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首个治疗基因1型的慢性丙肝（一日一次缓释剂）新药VIEKIRA XR（DASABUVIR SODIUM/OMBITASVIR/PARITAPREVIR/RITONAVIR）TABLET EXTENDED 获美国FDA批准上市
VIEKIRA XR administered with ribavirin for 12 weeks may be considered for some patients based on prior treatment history [See Clinical Studies (14.3)]. HCV/HIV-1 co-infection: For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in the table above. (2.2) 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 Patients with moderate to severe hepatic impairment. (4, 5.1, 8.6, 12.3) If VIEKIRA XR is administered with ribavirin, the contraindications to ribavirin also apply to this combination regimen. (4) 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) Known hypersensitivity to ritonavir (e.g. toxic epidermal necrolysis, Stevens-Johnson syndrome). (4) WARNINGS AND PRECAUTIONS 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) 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) 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) 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)]: genotype 1b infection without cirrhosis or with compensated cirrhosis 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. 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)]. Swallow tablets whole. Splitting, crushing, or chewing tablets may compromise the extended-release performance, efficacy, and/or safety of VIEKIRA XR. 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. Table 1. Treatment Regimen and Duration by Patient Population (Treatment-Naïve or Interferon-Experienced)
VIEKIRA XR administered with ribavirin for 12 weeks may be considered for some patients based on prior treatment history [see Clinical Studies (14.3)]. 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 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)]. 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. VIEKIRA XR 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. With drugs that are moderate or strong inducers of CYP3A and strong inducers of CYP2C8 and may lead to reduced efficacy of VIEKIRA XR. With drugs that are strong inhibitors of CYP2C8 and may increase dasabuvir plasma concentrations and the risk of QT prolongation. 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)].
5.1 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: Monitor for clinical signs and symptoms of hepatic decompensation (such as ascites, hepatic encephalopathy, variceal hemorrhage). 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. 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: 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 XR if ALT levels remain persistently greater than 10 times the ULN. 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: Loss of therapeutic effect of VIEKIRA XR and possible development of resistance 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: Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis [see Warnings and Precautions (5.1)] 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%. Table 3. Adverse Reactions with ≥5% Greater Frequency Reported in Subjects with Chronic HCV GT1 Infection without Cirrhosis Treated with the Components of VIEKIRA XR with Ribavirin Compared to Placebo for 12 Weeks
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, photosensitivity reaction, psoriasis, skin reaction, ulcer, urticaria. 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. Table 4. Adverse Events with ≥5% Greater Frequency Reported in Subjects with Chronic HCV GT1 Infection without Cirrhosis Treated with the Components of VIEKIRA XR with or without Ribavirin for 12 Weeks
The components of VIEKIRA XR with ribavirin were assessed in 380 subjects with genotype 1 infection and compensated cirrhosis who were treated with the components of VIEKIRA XR plus ribavirin for 12 (n=208) or 24 (n=172) weeks duration (TURQUOISE-II) [see Clinical Studies (14.1, 14.3)]. 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 the components of VIEKIRA XR for 12 and 24 weeks who experienced SAEs were 6% and 5%, respectively and 2% of subjects permanently discontinued treatment due to adverse events in each treatment arm. Components of VIEKIRA XR without Ribavirin in GT1b-Infected Subjects with Compensated Cirrhosis The components of VIEKIRA XR without ribavirin for 12 weeks was assessed in 60 subjects with genotype 1b infection and compensated cirrhosis (TURQUOISE-III) [see Clinical Studies (14.1, 14.3)]. The type and severity of adverse events and laboratory abnormalities in genotype 1b-infected subjects with compensated cirrhosis were comparable to subjects in other trials without ribavirin. Skin Reactions In PEARL-II, -III and -IV, 7% of subjects receiving the components of VIEKIRA XR alone and 10% of subjects receiving the components of VIEKIRA XR with ribavirin reported rash-related events. In SAPPHIRE-I and -II 16% of subjects receiving the components of VIEKIRA XR with ribavirin and 9% of subjects receiving placebo reported skin reactions. In TURQUOISE-II, 18% and 24% of subjects receiving the components of VIEKIRA XR 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 the components of VIEKIRA XR 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 [see Contraindications (4) and Warnings and Precautions (5.2)]. 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 [see Warnings and Precautions (5.2)]. Serum Bilirubin Elevations Post-baseline elevations in bilirubin at least 2 x ULN were observed in 15% of subjects receiving the components of VIEKIRA XR with ribavirin compared to 2% in those receiving the components of VIEKIRA XR without ribavirin. 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 the components of VIEKIRA XR with ribavirin was -2.4 g/dL and the mean change in subjects treated with the components of VIEKIRA XR without ribavirin 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 the components of VIEKIRA XR with ribavirin had hemoglobin levels decrease to less than 8.0 g/dL during treatment. Seven percent of subjects treated with the components of VIEKIRA XR 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 the components of VIEKIRA XR without ribavirin had a hemoglobin level less than 10 g/dL. Components of VIEKIRA XR with Ribavirin in HCV/HIV-1 Co-infected Subjects The components of VIEKIRA XR with ribavirin were assessed in 63 subjects with HCV/HIV-1 co-infection who were on stable antiretroviral therapy. The most common adverse events occurring in at least 10% of subjects were fatigue (48%), insomnia (19%), nausea (17%), headache (16%), pruritus (13%), cough (11%), irritability (10%), and ocular icterus (10%). 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 [see Warnings and Precautions (5.5), Adverse Reactions (6.1) and Clinical Studies (14.6)]. 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. Components of VIEKIRA XR with Ribavirin in Selected Liver Transplant Recipients The components of VIEKIRA XR with ribavirin were 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 [see Clinical Studies (14.5)]. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of the components of VIEKIRA XR. Because these reactions 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. Immune System Disorders: Hypersensitivity reactions (including angioedema). Hepatobiliary Disorders: Hepatic decompensation, hepatic failure [see Warnings and Precautions (5.1)]. 7 DRUG INTERACTIONS 7.1 Potential for VIEKIRA XR to Affect Other Drugs Dasabuvir, ombitasvir, and paritaprevir are inhibitors of UGT1A1, and ritonavir is an inhibitor of CYP3A4. Paritaprevir is an inhibitor of OATP1B1 and OATP1B3 and dasabuvir, paritaprevir, and ritonavir are inhibitors of BCRP. Co-administration of VIEKIRA XR with drugs that are substrates of CYP3A, UGT1A1, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs [see also Contraindications (4), Warnings and Precautions (5.4), and Clinical Pharmacology (12.3)]. 7.2 Potential for Other Drugs to Affect One or More Components of VIEKIRA XR Paritaprevir and ritonavir are primarily metabolized by CYP3A enzymes. Co-administration of VIEKIRA XR with strong inhibitors of CYP3A may increase paritaprevir and ritonavir concentrations. Dasabuvir is primarily metabolized by CYP2C8 enzymes. Co-administration of VIEKIRA XR 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 XR. 7.3 Established and Other Potential Drug Interactions If dose adjustments of concomitant medications are made due to treatment with VIEKIRA XR, doses should be re-adjusted after administration of VIEKIRA XR is completed. Table 5 provides the effect of co-administration of VIEKIRA XR on concentrations of concomitant drugs and the effect of concomitant drugs on the various components of VIEKIRA XR. Refer to Contraindications for drugs that are contraindicated with VIEKIRA XR [see Contraindications (4)]. Refer to the ritonavir prescribing information for other potentially significant drug interactions with ritonavir. Table 5. Established Drug Interactions Based on Drug Interaction Trials
The direction of the arrow indicates the direction of the change in exposures (Cmax and AUC) (↑ = increase of more than 20%, ↓ = decrease of more than 20%, ↔ = no change or change less than 20%). *not studied. 7.4 Drugs without Clinically Significant Interactions with VIEKIRA XR No dosage adjustments are recommended when VIEKIRA XR is co-administered with the following medications: abacavir, dolutegravir, digoxin, duloxetine, emtricitabine/tenofovir disoproxil fumarate, escitalopram, lamivudine, methadone, progestin only contraceptives, raltegravir, sofosbuvir, sulfamethoxazole, trimethoprim, warfarin and zolpidem. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary If VIEKIRA XR is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin prescribing information for more information on use in pregnancy. No adequate human data are available to establish whether or not VIEKIRA XR poses a risk to pregnancy outcomes. In animal reproduction studies, no adverse developmental effects were observed when the components of VIEKIRA XR were administered separately during organogenesis and lactation. During organogenesis, the exposures were up to 28 and 4 times (mice and rabbits, respectively; ombitasvir), 8 and 98 times (mice and rats, respectively; paritaprevir, ritonavir), and 24 and 6 times (rats and rabbits, respectively; dasabuvir) exposures at the recommended clinical dose of VIEKIRA XR. In rodent pre/postnatal developmental studies, maternal systemic exposures (AUC) to ombitasvir, paritaprevir and dasabuvir were approximately 25, 17 and 44 times, respectively, the exposure in humans at the recommended clinical dose [see Data]. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal data Dasabuvir Dasabuvir was administered orally to pregnant rats (0, 60, 300 and 800 mg/kg/day) and rabbits (0, 100, 200 or 400 mg/kg/day) during the period of organogenesis (on GD 6 to 17 and GD 7 to 20, respectively). There were no test article-related embryofetal effects (malformations or fetal toxicity) at any dose level in either species. The highest systemic exposure of dasabuvir was 24-times higher (rats) and 6-times higher (rabbits) than the exposures in humans at the recommended clinical dose. In a pre- and postnatal developmental study in rats, dasabuvir was administered orally at 0, 50, 200, or 800 mg/kg/day from GD 7 to lactation day 21. There were no treatment-related effects at maternal exposures 44-times higher than exposures in humans at the recommended clinical dose. Ombitasvir Ombitasvir was administered orally to pregnant mice (0, 15, 50, or 150 mg/kg/day) and rabbits (0, 10 or 60 mg/kg/day) during the period of organogenesis (on gestation days (GD) 6 to 15, and GD 7 to 19, respectively). There were no ombitasvir-related embryofetal effects (malformations or fetal toxicity) at any dose level in either species. The systemic exposures at the highest doses were 28-times higher (mice) and 4-times higher (rabbits) than the exposures in humans at the recommended clinical dose. In a pre- and postnatal developmental study in mice, ombitasvir was administered orally at 0, 10, 40, or 200 mg/kg/day from GD 6 to lactation day 20. There were no ombitasvir-related effects at maternal exposures 25-times higher than exposures in humans at the recommended clinical dose. The major human metabolites of ombitasvir, M29 and M36, were tested in pregnant mice during the period of organogenesis from GD 6 to 15. M29 was administered orally at doses of 0, 1, 2.5 or 4.5 mg/kg/day. M36 was dosed orally at doses 1.5, 3, or 6 mg/kg/day. In both cases, there were no treatment related embryofetal effects (malformations or fetal toxicity) at any dose level. The highest doses produced exposures approximately 26-times higher than the exposures in humans at the recommended clinical dose. Paritaprevir/ritonavir Paritaprevir/ritonavir was administered orally to pregnant rats (0/0, 30/15, 100/15, 450/45 mg/kg/day) and mice (0/0, 30/30, 100/30, or 300/30 mg/kg/day) during the period of organogenesis (on GD 6 to 17, and GD 6 to 15, respectively). There were no test article-related embryofetal effects (malformations or fetal toxicity) at any dose level in either species. The highest systemic exposure of paritaprevir was 8-times higher (rats) and 98-times higher (mice) than the exposures in humans at the recommended clinical dose. In a pre- and postnatal developmental study in rats, paritaprevir/ritonavir were administered orally at 0/0, 6/30, 30/30, or 300/30 mg/kg/day from GD 7 to lactation day 20. There were no treatment related effects at maternal exposures 17-times higher than exposures in humans at the recommended clinical dose. 8.2 Lactation Risk Summary It is not known whether VIEKIRA XR and its metabolites are present in human breast milk, affect human milk production or have effects on the breastfed infant. Unchanged ombitasvir, paritaprevir and its hydrolysis product M13, and dasabuvir were the predominant components observed in the milk of lactating rats, without effect on nursing pups [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VIEKIRA XR and any potential adverse effects on the breastfed child from VIEKIRA XR or from the underlying maternal condition. If VIEKIRA XR is administered with ribavirin, the nursing mother’s information for ribavirin also applies to this combination regimen. Refer to the ribavirin prescribing information for more information on use during lactation. Data Animal Data Dasabuvir No effects of dasabuvir on growth and postnatal development were observed in nursing pups at the highest dose tested (800 mg/kg/day) in rats. Maternal systemic exposure (AUC) to dasabuvir was approximately 44 times the exposure in humans at the recommended clinical dose. Although not measured directly, dasabuvir was likely present in the milk of lactating rats in this study, since systemic exposure was observed in nursing pups on post-natal day 14 (approximately 14% of maternal exposure). When dasabuvir was administered to lactating rats (5 mg/kg on post-partum day 10 to 11), milk exposure (AUC) was 2 times higher than that in plasma, with unchanged parent drug (78%) accounting for the majority of drug-related material in milk. Ombitasvir No effects of ombitasvir on growth and postnatal development were observed in nursing pups at the highest dose tested (200 mg/kg/day) in mice. Maternal systemic exposure (AUC) to ombitasvir was approximately 25 times the exposure in humans at the recommended clinical dose. Although not measured directly, ombitasvir was likely present in the milk of lactating mice in this study, since systemic exposure was observed in nursing pups on post-natal day 21 (approximately 16% of maternal exposure). When ombitasvir was administered to lactating rats (5 mg/kg on post-partum day 10 to 11), milk exposure (AUC) was 4 times higher than that in plasma, with unchanged parent drug (91%) accounting for the majority of drug-related material in milk. Paritaprevir/ritonavir No effects of paritaprevir/ritonavir on growth and postnatal development were observed in nursing pups at the highest dose tested (300/30 mg/kg/day) in rats. Maternal systemic exposure (AUC) to paritaprevir was approximately 17 times the exposure in humans at the recommended clinical dose. Although not measured directly, paritaprevir was likely present in the milk of lactating rats at the high dose in this study, since systemic exposure was observed in nursing pups on post-natal day 15 (approximately 0.3 % of maternal exposure). When paritaprevir/ritonavir was administered to lactating rats (30/15 mg/kg on post-partum day 10 to 11), milk exposure (AUC) was half that in plasma, with the hydrolysis product M13 (84%) and unchanged parent drug (16%) accounting for all paritaprevir-related material in milk. 8.3 Females and Males of Reproductive Potential If VIEKIRA XR is administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to ribavirin prescribing information for additional information. 8.4 Pediatric Use Safety and effectiveness of VIEKIRA XR in pediatric patients less than 18 years of age have not been established. 8.5 Geriatric Use No dosage adjustment of VIEKIRA XR is warranted in geriatric patients. Of the total number of subjects in clinical studies of the components of VIEKIRA XR, 8.5% (174/2053) were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment No dosage adjustment of VIEKIRA XR is required in patients with mild hepatic impairment (Child-Pugh A). VIEKIRA XR is contraindicated in patients with moderate to severe (Child-Pugh B and C) hepatic impairment [see Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No dosage adjustment of VIEKIRA XR is required in patients with mild, moderate or severe renal impairment, including those on dialysis. For patients that require ribavirin, refer to the ribavirin prescribing information for information regarding use in patients with renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted immediately. 11 DESCRIPTION VIEKIRA XR fixed dose combination, extended-release tablet includes a hepatitis C virus non-nucleoside NS5B palm polymerase inhibitor (dasabuvir), a hepatitis C virus NS5A inhibitor (ombitasvir), a hepatitis C virus NS3/4A protease inhibitor (paritaprevir), and a CYP3A inhibitor (ritonavir) that inhibits CYP3A mediated metabolism of paritaprevir, thereby providing increased plasma concentration of paritaprevir. The tablets are for oral administration. Dasabuvir The chemical name of dasabuvir is Sodium 3-(3-tert-butyl-4-methoxy-5-{6-[(methylsulfonyl)amino]naphthalene-2-yl}phenyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ide hydrate (1:1:1). The molecular formula is C26H26N3O5S•Na•H2O (salt, hydrate) and the molecular weight of the drug substance is 533.57 (salt, hydrate). The drug substance is white to pale yellow to pink powder, slightly soluble in water and very slightly soluble in methanol and isopropyl alcohol. Dasabuvir has the following molecular structure:
Ombitasvir
Paritaprevir
a.High fat meal of 753 Kcal; 55.3% calories from fat, 27.8% calories from carbohydrates, and 16.9% calories from protein. b.Similar results are expected for ombitasvir, paritaprevir and dasabuvir under moderate fat meal conditions. c.Steady state exposures are achieved after approximately 12 days of dosing. d.It is apparent volume of distribution (V/F) for ritonavir. e.Ombitasvir, paritaprevir, ritonavir, and dasabuvir do not inhibit organic anion transporter (OAT1) in vivo and based on in vitro data, are not expected to inhibit organic cation transporter (OCT2), organic anion transporter (OAT3), or multidrug and toxin extrusion proteins (MATE1 and MATE2K) at clinically relevant concentrations. f.t1/2 values refer to the mean elimination half-life. g.Dosing in mass balance studies: single dose administration of [14C] ombitasvir; single dose administration of [14C] paritaprevir co-dosed with 100 mg ritonavir; single dose administration of [14C] dasabuvir. 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 (5.4), 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 7. Drug Interactions: Change in Pharmacokinetic Parameters of Dasabuvir, Ombitasvir, Paritaprevir, and Ritonavir in the Presence of Co-administered Drug
b.30 mg cyclosporine was administered with the components of VIEKIRA XR in the test arm and 100 mg cyclosporine was administered in the reference arm without the components of VIEKIRA XR. c.Darunavir administered with the components of VIEKIRA XR in the morning was compared to darunavir administered with 100 mg ritonavir in the morning. d.Darunavir administered with the components of VIEKIRA XR in the morning and with 100 mg ritonavir in the evening was compared to darunavir administered with 100 mg ritonavir in the morning and evening. e.Darunavir plus 100 mg ritonavir administered in the evening, 12 hours after the morning dose of the components of VIEKIRA XR compared to darunavir administered with 100 mg ritonavir in the evening. f.N=3 for dasabuvir. g.Study was conducted with paritaprevir, ritonavir and dasabuvir. h.Lopinavir/ritonavir administered in the evening, 12 hours after morning dose of the components of VIEKIRA XR. i.Similar increases were observed when rilpivirine was dosed in the evening with food or 4 hours after food. NA: not available/not applicable; DAA: Direct-acting antiviral agent; CI: Confidence interval Doses of dasabuvir were 250 mg or 400 mg (both doses showed similar exposures). Doses of ombitasvir, paritaprevir, and ritonavir were 25 mg, 150 mg and 100 mg. Dasabuvir was dosed twice daily and ombitasvir, paritaprevir and ritonavir were dosed once daily in all the above studies except studies with gemfibrozil, ketoconazole and carbamazepine that used single doses. 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). Table 8. Drug Interactions: Change in Pharmacokinetic Parameters for Co-administered Drug in the Presence of VIEKIRA XR
b.Atazanavir or darunavir or lopinavir parameters are reported. c.Dose normalized parameters reported. d.30 mg cyclosporine was administered with the components of VIEKIRA XR in the test arm and 100 mg cyclosporine was administered in the reference arm without the components of VIEKIRA XR. e.Darunavir administered with the components of VIEKIRA XR in the morning was compared to darunavir administered with 100 mg ritonavir in the morning. f.Darunavir administered with the components of VIEKIRA XR in the morning and with 100 mg ritonavir in the evening was compared to darunavir administered with 100 mg ritonavir in the morning and evening. g.Darunavir plus 100 mg ritonavir administered in the evening, 12 hours after morning dose of the components of VIEKIRA XR compared to darunavir administered with 100 mg ritonavir in the evening. h.Lopinavir/ritonavir administered in the evening, 12 hours after morning dose of the components of VIEKIRA XR. i.Similar increases were observed when rilpivirine was dosed in the evening with food or 4 hours after food. NA: not available/not applicable; CI: Confidence interval Doses of dasabuvir were 250 mg or 400 mg (both doses showed similar exposures). Doses of ombitasvir, paritaprevir, and ritonavir were 25 mg, 150 mg and 100 mg. Dasabuvir was dosed twice daily and ombitasvir, paritaprevir and ritonavir were dosed once daily in all the above studies except studies with ketoconazole and carbamazepine that used single doses. 12.4 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. Table 9. Treatment-Emergent Amino Acid Substitutions in the Pooled Analysis of the Components of VIEKIRA XR with and without Ribavirin Regimens (12- or 24-week durations) in Phase 2b and Phase 3 Clinical Trials
b.Substitutions were observed in combination with other emergent substitutions at NS3 position R155 or D168. c.Position located in NS3 helicase domain. d.D168A/F/H/I/L/N/T/V/Y. 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. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis Dasabuvir Dasabuvir was not carcinogenic in a 6-month transgenic mouse study up to the highest dose tested (2000 mg per kg per day). Similarly, dasabuvir was not carcinogenic in a 2-year rat study up to the highest dose tested (800 mg per kg per day), resulting in dasabuvir exposures approximately 19-fold higher than those in humans at 500 mg. Dasabuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rat micronucleus assays. Ombitasvir Ombitasvir was not carcinogenic in a 6-month transgenic mouse study up to the highest dose tested (150 mg per kg per day). Similarly, ombitasvir was not carcinogenic in a 2-year rat study up to the highest dose tested (30 mg per kg per day), resulting in ombitasvir exposures approximately 16-fold higher than those in humans at 25 mg. Ombitasvir and its major inactive human metabolites (M29, M36) were not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays. Paritaprevir, ritonavir Paritaprevir, ritonavir was not carcinogenic in a 6-month transgenic mouse study up to the highest dose tested (300/30 mg per kg per day). Similarly, paritaprevir, ritonavir was not carcinogenic in a 2-year rat study up to the highest dose tested (300/30 mg per kg per day), resulting in paritaprevir exposures approximately 9-fold higher than those in humans at 150 mg. Paritaprevir was positive in an in vitro chromosome aberration test using human lymphocytes. Paritaprevir was negative in a bacterial mutation assay, and in two in vivo genetic toxicology assays (rat bone marrow micronucleus and rat liver Comet tests). If VIEKIRA XR is administered with ribavirin, refer to the prescribing information for ribavirin for information on carcinogenesis, and mutagenesis. Impairment of Fertility Dasabuvir Dasabuvir had no effects on embryo-fetal viability or on fertility when evaluated in rats up to the highest dose of 800 mg per kg per day. Dasabuvir exposures at this dose were approximately 16-fold the exposure in humans at the recommended clinical dose. Ombitasvir Ombitasvir had no effects on embryo-fetal viability or on fertility when evaluated in mice up to the highest dose of 200 mg per kg per day. Ombitasvir exposures at this dose were approximately 25-fold the exposure in humans at the recommended clinical dose. Paritaprevir, ritonavir Paritaprevir, ritonavir had no effects on embryo-fetal viability or on fertility when evaluated in rats up to the highest dose of 300/30 mg per kg per day. Paritaprevir exposures at this dose were approximately 2- to 5-fold the exposure in humans at the recommended clinical dose. If VIEKIRA XR is administered with ribavirin, refer to the prescribing information for ribavirin for information on Impairment of Fertility. 14 CLINICAL STUDIES 14.1 Description of Clinical Trials Table 10 presents the clinical trial design including different treatment arms that were conducted with the components of VIEKIRA XR with or without ribavirin in subjects with chronic hepatitis C (HCV) genotype 1 (GT1) infection. For detailed description of trial design and recommended regimen and duration [see Dosage and Administration (2) and Clinical Studies (14)]. Table 10. Clinical Trials Conducted with the Components of VIEKIRA XR With or Without Ribavirin (RBV) in Subjects with Chronic HCV GT1 Infection
HCV GT1-infected liver transplant recipients (CORAL-I) [see Clinical Studies (14.5)]. Subjects with HCV GT1 co-infected with HIV-1 (TURQUOISE-I) [see Clinical Studies (14.6)]. In all clinical trials, the ombitasvir, paritaprevir, ritonavir dose was 25/150/100 mg once daily and the dasabuvir dose was 250 mg twice daily and doses were not adjusted. For subjects who received RBV, the RBV dose was 1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects weighing greater than or equal to 75 kg. RBV dose adjustments were performed according to the RBV labeling. In all clinical trials, sustained virologic response was defined as HCV RNA below the lower limit of quantification (<LLOQ) 12 weeks after the end of treatment (SVR12). Plasma HCV RNA levels were measured using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System, which has an LLOQ of 25 IU per mL. Outcomes for subjects not achieving an SVR12 were recorded as on-treatment virologic failure (VF), post-treatment virologic relapse through post-treatment Week 12 or failure due to other non-virologic reasons (e.g., premature discontinuation, adverse event, lost to follow-up, consent withdrawn). 14.2 Clinical Trial Results in Adults with Chronic HCV Genotype 1a and 1b Infection without Cirrhosis Subjects with HCV GT1a infection without cirrhosis treated with the components of VIEKIRA XR with RBV for 12 weeks in SAPPHIRE-I and -II and in PEARL-IV [see Clinical Studies (14.1)] 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 (rs12979860) non-CC genotype; 85% had baseline HCV RNA levels of at least 800,000 IU per mL. Table 11 presents treatment outcomes for HCV GT1a treatment-naïve and treatment-experienced subjects treated with the components of VIEKIRA XR with RBV for 12 weeks in SAPPHIRE-I, PEARL-IV and SAPPHIRE-II. Treatment-naïve, HCV GT1a-infected subjects without cirrhosis treated with the components of VIEKIRA XR with RBV for 12 weeks in PEARL-IV had a significantly higher SVR12 rate than subjects treated with the components of VIEKIRA XR without RBV (97% and 90% respectively; difference +7% with 95% confidence interval, +1% to +12%). The components of VIEKIRA XR without RBV were 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 11. SVR12 for HCV Genotype 1a-Infected Subjects without Cirrhosis Who Were Treatment-Naïve or Previously Treated with PegIFN/RBV
Subjects with HCV GT1b infection without cirrhosis were treated with the components of VIEKIRA XR with or without RBV for 12 weeks in PEARL-II and -III [see Clinical Studies (14.1)]. 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 (rs12979860) 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 the components of VIEKIRA XR 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%. 14.3 Clinical Trial Results in Adults with Chronic HCV Genotype 1a and 1b Infection and Compensated Cirrhosis The components of VIEKIRA XR with and without ribavirin were evaluated in two clinical trials in patients with compensated cirrhosis. TURQUOISE-II was an open-label trial that enrolled 380 HCV GT1 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 the components of VIEKIRA XR 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 (rs12979860) 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. TURQUOISE-III was an open-label trial that enrolled 60 HCV GT1b-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 received the components of VIEKIRA XR without RBV for 12 weeks. Treated subjects had a median age of 61 years (range: 26 to 78); including 45% treatment-naïve and 55% pegIFN/RBV treatment-experienced; 25% were ≥65 years; 62% were male; 12% were Black; 5% were Hispanic or Latino; 28% had a body mass index of at least 30 kg per m2; 40% of patients were enrolled in US sites; 22% had platelet counts of less than 90 x 109 per L; 17% had albumin less than 35 g/L; 92% had baseline HCV RNA levels of at least 800,000 IU per mL; 83% had IL28B (rs12979860) non‑CC genotype. Table 12 presents treatment outcomes for GT1a- and GT1b-infected treatment-naïve and treatment-experienced subjects. In GT1a infected subjects, the overall SVR12 rate difference between 24 and 12 weeks of treatment with the components of VIEKIRA XR with RBV was +6% with 95% confidence interval (-0.1% to +13% with differences varying by pretreatment history). Table 12. TURQUOISE-II: SVR12 for Chronic HCV Genotype 1-Infected Subjects with Cirrhosis Who Were Treatment-Naïve or Previously Treated with pegIFN/RBV
Seven percent of subjects (101/1551) treated with the components of VIEKIRA XR with RBV had a RBV dose adjustment due to a decrease in hemoglobin level; of these, 98% (98/100) achieved an SVR12. 14.5 Clinical Trial of Selected Liver Transplant Recipients (CORAL-I) The components of VIEKIRA XR with RBV were 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 the components of VIEKIRA XR 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. 14.6 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 the components of VIEKIRA XR 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 the components of VIEKIRA XR with RBV. Atazanavir was taken with the morning dose. The ritonavir component of the HIV-1 ART regimen was restarted after completion of treatment. Treated subjects had a median age of 51 years (range: 31 to 69); 24% of subjects were black; 81% of subjects had IL28B (rs12979860) 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. 14.7 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 XR with or without RBV achieved SVR12, and 99% of those who achieved SVR12 maintained their response through 48 weeks post-treatment (SVR48). 16 HOW SUPPLIED/STORAGE AND HANDLING VIEKIRA XR 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 three tablets. The NDC number is 0074-0063-28. Dasabuvir, ombitasvir, paritaprevir, and ritonavir 200 mg/8.33 mg/50 mg/33.33 mg tablets are pale yellow-colored, film-coated, oblong shaped, debossed with “3QD” on one side. Store at or below 30°C (86°F). 17 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 (5.3)]. Risk of ALT Elevations or Hepatic Decompensation and Failure Inform patients to watch for early warning signs of liver inflammation or failure, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice, onset of confusion, abdominal swelling, and discolored feces, and to consult their health care professional without delay if such symptoms occur [see Warnings and Precautions (5.1 and 5.2) and Adverse Reactions (6)]. Pregnancy Advise patients taking VIEKIRA XR with ribavirin to avoid pregnancy during treatment and within 6 months of stopping ribavirin. Inform patients to notify their health care provider immediately in the event of a pregnancy [see Use in Specific Populations (8.1)]. Drug Interactions Inform patients that VIEKIRA XR 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 (5.4) and Drug Interactions (7)]. Inform patients that contraceptives containing ethinyl estradiol are contraindicated with VIEKIRA XR [see Contraindications (4) and Warnings and Precautions (5.2)]. Administration Advise patients to take VIEKIRA XR every day at the regularly scheduled time and that VIEKIRA XR must be taken with a meal because taking it under fasting conditions may result in reduced virologic response and possible development of resistance. Inform patients to swallow tablets whole and not to consume alcohol within 4 hours of taking VIEKIRA XR [see Dosage and Administration (2.2)]. Inform patients that it is important not to miss or skip doses and to take VIEKIRA XR for the duration that is recommended by the healthcare provider. Manufactured by AbbVie Inc., North Chicago, IL 60064. VIEKIRA XR and NORVIR are trademarks of AbbVie Inc. All other brands listed are trademarks of their respective owners and are not trademarks of AbbVie Inc. The makers of these brands are not affiliated with and do not endorse AbbVie Inc. or its products. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2e9dc175-80cb-b598-d035-4c3d5134c096 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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VIEKIRA XR TABLET（dasabuvir/ombitasvir/paritaprevir/ritonavir）简介：
首个治疗基因1型的慢性丙肝（一日一次缓释剂）新药VIEKIRA XR（DASABUVIR SODIUM/OMBITASVIR/PARITAPREVIR/RITONAVIR）TABLET EXTENDED 获美国FDA批准上市VIEKIRA XR是每日一次的缓释制剂，本剂与先前获 ... 责任编辑：p53 |
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