The FDA approved Epclusa (sofosbuvir and velpatasvir) oral pellets (200/50 mg and 150/37.5 mg) for the treatment of genotypes 1, 2, 3, 4, 5, or 6, chronic hepatitis C virus (HCV) infection in pediatric patients who are at least 3 years of age. The approval is based on a phase 2, open-label, multicenter, multi-cohort study to investigate the safety and efficacy of Epclusa in a cohort of HCV infected children 3 to less than 6 years of age. In addition, a study was conducted to show the pellets are bioequivalent to the tablet formulation.

Below is a summary of the major changes to the product labeling.

1 INDICATIONS AND USAGE

• Revised the minimum patient age from 6 to 3 years of age.
• Removed the minimum patient body weight requirement.

 2 DOSAGE AND ADMINISTRATION

• Revised section 2.4 to include dosage recommendations for pediatric patients 3 years of age and older as follows:

The recommended dosage of EPCLUSA in pediatric patients 3 years of age and older is based on weight and provided in Table 2. Table 3 provides the weight-based dosage of ribavirin when used in combination with EPCLUSA for pediatric patients. Take EPCLUSA oral pellets or tablets once daily with or without food. In pediatric patients less than 6 years of age, administer the oral pellets with food to increase tolerability related to palatability

Less than 17 kg: take one 150mg/37.5 mg packet of Epclusa oral pellets once daily

17 to less than 30 kgs: take one 200 mg/50 mg packet of Epclusa oral pellets once daily OR take one 200/50 mg Epclusa tablet once daily

At least 30 kgs: take two 200 mg/50 mg packets of Epclusa oral pellets once daily OR take one 400 mg/50 mg Epclusa tablet once daily (two 200/50 mg Epclusa tablet once daily can be used for patients who cannot swallow the 400mg/100mg tablet.

• Addition of subsection 2.5, entitled, “Preparation and Administration of Oral Pellets”.

See the EPCLUSA oral pellets full Instructions for Use for details on the preparation and administration of EPCLUSA oral pellets.

Do not chew EPCLUSA oral pellets to avoid a bitter aftertaste. EPCLUSA oral pellets can be taken directly in the mouth or with food (See Instructions for Use). In pediatric patients less than 6 years of age, administer the oral pellets with food to increase tolerability related to palatability. Sprinkle the oral 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, and ice cream. Take EPCLUSA oral pellets within 15 minutes of gently mixing with food and swallow the entire contents without chewing

 6 ADVERSE REACTIONS

• Added adverse reaction data for pediatric subjects 3 to less than 6 years of age.

Among the 41 pediatric subjects less than 6 years of age, gastrointestinal adverse reactions were reported more commonly compared to subjects 6 years of age and older. Vomiting and product use issue (spitting up the drug) were reported in 15% and 10% of subjects, respectively; these adverse reactions were mild (Grade 1 or 2) and led to treatment discontinuation in 5 (12%) subjects

8 USE IN SPECIFIC POPULATIONS

• 8.4 Pediatric use
  • Updated with data from pediatric patients 3 years of age and older

The safety and effectiveness in pediatric subjects were comparable to those observed in adults. However, among the 41 pediatric subjects less than 6 years of age, vomiting and product use issue (spitting up the drug) were reported more frequently (15% and 10%, respectively; all Grade 1 or 2) compared to subjects 6 years of age and older. Five subjects (12%) discontinued treatment after vomiting or spitting up the drug

12 CLINICAL PHARMACOLOGY

• 12.3 Pharmacokinetics
  • Under Specific Populations:  Pediatric Patients subsection, the pharmacokinetic data from patients 3 to 6 years of age and older were added.

Sofosbuvir AUCtau and Cmax and velpatasvir Cmax values were 67%, 69%, and 78% higher in pediatric subjects >30 kg, 68%, 70%, and 96% higher in pediatric subjects 17 to <30 kg, and 103%, 135%, and 92% higher in pediatric subjects <17 kg compared to those observed in adults. These differences were not considered clinically significant. GS-331007 exposures and velpatasvir AUCtau and Ctau values in pediatric subjects were similar to those observed in adults.

14 CLINICAL STUDIES

• 14.7 Clinical Trials in Pediatric Subjects
  • Updated to include data from pediatric subjects 3 to less than 6 years of age.

Subjects 3 Years to <6 Years of Age: EPCLUSA was evaluated in 41 treatment-naïve subjects 3 years to <6 years of age with genotype 1, 2, 3, or 4 HCV infection. The median age was 4 years (range: 3 to 5); 59% of the subjects were female; 78% were White, 7% were Black; 10% were Hispanic/Latino; mean body mass index was 17.0 kg/m2 (range: 13.9 to 22.0 kg/m2); mean weight was 19 kg (range: 13 to 35 kg); 49% had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; the proportions of subjects with genotype 1, 2, 3, or 4 HCV infection were 78%, 15%, 5%, and 2%, respectively; no subjects had known cirrhosis. The majority of subjects (98%) had been infected through vertical transmission.

The SVR12 rate among all subjects was 83% (34/41); with 88% (28/32) in subjects with genotype 1 HCV infection, 50% (3/6) in subjects with genotype 2 HCV infection, and 100% in subjects with genotype 3 (2/2) and genotype 4 (1/1) HCV infection. None of the 34 subjects who completed the treatment had virologic failure. Of the remaining seven subjects who did not achieve SVR12, five discontinued treatment on Day 1, one on Day 7, and one on Day 20