets need
to be taken in the morning and evening. The NDC number is NDC 0074-3093-28.
Ombitasvir, paritaprevir, ritonavir 12.5/75/50 mg tablets are pink-colored, film-coated, oblong
biconvex shaped, debossed with “AV1” on one side. Dasabuvir 250 mg tablets are beige-colored,
film-coated, oval-shaped, debossed with “AV2” on one side.
Store at or below 30°C (86°F).
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients to review the Medication Guide for ribavirin [see Warnings and Precautions
(5.2)].
Risk of ALT Elevations
Inform patients to watch for early warning signs of liver inflammation, such as fatigue,
weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice and
discolored feces, and to consult their health care professional without delay if such symptoms
occur [see Warnings and Precautions (5.1) and Adverse Reactions (6)].
Pregnancy Advise patients to avoid pregnancy during treatment with VIEKIRA PAK with ribavirin. Inform
patients to notify their health care provider immediately in the event of a pregnancy. Inform
pregnant patients that there is an Antiretroviral Pregnancy Registry that monitors pregnancy
outcomes in women who are HCV/HIV-1 co-infected and taking concomitant antiretrovirals [see
Use in Specific Populations (8.1)].
Drug Interactions
Inform patients that VIEKIRA PAK may interact with some drugs; therefore, patients should be
advised to report to their healthcare provider the use of any prescription, non-prescription
medication or herbal products [see Contraindications (4), Warnings and Precautions (5.3) and
Drug Interactions (7)].
Inform patients that contraceptives containing ethinyl estradiol are contraindicated with
VIEKIRA PAK [see Contraindications (4) and Warnings and Precautions (5.1)].
Hepatitis C Virus Transmission
Inform patients that the effect of treatment of hepatitis C virus infection on transmission is not
known, and that appropriate precautions to prevent transmission of the hepatitis C virus during
treatment should be taken.
Missed Dose
Inform patients that in case a dose of ombitasvir, paritaprevir, ritonavir is missed, the prescribed
dose can be taken within 12 hours.
In case a dose of dasabuvir is missed, the prescribed dose can be taken within 6 hours.
If more than 12 hours has passed since ombitasvir, paritaprevir, ritonavir is usually taken or more
than 6 hours has passed since dasabuvir is usually taken, the missed dose should NOT be taken
and the patient should take the next dose as per the usual dosing schedule.
Instruct patients not to take more than their prescribed dose of VIEKIRA PAK to make up for a
missed dose.
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