sofosbuvir 400 MG Oral Tablet [Sovaldi]

INDICATIONS AND USAGE VOSEVI is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have [see Dosage and Administration (2.2) and Clinical Studies (14) ]: genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with an HCV regimen containing an NS5A inhibitor. genotype 1a or 3 infection and have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor. Additional benefit of VOSEVI over sofosbuvir/velpatasvir was not shown in adults with genotype 1b, 2, 4, 5, or 6 infection previously treated with sofosbuvir without an NS5A inhibitor. VOSEVI is a fixed-dose combination of sofosbuvir, a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor, velpatasvir, an HCV NS5A inhibitor, and voxilaprevir, an HCV NS3/4A protease inhibitor, and is indicated for the treatment of adult patients with chronic HCV infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have ( 1 , 2.2 , 14 ): genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with an HCV regimen containing an NS5A inhibitor. genotype 1a or 3 infection and have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor. Additional benefit of VOSEVI over sofosbuvir/velpatasvir was not shown in adults with genotype 1b, 2, 4, 5, or 6 infection previously treated with sofosbuvir without an NS5A inhibitor.

DOSAGE AND ADMINISTRATION Testing prior to the initiation of therapy: Test all patients for HBV infection by measuring HBsAg and anti-HBc. ( 2.1 ) Recommended treatment regimen and duration in patients 3 years of age and older: ( 2.2 ) HCV Genotype Patient Population Regimen and Duration Genotype 1 Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 12 weeks Treatment-experienced without cirrhosis Ledipasvir and sofosbuvir 12 weeks Treatment-experienced with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 24 weeks Treatment-naïve and treatment-experienced with decompensated cirrhosis (Child-Pugh B or C) Ledipasvir and sofosbuvir + ribavirin 12 weeks Genotype 1 or 4 Treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis, or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir + ribavirin 12 weeks Genotype 4, 5, or 6 Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 12 weeks Recommended dosage in adults: One tablet (90 mg of ledipasvir and 400 mg of sofosbuvir) taken orally once daily with or without food. ( 2.3 ) Recommended dosage in pediatric patients 3 years and older: Recommended dosage of ledipasvir and sofosbuvir in pediatric patients 3 years of age and older is based on weight. Refer to Table 2 of the full prescribing information for specific dosing guidelines based on body weight. ( 2.4 ) Instructions for Use should be followed for preparation and administration of ledipasvir and sofosbuvir (HARVONI) oral pellets. ( 2.5 ) HCV/HIV-1 coinfection: For adult and pediatric patients with HCV/HIV-1 coinfection, follow the dosage recommendations in the tables in the full prescribing information. ( 2.3 , 2.4 ) If used in combination with ribavirin, follow the recommendations for ribavirin dosing and dosage modifications. ( 2.3 , 2.4 ) For patients with any degree of renal impairment, including end stage renal disease on dialysis, no ledipasvir and sofosbuvir dosage adjustment is recommended. ( 2.6 ) 2.1 Testing Prior to the Initiation of Therapy Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with ledipasvir and sofosbuvir [see Warnings and Precautions (5.1) ] . 2.2 Recommended Treatment Regimen and Duration in Patients 3 Years of Age and Older with Genotype 1, 4, 5, or 6 HCV Table 1 shows the recommended ledipasvir and sofosbuvir treatment regimen and duration based on patient population . Relapse rates are affected by baseline host and viral factors and differ between treatment durations for certain subgroups [see Clinical Studies (14) ]. For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 1 [see Clinical Studies (14) ]. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs. Table 1 Recommended Treatment Regimen and Duration for Ledipasvir and Sofosbuvir in Patients 3 Years of Age and Older with Genotype 1, 4, 5, or 6 HCV HCV Genotype Patient Population Treatment Regimen and Duration Genotype 1 Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 12 weeks Ledipasvir and sofosbuvir for 8 weeks can be considered in treatment-naïve genotype 1 patients without cirrhosis who have pretreatment HCV RNA less than 6 million IU/mL [see Clinical Studies (14.2) ] . Treatment-experienced Treatment-experienced adult and pediatric subjects have failed a peginterferon alfa +/- ribavirin based regimen with or without an HCV protease inhibitor. without cirrhosis Ledipasvir and sofosbuvir 12 weeks Treatment-experienced with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 24 weeks Ledipasvir and sofosbuvir + ribavirin for 12 weeks can be considered in treatment-experienced genotype 1 patients with cirrhosis who are eligible for ribavirin [see Dosage and Administration (2.3 and 2.4) and Clinical Studies (14.2) ] . Treatment-naïve and treatment-experienced with decompensated cirrhosis (Child-Pugh B or C) Ledipasvir and sofosbuvir + ribavirin See Dosage and Administration 2.3 and 2.4 for ribavirin dosage recommendations. 12 weeks Genotype 1 or 4 Treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis, or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir + ribavirin 12 weeks Genotype 4, 5, or 6 Treatment-naïve and treatment-experienced , without cirrhosis or with compensated cirrhosis (Child-Pugh A) Ledipasvir and sofosbuvir 12 weeks 2.3 Recommended Dosage in Adults The recommended dosage of ledipasvir and sofosbuvir in adults with genotype 1, 4, 5 or 6 HCV is one tablet (90 mg ledipasvir and 400 mg sofosbuvir) taken orally once daily with or without food [see Clinical Pharmacology (12.3) ] . The daily dosage of ribavirin is weight-based (1000 mg for patients <75 kg and 1200 mg for those ≥75 kg) administered orally in two divided doses with food. In patients with decompensated cirrhosis, the starting dosage of ribavirin is 600 mg and can be titrated up to 1000 mg for patients <75 kg and 1200 mg for those ≥75 kg in two divided doses with food. If the starting dosage of ribavirin is not well tolerated, the dosage should be reduced as clinically indicated based on hemoglobin levels. For further information on ribavirin dosing and dosage modifications, refer to the ribavirin prescribing information [see Dosage and Administration (2.4) , Use in Specific Populations (8.6) , and Clinical Studies (14.5) ] . 2.4 Recommended Dosage in Pediatric Patients 3 Years of Age and Older The recommended dosage of ledipasvir and sofosbuvir in pediatric patients 3 years of age and older with genotype 1, 4, 5, or 6 HCV is based on weight (Table 2). Table 3 provides the weight-based dosage of ribavirin when used in combination with ledipasvir and sofosbuvir for pediatric patients. Take ledipasvir and sofosbuvir (with or without food) once daily [see Dosage and Administration (2.5) , Clinical Pharmacology (12.3) , and Clinical Studies (14.7) ] . Ledipasvir and sofosbuvir (HARVONI) oral pellets can be taken in pediatric patients who cannot swallow the tablet formulation. Table 2 Dosing for Pediatric Patients 3 Years and Older Body Weight (kg) Dosing of Ledipasvir and Sofosbuvir Ledipasvir and Sofosbuvir Daily Dose at least 35 one Ledipasvir and Sofosbuvir 90 mg/400 mg tablet once daily or two Ledipasvir and Sofosbuvir (HARVONI) 45 mg/200 mg tablets once daily or two 45 mg/200 mg packets of Ledipasvir and Sofosbuvir (HARVONI) oral pellets once daily 90 mg/400 mg per day 17 to less than 35 one Ledipasvir and Sofosbuvir (HARVONI) 45 mg/200 mg tablet once daily or one 45 mg/200 mg packet of Ledipasvir and Sofosbuvir (HARVONI) oral pellets once daily 45 mg/200 mg per day less than 17 one 33.75 mg/150 mg packet of Ledipasvir and Sofosbuvir (HARVONI) oral pellets once daily 33.75 mg/150 mg per day Table 3 Recommended Dosing for Ribavirin in Combination Therapy with Ledipasvir and Sofosbuvir for Pediatric Patients 3 Years and Older Body Weight (kg) Oral Ribavirin Daily Dosage The daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food. less than 47 15 mg per kg per day (divided dose AM and PM) 47–49 600 mg per day (1 × 200 mg AM, 2 × 200 mg PM) 50–65 800 mg per day (2 × 200 mg AM, 2 × 200 mg PM) 66–80 1000 mg per day (2 × 200 mg AM, 3 × 200 mg PM) greater than 80 1200 mg per day (3 × 200 mg AM, 3 × 200 mg PM) 2.5 Preparation and Administration of Ledipasvir and Sofosbuvir (HARVONI) Oral Pellets See the ledipasvir and sofosbuvir (HARVONI) oral pellets full Instructions for Use for details on the preparation and administration of ledipasvir and sofosbuvir (HARVONI) pellets. Do not chew ledipasvir and sofosbuvir (HARVONI) oral pellets. If ledipasvi

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 ) Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver Disease: Hepatic decompensation/failure, including fatal outcomes, have been reported mostly in patients with cirrhosis and baseline moderate or severe liver impairment (Child-Pugh B or C) treated with HCV NS3/4A protease inhibitor-containing regimens. Monitor for clinical and laboratory evidence of hepatic decompensation. Discontinue VOSEVI in patients who develop evidence of hepatic decompensation/failure. ( 5.2 ) Bradycardia with Amiodarone Coadministration: Serious symptomatic bradycardia may occur in patients taking amiodarone with VOSEVI, 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 VOSEVI is not recommended. In patients without alternative viable treatment options, cardiac monitoring is recommended. ( 5.3 , 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 VOSEVI. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with VOSEVI and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. 5.2 Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver Disease Postmarketing cases of hepatic decompensation/failure, including those with fatal outcomes, have been reported in patients treated with HCV NS3/4A protease inhibitor-containing regimens, including treatment with VOSEVI. Reported cases occurred in patients with baseline cirrhosis with and without moderate or severe liver impairment (Child-Pugh B or C). 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. In patients with compensated cirrhosis (Child-Pugh A) or evidence of advanced liver disease such as portal hypertension, perform hepatic laboratory testing as clinically indicated; and monitor for signs and symptoms of hepatic decompensation such as the presence of jaundice, ascites, hepatic encephalopathy, and variceal hemorrhage. Discontinue VOSEVI in patients who develop evidence of hepatic decompensation/failure. VOSEVI is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh B or C) or those with any history of prior hepatic decompensation [see Dosage and Administration (2.4) , Adverse Reactions (6.2) , Use in Specific Populations (8.7) , and Clinical Pharmacology (12.3) ] . 5.3 Serious Symptomatic Bradycardia When Coadministered with Amiodarone Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with a sofosbuvir-containing regimen. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir-containing regimen (HARVONI ® (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 effect is unknown. Coadministration of amiodarone with VOSEVI is not recommended. For patients taking amiodarone who have no other alternative viable treatment options and who will be coadministered VOSEVI: Counsel patients about the risk of symptomatic bradycardia. Cardiac monitoring in an in-patient 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 VOSEVI who need to start amiodarone therapy due to no other alternative viable treatment options should undergo similar cardiac monitoring as outlined above. Due to amiodarone's long half-life, patients discontinuing amiodarone just prior to starting VOSEVI 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 pains, confusion, or memory problems [see Adverse Reactions (6.2) and Drug Interactions (7.3) ]. 5.4 Risk of Reduced Therapeutic Effect Due to Concomitant Use of VOSEVI with Inducers of P-gp and/or Moderate to Strong Inducers of CYP Drugs that are inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., St. John's wort, carbamazepine) may significantly decrease plasma concentrations of sofosbuvir, velpatasvir, and/or voxilaprevir, leading to potentially reduced therapeutic effect of VOSEVI. The use of these agents with VOSEVI is not recommended [see Drug Interactions (7.3) ].

CONTRAINDICATIONS When SOVALDI is used in combination with ribavirin or peginterferon alfa/ribavirin, the contraindications applicable to those agents are applicable to combination therapies. Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their contraindications. When used in combination with peginterferon alfa/ribavirin or ribavirin alone, all contraindications to peginterferon alfa and/or ribavirin also apply to SOVALDI combination therapy. ( 4 )

Mechanism of Action Ledipasvir and sofosbuvir tablets (90 mg/400 mg) are a fixed-dose combination of ledipasvir and sofosbuvir, which are direct-acting antiviral agents against the hepatitis C virus [see Microbiology (12.4) ].