Velpatasvir and Sofosbuvir

Sofosbuvir and velpatasvir is indicated for the treatment of adults and pediatric patients 3 years of age and older with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection [see Dosage and Administration (2.2 , 2.3 , 2.4 ) and Clinical Studies (14) ] : without cirrhosis or with compensated cirrhosis with decompensated cirrhosis for use in combination with ribavirin. Sofosbuvir and velpatasvir is a fixed-dose combination of sofosbuvir, a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor, and velpatasvir, an HCV NS5A inhibitor, and is indicated for the treatment of adults and pediatric patients 3 years of age and older with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection ( 1 ): without cirrhosis or with compensated cirrhosis with decompensated cirrhosis for use in combination with ribavirin.

Each sofosbuvir and velpatasvir tablet contains 400 mg of sofosbuvir and 100 mg of velpatasvir. The tablets are pink, diamond-shaped, film-coated, and debossed with "ASE" on one side and "9761" on the other side. Tablets: 400 mg of sofosbuvir and 100 mg of velpatasvir. ( 3 )

Sofosbuvir and velpatasvir and ribavirin combination regimen is contraindicated in patients for whom ribavirin is contraindicated. Refer to the ribavirin prescribing information for a list of contraindications for ribavirin [see Dosage and Administration (2.2 , 2.3 , 2.4) ]. Sofosbuvir and velpatasvir and ribavirin combination regimen is contraindicated in patients for whom ribavirin is contraindicated. ( 4 )

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 with amiodarone coadministration: Serious symptomatic bradycardia may occur in patients taking amiodarone, particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. Coadministration of amiodarone with sofosbuvir and velpatasvir is not recommended. In patients without alternative viable treatment options, cardiac monitoring is recommended. ( 5.2 , 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 immunosuppressants 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 sofosbuvir and velpatasvir. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with sofosbuvir and velpatasvir and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

5.2 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 sofosbuvir and velpatasvir is not recommended. For patients taking amiodarone who have no other alternative viable treatment options and who will be coadministered sofosbuvir and velpatasvir: 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 sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir 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) ] .

5.3 Risk of Reduced Therapeutic Effect Due to Concomitant Use of Sofosbuvir and Velpatasvir 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., rifampin, St. John's wort, carbamazepine) may significantly decrease plasma concentrations of sofosbuvir and/or velpatasvir, leading to potentially reduced therapeutic effect of sofosbuvir and velpatasvir. The use of these agents with sofosbuvir and velpatasvir is not recommended [see Drug Interactions (7.3) ] .

5.4 Risks Associated with Ribavirin and Sofosbuvir and Velpatasvir Combination Treatment If sofosbuvir and velpatasvir is administered with ribavirin, the warnings and precautions for ribavirin apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of the warnings and precautions for ribavirin [see Dosage and Administration (2.2) ].

The following serious adverse reactions are described below and elsewhere in labeling: Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see Warnings and Precautions (5.2) ]. The most common adverse reactions (incidence greater than or equal to 10%, all grades) observed in adults and pediatric subjects 6 years of age and older with treatment with sofosbuvir and velpatasvir for 12 weeks are headache and fatigue. ( 6.1 ) The most common adverse reactions (incidence greater than or equal to 10%, grade 1 or 2) observed in pediatric subjects less than 6 years of age are vomiting and product use issue (spitting up the drug). ( 6.1 ) The most common adverse reactions (incidence greater than or equal to 10%, all grades) observed with treatment with sofosbuvir and velpatasvir and ribavirin for 12 weeks in adult patients with decompensated cirrhosis are fatigue, anemia, nausea, headache, insomnia, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Asegua Therapeutics at 1-800-445-3235 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. If sofosbuvir and velpatasvir is administered with ribavirin, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions. Clinical Trials in Adult Subjects Adverse Reactions in Subjects without Cirrhosis or with Compensated Cirrhosis The adverse reactions data for sofosbuvir and velpatasvir in patients without cirrhosis or with compensated cirrhosis were derived from three Phase 3 clinical trials (ASTRAL-1, ASTRAL-2, and ASTRAL-3) which evaluated a total of 1035 subjects infected with genotype 1, 2, 3, 4, 5, or 6 HCV, without cirrhosis or with compensated cirrhosis, who received sofosbuvir and velpatasvir tablets (400 mg/100 mg) for 12 weeks. Sofosbuvir and velpatasvir were studied in placebo- and active-controlled trials [see Clinical Studies (14.2) ] . The proportion of subjects who permanently discontinued treatment due to adverse events was 0.2% for subjects who received sofosbuvir and velpatasvir for 12 weeks. The most common adverse reactions (adverse events assessed as causally related by the investigator and at least 10%) were headache and fatigue in subjects treated with sofosbuvir and velpatasvir for 12 weeks. Adverse reactions, all grades, observed in greater than or equal to 5% of subjects receiving 12 weeks of treatment with sofosbuvir and velpatasvir in ASTRAL-1 include headache (22%), fatigue (15%), nausea (9%), asthenia (5%), and insomnia (5%). Of subjects receiving sofosbuvir and velpatasvir who experienced these adverse reactions, 79% had an adverse reaction of mild severity (Grade 1). With the exception of asthenia, each of these adverse reactions occurred at a similar frequency or more frequently in subjects treated with placebo compared to subjects treated with sofosbuvir and velpatasvir (asthenia: 3% versus 5% for the placebo and sofosbuvir and velpatasvir groups, respectively). The adverse reactions observed in subjects treated with sofosbuvir and velpatasvir in ASTRAL-2 and ASTRAL-3 were consistent with those observed in ASTRAL-1. Irritability was also observed in greater than or equal to 5% of subjects treated with sofosbuvir and velpatasvir in ASTRAL-3. Adverse Reactions in Subjects Coinfected with HCV and HIV-1 The safety assessment of sofosbuvir and velpatasvir in subjects with HCV/HIV-1 coinfection was based on an open-label clinical trial (ASTRAL-5) in 106 subjects who were on stable antiretroviral therapy [see Clinical Studies (14.3) ] . The safety profile in HCV/HIV-1 coinfected subjects was similar to that observed in HCV mono-infected subjects. The most common adverse reactions occurring in at least 10% of subjects were fatigue (22%) and headache (10%). Adverse Reactions in Subjects with Decompensated Cirrhosis The safety assessment of sofosbuvir and velpatasvir in subjects infected with genotype 1, 2, 3, 4, or 6 HCV with decompensated cirrhosis was based on one Phase 3 trial (ASTRAL-4) including 87 subjects who received sofosbuvir and velpatasvir tablets (400 mg/100 mg) with ribavirin for 12 weeks. All 87 subjects had Child-Pugh B cirrhosis at screening. On the first day of treatment with sofosbuvir and velpatasvir with ribavirin, 6 subjects and 4 subjects were assessed to have Child-Pugh A and Child-Pugh C cirrhosis, respectively [see Clinical Studies (14.4) ] . The most common adverse reactions (adverse events assessed as causally related by the investigator, all grades with frequency of 10% or greater) in the 87 subjects who received sofosbuvir and velpatasvir with ribavirin for 12 weeks were fatigue (32%), anemia (26%), nausea (15%), headache (11%), insomnia (11%), and diarrhea (10%). Of subjects who experienced these adverse reactions, 98% had adverse reactions of mild to moderate severity. A total of 4 (5%) subjects permanently discontinued sofosbuvir and velpatasvir with ribavirin due to an adverse event; there was no adverse event leading to discontinuation that occurred in more than 1 subject. Decreases in hemoglobin to less than 10 g/dL and 8.5 g/dL during treatment were observed in 23% and 7% of subjects treated with sofosbuvir and velpatasvir with ribavirin for 12 weeks, respectively. Ribavirin was permanently discontinued in 17% of subjects treated with sofosbuvir and velpatasvir with ribavirin for 12 weeks, due to adverse reactions. Less Common Adverse Reactions Reported in Clinical Trials The following adverse reactions occurred in less than 5% of subjects without cirrhosis or with compensated cirrhosis treated with sofosbuvir and velpatasvir tablets (400 mg/100 mg) for 12 weeks and are included because of a potential causal relationship. Rash: In the ASTRAL-1 study, rash occurred in 2% of subjects treated with sofosbuvir and velpatasvir and in 1% of subjects treated with placebo. No serious adverse reactions of rash occurred, and all rashes were mild or moderate in severity. Depression: In the ASTRAL-1 study, depressed mood occurred in 1% of subjects treated with sofosbuvir and velpatasvir and was not reported by any subject taking placebo. No serious adverse reactions of depressed mood occurred, and all events were mild or moderate in severity. The following adverse reactions occurred in less than 10% of subjects with decompensated cirrhosis (ASTRAL-4) treated with sofosbuvir and velpatasvir with ribavirin for 12 weeks and are included because of a potential causal relationship. Rash: Rash occurred in 5% of subjects treated with sofosbuvir and velpatasvir with ribavirin. No serious adverse reactions of rash occurred, and all rashes were mild or moderate in severity. Laboratory Abnormalities Lipase Elevations: In ASTRAL-1, isolated, asymptomatic lipase elevations of greater than 3×ULN were observed in 3% and 1% of subjects treated with sofosbuvir and velpatasvir tablets (400 mg/100 mg) and placebo for 12 weeks, respectively; and in 6% and 3% of subjects treated with sofosbuvir and velpatasvir tablets (400 mg/100 mg) in ASTRAL-2 and ASTRAL-3, respectively. In the Phase 3 trial of subjects with decompensated cirrhosis (ASTRAL-4), lipase was assessed when amylase values were greater than or equal to 1.5×ULN. Isolated, asymptomatic lipase elevations of greater than 3×ULN were observed in 2% of subjects treated with sofosbuvir and velpatasvir tablets (400 mg/100 mg) with ribavirin for 12 weeks. […]

P-gp inducers and/or moderate to strong CYP inducers (e.g., rifampin, St. John's wort, carbamazepine): May decrease concentrations of sofosbuvir and/or velpatasvir. Use of sofosbuvir and velpatasvir with P-gp inducers and/or moderate to strong CYP inducers is not recommended. ( 5.3 , 7 ) Consult the full prescribing information prior to use for potential drug interactions. ( 5.2 , 5.3 , 7 ) Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact safe and effective use of concomitant medications. Frequent monitoring of relevant laboratory parameters (INR or blood glucose) and dose adjustments of certain concomitant medications may be necessary. ( 7.3 )

7.1 Potential for Other Drugs to Affect Sofosbuvir and Velpatasvir Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP while GS-331007 (the predominant circulating metabolite of sofosbuvir) is not. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed. Drugs that are inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., rifampin, St. John's wort, carbamazepine) may decrease plasma concentrations of sofosbuvir and/or velpatasvir, leading to reduced therapeutic effect of sofosbuvir and velpatasvir. The use of these agents with sofosbuvir and velpatasvir is not recommended [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ] . Sofosbuvir and velpatasvir may be coadministered with P-gp, BCRP, and CYP inhibitors.

7.2 Potential for Sofosbuvir and Velpatasvir to Affect Other Drugs Velpatasvir is an inhibitor of drug transporters P-gp, breast cancer resistance protein (BCRP), OATP1B1, OATP1B3, and OATP2B1. Coadministration of sofosbuvir and velpatasvir with drugs that are substrates of these transporters may increase the exposure of such drugs.

7.3 Established and Potentially Significant Drug Interactions Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies. Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment. Frequent monitoring of relevant laboratory parameters (e.g., International Normalized Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as cytochrome P450 substrates with a narrow therapeutic index (e.g., certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary. Table 4 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either sofosbuvir and velpatasvir tablets (400 mg/100 mg), or sofosbuvir and velpatasvir as individual agents, or are predicted drug interactions that may occur with sofosbuvir and velpatasvir [see Warnings and Precautions (5.2 , 5.3) and Clinical Pharmacology (12.3) ] . Table 4 Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction This table is not all inclusive. Concomitant Drug Class: Drug Name Effect on Concentration ↓ = decrease, ↑ = increase. Clinical Effect/Recommendation DF = disoproxil fumarate. Acid Reducing Agents: ↓ velpatasvir Velpatasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease concentration of velpatasvir. Antacids (e.g., aluminum and magnesium hydroxide) Separate antacid and sofosbuvir and velpatasvir administration by 4 hours. H 2 -receptor antagonists These interactions have been studied in healthy adults. (e.g., famotidine) H 2 -receptor antagonists may be administered simultaneously with or 12 hours apart from sofosbuvir and velpatasvir at a dose that does not exceed doses comparable to famotidine 40 mg twice daily. Proton-pump inhibitors (e.g., omeprazole) Coadministration of omeprazole or other proton-pump inhibitors is not recommended. If it is considered medically necessary to coadminister, sofosbuvir and velpatasvir should be administered with food and taken 4 hours before omeprazole 20 mg. Use with other proton-pump inhibitors has not been studied. Antiarrhythmics: amiodarone Effect on amiodarone, sofosbuvir, and velpatasvir concentrations unknown Coadministration of amiodarone with a sofosbuvir-containing regimen may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Coadministration of amiodarone with sofosbuvir and velpatasvir is not recommended; if coadministration is required, cardiac monitoring is recommended [see Warnings and Precautions (5.2) and Adverse Reactions (6.2) ]. digoxin ↑ digoxin Therapeutic concentration monitoring of digoxin is recommended when coadministered with sofosbuvir and velpatasvir. Refer to digoxin prescribing information for monitoring and dose modification recommendations for concentration increases of less than 50%. Anticancers: topotecan ↑ topotecan Coadministration is not recommended. Anticonvulsants: carbamazepine phenytoin phenobarbital ↓ sofosbuvir ↓ velpatasvir Coadministration is not recommended. Antimycobacterials: rifabutin rifampin rifapentine ↓ sofosbuvir ↓ velpatasvir Coadministration is not recommended. HIV Antiretrovirals: efavirenz ↓ velpatasvir Coadministration of sofosbuvir and velpatasvir with efavirenz-containing regimens is not recommended. Regimens containing tenofovir DF ↑ tenofovir Monitor for tenofovir-associated adverse reactions in patients receiving sofosbuvir and velpatasvir concomitantly with a regimen containing tenofovir DF. Refer to the prescribing information of the tenofovir DF-containing product for recommendations on renal monitoring. tipranavir/ritonavir ↓ sofosbuvir ↓ velpatasvir Coadministration is not recommended. Herbal Supplements: St. John's wort (Hypericum perforatum) ↓ sofosbuvir ↓ velpatasvir Coadministration is not recommended . HMG-CoA Reductase Inhibitors: rosuvastatin ↑ rosuvastatin Coadministration of sofosbuvir and velpatasvir with rosuvastatin may significantly increase the concentration of rosuvastatin, which is associated with increased risk of myopathy, including rhabdomyolysis. Rosuvastatin may be administered with sofosbuvir and velpatasvir at a dose that does not exceed 10 mg. atorvastatin ↑ atorvastatin Coadministration of sofosbuvir and velpatasvir with atorvastatin may be associated with increased risk of myopathy, including rhabdomyolysis. Monitor closely for HMG-CoA reductase inhibitor-associated adverse reactions, such as myopathy and rhabdomyolysis .

7.4 Drugs without Clinically Significant Interactions with Sofosbuvir and Velpatasvir Based on drug interaction studies conducted with sofosbuvir, velpatasvir, or sofosbuvir and velpatasvir tablets (400 mg/100 mg) no clinically significant drug interactions have been observed or are expected with the following drugs [see Clinical Pharmacology (12.3) ]: Sofosbuvir and velpatasvir: atazanavir/ritonavir, buprenorphine/naloxone, cyclosporine, darunavir/ritonavir, dolutegravir, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, emtricitabine, methadone, naltrexone, raltegravir, or rilpivirine. Sofosbuvir: ethinyl estradiol/norgestimate or tacrolimus. Velpatasvir: ethinyl estradiol/norgestimate, ketoconazole, or pravastatin. See Table 4 for use of sofosbuvir and velpatasvir with certain HIV antiretroviral regimens [see Drug Interactions (7.3) ] .

8.1 Pregnancy Risk Summary If sofosbuvir and velpatasvir 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 ribavirin-associated risks of use during pregnancy. No adequate human data are available to establish whether or not sofosbuvir and velpatasvir pose a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with sofosbuvir or velpatasvir at exposures greater than those in humans at the recommended human dose (RHD) [see Data ] . During organogenesis in the mouse, rat, and rabbit, systemic exposures (AUC) to velpatasvir were approximately 31 (mice), 6 (rats), and 0.4 (rabbits) times the exposure in humans at the RHD, while exposures to the predominant circulating metabolite of sofosbuvir (GS-331007) were approximately 4 (rats) and 10 (rabbits) times the exposure in humans at the RHD. In rat pre/postnatal development studies, maternal systemic exposures (AUC) to velpatasvir and GS-331007 were approximately 5 times the exposures of each component in humans at the RHD. 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 2–4% and 15–20%, respectively. Data Sofosbuvir: Sofosbuvir was administered orally to pregnant rats (up to 500 mg/kg/day) and rabbits (up to 300 mg/kg/day) on gestation days 6 to 18 and 6 to 19, respectively, and also to rats (oral doses up to 500 mg/kg/day) on gestation day 6 to lactation/post-partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested. The systemic exposures (AUC) of the predominant circulating metabolite of sofosbuvir (GS-331007) during gestation were approximately 4 (rats) and 10 (rabbits) times the exposure in humans at the RHD. Velpatasvir: Velpatasvir was administered orally to pregnant mice (up to 1000 mg/kg/day), rats (up to 200 mg/kg/day), and rabbits (up to 300 mg/kg/day) on gestation days 6 to 15, 6 to 17, and 7 to 20, respectively, and also to rats (oral doses up to 200 mg/kg) on gestation day 6 to lactation/post-partum day 20. No significant effects on embryo-fetal (mice, rats, and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested. The systemic exposures (AUC) of velpatasvir during gestation were approximately 31 (mice), 6 (rats), and 0.4 (rabbits) times the exposure in humans at the RHD.

8.2 Lactation Risk Summary It is not known whether sofosbuvir, velpatasvir, and their metabolites are present in human breast milk, affect human milk production, or have effects on the breastfed infant. The predominant circulating metabolite of sofosbuvir (GS-331007) was the primary component observed in the milk of lactating rats administered sofosbuvir, without effect on nursing pups. When administered to lactating rats, velpatasvir was detected in the milk of lactating rats and in the plasma of nursing pups without effects on the nursing pups [see Data ] . The development and health benefits of breastfeeding should be considered along with the mother's clinical need for sofosbuvir and velpatasvir and any potential adverse effects on the breastfed child from sofosbuvir and velpatasvir or from the underlying maternal condition. If sofosbuvir and velpatasvir 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 Sofosbuvir: No effects of sofosbuvir on growth and postnatal development were observed in nursing pups at the highest dose tested in rats. Maternal systemic exposure (AUC) to the predominant circulating metabolite of sofosbuvir (GS-331007) was approximately 5 times the exposure in humans at the RHD, with exposure of approximately 2% that of maternal exposure observed in nursing pups on lactation day 10. In a lactation study, sofosbuvir metabolites (primarily GS-331007) were excreted into the milk of lactating rats following administration of a single oral dose of sofosbuvir (20 mg/kg) on lactation day 2, with milk concentrations of approximately 10% that of maternal plasma concentrations observed 1-hour post-dose. Velpatasvir: No effects of velpatasvir on growth and postnatal development were observed in nursing pups at the highest dose tested in rats . Maternal systemic exposure (AUC) to velpatasvir was approximately 5 times the exposure in humans at the RHD. Velpatasvir was present in the milk (approximately 173% that of maternal plasma concentrations) of lactating rats following a single oral dose of velpatasvir (30 mg/kg), and systemic exposure (AUC) in nursing pups was approximately 4% that of maternal exposure on lactation day 10.

8.3 Females and Males of Reproductive Potential If sofosbuvir and velpatasvir 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 The pharmacokinetics, safety, and effectiveness of sofosbuvir and velpatasvir for treatment of HCV genotype 1, 2, 3, 4, or 6 infection in treatment-naïve and treatment-experienced pediatric patients 3 years of age and older without cirrhosis or with compensated cirrhosis have been established in an open-label, multicenter clinical trial (Study 1143, N=216; 190 treatment-naïve, 26 treatment-experienced). No clinically meaningful differences in pharmacokinetics were observed in comparison to those observed in adults. The safety and effectiveness in pediatric subjects were comparable to those observed in adults. However, among the 41 pediatric subjects less than 6 years of age, vomiting and product use issue (spitting up the drug) were reported more frequently (15% and 10%, respectively; all Grade 1 or 2) compared to subjects 6 years of age and older. Five subjects (12%) discontinued treatment after vomiting or spitting up the drug [see Dosage and Administration (2.4 , 2.5 ), Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.8) ]. The safety and effectiveness of sofosbuvir and velpatasvir for treatment of HCV genotype 5 in pediatric patients 3 years of age and older without cirrhosis or with compensated cirrhosis are supported by sofosbuvir, GS-331007, and velpatasvir exposures in adults and pediatric patients [see Dosage and Administration (2.2 and 2.4) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.8) ] . Similar rationale is used to support dosing recommendations for pediatric patients with HCV genotype 1, 2, 3, 4, 5, or 6 infection who have decompensated cirrhosis (Child-Pugh B or C). In patients with severe renal impairment, including those requiring dialysis, exposures of GS-331007, the inactive metabolite of sofosbuvir, are increased [see Clinical Pharmacology (12.3) ] . No data are available regarding the safety of sofosbuvir and velpatasvir in pediatric patients with renal impairment [see Use in Specific Populations (8.6) ]. The safety and effectiveness of sofosbuvir and velpatasvir have not been established in pediatric patients less than 3 years of age.

8.5 Geriatric Use Clinical trials of sofosbuvir and velpatasvir included 156 subjects aged 65 and over (12% of total number of subjects in the Phase 3 clinical trials). […]

Sofosbuvir and velpatasvir tablets (400 mg/100 mg) are a fixed-dose combination of sofosbuvir and velpatasvir, which are direct-acting antiviral agents against the hepatitis C virus [see Microbiology (12.4) ].