SOVALDI ACCESS- sofosbuvir tablet, film coated

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Active ingredient:
SOFOSBUVIR (UNII: WJ6CA3ZU8B) (SOFOSBUVIR - UNII:WJ6CA3ZU8B)
Available from:
Gilead Sciences, Inc.
INN (International Name):
SOFOSBUVIR
Composition:
SOFOSBUVIR 400 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Adult Patients: SOVALDI is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) infection as a component of a combination antiviral treatment regimen [see Dosage and Administration (2.2), and Clinical Studies (14)] - genotype 1 or 4 infection without cirrhosis or with compensated cirrhosis for use in combination with pegylated interferon and ribavirin - genotype 2 or 3 infection without cirrhosis or with compensated cirrhosis for use in combination with ribavirin. Pediatric Patients: SOVALDI is indicated for the treatment of chronic HCV genotype 2 or 3 infection in pediatric patients 12 years of age and older or weighing at least 35 kg without cirrhosis or with compensated cirrhosis for use in combination with ribavirin [see Dosage and Administration (2.3) and Clinical Studies (14.5)] . 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 prescribi
Product summary:
SOVALDI tablets are white, capsule-shaped, film-coated tablets containing 400 mg sofosbuvir debossed with "GSI" on one side and "7977" on the other side. Each bottle contains 28 tablets, a silica gel desiccant and polyester coil with a child-resistant closure. Store below 30°C (86°F).
Authorization status:
Export only
Authorization number:
61958-1502-2

SOVALDI ACCESS- sofosbuvir tablet, film coated

Gilead Sciences, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use SOVALDI safely and effectively. See full

prescribing information for SOVALDI.

GILEAD ACCESS PROGRAM

SOVALDI™ (sofosbuvir) tablets, for oral use

Initial U.S. Approval: 2013

WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV

AND HBV

See full prescribing information for complete boxed warning.

Hepatitis B virus (HBV) reactivation has been reported, in some cases resulting in fulminant hepatitis,

hepatic failure, and death. (5.1)

INDICATIONS AND USAGE

SOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of:

Adult patients with genotype 1, 2, 3 or 4 chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated

cirrhosis as a component of a combination antiviral treatment regimen. (1)

Pediatric patients 12 years of age and older or weighing at least 35 kg with genotype 2 or 3 chronic HCV infection

without cirrhosis or with compensated cirrhosis in combination with ribavirin. (1)

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 adult and pediatric dosage: One 400 mg tablet taken once daily with or without food. (2.2, 2.3)

HCV/HIV-1 coinfection: For adult and pediatric patients with HCV/HIV-1 coinfection, follow the dosage

recommendations in the tables below, respectively. (2.2, 2.3)

Recommended adult treatment regimen and duration: (2.2)

Adult Patient Population

Regimen and Duration

Genotype 1

or 4

Treatment-naïve without cirrhosis or with compensated cirrhosis

(Child-Pugh A)

SOVALDI + peginterferon alfa +

ribavirin

12 weeks

Genotype 2

Treatment-naïve and treatment-experienced without cirrhosis or with

compensated cirrhosis

(Child-Pugh A)

SOVALDI + ribavirin

12 weeks

Genotype 3

Treatment-naïve and treatment-experienced without cirrhosis or with

compensated cirrhosis

(Child-Pugh A)

SOVALDI + ribavirin

24 weeks

SOVALDI in combination with ribavirin for 24 weeks can be considered for adult patients with genotype 1 infection who

are interferon ineligible. (2.2)

Should be used in combination with ribavirin for treatment of HCV in adult patients with hepatocellular carcinoma

awaiting liver transplantation for up to 48 weeks or until liver transplantation, whichever occurs first. (2.2)

Recommended treatment regimen and duration for pediatric patients 12 years of age and older or weighing at least 35

kg: (2.3)

Pediatric Patient Population 12 Years of Age and Older or

Weighing at Least 35 kg

Regimen and Duration

Genotype 2

Treatment-naïve and treatment-experienced without cirrhosis or with

compensated cirrhosis

(Child-Pugh A)

SOVALDI + ribavirin

12 weeks

Genotype 3

Treatment-naïve and treatment-experienced without cirrhosis or with

compensated cirrhosis

SOVALDI + ribavirin

24 weeks

(Child-Pugh A)

24 weeks

A dosage recommendation cannot be made for patients with severe renal impairment or end stage renal disease. (2.6,

8.6)

DOSAGE FORMS AND STRENGTHS

Tablets: 400 mg. (3)

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)

WARNINGS AND PRECAUTIONS

Risk of Hepatitis B Virus Reactivation: Test all patients for evidence of current or prior HBV infection before initiation of

HCV treatment. Monitor HCV/HBV coinfected patients for HBV reactivation and hepatitis flare during HCV treatment

and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. (5.1)

Bradycardia with amiodarone coadministration: Serious symptomatic bradycardia may occur in patients taking

amiodarone with a sofosbuvir-containing regimen, particularly in patients also receiving beta blockers, or those with

underlying cardiac comorbidities and/or advanced liver disease. Coadministration of amiodarone with SOVALDI is not

recommended. In patients without alternative, viable treatment options, cardiac monitoring is recommended. (5.2, 6.2,

7.1)

ADVERSE REACTIONS

The most common adverse events (incidence greater than or equal to 20%, all grades) observed with SOVALDI in

combination with ribavirin were fatigue and headache. The most common adverse events observed with SOVALDI in

combination with peginterferon alfa and ribavirin were fatigue, headache, nausea, insomnia and anemia. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at safety_fc@gilead.com or the

US FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.

DRUG INTERACTIONS

Coadministration of amiodarone with a sofosbuvir-containing regimen may result in serious symptomatic bradycardia.

(5.2, 6.2, 7.1)

Drugs that are intestinal P-gp inducers (e.g., rifampin, St. John's wort) may alter the concentrations of sofosbuvir. (5.3, 7,

12.3)

Consult the full prescribing information prior to use for potential drug-drug interactions. (5.2, 5.3, 7, 12.3)

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. ( 7.1)

USE IN SPECIFIC POPULATIONS

Patients with HCV/HIV-1 coinfection: Safety and efficacy have been studied. (14.4)

Patients with hepatocellular carcinoma awaiting liver transplantation: Safety and efficacy have been studied. (8.8)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 9/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS

COINFECTED WITH HCV AND HBV

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Testing Prior to the Initiation of Therapy

2.2 Recommended Dosage in Adults

2.3 Recommended Dosage in Pediatric Patients 12 Years of Age and Older or Weighing at Least 35

2.4 Dosage Modification

2.5 Discontinuation of Dosing

2.6 Severe Renal Impairment and End Stage Renal Disease

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV

5.2 Serious Symptomatic Bradycardia When Coadministered with Amiodarone

5.3 Risk of Reduced Therapeutic Effect Due to Use with P-gp Inducers

5.4 Risks Associated with Combination Treatment

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Potentially Significant Drug Interactions

7.2 Drugs without Clinically Significant Interactions with SOVALDI

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

8.8 Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation

8.9 Post-Liver Transplant Patients

8.10 Patients with Genotype 5 or 6 HCV Infection

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Microbiology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Description of Clinical Trials

14.2 Clinical Trials in Subjects with Genotype 1 or 4 HCV

14.3 Clinical Trials in Subjects with Genotype 2 or 3 HCV

14.4 Clinical Trials in Adult Subjects Coinfected with HCV and HIV-1

14.5 Clinical Trial in Pediatrics

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS

COINFECTED WITH HCV AND HBV

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before

initiating treatment with SOVALDI. HBV reactivation has been reported in HCV/HBV

coinfected patients who were undergoing or had completed treatment with HCV direct

acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in

fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for

hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up.

Initiate appropriate patient management for HBV infection as clinically indicated [see

Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

Adult Patients:

SOVALDI is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) infection

as a component of a combination antiviral treatment regimen [see Dosage and Administration (2.2), and

Clinical Studies (14)]

genotype 1 or 4 infection without cirrhosis or with compensated cirrhosis for use in combination

with pegylated interferon and ribavirin

genotype 2 or 3 infection without cirrhosis or with compensated cirrhosis for use in combination

with ribavirin.

Pediatric Patients:

SOVALDI is indicated for the treatment of chronic HCV genotype 2 or 3 infection in pediatric patients

12 years of age and older or weighing at least 35 kg without cirrhosis or with compensated cirrhosis

for use in combination with ribavirin [see Dosage and Administration (2.3) and Clinical Studies (14.5)].

2 DOSAGE AND ADMINISTRATION

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

SOVALDI [see Warnings and Precautions (5.1)].

2.2 Recommended Dosage in Adults

The recommended dosage of SOVALDI is one 400 mg tablet, taken orally, once daily with or without

food [see Clinical Pharmacology (12.3)].

Administer SOVALDI in combination with ribavirin or in combination with pegylated interferon and

ribavirin for the treatment of HCV. The recommended treatment regimen and duration for SOVALDI

combination therapy is provided in Table 1.

For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 1. Refer to

Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs.

Table 1 Recommended Treatment Regimen and Duration in Adult Patients with

Genotype 1, 2, 3, or 4 HCV

Patient Population

Treatment Regimen and

Duration

Genotype 1 or 4

Treatment-naïve without

cirrhosis or with

compensated cirrhosis

(Child-Pugh A)

SOVALDI + peginterferon

alfa + ribavirin

12 weeks

Genotype 2

Treatment-naïve and

treatment-experienced

without cirrhosis or with

compensated cirrhosis

(Child-Pugh A)

SOVALDI + ribavirin

12 weeks

Genotype 3

Treatment-naïve and

treatment-experienced

without cirrhosis or with

compensated cirrhosis

(Child-Pugh A)

SOVALDI + ribavirin

24 weeks

Patients with Genotype 1 HCV Who are Ineligible to Receive an Interferon-Based Regimen

SOVALDI in combination with ribavirin for 24 weeks can be considered as a therapeutic option for

patients with genotype 1 infection who are ineligible to receive an interferon-based regimen [see

Clinical Studies (14.4)]. Treatment decision should be guided by an assessment of the potential benefits

and risks for the individual patient.

Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation

Administer SOVALDI in combination with ribavirin for up to 48 weeks or until the time of liver

transplantation, whichever occurs first, to prevent post-transplant HCV reinfection [see Use in Specific

Populations (8.8)].

2.3 Recommended Dosage in Pediatric Patients 12 Years of Age and Older or Weighing at Least

35 kg

The recommended dosage of SOVALDI in pediatric patients 12 years of age and older or weighing at

least 35 kg is one 400 mg tablet taken orally once daily with or without food in combination with

ribavirin [see Clinical Pharmacology (12.3) and Clinical Studies (14.5)].

The recommended treatment regimen and duration for SOVALDI combination therapy is provided in

Table 2. Table 3 provides the weight-based dosage of ribavirin when used in combination with

SOVALDI for pediatric patients. For patients with HCV/HIV-1 coinfection, follow the dosage

recommendations in Table 2 and Table 3. Refer to Drug Interactions (7) for dosage recommendations for

concomitant HIV-1 antiviral drugs.

Table 2 Recommended Treatment Regimen and Duration in Pediatric Patients 12 Years of Age

and Older or Weighing at Least 35 kg

Patient Population

Treatment Regimen And

Duration

Genotype 2

Treatment-naïve and treatment-

experienced without cirrhosis or

SOVALDI + ribavirin 12 weeks

See peginterferon alfa prescribing information for dosage recommendation for patients with

genotype 1 or 4 HCV.

Dosage of ribavirin is weight-based (<75 kg = 1000 mg and ≥75 kg = 1200 mg). The daily

dosage of ribavirin is administered orally in two divided doses with food. Patients with renal

impairment (CrCl ≤50 mL/min) require ribavirin dosage reduction; refer to ribavirin prescribing

information.

Treatment-experienced patients have failed an interferon based regimen with or without

ribavirin.

Genotype 2

with compensated cirrhosis

(Child-Pugh A)

SOVALDI + ribavirin 12 weeks

Genotype 3

Treatment-naïve and treatment-

experienced without cirrhosis or

with compensated cirrhosis

(Child-Pugh A)

SOVALDI + ribavirin 24 weeks

Table 3 Recommended Dosing for Ribavirin in Combination Therapy with SOVALDI for

Pediatric Patients 12 Years of Age and Older or Weighing at Least 35 kg

Body Weight kg

Ribavirin Daily Dosage

less than 47

15 mg/kg/day

47–49

600 mg/day

50–65

800 mg/day

66–80

1000 mg/day

greater than 80

1200 mg/day

2.4 Dosage Modification

Dosage reduction of SOVALDI is not recommended.

If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the

peginterferon alfa and/or ribavirin dosage should be reduced or discontinued, if appropriate, until the

adverse reaction abates or decreases in severity. Refer to the peginterferon alfa and ribavirin

prescribing information for additional information about how to reduce and/or discontinue the

peginterferon alfa and/or ribavirin dosage.

2.5 Discontinuation of Dosing

If the other agents used in combination with SOVALDI are permanently discontinued, SOVALDI should

also be discontinued.

2.6 Severe Renal Impairment and End Stage Renal Disease

No dosage recommendation can be given for patients with severe renal impairment (estimated

Glomerular Filtration Rate [eGFR] less than 30 mL/min/1.73m ) or with end stage renal disease (ESRD)

due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite [see Use in Specific

Populations (8.6) and Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

SOVALDI is available as a white-colored, capsule-shaped, film-coated tablet debossed with "GSI" on

one side and "7977" on the other side. Each tablet contains 400 mg sofosbuvir.

4 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.

5 WARNINGS AND PRECAUTIONS

Treatment-experienced patients have failed an interferon based regimen with or without ribavirin.

See Table 3 for weight-based ribavirin dosing recommendations.

*

The daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food.

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 SOVALDI. In patients with serologic evidence of HBV infection,

monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment

with SOVALDI 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 SOVALDI is not recommended. For patients taking amiodarone

who have no other alternative, viable treatment options and who will be coadministered SOVALDI:

Counsel patients about the risk of serious 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 SOVALDI 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 SOVALDI

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), Drug Interactions (7.1)].

5.3 Risk of Reduced Therapeutic Effect Due to Use with P-gp Inducers

Drugs that are P-gp inducers in the intestine (e.g., rifampin, St. John's wort) may significantly decrease

sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect of SOVALDI. The use

of rifampin and St. John's wort with SOVALDI is not recommended [see Drug Interactions (7.1)].

5.4 Risks Associated with Combination Treatment

Because SOVALDI is used in combination with other antiviral drugs for treatment of HCV infection,

consult the prescribing information for these drugs used in combination with SOVALDI. Warnings and

Precautions related to these drugs also apply to their use in SOVALDI combination treatment.

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see Warnings and

Precautions (5.2)].

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.

When SOVALDI is administered with ribavirin or peginterferon alfa/ribavirin, refer to the respective

prescribing information for a description of adverse reactions associated with their use.

Adverse Reactions in Adult Subjects

The safety assessment of SOVALDI was based on pooled Phase 3 clinical trial data (both controlled

and uncontrolled) including:

650 subjects who received SOVALDI + ribavirin (RBV) combination therapy for 12 weeks,

98 subjects who received SOVALDI + ribavirin combination therapy for 16 weeks,

250 subjects who received SOVALDI + ribavirin combination therapy for 24 weeks,

327 subjects who received SOVALDI + peginterferon (Peg-IFN) alfa + ribavirin combination

therapy for 12 weeks,

243 subjects who received peginterferon alfa + ribavirin for 24 weeks, and

71 subjects who received placebo (PBO) for 12 weeks [see Clinical Studies (14)].

The proportion of subjects who permanently discontinued treatment due to adverse events was 4% for

subjects receiving placebo, 1% for subjects receiving SOVALDI + ribavirin for 12 weeks, less than

1% for subjects receiving SOVALDI + ribavirin for 24 weeks, 11% for subjects receiving

peginterferon alfa + ribavirin for 24 weeks and 2% for subjects receiving SOVALDI + peginterferon

alfa + ribavirin for 12 weeks.

Adverse events observed in at least 15% of subjects in the Phase 3 clinical trials outlined above are

provided in Table 4. A side-by-side tabulation is displayed to simplify presentation; direct comparison

across trials should not be made due to differing trial designs.

The most common adverse events (at least 20%) for SOVALDI + ribavirin combination therapy were

fatigue and headache. The most common adverse events (at least 20%) for SOVALDI + peginterferon

alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia.

Table 4 Adverse Events (All Grades and without Regard to Causality) Reported in ≥15% of

Subjects with HCV in Any Treatment Arm

Interferon-free Regimens

Interferon-containing Regimens

PBO

12 weeks

SOVALDI +

RBV

12 weeks

SOVALDI +

RBV

24 weeks

Peg-IFN alfa +

RBV

24 weeks

SOVALDI + Peg-IFN

alfa + RBV

12 weeks

N=71

N=650

N=250

N=243

N=327

Fatigue

*

*

*

Headache

Nausea

Insomnia

Pruritus

Anemia

Asthenia

Rash

Decreased

Appetite

Chills

Influenza Like

Illness

Pyrexia

Diarrhea

Neutropenia

<1%

<1%

Myalgia

Irritability

With the exception of anemia and neutropenia, the majority of events presented in Table 4 occurred at

severity of grade 1 in SOVALDI-containing regimens.

Less Common Adverse Reactions Reported in Clinical Trials (less than 1%): The following adverse

reactions occurred in less than 1% of subjects receiving SOVALDI in a combination regimen in any one

trial. These events have been included because of their seriousness or assessment of potential causal

relationship.

Hematologic Effects: pancytopenia (particularly in subjects receiving concomitant pegylated interferon).

Psychiatric Disorders: severe depression (particularly in subjects with pre-existing history of

psychiatric illness), including suicidal ideation and suicide.

Laboratory Abnormalities:

Changes in selected hematological parameters are described in Table 5. A side-by-side tabulation is

displayed to simplify presentation; direct comparison across trials should not be made due to differing

trial designs.

Table 5 Percentage of Subjects Reporting Selected Hematological Parameters

Hematological

Parameters

Interferon-free Regimens

Interferon-containing Regimens

PBO

12 weeks

SOVALDI +

RBV

12 weeks

SOVALDI +

RBV

24 weeks

Peg-IFN +

RBV

24 weeks

SOVALDI + Peg-

IFN + RBV

12 weeks

N=71

N=647

N=250

N=242

N=327

Hemoglobin (g/dL)

<10

<8.5

<1%

Neutrophils (×10 /L)

≥0.5 – <0.75

<1%

<0.5

<1%

Subjects received weight-based ribavirin (1000 mg per day if weighing <75 kg or 1200 mg per day if weighing

≥75 kg).

Subjects received 800 mg ribavirin per day regardless of weight.

*

*

*

Platelets (×10 /L)

≥25 – <50

<1%

<1%

<25

Bilirubin Elevations

Total bilirubin elevation of more than 2.5×ULN was observed in none of the subjects in the SOVALDI

+ peginterferon alfa + ribavirin 12 weeks group and in 1%, 3% and 3% of subjects in the peginterferon

alfa + ribavirin 24 weeks, SOVALDI + ribavirin 12 weeks and SOVALDI + ribavirin 24 weeks groups,

respectively. Bilirubin levels peaked during the first 1 to 2 weeks of treatment and subsequently

decreased and returned to baseline levels by post-treatment Week 4. These bilirubin elevations were not

associated with transaminase elevations.

Creatine Kinase Elevations

Creatine kinase was assessed in the FISSION and NEUTRINO trials. Isolated, asymptomatic creatine

kinase elevation of greater than or equal to 10×ULN was observed in less than 1%, 1% and 2% of

subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + peginterferon alfa + ribavirin 12

weeks and SOVALDI + ribavirin 12 weeks groups, respectively.

Lipase Elevations

Isolated, asymptomatic lipase elevation of greater than 3×ULN was observed in less than 1%, 2%, 2%,

and 2% of subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks, SOVALDI + ribavirin

12 weeks, SOVALDI + ribavirin 24 weeks and peginterferon alfa + ribavirin 24 weeks groups,

respectively.

Patients with HCV/HIV-1 Coinfection

SOVALDI used in combination with ribavirin was assessed in 223 HCV/HIV-1 coinfected subjects [see

Clinical Studies (14.4)]. The safety profile in HCV/HIV-1 coinfected subjects was similar to that

observed in HCV mono-infected subjects. Elevated total bilirubin (grade 3 or 4) was observed in 30/32

(94%) subjects receiving atazanavir as part of the antiretroviral regimen. None of the subjects had

concomitant transaminase increases. Among subjects not taking atazanavir, grade 3 or 4 elevated total

bilirubin was observed in 2 (1.5%) subjects, similar to the rate observed with HCV mono-infected

subjects receiving SOVALDI + ribavirin in Phase 3 trials.

Adverse Reactions in Pediatric Subjects 12 Years of Age and Older

The safety assessment of SOVALDI in pediatric subjects 12 years of age and older is based on data

from 50 subjects who were treated with SOVALDI plus ribavirin for 12 weeks (genotype 2 subjects) or

24 weeks (genotype 3 subjects) in a Phase 2, open-label clinical trial. The adverse reactions observed

were consistent with those observed in clinical studies of SOVALDI plus ribavirin in adults [see

Clinical Studies 14.5)].

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of SOVALDI. Because

postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always

possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac Disorders

Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment

with a sofosbuvir-containing regimen [see Warnings and Precautions (5.2), Drug Interactions (7.1)].

Skin and Subcutaneous Tissue Disorders

Subjects received weight-based ribavirin (1000 mg per day if weighing <75 kg or 1200 mg per day if weighing

≥75 kg).

Subjects received 800 mg ribavirin per day regardless of weight.

Skin rashes, sometimes with blisters or angioedema-like swelling

Angioedema

7 DRUG INTERACTIONS

7.1 Potentially Significant Drug Interactions

Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while

the predominant circulating metabolite GS-331007 is not. Drugs that are P-gp inducers in the intestine

(e.g., rifampin or St. John's wort) may decrease sofosbuvir plasma concentration, leading to reduced

therapeutic effect of SOVALDI, and thus concomitant use with SOVALDI is not recommended [see

Warnings and Precautions (5.3)].

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.

Information on potential drug interactions with SOVALDI is summarized in Table 6. The table is not all-

inclusive [see Warnings and Precautions (5.2, 5.3) and Clinical Pharmacology (12.3)].

Table 6 Potentially Significant Drug Interactions: Alteration in Dosage or Regimen May Be

Recommended Based on Drug Interaction Studies or Predicted Interaction

Concomitant Drug

Class: Drug Name

Effect on

Concentration

Clinical Comment

Antiarrhythmics:

amiodarone

Effect on

amiodarone and

sofosbuvir

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 SOVALDI is not

recommended; if coadministration is required, cardiac

monitoring is recommended [see Warnings and Precautions

(5.2), Adverse Reactions (6.2)].

Anticonvulsants:

Carbamazepine

phenytoin

phenobarbital

oxcarbazepine

↓ sofosbuvir

↓ GS-331007

Coadministration of SOVALDI with carbamazepine,

phenytoin, phenobarbital or oxcarbazepine is expected to

decrease the concentration of sofosbuvir, leading to reduced

therapeutic effect of SOVALDI. Coadministration is not

recommended.

Antimycobacterials:

Rifabutin

rifampin

rifapentine

↓ sofosbuvir

↓ GS-331007

Coadministration of SOVALDI with rifabutin or rifapentine

is expected to decrease the concentration of sofosbuvir,

leading to reduced therapeutic effect of SOVALDI.

Coadministration is not recommended.

Coadministration of SOVALDI with rifampin, an intestinal P-

gp inducer, is not recommended [see Warnings and

Precautions (5.3)].

Herbal Supplements:

↓ sofosbuvir

Coadministration of SOVALDI with St. John's wort, an

*

St. John's wort

(Hypericum perforatum)

↓ sofosbuvir

↓ GS-331007

intestinal P-gp inducer, is not recommended [see Warnings

and Precautions (5.3)].

HIV Protease

Inhibitors:

tipranavir/ritonavir

↓ sofosbuvir

↓ GS-331007

Coadministration of SOVALDI with tipranavir/ritonavir is

expected to decrease the concentration of sofosbuvir,

leading to reduced therapeutic effect of SOVALDI.

Coadministration is not recommended.

7.2 Drugs without Clinically Significant Interactions with SOVALDI

In addition to the drugs included in Table 6, the interaction between SOVALDI and the following drugs

was evaluated in clinical trials and no dose adjustment is needed for either drug [See Clinical

Pharmacology (12.3)]: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, oral

contraceptives, raltegravir, rilpivirine, tacrolimus, or tenofovir disoproxil fumarate.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

If SOVALDI is administered with ribavirin or peginterferon alfa and ribavirin, the combination regimen

is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the

ribavirin and/or peginterferon alfa prescribing information for more information on ribavirin- and

peginterferon alfa-associated risks of use during pregnancy.

No adequate human data are available to establish whether or not SOVALDI poses a risk to pregnancy

outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was

observed with sofosbuvir at exposures greater than those in humans at the recommended human dose

(RHD) [see Data]. During organogenesis in the rat and rabbit, systemic exposures (AUC) to the

predominant circulating metabolite of sofosbuvir (GS-331007) were ≥5 (rats) and 12 (rabbits) times the

exposure in humans at the RHD. In the rat pre/postnatal development study, maternal systemic exposure

(AUC) to GS-331007 was ≥6 times the exposure 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

Animal Data

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.

Systemic exposures (AUC) to the predominant circulating metabolite of sofosbuvir (GS-331007) were

≥5 (rats) and 12 (rabbits) times the exposure in humans at the RHD, with exposures increasing during

gestation from approximately 5 to 10 (rats) and 12 to 28 (rabbits) times the exposure in humans at the

RHD.

8.2 Lactation

Risk Summary

It is not known whether sofosbuvir or its metabolites are present in human breast milk, affect human milk

production or have effects on the breastfed infant. The predominant circulating metabolite of sofosbuvir

This table is not all-inclusive.

↓ = decrease.

(GS-331007) was the primary component observed in the milk of lactating rats, without effect on nursing

pups [see Data].

The developmental and health benefits of breastfeeding should be considered along with the mother's

clinical need for SOVALDI and any potential adverse effects on the breastfed child from SOVALDI or

from the underlying maternal condition.

If SOVALDI 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

Animal Data

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 12 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.

8.3 Females and Males of Reproductive Potential

If SOVALDI is administered with ribavirin or peginterferon and ribavirin, the information for ribavirin

and peginterferon with regard to pregnancy testing, contraception, and infertility also applies to these

combination regimens. Refer to ribavirin and/or peginterferon prescribing information for additional

information.

8.4 Pediatric Use

The safety, pharmacokinetics, and efficacy of SOVALDI in pediatric patients 12 years of age and older

or weighing at least 35 kg with genotype 2 and 3 infection have been established. SOVALDI was

evaluated in an open-label clinical trial (Study 1112), which included 50 subjects (13 genotype 2; 37

genotype 3) 12 years of age and older. The safety, pharmacokinetics, and efficacy were comparable to

that observed in adults [see Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical

Pharmacology (12.3), and Clinical Studies (14.5)].

The safety and efficacy of SOVALDI in pediatric patients 12 years of age and older or weighing at

least 35 kg with compensated cirrhosis is supported by comparable sofosbuvir and GS-331007

exposures between: 1) adults and adolescents without cirrhosis and 2) adults without cirrhosis and

adults with compensated cirrhosis. Thus, similar efficacy would be expected for adolescent patients

with compensated cirrhosis as adults with compensated cirrhosis.

The safety and efficacy of SOVALDI have not been established in pediatric patients less than 12 years

of age and weighing less than 35 kg with HCV genotype 2 or 3. The safety and efficacy of SOVALDI

have not been established in pediatric patients with HCV genotype 1 or 4.

8.5 Geriatric Use

SOVALDI was administered to 90 subjects aged 65 and over. The response rates observed for subjects

over 65 years of age were similar to that of younger subjects across treatment groups. No dosage

adjustment of SOVALDI is warranted in geriatric patients [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

No dosage adjustment of SOVALDI is required for patients with mild or moderate renal impairment.

The safety and efficacy of SOVALDI have not been established in patients with severe renal impairment

The safety and efficacy of SOVALDI have not been established in patients with severe renal impairment

(eGFR less than 30 mL/min/1.73m ) or ESRD requiring hemodialysis. No dosage recommendation can

be given for patients with severe renal impairment or ESRD [see Dosage and Administration (2.6) and

Clinical Pharmacology (12.3)]. Refer also to ribavirin and peginterferon alfa prescribing information for

patients with CrCl less than 50 mL/min.

8.7 Hepatic Impairment

No dosage adjustment of SOVALDI is required for patients with mild, moderate or severe hepatic

impairment (Child-Pugh Class A, B or C) [see Clinical Pharmacology (12.3)]. Safety and efficacy of

SOVALDI have not been established in patients with decompensated cirrhosis. See peginterferon alfa

prescribing information for contraindication in hepatic decompensation.

8.8 Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation

SOVALDI was studied in HCV-infected adult subjects with hepatocellular carcinoma prior to

undergoing liver transplantation in an open-label clinical trial evaluating the safety and efficacy of

SOVALDI and ribavirin administered pre-transplant to prevent post-transplant HCV reinfection. The

primary endpoint of the trial was post-transplant virologic response (pTVR) defined as HCV RNA less

than lower limit of quantification (LLOQ) at 12 weeks post-transplant. HCV-infected subjects,

regardless of genotype, with hepatocellular carcinoma (HCC) meeting the MILAN criteria (defined as

the presence of a tumor 5 cm or less in diameter in patients with single hepatocellular carcinomas and no

more than three tumor nodules, each 3 cm or less in diameter in patients with multiple tumors and no

extrahepatic manifestations of the cancer or evidence of vascular invasion of tumor) received 400 mg

SOVALDI and weight-based 1000–1200 mg ribavirin daily for 24–48 weeks or until the time of liver

transplantation, whichever occurred first. An interim analysis was conducted on 61 subjects who

received SOVALDI and ribavirin; 45 subjects had HCV genotype 1; 44 subjects had a baseline CPT

score less than 7 and all subjects had a baseline unadjusted MELD score up to 14. Of these 61 subjects,

41 subjects underwent liver transplantation following up to 48 weeks of treatment with SOVALDI and

ribavirin; 37 had HCV RNA less than LLOQ at the time of transplantation. Of the 37 subjects, the post-

transplant virologic response (pTVR) rate is 64% (23/36) in the 36 evaluable subjects who have

reached the 12 week post-transplant time point. The safety profile of SOVALDI and ribavirin in HCV-

infected subjects prior to liver transplantation was comparable to that observed in subjects treated with

SOVALDI and ribavirin in Phase 3 clinical trials.

8.9 Post-Liver Transplant Patients

The safety and efficacy of SOVALDI have not been established in post-liver transplant patients.

8.10 Patients with Genotype 5 or 6 HCV Infection

Available data on subjects with genotype 5 or 6 HCV infection are insufficient for dosing

recommendations.

10 OVERDOSAGE

The highest documented dosage of sofosbuvir was a single dose of sofosbuvir 1200 mg (three times

the recommended dosage) administered to 59 healthy subjects. In that trial, there were no untoward

effects observed at this dosage level, and adverse events were similar in frequency and severity to

those reported in the placebo and sofosbuvir 400 mg treatment groups. The effects of higher dosages

are not known.

No specific antidote is available for overdose with SOVALDI. If overdose occurs, the patient must be

monitored for evidence of toxicity. Treatment of overdose with SOVALDI consists of general

supportive measures including monitoring of vital signs as well as observation of the clinical status of

the patient. A 4-hour hemodialysis session removed 18% of the administered dose.

11 DESCRIPTION

SOVALDI (sofosbuvir) is a nucleotide analog inhibitor of HCV NS5B polymerase.

The IUPAC name for sofosbuvir 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)phosphorylamino)propanoate. It has a molecular formula of C

H FN O P and a molecular

weight of 529.45. It has the following structural formula:

Sofosbuvir is a white to off-white crystalline solid with a solubility of ≥ 2 mg/mL across the pH range

of 2–7.7 at 37 °C and is slightly soluble in water.

SOVALDI tablets are for oral administration. Each tablet contains 400 mg of sofosbuvir. The tablets

include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium,

magnesium stearate, mannitol, and microcrystalline cellulose. The tablets are film-coated with a coating

material containing the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc and

titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Sofosbuvir is a direct-acting antiviral agent against the hepatitis C virus [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of sofosbuvir 400 and 1200 mg (three times the recommended dosage) on QTc interval was

evaluated in a randomized, single-dose, placebo- and active-controlled (moxifloxacin 400 mg) four

period crossover thorough QT trial in 59 healthy subjects. At a dosage three times the maximum

recommended dosage, SOVALDI does not prolong QTc to any clinically relevant extent.

12.3 Pharmacokinetics

Absorption

The pharmacokinetic properties of sofosbuvir and the predominant circulating metabolite GS-331007

have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral

administration of SOVALDI, sofosbuvir was absorbed with a peak plasma concentration observed at

~0.5–2 hour post-dose, regardless of dose level. Peak plasma concentration of GS-331007 was

observed between 2 to 4 hours post-dose. Based on population pharmacokinetic analysis in subjects

with genotype 1 to 6 HCV infection who were coadministered ribavirin (with or without pegylated

interferon), geometric mean steady state AUC

was 969 ng·hr/mL for sofosbuvir (N=838), and 6790

ng·hr/mL for GS-331007 (N=1695). Relative to healthy subjects administered sofosbuvir alone

(N=272), the sofosbuvir AUC

was 60% higher; and GS-331007 AUC

was 39% lower,

0–24

0–24

0–24

respectively, in HCV-infected subjects. Sofosbuvir and GS-331007 AUCs are near dose proportional

over the dose range of 200 mg to 1200 mg.

Effect of Food

Relative to fasting conditions, the administration of a single dose of SOVALDI with a standardized high

fat meal did not substantially affect the sofosbuvir C

or AUC

. The exposure of GS-331007 was

not altered in the presence of a high-fat meal. Therefore, SOVALDI can be administered without regard

to food.

Distribution

Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding is independent of

drug concentration over the range of 1 microgram/mL to 20 microgram/mL. Protein binding of GS-

331007 was minimal in human plasma. After a single 400 mg dose of [

C]-sofosbuvir in healthy

subjects, the blood to plasma ratio of

C-radioactivity was approximately 0.7.

Metabolism

Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside

analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of

the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and

phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by

phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the

formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks

anti-HCV activity in vitro.

After a single 400 mg oral dose of [

C]-sofosbuvir, sofosbuvir and GS-331007 accounted for

approximately 4% and greater than 90% of drug related material (sum of molecular weight-adjusted

AUC of sofosbuvir and its metabolites) systemic exposure, respectively.

Elimination

Following a single 400 mg oral dose of [

C]-sofosbuvir, mean total recovery of the dose was greater

than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, feces, and expired air,

respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while

3.5% was recovered as sofosbuvir. These data indicate that renal clearance is the major elimination

pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 were 0.4 and 27

hours, respectively.

Specific Populations

Race

Population pharmacokinetics analysis in HCV-infected subjects indicated that race had no clinically

relevant effect on the exposure of sofosbuvir and GS-331007.

Gender

No clinically relevant pharmacokinetic differences have been observed between men and women for

sofosbuvir and GS-331007.

Pediatric Patients

The pharmacokinetics of sofosbuvir and GS-331007 were determined in 50 pediatric subjects 12 years

of age and older, infected with HCV genotype 2 or 3, receiving a daily dose of SOVALDI (400 mg

sofosbuvir). The pharmacokinetic properties of sofosbuvir and GS-331007 in pediatric subjects 12

years of age and older are provided in Table 7. Exposures in pediatric subjects were similar to those

observed in adults.

Table 7 Pharmacokinetic Properties of SOVALDI in HCV-infected Pediatric Subjects

12 Years of Age and Older

0–24

0–24

0–inf

*

12 Years of Age and Older

Geometric Mean

Sofos buvir

GS-331007

(ng·hr/mL)

1060

7570

(ng/mL)

The pharmacokinetics of sofosbuvir have not been established in pediatric subjects less than 12 years

of age [see Use in Specific Populations (8.4)].

Geriatric Patients

Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (19 to

75 years) analyzed, age did not have a clinically relevant effect on the exposure to sofosbuvir and GS-

331007 [see Use in Specific Populations (8.5)].

Patients with Renal Impairment

The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild (eGFR between

50 to less than 80 mL/min/1.73m ), moderate (eGFR between 30 to less than 50 mL/min/1.73m ), severe

renal impairment (eGFR less than 30 mL/min/1.73m ) and subjects with end stage renal disease (ESRD)

requiring hemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with normal

renal function (eGFR greater than 80 mL/min/1.73m ), the sofosbuvir AUC

was 61%, 107% and

171% higher in mild, moderate and severe renal impairment, while the GS-331007 AUC

was 55%,

88% and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal

function, sofosbuvir and GS-331007 AUC

was 28% and 1280% higher when sofosbuvir was dosed

1 hour before hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour

after hemodialysis, respectively. A 4 hour hemodialysis session removed approximately 18% of

administered dose. No dosage adjustment is required for patients with mild or moderate renal

impairment. The safety and efficacy of SOVALDI have not been established in patients with severe

renal impairment or ESRD. No dosage recommendation can be given for patients with severe renal

impairment or ESRD [see Dosage and Administration (2.6) and Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in

HCV-infected subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C).

Relative to subjects with normal hepatic function, the sofosbuvir AUC

were 126% and 143%

higher in moderate and severe hepatic impairment, while the GS-331007 AUC

were 18% and 9%

higher, respectively. Population pharmacokinetics analysis in HCV-infected subjects indicated that

cirrhosis had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. No dosage

adjustment of SOVALDI is recommended for patients with mild, moderate or severe hepatic impairment

[see Use in Specific Populations (8.7)].

Assessment of Drug Interactions

Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while

GS-331007 is not. Drugs that are P-gp inducers in the intestine (e.g., rifampin or St. John's wort) may

decrease sofosbuvir plasma concentration, leading to reduced therapeutic effect of SOVALDI, and thus

concomitant use with SOVALDI is not recommended [see Warnings and Precautions (5.3) and Drug

Interactions (7.1)].

Coadministration of SOVALDI with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir

plasma concentration without increasing GS-331007 plasma concentration; accordingly, SOVALDI may

be coadministered with P-gp and/or BCRP inhibitors. Sofosbuvir and GS-331007 are not inhibitors of

P-gp and BCRP and thus are not expected to increase exposures of drugs that are substrates of these

transporters.

Population PK derived parameters

Sofosbuvir N=28; GS-331007 N=50

0–inf

0–inf

0–inf

0–24

0–24

The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low affinity and

high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by

concomitant drugs.

The effects of coadministered drugs on the exposure of sofosbuvir and GS-331007 are shown in Table

8. The effects of sofosbuvir on the exposure of coadministered drugs are shown in Table 9 [see Drug

Interactions (7.1, 7.2)].

Table 8 Drug Interactions: Changes in Pharmacokinetic Parameters for Sofosbuvir and the

Predominant Circulating Metabolite GS-331007 in the Presence of the Coadministered Drug

Coadminis tered

Drug

Dose of

Coadminis tered

Drug (mg)

Sofos buvir

Dose (mg)

N

Mean Ratio (90% CI) of Sofosbuvir

and GS-331007 PK With/Without

Coadministered Drug

No Effect=1.00

C

AUC

C

Cyclosporine

600 single dose

400 single

dose

sofosbuvir

2.54

(1.87,

3.45)

4.53

(3.26,

6.30)

331007

0.60

(0.53,

0.69)

1.04

(0.90,

1.20)

Darunavir

(boosted with

ritonavir)

800/100 once daily

400 single

dose

sofosbuvir

1.45

(1.10,

1.92)

1.34

(1.12,

1.59)

331007

0.97

(0.90,

1.05)

1.24

(1.18,

1.30)

Efavirenz

600 once daily

400 single

dose

sofosbuvir

0.81

(0.60,

1.10)

0.94

(0.76,

1.16)

Emtricitabine

200 once daily

Tenofovir

disoproxil

fumarate

300 once daily

331007

0.77

(0.70,

0.84)

0.84

(0.76,

0.92)

Methadone

30 to 130 once daily 400 once daily 14

sofosbuvir

0.95

(0.68,

1.33)

1.30

(1.00,

1.69)

331007

0.73

(0.65,

0.83)

1.04

(0.89,

1.22)

Rilpivirine

25 once daily

400 single

dose

sofosbuvir

1.21

(0.90,

1.62)

1.09

(0.94,

1.27)

331007

1.06

(0.99,

1.14)

1.01

(0.97,

1.04)

Tacrolimus

5 single dose

400 single

dose

sofosbuvir

0.97

(0.65,

1.43)

1.13

(0.81,

1.57)

331007

0.97

(0.83,

1.14)

1.00

(0.87,

1.13)

*

max

min

NA = not available/not applicable

No effect on the pharmacokinetic parameters of sofosbuvir and GS-331007 was observed with

raltegravir.

Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in

the Presence of Sofosbuvir

Coadminis tered

Drug

Dose of

Coadminis tered

Drug (mg)

Sofos buvir

Dose (mg)

N

Mean Ratio (90% CI) of

Coadministered Drug PK With/Without

Sofos buvir

No Effect=1.00

C

AUC

C

NA = not available/not applicable

Norelgestromin

norgestimate

0.18/0.215/0.25/ethinyl

estradiol 0.025 once

daily

400 once

daily

1.07

(0.94, 1.22)

1.06

(0.92, 1.21)

1.07

(0.89, 1.28)

Norgestrel

1.18

(0.99, 1.41)

1.19

(0.98, 1.45)

1.23

(1.00, 1.51)

Ethinyl estradiol

1.15

(0.97, 1.36)

1.09

(0.94, 1.26)

0.99

(0.80, 1.23)

Raltegravir

400 twice daily

400 single

dose

0.57

(0.44, 0.75)

0.73

(0.59, 0.91)

0.95

(0.81, 1.12)

Tacrolimus

5 single dose

400 single

dose

0.73

(0.59, 0.90)

1.09

(0.84, 1.40)

Tenofovir

disoproxil

fumarate

300 once daily

400 single

dose

1.25

(1.08, 1.45)

0.98

(0.91, 1.05)

0.99

(0.91, 1.07)

No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with

sofosbuvir: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, or rilpivirine.

12.4 Microbiology

Mechanism of Action

Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for

viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the

pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into

HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203

inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a, 3a and 4a with

values ranging from 0.7 to 2.6 micromolar. GS-461203 is neither an inhibitor of human DNA and

RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.

Antiviral Activity

In HCV replicon assays, the EC

values of sofosbuvir against full-length replicons from genotype 1a,

1b, 2a, 3a and 4a, and chimeric 1b replicons encoding NS5B from genotype 2b, 5a or 6a ranged from

0.014 to 0.11 micromolar. The median EC

value of sofosbuvir against chimeric replicons encoding

NS5B sequences from clinical isolates was 0.062 micromolar for genotype 1a (range 0.029–0.128

All interaction studies conducted in healthy volunteers

Administered as efavirenz/emtricitabine/tenofovir disoproxil fumarate fixed dose tablet

Comparison based on historic control

*

max

min

All interaction studies conducted in healthy volunteers

Administered as efavirenz/emtricitabine/tenofovir disoproxil fumarate fixed dose tablet

micromolar; N=67), 0.102 micromolar for genotype 1b (range 0.045–0.170 micromolar; N=29), 0.029

micromolar for genotype 2 (range 0.014–0.081 micromolar; N=15) and 0.081 micromolar for genotype

3a (range 0.024–0.181 micromolar; N=106). In infectious virus assays, the EC

values of sofosbuvir

against genotype 1a and 2a were 0.03 and 0.02 micromolar, respectively. The presence of 40% human

serum had no effect on the anti-HCV activity of sofosbuvir. Evaluation of sofosbuvir in combination

with interferon alpha or ribavirin showed no antagonistic effect in reducing HCV RNA levels in

replicon cells.

Resistance

In Cell Culture

HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple

genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated

with the primary NS5B substitution S282T in all replicon genotypes examined. An M289L substitution

developed along with the S282T substitution in genotype 2a, 5 and 6 replicons. Site-directed

mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced

susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to the

corresponding wild-type. In biochemical assays, recombinant NS5B polymerase from genotypes 1b, 2a,

3a and 4a expressing the S282T substitution showed reduced susceptibility to GS-461203 compared to

respective wild-types.

In Clinical Trials

In a pooled analysis of 982 subjects who received SOVALDI in Phase 3 trials, 224 subjects had post-

baseline NS5B genotypic data from next generation nucleotide sequencing (assay cutoff of 1%).

Treatment-emergent substitutions L159F (n=6) and V321A (n=5) were detected in post-baseline samples

from GT3a-infected subjects across the Phase 3 trials. No detectable shift in the phenotypic

susceptibility to sofosbuvir of subject isolates with L159F or V321A substitutions was seen. The

sofosbuvir-associated resistance substitution S282T was not detected at baseline or in the failure

isolates from Phase 3 trials. However, an S282T substitution was detected in one genotype 2b subject

who relapsed at Week 4 post-treatment after 12 weeks of sofosbuvir monotherapy in the Phase 2 trial

P7977-0523 [ELECTRON]. The isolate from this subject displayed a mean 13.5-fold reduced

susceptibility to sofosbuvir. For this subject, the S282T substitution was no longer detectable at Week

12 post-treatment by next generation sequencing with an assay cutoff of 1%.

In the trial done in subjects with hepatocellular carcinoma awaiting liver transplantation where subjects

received up to 48 weeks of sofosbuvir and ribavirin, the L159F substitution emerged in multiple

subjects with GT1a or GT2b HCV who experienced virologic failure (breakthrough and relapse).

Furthermore, the presence of substitutions L159F and/or C316N at baseline was associated with

sofosbuvir breakthrough and relapse post-transplant in multiple subjects infected with GT1b HCV. In

addition, S282R and L320F substitutions were detected on-treatment by next generation sequencing in a

subject infected with GT1a HCV with a partial treatment response.

The clinical significance of these substitutions is not known.

Cross Resistance

HCV replicons expressing the sofosbuvir-associated resistance substitution S282T were susceptible to

NS5A inhibitors and ribavirin. HCV replicons expressing the ribavirin-associated substitutions T390I

and F415Y were susceptible to sofosbuvir. Sofosbuvir was active against HCV replicons with NS3/4A

protease inhibitor, NS5B non-nucleoside inhibitor and NS5A inhibitor resistant variants.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis

Carcinogenesis and Mutagenesis

Use with Ribavirin and/or Peginterferon alfa: Refer to prescribing information for ribavirin and/or

peginterferon alfa for information on carcinogenesis and mutagenesis.

Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity,

chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus

assays.

Two-year carcinogenicity studies in mice and rats were conducted with sofosbuvir. Mice were

administered doses of up to 200 mg/kg/day in males and 600 mg/kg/day in females, while rats were

administered doses of up to 750 mg/kg/day in males and females. No increase in the incidence of drug-

related neoplasms were observed at the highest doses tested in mice and rats, resulting in AUC

exposure to the predominant circulating metabolite GS-331007 of approximately 7 and 30 times (in

mice) and 13 and 17 times (in rats), in males and females respectively, the exposure in humans at the

recommended clinical dose.

Impairment of Fertility

Use with Ribavirin and/or Peginterferon alfa: Refer to prescribing information for ribavirin and/or

peginterferon alfa for information on impairment of fertility.

Sofosbuvir had no effects on embryo-fetal viability or on fertility when evaluated in rats. At the highest

dose tested, AUC exposure to the predominant circulating metabolite GS-331007 was approximately 8

times the exposure in humans at the recommended clinical dose.

14 CLINICAL STUDIES

14.1 Description of Clinical Trials

The safety and efficacy of SOVALDI was evaluated in five Phase 3 trials in a total of 1724 HCV mono-

infected subjects with genotypes 1 to 6 chronic hepatitis C virus, one Phase 3 trial in 223 HCV/HIV-1

coinfected subjects with genotype 1, 2 or 3 HCV, and one trial in 50 pediatric subjects 12 years of age

and older with genotype 2 or 3 HCV, as summarized in Table 10 [see Clinical Studies (14.2, 14.3, 14.4,

and 14.5)].

Table 10 Trials Conducted with SOVALDI with Peginterferon Alfa and/or Ribavirin in Subjects

with Chronic HCV Genotype 1, 2, 3, or 4 Infection

T rial

Population

Study Arms (Number of Subjects Treated)

NEUTRINO

Treatment naïve (TN) (GT1, 4, 5 or

SOVALDI+Peg-IFN alfa+RBV 12 weeks (327)

FISSION

TN (GT2 or 3)

SOVALDI+RBV 12 Weeks (256)

Peg-IFN alfa+RBV 24 weeks (243)

POSITRON

Interferon intolerant, ineligible or

unwilling subjects (GT2 or 3)

SOVALDI+RBV 12 Weeks (207)

Placebo 12 weeks (71)

FUSION

Previous interferon relapsers or

nonresponders (GT2 or 3)

SOVALDI+RBV 12 Weeks (103)

SOVALDI+RBV 16 Weeks (98)

VALENCE

TN or previous interferon

relapsers or nonresponders (GT2

or 3)

SOVALDI+RBV 12 Weeks for GT2 (73)

SOVALDI+RBV 12 Weeks for GT3 (11)

SOVALDI+RBV 24 Weeks for GT3 (250)

Placebo for 12 weeks (85)

PHOTON-1

HCV/HIV-1 coinfected TN

(GT1)

HCV/HIV-1 coinfected TN or

previous interferon relapsers or

nonresponders (GT2 or 3)

SOVALDI+RBV 24 Weeks for GT1 (114)

SOVALDI+RBV 12 Weeks for GT2 or 3 TN (68)

SOVALDI+RBV 24 Weeks for GT2 or 3 previous

interferon relapsers or nonresponders (41)

Study 1112

(open-label)

GT2 or GT3 pediatric subjects 12

years of age and older

SOVALDI+RBV 12 Weeks for GT2 (13)

SOVALDI+RBV 24 Weeks for GT3 (37)

Subjects in the adult trials did not have cirrhosis or had compensated cirrhosis. SOVALDI was

administered at a dose of 400 mg once daily. The ribavirin (RBV) dosage for adult subjects was

weight-based at 1000–1200 mg daily administered in two divided doses when used in combination with

SOVALDI, and the peginterferon alfa 2a dosage, where applicable, was 180 micrograms per week.

Treatment duration was fixed in each trial and was not guided by subjects' HCV RNA levels (no

response guided algorithm). Plasma HCV RNA values were measured during the clinical trials using

the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a lower

limit of quantification (LLOQ) of 25 IU per mL. Sustained virologic response (SVR12) was the primary

endpoint which was defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment.

14.2 Clinical Trials in Subjects with Genotype 1 or 4 HCV

Treatment-Naïve Adults ─ NEUTRINO (Study 110)

NEUTRINO was an open-label, single-arm trial that evaluated 12 weeks of treatment with SOVALDI in

combination with peginterferon alfa 2a and ribavirin in treatment-naïve subjects with genotype 1, 4, 5 or

6 HCV infection compared to pre-specified historical control.

Treated subjects (N=327) had a median age of 54 years (range: 19 to 70); 64% of the subjects were

male; 79% were White, 17% were Black; 14% were Hispanic or Latino; mean body mass index was 29

kg/m (range: 18 to 56 kg/m ); 78% had baseline HCV RNA greater than 6 log

IU per mL; 17% had

cirrhosis; 89% had HCV genotype 1; 9% had HCV genotype 4 and 2% had HCV genotype 5 or 6.

Table 11 presents the SVR12 for the treatment group of SOVALDI + peginterferon alfa + ribavirin in

subjects with genotype 1 or 4 HCV. Available data on subjects with genotype 5 or 6 HCV treated with

SOVALDI + peginterferon alfa + ribavirin for 12 weeks were insufficient for dosing recommendations;

therefore these results are not presented in Table 11 [see Use in Specific Populations (8.10)].

Table 11 Study NEUTRINO: SVR12 for Treatment-Naïve Subjects with Genotype 1 or

4 HCV

SOVALDI + Peg-IFN alfa + RBV 12 weeks

N=320

Overall SVR

90% (289/320)

Genotype 1

90% (262/292)

Genotype 1a

92% (206/225)

Genotype 1b

83% (55/66)

Genotype 4

96% (27/28)

Outcome for subjects without SVR

On-treatment virologic failure

0/320

Relapse

9% (28/319)

Other

1% (3/320)

SVR12 for selected subgroups are presented in Table 12.

One subject had genotype 1a/1b mixed infection.

The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-

treatment assessment.

Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost

to follow-up).

Table 12 SVR12 Rates for Selected Subgroups in NEUTRINO in Subjects with

Genotype 1 or 4 HCV

SOVALDI + Peg-IFN alfa + RBV 12 weeks

Cirrhosis

93% (247/267)

79% (42/53)

Race

Black

87% (47/54)

Non-black

91% (242/266)

Multiple Baseline Factors

Genotype 1, Metavir F3/F4

fibrosis, IL28B non-C/C, HCV RNA

>800,000 IU/mL

71% (37/52)

SVR12 rates were 99% (89/90) in subjects with genotype 1 or 4 HCV and baseline IL28B C/C allele

and 87% (200/230) in subjects with genotype 1 or 4 HCV and baseline IL28B non-C/C alleles.

It is estimated that the SVR12 in patients who previously failed pegylated interferon and ribavirin

therapy will approximate the observed SVR12 in NEUTRINO subjects with multiple baseline factors

traditionally associated with a lower response to interferon-based treatment (Table 12). The SVR12 rate

in the NEUTRINO trial in genotype 1 subjects with IL28B non-C/C alleles, HCV RNA greater than

800,000 IU/mL and Metavir F3/F4 fibrosis was 71% (37/52).

14.3 Clinical Trials in Subjects with Genotype 2 or 3 HCV

Treatment-Naïve Adults ─ FISSION (Study 1231)

FISSION was a randomized, open-label, active-controlled trial that evaluated 12 weeks of treatment with

SOVALDI and ribavirin compared to 24 weeks of treatment with peginterferon alfa 2a and ribavirin in

treatment-naïve subjects with genotype 2 and 3 HCV. The ribavirin dosage used in the SOVALDI +

ribavirin and peginterferon alfa 2a + ribavirin arms were weight-based 1000–1200 mg per day and 800

mg per day regardless of weight, respectively. Subjects were randomized in a 1:1 ratio and stratified by

cirrhosis (presence vs. absence), HCV genotype (2 vs. 3) and baseline HCV RNA level (less than 6

IU/mL vs. at least 6 log

IU/mL). Subjects with genotype 2 or 3 HCV were enrolled in an

approximately 1:3 ratio.

Treated subjects (N=499) had a median age of 50 years (range: 19 to 77); 66% of the subjects were

male; 87% were White, 3% were Black; 14% were Hispanic or Latino; mean body mass index was 28

kg/m (range: 17 to 52 kg/m ); 57% had baseline HCV RNA levels greater than 6 log

IU per mL; 20%

had cirrhosis; 72% had HCV genotype 3. Table 13 presents the SVR12 for the treatment groups of

SOVALDI + ribavirin and peginterferon alfa + ribavirin in subjects with genotype 2 HCV. SVR12 for

genotype 3 subjects treated with SOVALDI + ribavirin for 12 weeks was suboptimal; therefore these

results are not presented in Table 13.

Table 13 Study FISSION: SVR12 in Treatment-Naïve Subjects with Genotype 2 HCV

SOVALDI + RBV 12 weeks

Peg-IFN alfa + RBV 24 weeks

N=73

N=67

SVR12

95% (69/73)

78% (52/67)

Outcome for subjects without SVR12

On-treatment virologic failure

0/73

4% (3/67)

Relapse

5% (4/73)

15% (9/62)

Other

0/73

4% (3/67)

*

*

SVR12 for genotype 2 HCV-infected subjects with cirrhosis at baseline are presented in Table 14.

Table 14 SVR12 Rates by Cirrhosis in Study FISSION in Subjects with

Genotype 2 HCV

SOVALDI + RBV

12 weeks

Peg-IFN alfa + RBV

24 weeks

N=73

N=67

Cirrhosis

97% (59/61)

81% (44/54)

83% (10/12)

62% (8/13)

Interferon Intolerant, Ineligible or Unwilling Adults ─ POSITRON (Study 107)

POSITRON was a randomized, double-blinded, placebo-controlled trial that evaluated 12 weeks of

treatment with SOVALDI and ribavirin (N=207) compared to placebo (N=71) in subjects who are

interferon intolerant, ineligible or unwilling. Subjects were randomized in 3:1 ratio and stratified by

cirrhosis (presence vs. absence).

Treated subjects (N=278) had a median age of 54 years (range: 21 to 75); 54% of the subjects were

male; 91% were White, 5% were Black; 11% were Hispanic or Latino; mean body mass index was 28

kg/m (range: 18 to 53 kg/m ); 70% had baseline HCV RNA levels greater than 6 log

IU per mL; 16%

had cirrhosis; 49% had HCV genotype 3. The proportions of subjects who were interferon intolerant,

ineligible, or unwilling were 9%, 44%, and 47%, respectively. Most subjects had no prior HCV

treatment (81%). Table 15 presents the SVR12 for the treatment groups of SOVALDI + ribavirin and

placebo in subjects with genotype 2 HCV. SVR12 for genotype 3 subjects treated with SOVALDI +

ribavirin for 12 weeks was suboptimal; therefore these results are not presented in Table 15.

Table 15 Study POSITRON: SVR12 in Interferon Intolerant, Ineligible or Unwilling Subjects with

Genotype 2 HCV

SOVALDI + RBV 12 weeks

Placebo 12 weeks

N=109

N= 34

SVR12

93% (101/109)

0/34

Outcome for subjects without SVR12

On-treatment virologic failure

0/109

97% (33/34)

Relapse

5% (5/107)

Other

3% (3/109)

3% (1/34)

Table 16 presents the subgroup analysis for cirrhosis and interferon classification in subjects with

genotype 2 HCV.

Including three subjects with recombinant genotype 2/1 HCV infection.

The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment

assessment.

Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-

up).

The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment

assessment.

Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-

up).

Table 16 SVR12 Rates for Selected Subgroups in POSITRON in Subjects

with Genotype 2 HCV

SOVALDI + RBV 12 weeks

N=109

Cirrhosis

92% (85/92)

94% (16/17)

Interferon Classification

Ineligible

88% (36/41)

Intolerant

100% (9/9)

Unwilling

95% (56/59)

Previously Treated Adults ─ FUSION (Study 108)

FUSION was a randomized, double-blinded trial that evaluated 12 or 16 weeks of treatment with

SOVALDI and ribavirin in subjects who did not achieve SVR with prior interferon-based treatment

(relapsers and nonresponders). Subjects were randomized in a 1:1 ratio and stratified by cirrhosis

(presence vs. absence) and HCV genotype (2 vs. 3).

Treated subjects (N=201) had a median age of 56 years (range: 24 to 70); 70% of the subjects were

male; 87% were White; 3% were Black; 9% were Hispanic or Latino; mean body mass index was 29

kg/m (range: 19 to 44 kg/m ); 73% had baseline HCV RNA levels greater than 6 log

IU per mL; 34%

had cirrhosis; 63% had HCV genotype 3; 75% were prior relapsers. Table 17 presents the SVR12 for

the treatment groups of SOVALDI + ribavirin for 12 weeks in subjects with genotype 2 HCV. Treatment

of 16 weeks in subjects with genotype 2 HCV was not shown to increase the SVR12 observed with 12

weeks of treatment. SVR12 for genotype 3 subjects treated with SOVALDI + ribavirin for 12 or 16

weeks was suboptimal; therefore these results are not presented in Table 17.

Table 17 Study FUSION: SVR12 in Previous Interferon Relapsers and

Nonresponders with Genotype 2 HCV

SOVALDI + RBV

12 weeks

N=39

SVR12

82% (32/39)

Outcome for subjects without SVR12

On-treatment virologic failure

0/39

Relapse

18% (7/39)

Other

0/39

Table 18 presents the subgroup analysis for cirrhosis and response to prior HCV treatment in subjects

with genotype 2 HCV.

Table 18 SVR12 Rates for Selected Subgroups in Study FUSION in Subjects with

Genotype 2 HCV

SOVALDI + RBV 12 weeks

*

Including three subjects with recombinant genotype 2/1 HCV infection.

The denominator for relapse is the number of subjects with HCV RNA <LLOQ at

their last on-treatment assessment.

Other includes subjects who did not achieve SVR and did not meet virologic failure

criteria (e.g., lost to follow-up).

N=39

Cirrhosis

90% (26/29)

60% (6/10)

Response to prior HCV treatment

Relapser/ breakthrough

86% (25/29)

Nonresponder

70% (7/10)

Treatment-Naïve and Previously Treated Adults ─ VALENCE (Study 133)

The VALENCE trial evaluated SOVALDI in combination with weight-based ribavirin for the treatment

of genotype 2 or 3 HCV infection in treatment-naïve subjects or subjects who did not achieve SVR with

prior interferon-based treatment, including subjects with compensated cirrhosis. The original trial

design was a 4 to 1 randomization to SOVALDI + ribavirin for 12 weeks or placebo. Based on

emerging data, this trial was unblinded and all genotype 2 HCV-infected subjects continued the original

planned treatment and received SOVALDI + ribavirin for 12 weeks, and duration of treatment with

SOVALDI + ribavirin in genotype 3 HCV-infected subjects was extended to 24 weeks. Eleven

genotype 3 subjects had already completed SOVALDI + ribavirin for 12 weeks at the time of the

amendment.

Treated subjects (N=419) had a median age of 51 years (range: 19 to 74); 60% of the subjects were

male; mean body mass index was 26 kg/m (range: 17 to 44 kg/m ); the mean baseline HCV RNA level

was 6.4 log

IU per mL; 78% had HCV genotype 3; 58% of the subjects were treatment-experienced

and 65% of those subjects experienced relapse/breakthrough to prior HCV treatment.

Table 19 presents the SVR12 for the treatment groups of SOVALDI + ribavirin for 12 weeks and 24

weeks.

Table 19 Study VALENCE : SVR12 in Subjects with Genotype 2 or 3 HCV Who were

Treatment-Naïve or Who Did Not Achieve SVR12 with Prior Interferon-Based Treatment

Genotype 2 SOVALDI

+ RBV

12 weeks

Genotype 3 SOVALDI

+ RBV

24 weeks

N=73

N=250

Overall SVR

93% (68/73)

84% (210/250)

Outcome for subjects without SVR

On-treatment virologic failure

0% (0/73)

<1% (1/250)

Relapse

7% (5/73)

14% (34/249)

Treatment-naïve

3% (1/32)

5% (5/105)

Treatment-experienced

10% (4/41)

20% (29/144)

Other

0% (0/73)

2% (5/250)

Table 20 presents the subgroup analysis by genotype for cirrhosis and prior HCV treatment experience.

Table 20 SVR12 Rates for Selected Subgroups by Genotype in Study VALENCE in Subjects with

Genotype 2 or 3 HCV

*

Placebo subjects (N=85) were not included as none achieved SVR12.

The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment

assessment.

Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to

follow- up).

Genotype 2 SOVALDI

+ RBV

12 weeks

Genotype 3 SOVALDI

+ RBV

24 weeks

N=73

N=250

Treatment-naïve

97% (31/32)

93% (98/105)

Non-cirrhotic

97% (29/30)

93% (86/92)

Cirrhotic

100% (2/2)

92% (12/13)

Treatment-experienced

90% (37/41)

77% (112/145)

Non-cirrhotic

91% (30/33)

85% (85/100)

Cirrhotic

88% (7/8)

60% (27/45)

14.4 Clinical Trials in Adult Subjects Coinfected with HCV and HIV-1

SOVALDI was studied in an open-label clinical trial (Study PHOTON-1) evaluating the safety and

efficacy of 12 or 24 weeks of treatment with SOVALDI and ribavirin in adult subjects with genotype 1,

2 or 3 chronic hepatitis C coinfected with HIV-1. Genotype 2 and 3 subjects were either HCV

treatment-naïve or experienced, whereas genotype 1 subjects were all treatment-naïve. Subjects

received 400 mg SOVALDI and weight-based ribavirin (1000 mg for subjects weighing less than 75 kg

or 1200 mg for subjects weighing at least 75 kg) daily for 12 or 24 weeks based on genotype and prior

treatment history. Subjects were either not on antiretroviral therapy with a CD4+ cell count greater than

500 cells/mm or had virologically suppressed HIV-1 with a CD4+ cell count greater than 200

cells/mm . Efficacy data 12 weeks post treatment are available for 210 subjects (see Table 21).

Table 21 Study PHOTON-1 : SVR12 in Treatment-Naïve or Treatment-Experienced

Subjects with Genotype 1, 2, or 3 HCV

HCV genotype 1

HCV genotype 2

HCV genotype 3

SOVALDI + RBV

24 weeks

TN (N=114)

SOVALDI + RBV

12 weeks

TN (N=26)

SOVALDI + RBV

24 weeks

TE (N=13)

TN = Treatment-naïve; TE = Treatment-experienced

Overall

76% (87/114)

88% (23/26)

92% (12/13)

Outcome for subjects without SVR12

On-treatment virologic

failure

1% (1/114)

4% (1/26)

0/13

Relapse

22% (25/113)

0/25

8% (1/13)

Other

1% (1/114)

8% (2/26)

0/13

In subjects with HCV genotype 1 infection, the SVR12 rate was 82% (74/90) in subjects with genotype

1a infection and 54% (13/24) in subjects with genotype 1b infection, with relapse accounting for the

majority of treatment failures. SVR12 rates in subjects with HCV genotype 1 infection were 80%

(24/30) in subjects with baseline IL28B C/C allele and 75% (62/83) in subjects with baseline IL28B non-

C/C alleles.

In the 223 HCV subjects with HIV-1 coinfection, the percentage of CD4+ cells did not change during

treatment. Median CD4+ cell count decreases of 85 cells/mm and 84 cells/mm were observed at the

*

Subjects with genotype 2 HCV treated with SOVALDI + RBV for 24 weeks (N=15) and subjects with

genotype 3 HCV treated with SOVALDI + RBV for 12 weeks (N=4 2) are not included in the table.

The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment

assessment.

Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to

follow- up).

end of treatment with SOVALDI + ribavirin for 12 or 24 weeks, respectively. HIV-1 rebound during

SOVALDI + ribavirin treatment occurred in 2 subjects (0.9%) on antiretroviral therapy.

14.5 Clinical Trial in Pediatrics

The efficacy of SOVALDI in HCV-infected pediatric subjects 12 years of age and older was evaluated

in 50 subjects with HCV genotype 2 (N = 13) or genotype 3 (N = 37) in a Phase 2, open label clinical

trial. Subjects with HCV genotype 2 or 3 infection in the trial were treated with SOVALDI and weight-

based ribavirin for 12 or 24 weeks, respectively [see Dosage and Administration (2.3)].

Of the 50 treated subjects, the median age was 15 years (range: 12 to 17); 42% of the subjects were

female; 90% were White, 4% were Black, and 2% were Asian; 4% were Hispanic/Latino; mean weight

was 61 kg (range: 30 to 101 kg); 18% were treatment experienced; 66% had baseline HCV RNA levels

greater than or equal to 800,000 IU/mL; 74% of subjects had non-CC IL28B alleles (CT or TT); and no

subjects had known cirrhosis. The majority of subjects (69%) had been infected through vertical

transmission.

The SVR12 rate was 100% (13/13) in genotype 2 subjects and 97% (36/37) in genotype 3 subjects. No

subject experienced on-treatment virologic failure or relapse.

16 HOW SUPPLIED/STORAGE AND HANDLING

SOVALDI tablets are white, capsule-shaped, film-coated tablets containing 400 mg sofosbuvir

debossed with "GSI" on one side and "7977" on the other side. Each bottle contains 28 tablets, a silica

gel desiccant and polyester coil with a child-resistant closure.

Store below 30°C (86°F).

Dispense only in original container

Do not use if seal over bottle opening is broken or missing

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the approved patient labeling (Patient Information).

Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV

Inform patients that HBV reactivation can occur in patients coinfected with HBV during or after

treatment of HCV infection. Advise patients to tell their healthcare provider if they have a history of

HBV infection [see Warnings and Precautions (5.1)].

Serious Symptomatic Bradycardia When Coadministered with Amiodarone

Advise patients to seek medical evaluation immediately for symptoms of bradycardia such as near-

fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of

breath, chest pain, confusion or memory problems [see Warnings and Precautions (5.2), Adverse

Reactions (6.2), and Drug Interactions (7.1)].

Pregnancy

Advise patients to avoid pregnancy during combination treatment with SOVALDI and ribavirin or

SOVALDI and peginterferon and ribavirin. Inform patients to notify their health care provider

immediately in the event of a pregnancy [see Use in Specific Populations (8.1)].

Drug Interactions

Advise patients that SOVALDI may interact with some drugs; therefore, patients should be advised to

report the use of any prescription, non-prescription medication or herbal products to their healthcare

provider [see Warnings and Precautions (5.3) and Drug Interactions (7.1)].

Hepatitis C Virus Transmission

Inform patients that the effect of treatment of hepatitis C infection on transmission is not known, and that

appropriate precautions to prevent transmission of the hepatitis C virus during treatment or in the event

of treatment failure should be taken.

Important Information on Coadministration with Ribavirin or Peginterferon and Ribavirin

Advise patients that the recommended regimen for patients with genotype 1 or 4 HCV infection is

SOVALDI administered in combination with peginterferon alfa and ribavirin and the recommended

regimen for patients with genotype 2 or 3 HCV infection is SOVALDI administered in combination with

ribavirin. If peginterferon and/or ribavirin are permanently discontinued, SOVALDI should also be

discontinued.

Manufactured and distributed by:

Gilead Sciences, Inc.

Foster City, CA 94404

SOVALDI and HARVONI are trademarks of Gilead Sciences, Inc., or its related companies. All other

trademarks referenced herein are the property of their respective owners.

©2019 Gilead Sciences, Inc. All rights reserved.

204671-GS-009A

Patient Information

SOVALDI™ (soh-VAHL-dee)

(s ofos buvir)

tablets

Important: SOVALDI is used in combination with other antiviral medicines. When taking

SOVALDI with ribavirin or in combination with peginterferon alfa and ribavirin you should also

read those Medication Guides. The information in this Patient Information Leaflet talks about

SOVALDI when it is used with ribavirin and in combination with peginterferon alfa and ribavirin.

What is the most important information I should know about SOVALDI?

SOVALDI can cause serious side effects, including:

Hepatitis B virus reactivation: Before starting treatment with SOVALDI, your healthcare provider

will do blood tests to check for hepatitis B virus infection. If you have ever had hepatitis B virus

infection, the hepatitis B virus could become active again during or after treatment of hepatitis C

virus with SOVALDI. Hepatitis B virus becoming active again (called reactivation) may cause

serious liver problems including liver failure and death. Your healthcare provider will monitor you

if you are at risk for hepatitis B virus reactivation during treatment and after you stop taking

SOVALDI.

For more information about side effects, see the section "What are the possible side effects of

SOVALDI?"

What is SOVALDI?

SOVALDI is a prescription medicine used with other antiviral medicines to treat adults with chronic

(lasting a long time) hepatitis C virus (HCV):

genotype 1 or 4 infection without cirrhosis or with compensated cirrhosis in combination with

peginterferon alfa and ribavirin

genotype 2 or 3 infection without cirrhosis or with compensated cirrhosis in combination with

ribavirin

SOVALDI is used to treat children 12 years of age and older or weighing at least 77 pounds (at least 35

kg) with chronic HCV genotype 2 or 3 infection without cirrhosis or with compensated cirrhosis in

combination with ribavirin.

It is not known if SOVALDI is safe and effective in children under 12 years of age and weighing less

than 77 pounds (less than 35 kg) with HCV genotype 2 or 3 infection, or with HCV genotype 1 or 4

infection.

It is not known if SOVALDI is safe and effective in people who have had a liver transplant.

Before taking SOVALDI, tell your healthcare provider about all of your medical conditions,

including if you:

have ever had hepatitis B virus infection

have liver problems other than hepatitis C infection

have had a liver transplant

have severe kidney problems or you are on dialysis

have HIV infection

are pregnant or plan to become pregnant. It is not known if SOVALDI will harm your unborn baby.

Males and females who take SOVALDI in combination with ribavirin should also read the

ribavirin Medication Guide for important pregnancy, contraception, and infertility

information.

are breastfeeding or plan to breastfeed. It is not known if SOVALDI passes into your breast milk.

Talk to your healthcare provider about the best way to feed your baby during treatment with

SOVALDI.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-

counter medicines, vitamins, and herbal supplements. SOVALDI and other medicines may affect each

other. This can cause you to have too much or not enough SOVALDI or other medicines in your body.

This may affect the way SOVALDI or your other medicines work, or may cause side effects.

Keep a list of your medicines to show your healthcare provider and pharmacist.

You can ask your healthcare provider or pharmacist for a list of medicines that interact with

SOVALDI.

Do not start taking a new medicine without telling your healthcare provider. Your healthcare

provider can tell you if it is safe to take SOVALDI with other medicines.

How should I take SOVALDI?

Take SOVALDI exactly as your healthcare provider tells you to take it. Do not change your dose

unless your healthcare provider tells you to.

Do not stop taking SOVALDI without first talking with your healthcare provider.

Take 1 SOVALDI tablet one time each day only.

Take SOVALDI with or without food.

If you take too much SOVALDI, call your healthcare provider or go to the nearest hospital

emergency room right away.

What are the possible side effects of SOVALDI?

SOVALDI can cause serious side effects, including:

Hepatitis B virus reactivation. See "What is the most important information I should know about

SOVALDI?"

Slow heart rate (bradycardia). SOVALDI treatment may result in slowing of the heart rate along

with other symptoms when taken with amiodarone (Cordarone™, Nexterone™, Pacerone™), a

medicine used to treat certain heart problems. In some cases bradycardia has led to death or the need

for a heart pacemaker when amiodarone is taken with SOVALDI. Get medical help right away if you

take amiodarone with SOVALDI and get any of the following symptoms:

fainting or near-fainting

dizziness or lightheadedness

not feeling well

weakness

extreme tiredness

shortness of breath

chest pain

confusion

memory problems

The most common side effects of SOVALDI when used in combination with ribavirin include:

tiredness

headache

The most common side effects of SOVALDI when used in combination with peginterferon alfa and

ribavirin include:

tiredness

headache

nausea

difficulty sleeping

low red blood cell count

These are not all the possible side effects of SOVALDI. For more information, ask your healthcare

provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to the US FDA at

www.fda.gov/medwatch or at 1-800-FDA-1088.

How should I store SOVALDI?

Store SOVALDI below 30°C (86°F).

Keep SOVALDI in its original container.

Do not use SOVALDI if the seal over the bottle opening is broken or missing.

Keep SOVALDI and all medicines out of the reach of children.

General information about the safe and effective use of SOVALDI.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information

leaflet. Do not use SOVALDI for a condition for which it was not prescribed. Do not give SOVALDI

to other people, even if they have the same symptoms you have. It may harm them. You can ask your

healthcare provider or pharmacist for information about SOVALDI that is written for health

professionals. For more information, go to www.SOVALDI.com.

What are the ingredients in SOVALDI?

Active ingredient: sofosbuvir

Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol,

and microcrystalline cellulose.

The tablet film-coat contains polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.

Manufactured and distributed by:

Gilead Sciences, Inc., Foster City, CA 94404

Issued: November 2017

SOVALDI and HARVONI are trademarks of Gilead Sciences, Inc., or its related companies. All other

trademarks referenced herein are the property of their respective owners.

©2019 Gilead Sciences, Inc. All rights reserved.

204671-GS-009A

PRINCIPAL DISPLAY PANEL - 400 mg Tablet Bottle Label

61958-1502-2

28 tablets

Sovaldi

(sofosbuvir) Tablets

400 mg

GILEAD ACCESS PROGRAM

Note to pharmacist:

Do not cover ALERT box with pharmacy label.

ALERT: Find out about medicines that

should NOT be taken with Sovaldi

SOVALDI ACCESS

sofosbuvir tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 19 58 -150 2

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

SO FO SBUVIR (UNII: WJ6 CA3ZU8 B) (SOFOSBUVIR - UNII:WJ6 CA3ZU8 B)

SOFOSBUVIR

40 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

MANNITO L (UNII: 3OWL53L36 A)

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

PO LYVINYL ALCO HO L, UNSPECIFIED (UNII: 532B59 J9 9 0 )

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

PO LYETHYLENE GLYCO L, UNSPECIFIED (UNII: 3WJQ0 SDW1A)

TALC (UNII: 7SEV7J4R1U)

WATER (UNII: 0 59 QF0 KO0 R)

Product Characteristics

Color

white

S core

no sco re

S hap e

OVAL (Capsule-shaped)

S iz e

20 mm

Flavor

Imprint Code

GSI;79 77

Gilead Sciences, Inc.

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 19 58 -150 2-2

28 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

12/0 6 /20 13

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

Expo rt o nly

12/0 6 /20 13

Labeler -

Gilead Sciences, Inc. (185049848)

Revised: 11/2019

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