SOVALDI
INDICATIONS AND USAGE
SOVALDI is indicated for the treatment of chronic HCV genotype 2 or 3 infection in pediatric patients 3 years of age and older without cirrhosis or with compensated cirrhosis for use in combination with ribavirin.
DOSAGE AND ADMINISTRATION
Recommended Dosage in Pediatric Patients 3 Years of Age and Older with Genotype 2 or 3 HCV
The recommended treatment regimen, duration, and recommended dosage for SOVALDI combination therapy is provided below along with 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 below. In pediatric 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.
Recommended Treatment Regimen and Duration in Pediatric Patients 3 Years and Older with Genotype 2 or 3 HCV
- Genotype 2: Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A)
o SOVALDI + ribavirin 12 weeks
- Genotype 3: Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A)
o SOVALDI + ribavirin 24 weeks
The recommended dosage of SOVALDI in pediatric patients 3 years and older with genotype 2 or 3 HCV using SOVALDI tablets or oral pellets (with or without food) is based on weight, and is to be taken orally once daily in combination with ribavirin SOVALDI pellets can be taken by pediatric patients who cannot swallow the tablet formulation.
Dosing for Pediatric Patients 3 Years and Older Using SOVALDI Tablets or Oral Pellets
At least 35 kg- SOVALDI Daily Dose of 400 mg per day taken as
- one 400 mg tablet once daily
or
- two 200 mg tablets once daily
or
- two 200 mg packets of pellets once daily
17 to less than 35 kg - SOVALDI Daily Dose of 200 mg per day taken as
- one 200 mg tablet once daily
or
- one 200 mg packet of pellets once daily
less than 17 kg - SOVALDI Daily Dose of 150 mg per day taken as
- one 150 mg packet of pellets once daily
Recommended Dosing for Ribavirin in Combination Therapy with SOVALDI for Pediatric Patients 3 Years and Older
Less than 47 kg: Oral Ribavirin Daily Dosage = 15 mg per kg per day (divided dose AM and PM)
47–49 kg: Oral Ribavirin Daily Dosage = 600 mg per day (1 x 200 mg AM, 2 x 200 mg PM)
50–65 kg: Oral Ribavirin Daily Dosage = 800 mg per day (2 x 200 mg AM, 2 x 200 mg PM)
66–80 kg: Oral Ribavirin Daily Dosage = 1000 mg per day (2 x 200 mg AM, 3 x 200 mg PM)
greater than 80 kg: Oral Ribavirin Daily Dosage = 1200 mg per day (3 x 200 mg AM, 3 x 200 mg PM)
Preparation and Administration of Oral Pellets
Do not chew SOVALDI pellets. If SOVALDI pellets are administered with food, sprinkle the pellets on one or more spoonfuls of non-acidic soft food at or below room temperature. Examples of non-acidic foods include pudding, chocolate syrup, mashed potato, and ice cream. Take SOVALDI pellets within 30 minutes of gently mixing with food and swallow the entire contents without chewing to avoid a bitter aftertaste.
DOSAGE FORMS AND STRENGTHS
SOVALDI is available as tablets or pellets for oral use. Each dosage form is available in two dose strengths.
- 400 mg Tablets: 400 mg sofosbuvir: yellow, capsule-shaped, film-coated tablet debossed with “GSI” on one side and “7977” on the other side.
- 200 mg Tablets: 200 mg sofosbuvir: yellow, oval-shaped, film-coated tablet debossed with “GSI” on one side and “200” on the other side.
- 200 mg Pellets: 200 mg sofosbuvir: white to off-white pellets in unit-dose packets.
- 150 mg Pellets: 150 mg sofosbuvir: white to off-white pellets in unit-dose packets.
ADVERSE REACTIONS
Adverse Reactions in Pediatric Subjects 3 Years of Age and Older
The safety assessment of SOVALDI in pediatric subjects 3 years of age and older is based on data from 106 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. Among pediatric subjects 3 years to < 12 years of age taking SOVALDI in combination with ribavirin oral solution, decreased appetite was observed in 13% (7/54) subjects.
USE IN SPECIFIC POPULATIONS
Pediatric Use
The safety, pharmacokinetics, and efficacy of SOVALDI in pediatric patients 3 years of age and older with genotype 2 and 3 infection have been established. SOVALDI was evaluated in an open-label clinical trial (Study 1112), which included 106 subjects (31 genotype 2; 75 genotype 3) 3 years of age and older. The safety, pharmacokinetics, and efficacy were comparable to that observed in adults.
The safety and efficacy of SOVALDI in pediatric patients 3 years of age and older with compensated cirrhosis is supported by comparable sofosbuvir and GS-331007 exposures between: 1) adults and pediatric patients without cirrhosis and 2) adults without cirrhosis and adults with compensated cirrhosis. Thus, similar efficacy would be expected for pediatric patients with compensated cirrhosis as adults with compensated cirrhosis.
The safety and efficacy of SOVALDI have not been established in pediatric patients less than 3 years of age 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.
Pharmacokinetics
Pediatric Patients
Exposures in pediatric subjects were similar to those observed in adults. Refer to Package Insert for specific details.
The pharmacokinetics of sofosbuvir and GS-331007 have not been established in pediatric subjects less than 3 years of age.
CLINICAL STUDIES
Clinical Trial in Pediatrics (Study 1112)
The efficacy of SOVALDI in HCV-infected pediatric subjects 3 years of age and older was evaluated in 106 subjects with HCV genotype 2 (N = 31) or genotype 3 (N = 75) 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.
Subjects 6 Years to < 12 Years of Age: SOVALDI was evaluated in 41 subjects 6 years to < 12 years of age with HCV genotype 2 (N = 13) or genotype 3 (N = 28) infection. The median age was 9 years (range: 6 to 11); 73% of the subjects were female; 71% were White and 20% were Asian; 15% were Hispanic/Latino; mean body mass index was 19 kg/m2 (range: 13 to 32 kg/m2); mean weight was 34 kg (range 15 to 80 kg); 98% were treatment naive; 46% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; and no subjects had known cirrhosis. The majority of subjects (98%) had been infected through vertical transmission.
The SVR12 rate was 100% (13/13) in genotype 2 and 100% (28/28) in genotype 3 subjects.). No subjects experienced on-treatment virologic failure or relapse.
Subjects 3 Years to < 6 Years of Age: SOVALDI was evaluated in 13 subjects 3 years to < 6 years of age with HCV genotype 2 (N = 5) or genotype 3 (N = 8) infection. The median age was 4 years (range: 3 to 5); 77% of the subjects were female; 69% were White, 8% were Black, and 8% were Asian; 8% were Hispanic/Latino; mean body mass index was 15 kg/m2 (range: 13 to 17 kg/m2); mean weight was 17 kg (range 13 to 19 kg); 100% were treatment naive; 23% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; and no subjects had known cirrhosis. The majority of subjects (85%) had been infected through vertical transmission.
The SVR12 rate was 80% (4/5) in genotype 2 subjects and 100% (8/8) in genotype 3 subjects. No subjects experienced on-treatment virologic failure or relapse. One subject prematurely discontinued study treatment due to an adverse event.
HARVONI
INDICATIONS AND USAGE
HARVONI is indicated for the treatment of adults and pediatric patients 3 years of age and older with chronic hepatitis C virus (HCV):
- genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis
- genotype 1 infection with decompensated cirrhosis, for use in combination with ribavirin
- genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, for use in combination with ribavirin
DOSAGE AND ADMINISTRATION
Recommended Treatment Regimen and Duration in Patients 3 Years of Age and Older with Genotype 1, 4, 5, or 6 HCV
Below are the recommended HARVONI treatment regimen and duration based on patient population. Relapse rates are affected by baseline host and viral factors and differ between treatment durations for certain subgroups
For patients with HCV/HIV-1 coinfection, follow the dosage recommendations below.
Genotype 1
Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A):
Treatment-experienced without cirrhosis:
Treatment-experienced with compensated cirrhosis (Child-Pugh A):
Treatment-naïve and treatment-experienced with decompensated cirrhosis (Child-Pugh B or C):
- HARVONI + ribavirin 12 weeks
Genotype 1 or 4
Treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis, or with compensated cirrhosis (Child-Pugh A)
- HARVONI + ribavirin 12 weeks
Genotype 4, 5, or 6
Treatment-naïve and treatment-experienced, without cirrhosis or with compensated cirrhosis (Child-Pugh A)
Recommended Dosage in Pediatric Patients 3 Years of Age and Older
The recommended dosage of HARVONI in pediatric patients 3 years of age and older with genotype 1, 4, 5, or 6 HCV using HARVONI tablets or oral pellets is based on weight. Below is the weight-based dosage of ribavirin when used in combination with HARVONI for pediatric patients. Take HARVONI tablets or pellets (with or without food) once daily. HARVONI pellets can be taken in pediatric patients who cannot swallow the tablet formulation.
Dosing for Pediatric Patients 3 Years and Older Using HARVONI Tablets or Oral Pellets
At least 35 kg- HARVONI Daily Dose of 90 mg/400 mg per day taken as
- one 90 mg/400 mg tablet once daily
or
- two 45 mg/200 mg tablets once daily
or
- two 45 mg/200 mg packets of pellets once daily
17 to less than 35 kg- HARVONI Daily Dose of 45 mg/200 mg per day taken as
- one 45 mg/200 mg tablet once daily
or
- one 45 mg/200 mg packet of pellets once daily
less than 17 kg- HARVONI Daily Dose of 33.75 mg/150 mg per day taken as
- one 33.75 mg/150 mg packet of pellets once daily
Recommended Dosing for Ribavirin in Combination Therapy with HARVONI for Pediatric Patients 3 Years and Older
Less than 47 kg: Oral Ribavirin Daily Dosage = 15 mg per kg per day (divided dose AM and PM)
47–49 kg: Oral Ribavirin Daily Dosage = 600 mg per day (1 x 200 mg AM, 2 x 200 mg PM)
50–65 kg: Oral Ribavirin Daily Dosage = 800 mg per day (2 x 200 mg AM, 2 x 200 mg PM)
66–80 kg: Oral Ribavirin Daily Dosage = 1000 mg per day (2 x 200 mg AM, 3 x 200 mg PM)
greater than 80 kg: Oral Ribavirin Daily Dosage = 1200 mg per day (3 x 200 mg AM, 3 x 200 mg PM)
Preparation and Administration of Oral Pellets
Do not chew HARVONI pellets. If HARVONI pellets are administered with food, sprinkle the pellets on one or more spoonfuls of non-acidic soft food at or below room temperature. Examples of non-acidic foods include pudding, chocolate syrup, mashed potato, and ice cream. Take HARVONI pellets within 30 minutes of gently mixing with food and swallow the entire contents without chewing to avoid a bitter aftertaste.
DOSAGE FORMS AND STRENGTHS
HARVONI is available as tablets or pellets for oral use. Each dosage form is available in two dose strengths.
- 90 mg/400 mg Tablets: orange, diamond-shaped, film-coated tablet debossed with “GSI” on one side and “7985” on the other side of the tablet. Each tablet contains 90 mg ledipasvir and 400 mg sofosbuvir.
- 45 mg/200 mg Tablets: white, capsule-shaped, film-coated tablets, debossed with “GSI” on one side and “HRV” on the other side. Each tablet contains 45 mg ledipasvir and 200 mg sofosbuvir.
- 45 mg/200 mg Pellets: orange pellets in unit-dose packets. Each packet contains 45 mg ledipasvir and 200 mg sofosbuvir.
- 33.75 mg/150 mg Pellets: orange pellets in unit-dose packets. Each packet contains 33.75 mg ledipasvir and 150 mg sofosbuvir.
ADVERSE REACTIONS
Adverse Reactions in Pediatric Subjects 3 Years of Age and Older
The safety assessment of HARVONI in pediatric subjects 3 years of age and older is based on data from a Phase 2, open-label clinical trial (Study 1116). In total, 226 subjects were enrolled, which included 223 subjects without cirrhosis or with compensated cirrhosis who were treated with HARVONI for 12 weeks; one genotype 1 treatment-experienced subject with cirrhosis who was treated with HARVONI for 24 weeks; and two genotype 3 subjects who were treated with HARVONI + ribavirin for 24 weeks. The adverse reactions observed were consistent with those observed in clinical studies of HARVONI in adults. Limited safety data are available in pediatric subjects receiving HARVONI for 24 weeks. No Grade 3 or 4 adverse reactions or discontinuation due to an adverse reaction was observed in those pediatric subjects receiving HARVONI for 24 weeks.
USE IN SPECIFIC POPULATIONS
Pediatric Use
The safety, pharmacokinetics, and efficacy of HARVONI for treatment of HCV genotype 1 and 4 infection in treatment-naïve and treatment-experienced pediatric patients 3 years of age and older without cirrhosis or with compensated cirrhosis have been established in an open-label, multicenter clinical trial (Study 1116, N=226; 186 treatment-naïve, 40 treatment-experienced) and are comparable to that observed in adults.
The safety and efficacy of HARVONI for treatment of HCV genotypes 5 or 6 infection in pediatric patients 3 years of age and older without cirrhosis or with compensated cirrhosis is supported by comparable ledipasvir, sofosbuvir, and GS-331007 exposures between adults and pediatric patients with HCV genotype 1 and 4, and similar efficacy and exposures across HCV genotypes 1, 4, 5, and 6 in adults. Similar rationale is used to support dosing recommendations for pediatric patients with HCV genotype 1 infection who have decompensated cirrhosis (Child-Pugh B or C) and for pediatric patients with HCV genotype 1 and 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis.
The safety and efficacy of HARVONI have not been established in pediatric patients less than 3 years of age.
Pharmacokinetics
Pediatric Patients: Exposures in pediatric subjects were similar to those observed in adults. Please refer to the package insert for details.
The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 have not been established in pediatric subjects less than 3 years of age.
CLINICAL STUDIES
Clinical Trial in Pediatric Subjects
The efficacy of HARVONI was evaluated in an open-label trial (Study 1116) in 224 HCV treatment-naïve (N=186) and treatment-experienced (N=38) pediatric subjects 3 years of age or older. This study evaluated 12 weeks of treatment with HARVONI once daily in genotype 1 (N=183) or genotype 4 (N=3) treatment-naive subjects without cirrhosis or with compensated cirrhosis; genotype 1 treatment-experienced subjects without cirrhosis (N=37); and evaluated 24 weeks of treatment with HARVONI once daily in one genotype 1 subject who was both treatment-experienced and cirrhotic.
Subjects 6 Years to < 12 Years of Age: HARVONI was evaluated in 90 subjects 6 years to < 12 years of age with HCV genotype 1 or 4 infection. Among these subjects, 72 (80%) were treatment-naïve and 18 (20%) were treatment-experienced. Eighty-nine of the subjects (87 with genotype 1 HCV infection and 2 with genotype 4 HCV infection) were treated with HARVONI for 12 weeks, 1 subject with genotype 1 HCV infection was treated with HARVONI for 24 weeks. The median age was 9 years (range: 6 to 11); 59% of the subjects were male; 79% were White, 8% were Black, and 6% were Asian; 10% were Hispanic/Latino; mean body mass index was 18 kg/m2 (range: 13 to 31kg/m2); mean weight was 33 kg (range 18 to 76 kg); 59% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 86% had genotype 1a HCV infection; 2 subjects (1 treatment-naïve, 1 treatment-experienced) had known compensated cirrhosis. The majority of subjects (97%) had been infected through vertical transmission.
The SVR12 rate was 99% (86/87) in subjects with genotype 1 HCV infection, and 100% (2/2) in subjects with genotype 4 HCV infection. The one genotype 1 subject treated with HARVONI for 24 weeks also achieved SVR12. The one subject (genotype 1) who did not achieve SVR12 and relapsed had been treated with HARVONI for 12 weeks.
Subjects 3 Years to < 6 Years of Age: HARVONI was evaluated in 34 subjects 3 years to < 6 years of age with HCV genotype 1 (N = 33) or genotype 4 (N = 1) infection. All of the subjects were treatment-naïve and treated with HARVONI for 12 weeks. The median age was 5 years (range: 3 to 5); 71% of the subjects were female; 79% were White, 3% were Black, and 6% were Asian; 18% were Hispanic/Latino; mean body mass index was 17 kg/m2 (range: 13 to 25 kg/m2); mean weight was 19 kg (range 11 to 34 kg); 56% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 82% had genotype 1a HCV infection; no subjects had known cirrhosis. All subjects (100%) had been infected through vertical transmission.
The SVR12 rate was 97% (32/33) in subjects with genotype 1 HCV infection, and the one subject with genotype 4 HCV infection also achieved SVR12. One subject prematurely discontinued study treatment due to an adverse event.
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