Sovaldi

Common name: Sofosbuvir tablets

Trade name: SOVALDI

All names: Sofosbuvir, Sofosbuvir, Sofosbuvir, Sofosbuvir, MyHep, Hepcinat, Sofovi r

[Ingredients of sofosbuvir]

The main ingredient of sofosbuvir is sofosbuvir, and its chemical name is: (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2) ,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamine)propionate

Chemical structural formula:

Molecular formula: C22H29FN3O9P

Molecular weight: 529.45

[Indications of Sofosbuvir]

Sofosbuvir is suitable for use in combination with other drugs to treat chronic hepatitis C virus (HCV) infection in adults and adolescents aged 12 to 18 years old.

[Sofosbuvir Dosage]

Sofosbuvir treatment should be implemented and monitored by physicians with extensive experience in the management of patients with chronic HCV infection.

Dosage

Adults

The recommended dose is one 400 mg tablet taken orally once daily with food.

Sovalid should be used in combination with other drugs. Monotherapy is not recommended. Also see prescribing information for medicines used with Sovaldi. Recommended concomitant medications and treatment duration for Sowardid combination therapy.

Recommended co-medications and treatment durations for Sovaldi combination therapy in adults

*Includes patients co-infected with human immunodeficiency virus (HIV).

a. There is no overseas Phase 3 data for patients with HCV genotype 1 infection who have previously received treatment. Data are available for Chinese subjects receiving the combination of Sovaldi, ribavirin, and peginterferon alfa (see [Precautions] and [Clinical Studies]) Clinical efficacy and safety in Chinese adult patients with chronic HCV genotype 1, 2, 3, or 6 infection. ” section).

b. Consideration should be given to the potential for extended treatment duration beyond 12 weeks and up to 24 weeks; particularly in patients with one or more factors that have been associated with lower response rates to interferon-based therapies (e.g., advanced fibrosis/cirrhosis, baseline viral concentration High, black race, IL28B non-CC genotype, and previous failure to respond to peginterferon alfa and ribavirin treatment) subgroups.

c. See below for Special Patient Populations—Patients Awaiting Liver Transplantation.

When used in combination with Sovaldi, the dose of ribavirin needs to be based on body weight (<75kg=1000mg, ≥75kg=1200mg), and this dose needs to be divided into two times and taken orally with food.

For information on coadministration with other direct-acting antiviral drugs for HCV, see [Precautions ] section.

Adult Dose Adjustment

Dose reduction of Sovaldi is not recommended.

If sofosbuvir is used concomitantly with peginterferon alfa and the patient experiences serious adverse reactions that may be related to the drug, the dose of peginterferon alfa should be reduced or use should be discontinued. For additional information on how to reduce and/or discontinue peginterferon alfa administration, see Peginterferon alfa Prescribing Information.

If the patient experiences serious adverse reactions that may be related to ribavirin, the dose of ribavirin should be adjusted or the drug should be discontinued (if appropriate) until the adverse reaction resolves or decreases in severity. Table 2 provides guidelines for dose adjustment and discontinuation based on the patient's hemoglobin concentration and cardiac functional status.

After ribavirin is discontinued due to laboratory abnormalities or clinical manifestations, attempts can be made to restart ribavirin at a dose of 600 mg per day and further increase the dose to 800 mg per day. However, increasing ribavirin to the originally specified dose (1000 mg to 1200 mg daily) is not recommended.

Children

Between 12 andIn adolescents <18 years of age, the recommended dose of Sovaldi is one 400 mg tablet taken by mouth once daily with food.

Sovalid should be used in combination with other drugs. Monotherapy is not recommended. The recommended treatment regimen and duration of Sowardid combination therapy are shown in Tables 3 and 4.

Recommended treatment regimen and duration for adolescents 12 to <18 years of age receiving Sovaldi

Dosing recommendations for combination therapy with ribavirin and Sovaldi in adolescents 12 to <18 years of age

*The daily dose of ribavirin is based on body weight and should be taken orally in two divided doses with food.

Dose Adjustment in the Pediatric Population

Dosage reduction of Sovaldi is not recommended.

If a patient experiences a serious adverse reaction that may be related to ribavirin, the ribavirin dose should be adjusted or, if appropriate, discontinued until the adverse reaction resolves or decreases in severity. For guidelines on dose adjustment or discontinuation of ribavirin, see the ribavirin prescribing information.

Discontinuation in Adults and Adolescents

Sovaldi should also be discontinued if other medicines being used with Sovaldi are discontinued (see Precautions).

Special Patient Populations

Geriatric

For elderly patients, no dose adjustment is necessary (see [Pharmacokinetics]).

Renal Impairment

No dose adjustment of Sovaldi is required in patients with mild or moderate renal impairment. The safety and appropriate dosage of Sovaldi has not been established in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) or in patients with end-stage renal disease (ESRD) requiring hemodialysis (see Pharmacokinetics).

Hepatic Impairment

In patients with mild, moderate, or severe hepatic impairment (Child-Pugh-Turcotte [CPT] class A, B, or C), no dose adjustment of Sovaldi is required (see Pharmacokinetics). The safety and efficacy of Sovaldi in patients with decompensated cirrhosis have not been established.

Patients waiting for liver transplantation

Patients waiting for liver transplantation should evaluate the benefits and risks of medication based on their personal conditions to guide Sovaldi's medication course.

Liver transplant recipients

In liver transplant recipients, the recommended combined duration of Sovaldi and ribavirin is 24 weeks. The recommended starting dose of ribavirin is 400 mg taken orally in two divided doses with food. If the initial dose of ribavirin is well tolerated, the dose can be titrated up to 1,000 to 1,200 mg daily (1,000 mg for patients weighing <75 kg; 1,200 mg for patients weighing ≥75 kg). If the initial dose of ribavirin is not tolerated, the dose should be reduced as clinically indicated based on hemoglobin levels.

Pediatric Population

The safety and efficacy of Sovaldi in children and adolescent patients under 18 years of age have not been established.

Dosage

Film-coated tablets are suitable for oral administration. Patients should be instructed to swallow the tablets whole. Because the active ingredient tastes bitter, the film-coated tablets should not be chewed or crushed. This tablet should be taken with food.

Patients should be instructed to take another tablet if vomiting occurs within 2 hours of taking the drug. If vomiting occurs more than 2 hours after taking the medicine, no additional dose is needed. These recommendations are based on the absorption kinetics of sofosbuvir and GS331007, which indicate that most of the dose is absorbed within 2 hours of administration.

If a dose is missed but within 18 hours of the normal dosing time, the patient should be instructed to take the tablet as soon as possible, and then the patient should take the next dose at the usual dosing time. If more than 18 hours have passed, the patient should be instructed to wait until the usual dosing time for the next dose. Patients should be instructed not to take double the dose.

[Adverse reactions of Sowardid]

Summary of adult sexual characteristics in foreign clinical studies

The most commonly reported adverse drug reactions during treatment of sofosbuvir with ribavirin or with pegylated interferon alfa and ribavirin were consistent with those expected during treatment with ribavirin and pegylated interferon alfa, with no increase in the frequency or severity of expected adverse drug reactions.

The assessment of adverse reactions is based on the summary data of five foreign phase 3 clinical studies (including controlled studies and uncontrolled studies).

After receiving placebo, 12 weeks of sofosbuvir + ribavirin, 16 weeks of sofosbuvir XxX ribavirin, 24 weeks of peginterferon alfa XxX ribavirin, and 12 weeks of sofosbuvir Among the subjects treated with XxX peginterferon αXxX ribavirin, the proportions of subjects who discontinued treatment due to adverse reactions were 1.4%, 0.5%, 0%, 11.1% and 2.4% respectively.

Summary table of adverse reactions in adults in foreign clinical studies

The combination of Sovaldi and ribavirin (with or without peginterferon α) was mainly studied. In this case, no adverse drug reactions specific to sofosbuvir were identified. Among subjects receiving sofosbuvir XxX ribavirin or sofosbuvir XxX ribavirin XxX pegylated interferon alfa, the most common adverse drug reactions were fatigue, headache, nausea and insomnia.

In the combined treatment of sofosbuvir XxX ribavirin or sofosbuvir XxX pegylated interferon αXxX ribavirin, the following adverse drug reactions were found (Table 5). Adverse reactions are listed below according to body system organ classification and frequency of occurrence. Frequencies were defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), or extremely rare (<1/10000).

Summary of sexual characteristics in Chinese adult patients with chronic HCV infection

In Chinese subjects infected with HCV, the sexual characteristics of sofosbuvir combined with ribavirin or peginterferon alfa and ribavirin were basically similar to those observed in foreign phase 3 clinical studies.

Among HCV-infected Chinese subjects, the proportion of subjects who discontinued treatment due to adverse events (regardless of causality) was lower: after receiving 12 weeks of sofosbuvir This proportion was 1.6% (1/64), 0.5% (1/195), and 0.8% (1/130) of subjects treated with bavirin and 12 weeks of sofosbuvir XxX pegylated interferon alfa XxX ribavirin, respectively.

The most commonly reported adverse events during treatment with sofosbuvir plus ribavirin or with pegylated interferon alfa and ribavirin were generally consistent with the expected characteristics during treatment with pegylated interferon alfa and ribavirin.

During 12 weeks of co-administration of sofosbuvir and ribavirin, the most common treatment-related adverse events were as follows: increased reticulocyte count (21.9%, 14/64 subjects), anemia (10.9%, 7/64 subjects), and decreased hemoglobin (10.9%, 7/64 subjects).

During 24 weeks of co-administration of sofosbuvir and ribavirin, the most common treatment-related adverse events were as follows: increased reticulocyte count (16.4%, 32/195 subjects), increased blood bilirubin (16.9%, 33/195 subjects), and anemia (10.3%, 20/195 subjects).

During 12 weeks of co-administration of sofosbuvir with peginterferon alfa and ribavirin, the most common treatment-related adverse events were as follows: pyrexia (35.4%, 46/130 subjects), decreased platelet count (26.9%, 35/130 subjects), Decreased neutrophil count (26.9%, 35/130 subjects), decreased white blood cell count (24.6%, 32/130 subjects), leukopenia (20.8%, 27/130 subjects), anemia (18.5%, 24/130 subjects), neutropenia (16.9%, 22/130 subjects), myalgia (14.6%, 19/130 subjects), fatigue (13.8%, 18/130 subjects), asthenia (13.8%, 18/130 subjects) ), decreased hemoglobin (13.8%, 18/130 subjects), headache (13.1%, 17/130 subjects), dizziness (10.0%, 13/130 subjects) and thrombocytopenia (10.0%, 13/130 subjects).

Other Special Populations

HIV/HCV Co-infection

The sexual characteristics of sofosbuvir XxX ribavirin in subjects co-infected with HCV/HIV were similar to those observed in Phase 3 clinical studies in subjects infected only with HCV who received sofosbuvir XxX ribavirin.

Patients awaiting liver transplantation

The sexual characteristics of sofosbuvir XXxribavirin in adult subjects with HCV infection prior to liver transplantation were similar to those observed in subjects receiving sofosbuvir XXXribavirin in a Phase 3 clinical study.

Liver transplant recipients

In adult liver transplant recipients with chronic hepatitis C virus infection, the sexual characteristics of sofosbuvir and ribavirin were similar to those observed in subjects treated with sofosbuvir and ribavirin in a Phase 3 clinical study. In Study 0126, hemoglobin decreases during treatment were common, with 32.5% of subjects (13/40 subjects) having hemoglobin decreases to <10 g/dL, including 1 to <8.5 g/dL. Eight subjects (20%) received epoetin and/or blood products. Study drug was discontinued, adjusted, or interrupted due to adverse events in 5 subjects (12.5%).

Pediatric Population

The safety and efficacy of Sovaldi in adolescents 12 to <18 years of age are based on data from 50 patients who received 12 weeks (genotype 2 patients) and 24 weeks (genotype 3 patients) of SovaldiXxX ribavirin in a Phase 2 open-label clinical trial. The adverse reactions observed were consistent with those observed in adult clinical studies of SovaldiXxX ribavirin (see Table 5).

Description of selected adverse reactions

Cardiac arrhythmias

Severe bradycardia and heart block have been observed when sofosbuvir was given with another DAA (including daclatasvir, simeprevir, and ledipasvir) and the co-medicine amiodarone and/or other drugs that reduce heart rate (see Precautions and Drug Interactions).

Reporting of suspected adverse reactions

It is very important to report suspected adverse reactions after a drug is approved for marketing. This allows continuous monitoring of the benefit/risk balance of use of the medicinal product. In China, healthcare professionals are required to report any suspected adverse reactions through a national reporting system.

[Sowardy Contraindications]

Allergic to the active ingredient or any of the excipients listed below:

Tablet core: mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate.

Film coating: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide yellow.

Combined use with potent P-gp inducers

Pharmaceuticals that are potent intestinal P-glycoprotein (P-gp) inducers (rifampicin, rifabutin, St. John's wort [Hypericumperforatum], carbamazepine, phenobarbital, and phenytoin). Coadministration significantly decreases sofosbuvir plasma concentrations and may result in loss of efficacy of Sovaldi (see Drug Interactions).

[Precautions for Sovaldi]

Overview

It is not recommended to administer Sovaldi as a monotherapy and should be used in combination with other drugs to treat hepatitis C infection. If other medicinal products used with Sovaldi are discontinued, Sovaldi should also be discontinued (see Dosage and Administration). Before starting treatment with Sovaldi, check the prescribing information for the co-prescribed medicine.

Severe bradycardia and heart block

Severe bradycardia and heart block have been observed when sofosbuvir was given with another direct-acting antiviral (DAA, including daclatasvir, simeprevir, and ledipasvir) and the concomitant drug amiodarone (with or without other drugs that lower the heart rate). The mechanism has not yet been determined.

During the entire clinical development process of sofosbuvir plus DAA, the combined use of amiodarone was restricted. The above conditions can be life-threatening, so amiodarone should only be used in patients receiving Sovaldi and another DAA if other alternative antiarrhythmic treatments are intolerable or contraindicated. The risk of symptomatic bradycardia may be increased when coadministered with amiodarone in patients who are also taking beta-blockers or who have underlying cardiac comorbidities and/or advanced liver disease.

If coadministration of amiodarone is deemed necessary, close patient monitoring is recommended when initiating treatment with Sovaldi and another DAA. Patients identified as being at higher risk for bradyarrhythmias should be monitored continuously for 48 hours in an appropriate clinical setting.

Due to the long half-life of amiodarone, patients who have discontinued amiodarone within the past few months and are about to start Sovaldi in combination with another DAA should also be appropriately monitored.

In addition, all patients receiving Sovaldi and another DAA in combination with amiodarone, with or without other drugs that reduce heart rate, should be alerted to the symptoms of bradycardia and heart block and should be advised to seek immediate medical attention if such symptoms occur.

Treated patients with HCV genotypes 1, 4, 5 and 6 infection

Sovaldi has not been studied in patients with previously treated HCV genotypes 1, 4, 5 and 6 infections in any foreign Phase 3 study. Therefore, the duration of treatment in this population has not been established (see also [Dosage and Administration]). When treating such patients, it should be considered that the duration of treatment with sofosbuvir, peginterferon alfa, and ribavirin may extend beyond 12 weeks and up to 24 weeks; particularly in those subgroups with one or more factors previously associated with lower response rates to interferon-containing therapies (advanced fibrosis/cirrhosis, high baseline viral concentrations, black race, IL28B non-CC genotype).

In the Phase 3b study GS-US-334-0115, the SVR12 rate was 90.4% (47/52) in treatment-experienced Chinese genotype 1 or 6 HCV-infected patients receiving 12 weeks of Sovaldi, peginterferon, and ribavirin (see [Clinical Studies]).

Treatment of patients with HCV genotype 5 or 6 infection

There are limited clinical data supporting Sovaldi treatment in patients with genotype 5 and 6 HCV infection.

Interferon-free treatment for HCV genotypes 1, 4, 5 and 6 infections

The interferon-free Sovaldi treatment regimen has not been studied in patients with genotype 1, 4, 5 and 6 HCV infection in foreign phase 3 studies. The regimen and duration of treatment have not yet been determined. These treatment options should be used only in patients who are intolerant or unsuitable for interferon therapy and in patients in urgent need of treatment. In the Phase 3b study GS-US-334-0115, Chinese patients with HCV genotype 1 or 6 infection who received 24 weeks of Sovaldi and ribavirin had a combined SVR12 rate of 95.7% (66/69) (see [Clinical Studies]).

Co-administration with other direct-acting antiviral drugs against HCV

Sovaldi should only be used in combination with other direct-acting antiviral drugs if the benefits outweigh the risks based on available data. There are no data to support the use of Sovaldi in combination with telaprevir or boceprevir. Such coadministration is not recommended (see also [Drug Interactions]).

Pregnancy and combined use with ribavirin

When Sovaldi is coadministered with ribavirin or peginterferon alfa/ribavirin, women of childbearing potential and their male partners must use the contraceptive measures recommended in the ribavirin prescribing information during and for a period after treatment. For additional information, see Prescribing Information for ribavirin.

Combined use with moderate P-gp inducers

Intestinal moderate Pgp inducer drugs (such as oxcarbazepine and modafinil) may reduce the plasma concentration of sofosbuvir, resulting in a reduction in the efficacy of Sovaldi. The concomitant use of these medicines is not recommended while using Sovaldi (see Drug Interactions).

Renal Impairment

The safety of Sovaldi has not been evaluated in subjects with severe renal impairment (eGFR<30mL/min/1.73m2) or ESRD requiring hemodialysis. Additionally, appropriate dosage has not yet been established. For patients with creatinine clearance (CrCl) <50 mL/min, also see prescribing information for ribavirin when using Sovaldi in combination with ribavirin or peginterferon alfa/ribavirin (see also Pharmacokinetics).

HCV/HBV (hepatitis B virus) co-infection

Reactivation cases of hepatitis B virus (HBV) during or after treatment with direct-acting antivirals have been reported, with individual reports of fatal cases. All patients should be screened for HBV before starting treatment. HBV/HCV co-infected patients are at risk for HBV reactivation and should therefore be monitored and managed according to current clinical guidelines.

Pediatric Population

Sovaldi is not recommended for use in pediatric patients <12 years of age as the safety and efficacy of the drug in these populations have not been established.

[Sovaldi use in pregnant and lactating women]

Females of childbearing potential/male and female contraception

Use extreme caution when coadministering Sovaldi with ribavirin or peginterferon alfa/ribavirin to avoid pregnancy in female patients and the female partners of male patients. Significant teratogenic and/or embryonic effects have been demonstrated in various animals exposed to ribavirin (see Precautions). Women of childbearing potential and their male partners must use contraceptive measures as recommended in the ribavirin prescribing information during treatment and for a period after treatment. For additional information, see Prescribing Information for ribavirin.

Pregnancy

There are no or very limited data on the use of sofosbuvir in pregnant women (less than 300 pregnancy outcomes).

Animal studies have shown no direct or indirect harmful effects on reproductive toxicity. No effects on fetal development were observed in rats and rabbits at the doses tested. However, the margin ratio of sofosbuvir exposure achieved in rats cannot be adequately estimated relative to human exposure at recommended clinical doses.

As a precautionary measure, avoid use of Sovaldi during pregnancy.

However, the same contraindications for ribavirin during pregnancy apply when ribavirin is given concomitantly with sofosbuvir (see also Ribavirin Prescribing Information).

Lactation

It is unknown whether sofosbuvir and its metabolites are excreted in human milk.

The resulting animal pharmacokinetic data showed that the metabolite was secreted into milk.

Risk to newborns or infants cannot be excluded. Therefore, Sovaldi should not be used during breastfeeding.

Fertility

There are no data on the effects of Sovaldi on human fertility. Animal studies have not shown harmful effects on fertility.

[Sovaldi Pediatric Medication]

The safety and efficacy of Sovaldi in children and adolescent patients under 18 years of age have not been determined.

[Sowardid for the Elderly]

The foreign clinical study of sofosbuvir included 65 subjects aged 65 years and above. Across treatment groups, response rates in subjects older than 65 years were similar to those in younger subjects.

[Sovaldi drug interactions]

Sofosbuvir is a nucleotide prodrug. After oral administration of Sovaldi, sofosbuvir is rapidly absorbed and undergoes extensive hepatic and intestinal first-pass metabolism. Hydrolytic cleavage of intracellular prodrugs catalyzed by enzymes such as carboxylesterase 1 and sequential phosphorylation steps catalyzed by nucleotide kinases form the pharmacologically active uridine nucleoside analogue triphosphate. More than 90% of systemic exposures to drug-related substances are from the major inactive circulating metabolite GS331007, which is produced via metabolic pathways that are parallel and sequential to the formation of active metabolites. Parent sofosbuvir accounts for approximately 4% of systemic exposure to drug-related substances (see Pharmacokinetics). In clinical pharmacology studies, both sofosbuvir and GS331007 were monitored for pharmacokinetic analysis purposes.

Sofosbuvir is a substrate of the drug transporter Pgp and breast cancer resistance protein (BCRP), but GS331007 is not.

Intestinal potent Pgp inducer drugs (rifampicin, rifabutin, St. John's wort, carbamazepine, phenobarbital and phenytoin) may significantly reduce the plasma concentration of sofosbuvir, resulting in a reduction in the efficacy of Sovaldi, so such drugs should be prohibited when using Sovaldi (see [Contraindications]). Drugs that are moderate intestinal Pgp inducers (such as oxcarbazepine and modafinil) may reduce the plasma concentration of sofosbuvir, resulting in reduced efficacy of Sovaldi. The concomitant use of these medicines is not recommended when using Sovaldi (see Precautions). Co-administration of Sovaldi with drugs that inhibit Pgp and/or BCRP may increase the plasma concentration of sofosbuvir but not the plasma concentration of GS331007. Therefore, Sovaldi can be co-administered with Pgp and/or BCRP inhibitors. Neither sofosbuvir nor GS331007 is an inhibitor of Pgp or BCRP, and therefore is not expected to increase exposure to drugs that are substrates of these transporters.

The intracellular metabolic activation pathways of sofosbuvir are mediated by hydrolases and nucleotide phosphorylation pathways that generally have low affinity and high activity, and these pathways are unlikely to be affected by co-administered drugs (see [Pharmacokinetics]).

Patients receiving vitamin K antagonists

Because liver function may change during treatment with Sovaldi, close monitoring of the international normalized ratio (INR) is recommended.

Other Interactions

Information on drug interactions between Sovaldi and possible co-administered medicinal products is summarized in Table 4 below (where the 90% confidence intervals (CI) for the geometric mean of least squares (GLSM) ratios are marked below, within the predetermined equivalence interval with "?", "↑" above, or "↓" below). This table is not all-inclusive.

Interactions between Sovaldi and other drugs

a. Pharmacokinetic mean ratios (90% CI) of co-administered drugs with/without sofosbuvir, and mean ratios of sofosbuvir and GS331007 with/without co-administered drugs. No effect = 1.00

b. All interaction studies were conducted in healthy volunteers

c. Comparison based on historical controls

d. Atripla administered

e. Bioequivalence range is 80% to 125%

f. The range of equivalence is 70% to 143%

[Sofosbuvir overdose]

The recorded sofosbuvir dose was a single supratherapeutic dose of 1200 mg sofosbuvir given to 59 healthy subjects. In this study, no adverse effects were observed at this dose level, and the frequency and severity of adverse effects were similar to those reported with placebo and sofosbuvir 400 mg treatment groups. The effects of higher doses are unknown.

There is no specific antidote for Sovaldi overdose. If overdose occurs, the patient must be monitored for signs of toxicity. Treatment of Sovaldi overdose requires basic supportive measures, including monitoring of vital signs and observation of the patient's clinical status. Hemodialysis can remove (extraction rate 53%) the main circulating metabolite GS331007. 4 hours of hemodialysis can remove 18% of the administered dose.

[Sowardid Clinical Trial]

Clinical efficacy and safety in foreign studies

The efficacy of sofosbuvir was evaluated in five foreign Phase 3 studies, including a total of 1,568 adult subjects with chronic hepatitis C virus genotypes 1 to 6 infection. One study included sofosbuvir, peginterferon alfa 2a, and ribavirin in treatment-naïve subjects with chronic hepatitis C virus genotype 1, 4, 5, or 6 infection; the other four studies examined treatment-naïve subjects with chronic hepatitis C virus genotype 1, 4, 5, or 6 infection. They conducted combination therapy with sofosbuvir and ribavirin. The four studies were in treatment-naïve subjects; subjects who were intolerant, ineligible, or unwilling to receive interferon therapy; subjects who had been previously treated with an interferon-containing regimen; and all subjects regardless of previous treatment history or ability to receive interferon therapy. Subjects in these studies had compensated liver disease, including cirrhosis. The dosage of sofosbuvir is 400 mg once daily. Ribavirin dose is 1000–1200 mg daily based on body weight in two divided doses, and peginterferon alfa 2a dose (if applicable) is 180 μg weekly. Treatment duration was fixed for each study and was not guided by subject HCVRNA levels (non-response bootstrapping rule).

Plasma HCVRNA values ​​were measured during clinical studies using the COBASTaqManHCV Assay (version 2.0) in conjunction with the HighPureSystem. The lower limit of quantification (LLOQ) of this assay is 25IU/mL. All studies used sustained virological response (SVR) as the primary endpoint to determine HCV, which was defined as HCV RNA lower than the LLOQ (SVR12) at 12 weeks after the end of treatment.

Overseas clinical studies in subjects with chronic hepatitis C virus infection genotypes 1, 4, 5 and 6

Treatment-naïve adult subjects - NEUTRINO (Study 110)

NEUTRINO was an open-label, single-arm overseas study evaluating sofosbuvir in combination with peginterferon alfa 2a and ribavirin for 12 weeks in treatment-naïve subjects infected with HCV genotype 1, 4, 5 or 6.

The median age of treated subjects (n=327) was 54 years (range: 19 to 70); 64% of subjects were male; 79% were white; 17% were black; 14% were Hispanic or Latino; mean body mass index was 29k g/m2 (range: 18 to 56 kg/m2); 78% of subjects had baseline HCV RNA levels greater than 6 log10 IU/mL; 17% had cirrhosis; 89% were infected with HCV genotype 1, and 11% were infected with HCV genotype 4, 5, or 6. Table 7 lists the response rates for the sofosbuvir XxX pegylated interferon alfa XxX ribavirin treatment group.

SVR12 rates were higher in subjects with the IL28BC/C allele [94/95 (99%)] and with the non-C/C (C/T or T/T) allele [202/232 (87%)] at baseline.

Among 28 patients infected with genotype 4HCV, 27 achieved SVR12. In this study, one genotype 5 HCV-infected subject and all six genotype 6 HCV-infected subjects achieved SVR12.

Foreign clinical study in subjects with chronic hepatitis C virus infection genotypes 2 and 3

Treatment-naïve adults - FISSION (Study 1231)

FISSION is a randomized This compounded, open-label, active-controlled study evaluated 12 weeks of treatment with sofosbuvir XxX ribavirin compared with 24 weeks of treatment with peginterferon alfa2aXxX ribavirin in treatment-naïve subjects infected with genotype 2 or 3 HCV infection. Ribavirin doses were 1000–1200 mg/day (based on body weight) and 800 mg/day (independent of body weight) in the sofosbuvir and peginterferon alfa2aXxX ribavirin treatment groups, respectively. Subjects were randomly assigned in a 1:1 ratio and classified according to cirrhosis (with or without), HCV genotype (2 and 3), and baseline HCV RNA level (<6log10IU/mL and ≥6log10IU/mL) to stratify patients. The inclusion ratio of subjects infected with genotype 2 or 3 HCV was approximately 1:3.

The median age of treated subjects (n=499) was 50 years (range: 19 to 77); 66% of subjects were male; 87% were white; 3% were black; 14% were Hispanic or Latino; average body size Mass index was 28 kg/m2 (range: 17 to 52 kg/m2); 57% of subjects had baseline HCV RNA levels greater than 6 log10 IU/mL; 20% had cirrhosis; 72% were infected with genotype 3 HCV. Table 9 lists the response rates for the sofosbuvir XxX ribavirin and peginterferon alfa XxX ribavirin treatment groups.

The overall SVR12 rate differed by 0.3% (95% confidence interval: -7.5% to 8.0%) between the sofosbuvir XxX ribavirin treatment group and the pegylated interferon alfa XxX ribavirin treatment group, and this study met the predefined non-inferiority criteria.

Table 10 lists the response rates by HCV genotype for subjects with cirrhosis at baseline.

Study in Adults with Interferon Intolerance, Ineligibility, or Reluctance to Take Interferon - POSITRON (Study 107)

POSITRON was a randomized, double-blind, placebo-controlled study evaluating 12 weeks of sofosbuvir XxX ribavirin (n=207) versus placebo (n=71) in subjects who were intolerant, ineligible, or unwilling to receive interferon. Subjects were randomly assigned in a 3:1 ratio and stratified by cirrhosis (with or without).

The median age of treated subjects (n=278) was 54 years (range: 21 to 75); 54% of subjects were male; 91% were white; 5% were black; 11% were Hispanic or Latino; average body size Mass index was 28 kg/m2 (range: 18 to 53 kg/m2); 70% of subjects had baseline HCV RNA levels greater than 6 log10 IU/mL; 16% had cirrhosis; 49% were infected with genotype 3 HCV. The proportions of subjects who were intolerant, incompatible or unwilling to receive interferon treatment were 9%, 44% and 47% respectively. The majority of subjects had not received prior HCV treatment (81.3%). Table 11 lists the response rates for the sofosbuvir XxX ribavirin treatment group and the placebo treatment group.

Compared with the placebo group, the SVR12 rate in the sofosbuvir XxX ribavirin treatment group was statistically significant (p<0.001).

Study in Previously Treated Adults - FUSION (Study 108)

FUSION was a randomized, double-blind study evaluating 12 or 16 weeks of sofosbuvir XxX ribavirin in subjects who had not achieved SVR on prior interferon-based therapy (relapsers and non-responders). Subjects were randomly assigned in a 1:1 ratio and stratified by cirrhosis (with or without) and HCV genotype (2 versus 3).

The median age of treated subjects (n=201) was 56 years (range: 24 to 70); 70% of subjects were male; 87% were white; 3% were black; 9% were Hispanic or Latino; the average body mass index was 29 kg/m2 (range: 19 to 44 kg/m2); 73% of subjects had baseline HCV RNA levels greater than 6 log10 IU/mL; 34% had cirrhosis; 63% were infected with genotype 3 HCV; 75% had previous relapses. Table 13 lists the response rates for the 12-week and 16-week sofosbuvir XxX ribavirin treatment groups.

Study of treatment-naïve and previously treated adults—VALENCE (Study 133)

VALENCE is an overseas Phase 3 study evaluating sofosbuvir in combination with weight-based ribavirin for HCV genotype 2 or 3 infection in treatment-naïve subjects or those who have not achieved SVR on prior interferon-based therapy, including those with compensated cirrhosis. The study was designed as a direct comparison of sofosbuvir XxX ribavirin versus placebo for 12 weeks. However, based on emerging data, the study was unblinded and all genotype 2 HCV-infected subjects continued to receive sofosbuvir and ribavirin for 12 weeks, while treatment was extended to 24 weeks for genotype 3 HCV-infected subjects. At the time of revision, eleven HCV genotype 3-infected subjects had completed 12 weeks of sofosbuvir and ribavirin treatment.

The median age of treated subjects (n=419) was 51 years (range: 19 to 74); 60% of subjects were male; the median body mass index was 25kg/m2 (range: 17 to 44kg/m2); the mean baseline HCVRNA level was 6.4log10IU/mL; 21% had cirrhosis; 78% were infected with genotype 3 HCV; 65% had previous relapses. Table 15 lists the response rates for the sofosbuvir XxX ribavirin treatment groups at 12 and 24 weeks.

Consistency between SVR12 and SVR24 in foreign studies

SVR12 and SVR24 (SVR 24 weeks after the end of treatment) are consistent after treatment with sofosbuvir combined with ribavirin or combined ribavirin and pegylated interferon, indicating that the positive predictive value and negative predictive value are both 99%.

Clinical efficacy and safety in Chinese adult patients with chronic HCV genotype 1, 2, 3, or 6 infection

Sofosbuvir was studied in a domestic open-label clinical study that evaluated 12 or 24 weeks Safety and efficacy of sofosbuvir and ribavirin therapy and 12 weeks of sofosbuvir, peginterferon alfa 2a, and ribavirin combination therapy in Chinese subjects with treatment-naïve or treatment-experienced chronic hepatitis C virus genotype 1, 2, 3, or 6 infection.

The mean age of treated Chinese subjects (n=389) was 43 years (range: 19 to 79); 49.9% of subjects were male and all subjects (100%) were Chinese; the mean body mass index was 23 .2kg/m2 (range: 16.2 to 35.9kg/m2); a total of 59/389 subjects (15.2%) had compensated cirrhosis at baseline and 162/389 subjects (41.6%) had prior HCV treatment experience. Among 162 subjects with prior HCV treatment, the reasons for prior treatment failure were relapse/on-treatment virologic failure (38.9%; 63 subjects), nonresponse (21.0%; 34 subjects), and interferon intolerance (40.1%; 65 subjects). Of the 227 treatment-naïve subjects, the majority (89.9%; 204 subjects) were considered interferon-eligible.

The majority of subjects carried the IL28BCC allele (76.9%). The overall mean (SD) baseline HCVRNA was 6.4 (0.71) log10 IU/mL, and 80.2% of subjects had a baseline HCVRNA value of ?800,000 IU/mL; 51% (199 subjects) were infected with genotype 1 or 6 HCV, 16% (64 subjects) with genotype 2 HCV, and 32% (126 subjects) with genotype 3 HCV. Table 17 lists response rates by genotype and treatment group.

HCVRNA was analyzed using RocheTaqManV2.0 detection suitable for use in combination with HighPureSystem, with a quantification limit of 25IU/mL.

SVR12 is the sustained virological response (HCVRNA) 12 weeks after stopping study treatmentSVR12 rates were higher across all treatment groups, ranging from 92.2% to 95.7%. Regardless of treatment, all but 1 genotype 6 HCV-infected subjects (35/36) achieved SVR12, and 94.5% of genotype 1 HCV-infected subjects (154/163) achieved SVR12. For treatment-experienced genotype 1 HCV-infected subjects receiving 12 weeks of sofosbuvir XxX ribavirin XxX pegylated interferon alfa and 24 weeks of sofosbuvir XxX ribavirin, the SVR12 rates were 90% (38/42) and 94% (48/51), respectively. Across all genotypes, 21 patients did not achieve SVR12; 20 patients relapsed and 1 patient with genotype 2 HCV died before completing treatment.

Clinical efficacy and efficacy in special populations

Patients coinfected with HCV/HIV - PHOTON1 (Study 123)

Sofosbuvir was studied in an open-label clinical study that evaluated the efficacy and efficacy of 12 or 24 weeks of sofosbuvir and ribavirin treatment in subjects coinfected with chronic hepatitis C virus genotypes 1, 2, or 3 and HIV1. Subjects infected with genotype 2 and 3 viruses were treatment naïve or previously treated, whereas subjects infected with genotype 1 virus were previously untreated. The duration of treatment is 12 weeks for treatment-naïve subjects with genotype 2 or 3 HCV infection and 24 weeks for treatment-experienced subjects with genotype 3 HCV infection and genotype 1 HCV infection. Subjects received 400 mg of sofosbuvir and a weight-based dose of ribavirin (1000 mg for body weight <75 kg; 1200 mg for body weight ≥75 kg). Subjects are antiretroviral therapy naïve and have a CD4XxX cell count greater than 500 cells/mm3, or are virologically HIV1 suppressed and have a CD4XxX cell count greater than 200 cells/mm3. At study entry, 95% of patients were on antiretroviral therapy.

Patients Awaiting Liver Transplantation - Study 2025

In an open-label clinical study to evaluate the safety and efficacy of sofosbuvir given before transplantation compared with ribavirin in preventing HCV reinfection after transplantation, sofosbuvir was studied in subjects who were infected with HCV before undergoing liver transplantation. The primary endpoint of the study was post-transplant virological response (pTVR, HCVRNA 12 weeks after transplantation). Subjects with hepatocellular carcinoma (HCC) who met the Milan criteria, regardless of which HCV genotype they were infected with, received 40 doses daily. 0 mg of sofosbuvir and 1000–1200 mg of ribavirin for up to 24 weeks, later revised to 48 weeks or until liver transplantation, whichever occurred first, among the 61 subjects who received sofosbuvir and ribavirin. Most subjects were infected with genotype 1 HCV, 44 subjects were CPTA grade, and 17 subjects were CPTB grade. Of these 61 subjects, 44 subjects received liver transplantation after receiving sofosbuvir and ribavirin for up to 48 weeks; at the time of liver transplantation, 41 subjects had HCVRNA. Among patients who discontinued treatment at 24 weeks, the relapse rate was 11/15 per protocol.

Liver Transplant Recipients - Study 0126

In Sofosbuvir was studied in an open-label clinical study that evaluated the safety and efficacy of 24 weeks of treatment with sofosbuvir and ribavirin in liver transplant recipients with chronic hepatitis C virus infection. Eligible subjects were ≥18 years of age and had received a liver transplant 6 to 150 months before screening. Subjects had HCVRNA ≥104IU/mL at screening and had documented signs of chronic HCV infection before transplantation. The starting dose of ribavirin is 400mg daily, taken in divided doses. If the subject's hemoglobin level remains ≥12 g/dL, increase the ribavirin dose at weeks 2, 4, and every 4 weeks thereafter until the appropriate weight-based dose is reached (1000 mg daily dose for subjects <75 kg; 1200 mg daily dose for subjects ≥75 kg). The median ribavirin dose during weeks 4 to 24 was 600 mg–800 mg daily.

Forty subjects were included (33 infected with genotype 1 HCV, 6 infected with genotype 3 HCV, and 1 infected with genotype 4 HCV), 35 of whom had previously failed interferon-based therapy and 16 had cirrhosis. Of 40 subjects, 28 (70%) achieved SVR12: 22/33 (73%) subjects infected with genotype 1 HCV, 6/6 (100%) subjects infected with genotype 3 HCV and 0/1 (0%) subjects infected with genotype 4 HCV. All subjects achieving SVR12 also achieved SVR24 and SVR48.

Overview of results for different treatment regimens and treatment durations - comparison across studies

The following tables (Table 21 to Table 24) present dose-related data from the Phase 2 and Phase 3 studies to help clinicians determine the regimen for individual patients.

Table 21: Results of different treatment regimens and treatment durations - Comparison of studies in genotype 1 HCV infection

n = number of subjects achieving SVR12 response; N = total number of subjects in each group.

a. There are no overseas Phase 3 data for previously treated HCV genotype 1-infected patients, but relevant data are available for Chinese subjects who received a combination of Sovaldi, ribavirin, and pegylated interferon alfa (please see [Precautions] and [Clinical Research]).

b. When treating such patients, it should be considered that the duration of treatment with sofosbuvir, peginterferon alfa, and ribavirin may require more than 12 weeks and up to 24 weeks; This is particularly true in subgroups associated with factors associated with lower treatment response rates (previous failure to respond to peginterferon alfa and ribavirin therapy, advanced liver fibrosis/cirrhosis, high baseline viral concentrations, black race, IL28B non-CC genotype).

c. These are exploratory or Phase 2 studies. The results should be interpreted with caution, as the number of subjects was small and the SVR rate may have been affected by patient selection.

d. Summary data from two studies.

Results of different treatment regimens and treatment durations - comparison across studies of genotype 2 HCV infection

n = number of subjects achieving SVR12 response; N = total number of subjects in each group.

a. These are exploratory or Phase 2 studies. The results should be interpreted with caution, as the number of subjects was small and the SVR rate may have been affected by patient selection.

In the ELECTRON study (N=11), the duration of peginterferon alfa in combination with sofosbuvir XxX ribavirin was 4–12 weeks.

b. In both studies, none of the patients had cirrhosis.

Results of different treatment regimens and treatment durations - comparison across studies of genotype 3 HCV infection

n = number of subjects achieving SVR12 response; N = total number of subjects in each group.

a. These are exploratory or Phase 2 studies. The results should be interpreted with caution, as the number of subjects was small and the SVR rate may have been affected by patient selection.

In the ELECTRON study (N=11), the duration of peginterferon alfa in combination with sofosbuvir XxX ribavirin was 4–12 weeks.

b. In both studies, none of the patients had cirrhosis.

Results of Different Treatment Regimen and Duration of Treatment—Across-Study Comparison of Genotype 4, 5, and 6 HCV Infection

Pediatric Population

The efficacy of sofosbuvir in HCV-infected patients aged 12 to <18 years was evaluated in a phase 2 open-label clinical trial of 50 patients with chronic HCV infection with genotype 2 (n=13) or genotype 3 (n=37). Patients with HCV genotype 2 or 3 infection in this trial received sofosbuvir plus ribavirin for 12 or 24 weeks, respectively.

Of the 50 patients treated, the median age was 15 years (range: 12 to 17 years); 42% of patients were female; 90% were white; 4% were black; 2% were Asian; 4% were Hispanic/Latinx; mean body mass index was 22 kg/m2 (range: 16 to 32 kg/m2); 18% had received treatment; 66% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 74% of patients carried non-CCIL28B alleles (CT or TT); no patients had known cirrhosis. Most patients (69%) acquired the infection through vertical transmission.

The SVR12 rate of genotype 2 patients was 100% (13/13), and the SVR12 rate of genotype 3 patients was 97% (36/37). No patient experienced virological failure or relapse during treatment. One patient with genotype 3 HCV infection achieved SVR4 but did not return for the SVR12 visit.