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VIEKIRA XR (dasabuvir, ombitasvir, paritaprevir, and ritonavir) extended-release tablets
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use VIEKIRA XR safely and effectively. See full prescribing information for VIEKIRA XR.
VIEKIRA XR (dasabuvir, ombitasvir, paritaprevir, and ritonavir) extended-release tablets, for oral use
Initial U.S. Approval: 2014
INDICATIONS AND USAGE
VIEKIRA XR includes dasabuvir, a hepatitis C virus non-nucleoside NS5B palm polymerase inhibitor, ombitasvir, a hepatitis C virus NS5A inhibitor, paritaprevir, a hepatitis C virus NS3/4A protease inhibitor, and ritonavir, a CYP3A inhibitor and is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV):
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genotype 1b infection without cirrhosis or with compensated cirrhosis
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genotype 1a infection without cirrhosis or with compensated cirrhosis for use in combination with ribavirin. (1)
DOSAGE AND ADMINISTRATION
Testing Prior to Initiation - Assess for laboratory and clinical evidence of hepatic decompensation. (2.1)
Recommended dosage: Three tablets taken once daily. VIEKIRA XR must be taken with a meal because administration under fasting conditions may result in reduced virologic response and possible development of resistance. (2.2)
Treatment Regimen and Duration by Patient Population
|
Patient Population |
Treatment* |
Duration |
Genotype 1a,
without cirrhosis |
VIEKIRA XR + ribavirin |
12 weeks |
Genotype 1a,
with compensated cirrhosis |
VIEKIRA XR + ribavirin |
24 weeks** |
Genotype 1b,
with or without compensated cirrhosis |
VIEKIRA XR |
12 weeks |
*Note: Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection.
**VIEKIRA XR administered with ribavirin for 12 weeks may be considered for some patients based on prior treatment history [See Clinical Studies (14.3)]. |
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HCV/HIV-1 co-infection: For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in the table above. (2.2)
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Liver Transplant Recipients: In liver transplant recipients with normal hepatic function and mild fibrosis (Metavir fibrosis score ≤2), the recommended duration of VIEKIRA XR with ribavirin is 24 weeks. (2.4)
DOSAGE FORMS AND STRENGTHS
Extended-release tablets: 200 mg dasabuvir, 8.33 mg ombitasvir, 50 mg paritaprevir, and 33.33 mg ritonavir (3)CONTRAINDICATIONS
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Patients with moderate to severe hepatic impairment. (4, 5.1, 8.6, 12.3)
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If VIEKIRA XR is administered with ribavirin, the contraindications to ribavirin also apply to this combination regimen. (4)
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Co-administration with drugs that are: highly dependent on CYP3A for clearance; moderate or strong inducers of CYP3A or strong inducers of CYP2C8; and strong inhibitors of CYP2C8. (4)
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Known hypersensitivity to ritonavir (e.g. toxic epidermal necrolysis, Stevens-Johnson syndrome). (4)
WARNINGS AND PRECAUTIONS
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Hepatic Decompensation and Hepatic Failure in Patient with Cirrhosis: Hepatic decompensation and hepatic failure, including liver transplantation or fatal outcomes, have been reported mostly in patients with advanced cirrhosis. Monitor for clinical signs and symptoms of hepatic decompensation. (5.1)
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ALT Elevations: Discontinue ethinyl estradiol-containing medications prior to starting VIEKIRA XR (alternative contraceptive methods are recommended). Perform hepatic laboratory testing on all patients during the first 4 weeks of treatment. For ALT elevations on VIEKIRA XR, monitor closely and follow recommendations in full prescribing information. (5.2)
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Risks Associated With Ribavirin Combination Treatment: If VIEKIRA XR is administered with ribavirin, the warnings and precautions for ribavirin also apply to this combination regimen. (5.3)
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Drug Interactions: The concomitant use of VIEKIRA XR 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 XR. (5.4)
ADVERSE REACTIONS
In subjects receiving the combination of dasabuvir with ombitasvir, paritaprevir, ritonavir with ribavirin, the most commonly reported adverse reactions (greater than 10% of subjects) were fatigue, nausea, pruritus, other skin reactions, insomnia and asthenia. In subjects receiving the combination of dasabuvir with ombitasvir, paritaprevir, ritonavir without ribavirin, the most commonly reported adverse reactions (greater than or equal to 5% of subjects) were nausea, pruritus and insomnia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Co-administration of VIEKIRA XR can alter the plasma concentrations of some drugs and some drugs may alter the plasma concentrations of VIEKIRA XR. The potential for drug interactions must be considered before and during treatment. Consult the full prescribing information prior to and during treatment for potential drug interactions. (4, 5.4, 7, 12.3)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 7/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
VIEKIRA XR is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) [see Dosage and Administration (2.2) and Clinical Studies (14)]:
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genotype 1b infection without cirrhosis or with compensated cirrhosis
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genotype 1a infection without cirrhosis or with compensated cirrhosis for use in combination with ribavirin.
2 DOSAGE AND ADMINISTRATION
2.1 Testing Prior to Initiation of VIEKIRA XR
Prior to initiation of VIEKIRA XR, assess for laboratory and clinical evidence of hepatic decompensation [see Warnings and Precautions (5.1 and 5.2)].
2.2 Recommended Dosage in Adults
VIEKIRA XR is a 4-drug fixed-dose combination, extended-release tablet containing 200 mg of dasabuvir, 8.33 mg of ombitasvir, 50 mg of paritaprevir, and 33.33 mg of ritonavir.
The recommended dosage of VIEKIRA XR is three tablets taken orally once daily.
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VIEKIRA XR must be taken with a meal because administration under fasting conditions may result in reduced virologic response and possible development of resistance [see Clinical Pharmacology (12.3)].
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Swallow tablets whole. Splitting, crushing, or chewing tablets may compromise the extended-release performance, efficacy, and/or safety of VIEKIRA XR.
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For optimal release of dasabuvir, alcohol should not be consumed within 4 hours of taking VIEKIRA XR.
VIEKIRA XR is used in combination with ribavirin (RBV) in certain patient populations (see Table 1). When administered with VIEKIRA XR, the recommended dosage of RBV is based on weight: 1000 mg/day for subjects <75 kg and 1200 mg/day for those ≥75 kg, divided and administered twice-daily with food. The starting dosage and on-treatment dosage of RBV can be decreased based on changes in hemoglobin levels and/or creatinine clearance. 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.
Table 1 shows the recommended VIEKIRA XR treatment regimen and duration based on patient population.
2.3 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 XR with ribavirin is 24 weeks, irrespective of HCV genotype 1 subtype [see Clinical Studies (14.6)]. When VIEKIRA XR is administered with calcineurin inhibitors in liver transplant recipients, dosage adjustment of calcineurin inhibitors is needed [see Drug Interactions (7)].
2.4 Hepatic Impairment
VIEKIRA XR is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C) [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
3 DOSAGE FORMS AND STRENGTHS
Extended-release tablet: 200 mg of dasabuvir (equivalent to 216.2 mg of dasabuvir sodium monohydrate), 8.33 mg of ombitasvir, 50 mg of paritaprevir, and 33.33 mg of ritonavir. The tablets are pale yellow-colored, film-coated, oblong shaped, debossed with “3QD” on one side.
4 CONTRAINDICATIONS
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VIEKIRA XR is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C) due to risk of potential toxicity [see Warnings and Precautions (5.1), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
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If VIEKIRA XR 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.
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VIEKIRA XR is contraindicated:
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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.
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With drugs that are moderate or strong inducers of CYP3A and strong inducers of CYP2C8 and may lead to reduced efficacy of VIEKIRA XR.
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With drugs that are strong inhibitors of CYP2C8 and may increase dasabuvir plasma concentrations and the risk of QT prolongation.
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In patients with known hypersensitivity to ritonavir (e.g. toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome).
Table 2 lists drugs that are contraindicated with VIEKIRA XR [see Drug Interactions (7)].
5 WARNINGS AND PRECAUTIONS
5.1 Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis
Hepatic decompensation and hepatic failure, including liver transplantation or fatal outcomes, have been reported postmarketing in patients treated with the components of VIEKIRA XR. Most patients with these severe outcomes had evidence of advanced cirrhosis prior to initiating therapy. Reported cases typically occurred within one to four weeks of initiating therapy and were characterized by the acute onset of rising direct serum bilirubin levels without ALT elevations in association with clinical signs and symptoms of hepatic decompensation. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
VIEKIRA XR is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C) [see Contraindications (4), Adverse Reactions (6.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
For patients with cirrhosis:
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Monitor for clinical signs and symptoms of hepatic decompensation (such as ascites, hepatic encephalopathy, variceal hemorrhage).
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Hepatic laboratory testing including direct bilirubin levels should be performed at baseline and during the first 4 weeks of starting treatment and as clinically indicated.
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Discontinue VIEKIRA XR in patients who develop evidence of hepatic decompensation.
5.2 Increased Risk of ALT Elevations
During clinical trials with the combination of dasabuvir tablets and ombitasvir, paritaprevir, and ritonavir tablets (components of VIEKIRA XR) with or without ribavirin, elevations of ALT to greater than 5 times the upper limit of normal (ULN) occurred in approximately 1% of all subjects [see Adverse Reactions (6.1)]. 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.
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 XR [see Contraindications (4)]. Alternative methods of contraception (e.g., progestin only contraception or non-hormonal methods) are recommended during VIEKIRA XR therapy. Ethinyl estradiol-containing medications can be restarted approximately 2 weeks following completion of treatment with VIEKIRA XR.
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 XR [see Adverse Reactions (6.1)].
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:
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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.
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Consider discontinuing VIEKIRA XR if ALT levels remain persistently greater than 10 times the ULN.
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Discontinue VIEKIRA XR if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing direct bilirubin, alkaline phosphatase, or INR.
5.3 Risks Associated With Ribavirin Combination Treatment
If VIEKIRA XR 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.
5.4 Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions
The concomitant use of VIEKIRA XR and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to:
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Loss of therapeutic effect of VIEKIRA XR and possible development of resistance
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Possible clinically significant adverse reactions from greater exposures of concomitant drugs or components of VIEKIRA XR.
See Table 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during VIEKIRA XR therapy; review concomitant medications during VIEKIRA XR therapy; and monitor for the adverse reactions associated with the concomitant drugs [see Contraindications (4) and Drug Interactions (7)].
5.5 Risk of HIV-1 Protease Inhibitor Drug Resistance in HCV/HIV-1 Co-infected Patients
The ritonavir component of VIEKIRA XR 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 XR should also be on a suppressive antiretroviral drug regimen to reduce the risk of HIV-1 protease inhibitor drug resistance.
6 ADVERSE REACTIONS
The following adverse reaction is described below and elsewhere in the labeling:
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Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis [see Warnings and Precautions (5.1)]
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Increased Risk of ALT Elevations [see Warnings and Precautions (5.2)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of VIEKIRA XR cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
If VIEKIRA XR is administered with ribavirin (RBV), refer to the prescribing information for ribavirin for a list of ribavirin-associated adverse reactions.
The safety assessment was based on data from seven clinical trials in more than 2,000 subjects who received the components of VIEKIRA XR with or without ribavirin for 12 or 24 weeks.
Components of VIEKIRA XR with Ribavirin in GT 1-Infected Subjects without Cirrhosis
The safety of the components of VIEKIRA XR with ribavirin were assessed in 770 subjects with chronic HCV genotype 1 (GT1) infection without cirrhosis in two placebo-controlled trials (SAPPHIRE-I and -II) [see Clinical Studies (14.1, 14.2)]. Adverse reactions that occurred more often in subjects treated with the components of VIEKIRA XR 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%.
Components of VIEKIRA XR with and without Ribavirin in GT1-Infected Subjects without Cirrhosis
The components of VIEKIRA XR with and without ribavirin were assessed in 401 and 509 subjects with chronic HCV infection GT1 infection without cirrhosis, respectively, in three clinical trials (PEARL-II, PEARL-III and PEARL-IV) [see Clinical Studies (14.1, 14.2)]. Pruritus, nausea, insomnia, and asthenia were identified as adverse events occurring more often in subjects treated with the components of VIEKIRA XR 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 the components of VIEKIRA XR with or without ribavirin.
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