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 DAKLINZA. 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 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)
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warnings and cautions
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) • Bradycardia When Coadministered with Sofosbuvir and Amiodarone: Serious symptomatic bradycardia may occur in patients taking amiodarone with a sofosbuvir-containing regimen, particularly in patients also receiving beta blockers or those with underlying cardiac comorbidities and/or advanced liver disease. Coadministration of amiodarone with DAKLINZA in combination with sofosbuvir is not recommended. In patients with no alternative treatment options, cardiac monitoring is recommended. ( 5.3 , 6.2 , 7.3 ) 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., increases 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 DAKLINZA. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with DAKLINZA and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. 5.2 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of DAKLINZA and other drugs may result in known or potentially significant drug interactions, some of which may lead to [ see Contraindications (4) and Drug Interactions (7) ]: • loss of therapeutic effect of DAKLINZA and possible development of resistance, • dosage adjustments of concomitant medications or DAKLINZA, • possible clinically significant adverse reactions from greater exposures of concomitant drugs or DAKLINZA. See Table 3 for drugs contraindicated with DAKLINZA due to loss of efficacy and possible development of resistance [ see Contraindications (4) ]. See Table 7 for steps to prevent or manage other possible and known significant drug interactions [ see Drug Interactions (7) ]. Consider the potential for drug interactions before and during DAKLINZA therapy, review concomitant medications during DAKLINZA therapy, and monitor for the adverse reactions associated with the concomitant drugs. 5.3 Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone was coadministered with a sofosbuvir-containing regimen. A fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir/sofosbuvir). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this bradycardia effect is unknown. Coadministration of amiodarone with DAKLINZA in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no alternative treatment options and who will be coadministered DAKLINZA and sofosbuvir: • Counsel patients about the risk of serious symptomatic bradycardia. • Cardiac monitoring in an inpatient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Patients who are taking sofosbuvir in combination with DAKLINZA who need to start amiodarone therapy due to no other alternative treatment options should undergo similar cardiac monitoring as outlined above. Due to amiodarone’s long elimination half-life, patients discontinuing amiodarone just prior to starting sofosbuvir in combination with DAKLINZA should also undergo similar cardiac monitoring as outlined above. Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, or memory problems [ see Adverse Reactions (6.2) and Drug Interactions (7.3), Table 7 ]. 5.4 Risks Associated with Ribavirin Combination Treatment If DAKLINZA and sofosbuvir are 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.
6 ADVERSE REACTIONS If DAKLINZA and sofosbuvir are administered with ribavirin, refer to the prescribing information for ribavirin regarding ribavirin-associated adverse reactions. The following serious adverse reaction is described below and elsewhere in the labeling: • Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone [ see Warnings and Precautions (5.3) ]. Most common adverse reactions (≥10%) observed with DAKLINZA in combination with sofosbuvir were headache and fatigue. (6.1) Most common adverse reactions (≥10%) observed with DAKLINZA in combination with sofosbuvir and ribavirin were headache, anemia, fatigue, and nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 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 the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Approximately 2400 subjects with chronic HCV infection have been treated with the recommended dose of DAKLINZA in combination with other anti-HCV drugs in clinical trials. Six hundred seventy-nine subjects have received a DAKLINZA and sofosbuvir-based regimen. Safety experience from three clinical trials of DAKLINZA and sofosbuvir with or without ribavirin is presented. DAKLINZA and Sofosbuvir In the ALLY-3 trial, 152 treatment-naive and treatment-experienced subjects with HCV genotype 3 infection were treated with DAKLINZA 60 mg once daily in combination with sofosbuvir for 12 weeks. The most common adverse reactions (frequency of 10% or greater) were headache and fatigue. All adverse reactions were mild to moderate in severity. No subjects discontinued therapy for adverse events. In the ALLY-2 trial, 153 treatment-naive and treatment-experienced subjects with HCV/HIV-1 coinfection were treated with DAKLINZA 60 mg once daily (dose-adjusted for concomitant antiretroviral use) in combination with sofosbuvir for 12 weeks. The most common adverse reaction (frequency of 10% or greater) was fatigue. The majority of adverse reactions were mild to moderate in severity. No subjects discontinued therapy for adverse events. Adverse reactions considered at least possibly related to treatment and occurring at a frequency of 5% or greater in ALLY-3 or ALLY-2 are presented in Table 4. Table 4: Adverse Reactions (All Severity) Reported at ≥5% Frequency, DAKLINZA + Sofosbuvir, Studies ALLY-3 and ALLY-2 Adverse Reaction ALLY-3: HCV Genotype 3 n=152 ALLY-2: HCV/HIV-1 Coinfection n=153 Headache 14% 8% Fatigue 14% 15% Nausea 8% 9% Diarrhea 5% 7% DAKLINZA, Sofosbuvir, and Ribavirin In the ALLY-1 trial, 113 subjects with chronic HCV infection, including 60 subjects with Child-Pugh A, B, or C cirrhosis and 53 subjects with recurrence of HCV after liver transplantation, were treated with DAKLINZA 60 mg once daily in combination with sofosbuvir and ribavirin for 12 weeks. The most common adverse reactions (frequency of 10% or greater) among the 113 subjects were headache, anemia, fatigue, and nausea. The majority of adverse reactions were mild to moderate in severity. Of the 15 (13%) subjects who discontinued study drug for adverse events, 13 (12%) subjects discontinued ribavirin only and 2 (2%) subjects discontinued all study drugs. During treatment, 4 subjects in the cirrhotic cohort underwent liver transplantation. Adverse reactions considered at least possibly related to treatment and occurring at a frequency of 5% or greater in either treatment cohort in ALLY-1 are presented in Table 5. Table 5: Adverse Reactions (All Severity) Reported at ≥5% Frequency in Either Treatment Cohort, DAKLINZA + Sofosbuvir + Ribavirin, Study ALLY-1 Adverse Reaction Child-Pugh A, B, or C Cirrhosis n=60 Recurrence after Liver Transplantation n=53 Headache 12% 30% Anemia 20% 19% Fatigue 15% 17% Nausea 15% 6% Rash 8% 2% Diarrhea 3% 6% Insomnia 3% 6% Dizziness 0 6% Somnolence 5% 0 Laboratory Abnormalities Selected Grade 3 and 4 treatment-emergent laboratory abnormalities observed in clinical trials of DAKLINZA in combination with sofosbuvir with or without ribavirin are presented in Table 6. Table 6: Selected Grade 3 and 4 Laboratory Abnormalities in Clinical Trials of DAKLINZA + Sofosbuvir ± Ribavirin, Studies ALLY-3, ALLY-2, and ALLY-1 Parameter Percent with Abnormality ALLY-3: HCV Genotype 3 DAKLINZA + Sofosbuvir n=152 ALLY-2: HCV/HIV-1 Coinfection DAKLINZA + Sofosbuvir n=153 ALLY-1: Child-Pugh A, B, or C with Cirrhosis and Post-transplant DAKLINZA + Sofosbuvir + Ribavirin n=113 a In the ALLY-2 trial, Grade 3 and 4 increases in total bilirubin were observed only in subjects receiving concomitant atazanavir. Hemoglobin (≤8.9 g/dL) 0 0 6% Alanine aminotransferase (ALT) increased (≥5.1 × ULN) 0 0 2% Aspartate aminotransferase (AST) increased (≥5.1 × ULN) 0 0 3% Total bilirubin increased (≥2.6 × ULN) 0 5% a 8% Lipase increased (≥3.1 × ULN) 2% 4% 4% 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of DAKLINZA. 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. Cardiac Disorders: Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with a sofosbuvir-containing regimen [ see Warnings and Precautions (5.3) and Drug Interactions (7.3) ].