(FDA) has approved supplemental indications for Harvoni® (ledipasvir 90 mg/sofosbuvir 400 mg) tablets and Sovaldi® (sofosbuvir 400 mg) tablets for the treatment of chronic hepatitis C virus (HCV) infection in adolescents without cirrhosis or with compensated cirrhosis, 12 years of age and older, or weighing at least 35kg. Harvoni was approved for pediatric patients with genotype 1, 4, 5 or 6 chronic HCV infection. Sovaldi was approved for pediatric patients with genotype 2 or 3 chronic HCV infection, in combination with ribavirin. There are an estimated 23,000-46,000 pediatric HCV patients in the United States, most of whom were infected with the virus at birth.
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FDA Update
FDA approves two Hepatitis C drugs for pediatric patients
Today, April 7, 2017 the FDA approved supplemental applications for Sovaldi (sofosbuvir) and Harvoni (ledipasvir and sofosbuvir) to treat hepatitis C virus (HCV) in children ages 12 to 17 or weighing at least 35 kilograms.
These approvals provide pediatric treatment options for six major genotypes, or strains, of the HCV virus. Harvoni is indicated for the treatment of pediatric patients 12 years of age and older or weighing at least 35 kilograms with HCV genotype 1, 4, 5 or 6 infection without cirrhosis or with compensated cirrhosis. Sovaldi in combination with ribavirin is indicated for the treatment of pediatric patients 12 years of age and older or weighing at least 35 kilograms with genotype 2 or 3 HCV infection without cirrhosis or with compensated cirrhosis.
The specific changes for each label are summarized below
Sovaldi
Section 1: INDICATIONS AND USAGE
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
Section 2: DOSAGE AND ADMINISTRATION
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. 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-experienceda without cirrhosis or with compensated cirrhosis (Child-Pugh A)
|
SOVALDI + ribavirinb 12 weeks
|
Genotype 3
|
Treatment-naïve and treatment-experienceda without cirrhosis or with compensated cirrhosis (Child-Pugh A)
|
SOVALDI + ribavirinb 24 weeks
|
b. See Table 3 for weight-based ribavirin dosing recommendations.
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 Dosagea
|
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
|
Section 6: ADVERSE REACTIONS
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.
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.
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.Section 12: CLINICAL PHARMACOLOGY
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 4. Exposures in pediatric subjects were similar to those observed in adults.
Table 4 Pharmacokinetic Properties of SOVALDI in HCV-infected
Pediatric Subjects 12 Years of Age and Oldera | ||
Geometric Mean
|
Sofosbuvirb
|
GS-331007b
|
|---|---|---|
AUCtau (ng•hr/mL)
|
1060
|
7570
|
Cmax (ng/mL)
|
472
|
572
|
b. Sofosbuvir N=28; GS-331007 N=50
The pharmacokinetics of sofosbuvir have not been established in pediatric subjects less than 12 years of age.
Section 14: CLINICAL STUDIES
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.
Harvoni
S
ection 1: INDICATIONS AND USAGE
Pediatric Patients:
HARVONI is indicated for the treatment of pediatric patients 12 years of age and older or weighing at least 35 kg with HCV genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis
Section 2: DOSAGE AND ADMINISTRATION
2.3 Recommended Dosage in Pediatric Patients 12 Years of Age and Older or Weighing at Least 35 kg
The recommended dosage of HARVONI in pediatric patients 12 years of age and older or weighing at least 35 kg is one tablet (90 mg ledipasvir and 400 mg sofosbuvir) taken orally once daily with or without food for 12 weeks.
Table 2 shows the recommended HARVONI duration based on pediatric patient population.
For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 2 [.
Table 2 Recommended Regimen and Duration for HARVONI in Pediatric Patients 12 Years of Age or Older or Weighing at Least 35 kg with Genotype 1, 4, 5, or 6 HCV without Cirrhosis or with Compensated Cirrhosis
| ||
|---|---|---|
| Patient Population | Treatment Regimen and Duration | |
| Genotype 1 | Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A) | HARVONI 12 weeks |
| Treatment-experienceda without cirrhosis | HARVONI 12 weeks | |
| Treatment-experienceda with compensated cirrhosis (Child-Pugh A) | HARVONI 24 weeks | |
| Genotype 4, 5, or 6 | Treatment-naïve and treatment-experienceda without cirrhosis or with compensated cirrhosis (Child-Pugh A) | HARVONI 12 weeks |
Section 6: ADVERSE REACTIONS
Adverse Reactions in Pediatric Subjects 12 Years of Age and Older
The safety assessment of HARVONI in pediatric subjects 12 years of age and older is based on data from a Phase 2, open-label clinical trial (Study 1116) that enrolled 100 subjects without cirrhosis or with compensated cirrhosis who were treated with HARVONI for 12 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.
6.2 Postmarketing Experience
Skin and Subcutaneous Tissue Disorders
AngioeAngioedema
8.4 Pediatric Use
The safety, pharmacokinetics, and efficacy of HARVONI for treatment of HCV genotype 1 infection in treatment-naïve and treatment-experienced pediatric patients 12 years of age and older without cirrhosis or with compensated cirrhosis have been established in an open-label, multicenter clinical trial (Study 1116, N=100; 80 treatment-naïve, 20 treatment-experienced) and are comparable to that observed in adults. The safety and efficacy of HARVONI for treatment of HCV genotypes 4, 5, or 6 infection in pediatric patients 12 years of age and older or weighing at least 35 kg without cirrhosis or with compensated cirrhosis is supported by comparable ledipasvir, sofosbuvir, and GS-331007 exposures between adults and adolescents with HCV genotype 1 and similar efficacy and exposures across HCV genotypes 1, 4, 5, and 6 in adults.
The safety and efficacy of HARVONI have not been established in pediatric patients less than 12 years of age and weighing less than 35 kg, in pediatric patients with decompensated cirrhosis, or in pediatric liver transplant recipients
Section 12: CLINICAL PHARMACOLOGY
Pediatric Patients: The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were determined in 100 pediatric subjects 12 years of age and older infected with HCV genotype 1 receiving a daily dose of HARVONI (90 mg ledipasvir and 400 mg sofosbuvir). The pharmacokinetic properties of ledipasvir, sofosbuvir, and GS-331007 in pediatric subjects 12 years of age and older are provided in Table 6. Exposures in pediatric subjects were similar to those observed in adults.
The pharmacokinetics of ledipasvir or sofosbuvir have not been established in pediatric patients less than 12 years of age
Section 14: CLINICAL STUDIES
14.6 Clinical Trial in Pediatric Subjects
The efficacy of HARVONI was evaluated in an open-label trial (Study 1116) that evaluated 12 weeks of treatment with HARVONI once daily in genotype 1 HCV treatment-naïve (N=80) and treatment-experienced (N=20) pediatric subjects 12 years of age and older without cirrhosis or with compensated cirrhosis.
Demographics and baseline characteristics were balanced across treatment-naïve and treatment-experienced subjects (patients had failed an interferon based regimen with or without ribavirin). Of the 100 treated subjects, the median age was 15 years (range: 12 to 17); 63% of the subjects were female; 90% were White, 7% were Black, and 2% were Asian; 13% were Hispanic/Latino; mean body mass index was 23 kg/m2 (range: 13.1 to 36.6 kg/m2); mean weight was 61 kg (range 33 to 126 kg); 55% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 81% had genotype 1a HCV infection; 76% had non-CC IL28B alleles (CT or TT). One subject had known compensated cirrhosis. The majority of subjects (84%) had been infected through vertical transmission.
The SVR12 rate was 98% overall (98% [78/80] in treatment-naïve subjects and 100% [20/20] in treatment-experienced subjects). No subject experienced on-treatment virologic failure or relapse. Two subjects were lost to follow-up.
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
Office of Health and Constituent Affairs
Food and Drug Administration
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Division of Antiviral Products
Food and Drug Administration
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