FDA label 75a84702-eb6d-5b0b-5091-765fa961057d

WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with VIEKIRA XR. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated [see Warnings and Precautions ( 5.1 )] . WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV See full prescribing information for complete boxed warning. Hepatitis B virus (HBV) reactivation has been reported, in some cases resulting in fulminant hepatitis, hepatic failure, and death. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Risk of Hepatitis B Virus Reactivation : Test all patients for evidence of current or prior HBV infection before initiation of HCV treatment. Monitor HCV/HBV coinfected patients for HBV reactivation and hepatitis flare during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. ( 5.1 ) 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. ( 5.2 ) 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. ( 5.3 ) 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. ( 5.4 ) 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. ( 5.5 ) 5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients. HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increase in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur. Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti- HBc before initiating HCV treatment with VIEKIRA XR. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with VIEKIRA XR and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. 5.2 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. 5.3 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. 5.4 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. 5.5 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 4 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 )] . 5.6 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.

5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients. HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increase in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur. Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti- HBc before initiating HCV treatment with VIEKIRA XR. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with VIEKIRA XR and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

5.2 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.

5.3 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.

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 ( 5.2 )] Increased Risk of ALT Elevations [see Warnings and Precautions ( 5.3 )] 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. 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 2 ). 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 2. 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 SAPPHIRE-I and -II Components of VIEKIRA XR + RBV 12 Weeks N = 770 % Placebo 12 Weeks N = 255 % Fatigue 34 26 Nausea 22 15 Pruritus* 18 7 Skin reactions $ 16 9 Insomnia 14 8 Asthenia 14 7 *Grouped term ‘pruritus’ included the preferred terms pruritus and pruritus generalized. $ Grouped terms: rash, erythema, eczema, rash maculo-papular, rash macular, dermatitis, rash papular, skin exfoliation, rash pruritic, rash erythematous, rash generalized, dermatitis allergic, dermatitis contact, exfoliative rash, 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 3 ). 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 3. 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 PEARL-II, -III and -IV Components of VIEKIRA XR + RBV 12 Weeks N = 401 % Components of VIEKIRA XR without RBV 12 Weeks N = 509 % Nausea 16 8 Pruritus* 13 7 Insomnia 12 5 Asthenia 9 4 *Grouped term ‘pruritus’ included the preferred terms pruritus and pruritus generalized. Components of VIEKIRA XR with Ribavirin in GT1-Infected Subjects with Compensated Cirrhosis 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. 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 ( 5.3 )] . 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 ( 5.3 )] . 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 ( 5.6 ), 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/mm 3 and 62 cells/mm 3 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/mm 3 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: Anaphylactic reactions and other hypersensitivity reactions (including angioedema). Hepatobiliary Disorders: Hepatic decompensation, hepatic failure [see Warnings and Precautions ( 5.2 )] . Skin and Subcutaneous Tissue Disorders: Erythema multiforme (EM).

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 2 ). 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 2. 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 SAPPHIRE-I and -II Components of VIEKIRA XR + RBV 12 Weeks N = 770 % Placebo 12 Weeks N = 255 % Fatigue 34 26 Nausea 22 15 Pruritus* 18 7 Skin reactions $ 16 9 Insomnia 14 8 Asthenia 14 7 *Grouped term ‘pruritus’ included the preferred terms pruritus and pruritus generalized. $ Grouped terms: rash, erythema, eczema, rash maculo-papular, rash macular, dermatitis, rash papular, skin exfoliation, rash pruritic, rash erythematous, rash generalized, dermatitis allergic, dermatitis contact, exfoliative rash, 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 3 ). 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 3. 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 PEARL-II, -III and -IV Components of VIEKIRA XR + RBV 12 Weeks N = 401 % Components of VIEKIRA XR without RBV 12 Weeks N = 509 % Nausea 16 8 Pruritus* 13 7 Insomnia 12 5 Asthenia 9 4 *Grouped term ‘pruritus’ included the preferred terms pruritus and pruritus generalized. Components of VIEKIRA XR with Ribavirin in GT1-Infected Subjects with Compensated Cirrhosis 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. 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 ( 5.3 )] . 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 ( 5.3 )] . 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 ( 5.6 ), 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/mm 3 and 62 cells/mm 3 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/mm 3 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: Anaphylactic reactions and other hypersensitivity reactions (including angioedema). Hepatobiliary Disorders: Hepatic decompensation, hepatic failure [see Warnings and Precautions ( 5.2 )] . Skin and Subcutaneous Tissue Disorders: Erythema multiforme (EM).

<table ID="table_2" frame="box" width="100%"> <caption>Table 2. Adverse Reactions with &#x2265;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</caption> <colgroup> <col width="33*"/> <col width="33*"/> <col width="33*"/> </colgroup> <tbody> <tr> <td styleCode="Toprule Botrule Lrule Rrule"> </td> <td styleCode="Toprule Botrule Lrule Rrule" colspan="2" align="center"> <content styleCode="bold">SAPPHIRE-I and -II</content> </td> </tr> <tr> <td styleCode="Toprule Botrule Lrule Rrule"/> <td styleCode="Toprule Botrule Lrule Rrule" align="center"> <content styleCode="bold">Components of VIEKIRA XR + RBV</content> <content styleCode="bold">12 Weeks</content> <content styleCode="bold">N = 770</content> <content styleCode="bold">%</content> </td> <td styleCode="Toprule Botrule Lrule Rrule" align="center" valign="top"> <content styleCode="bold">Placebo</content> <content styleCode="bold">12 Weeks</content> <content styleCode="bold">N = 255</content> <content styleCode="bold">%</content> </td> </tr> <tr> <td styleCode="Toprule Botrule Lrule Rrule" align="center">Fatigue</td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">34 </td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">26</td> </tr> <tr> <td styleCode="Toprule Botrule Lrule Rrule" align="center">Nausea</td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">22 </td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">15 </td> </tr> <tr> <td styleCode="Toprule Botrule Lrule Rrule" align="center">Pruritus*</td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">18 </td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">7 </td> </tr> <tr> <td styleCode="Toprule Botrule Lrule Rrule" align="center">Skin reactions^$ </td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">16</td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">9</td> </tr> <tr> <td styleCode="Toprule Botrule Lrule Rrule" align="center">Insomnia</td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">14</td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">8 </td> </tr> <tr> <td styleCode="Toprule Botrule Lrule Rrule" align="center">Asthenia</td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">14 </td> <td styleCode="Toprule Botrule Lrule Rrule" align="center">7</td> </tr> <tr> <td styleCode="Toprule Botrule Lrule Rrule" colspan="3">*Grouped term &#x2018;pruritus&#x2019; included the preferred terms pruritus and pruritus generalized. ^$Grouped terms: rash, erythema, eczema, rash maculo-papular, rash macular, dermatitis, rash papular, skin exfoliation, rash pruritic, rash erythematous, rash generalized, dermatitis allergic, dermatitis contact, exfoliative rash, photosensitivity reaction, psoriasis, skin reaction, ulcer, urticaria.</td> </tr> </tbody> </table>