On February 12, 2016, the FDA approved changes to the Harvoni (ledipasvir and sofosbuvir) fixed-dose combination label to expand the patient population to include those with chronic hepatitis C virus genotype 1, infection who are liver transplant recipients, genotype 4 infection who are liver transplant recipients without cirrhosis, or with compensated cirrhosis, and genotype 1 infection with decompensated cirrhosis. The major changes to the label are the following.
INDICATIONS AND USAGE
HARVONI is indicated with or without ribavirin for the treatment of patients with chronic hepatitis C virus (HCV) genotype 1, 4, 5, or 6 infection.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
Recommended Treatment Regimen and Duration for HARVONI in Patients with Genotype 1, 4, 5 or 6 HCV
|
Patient Population |
Treatment Regimen and Duration | |
|---|---|---|
|
Genotype 1 |
Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A) |
HARVONI 12 weeks* |
|
Treatment-experienced** without cirrhosis |
HARVONI 12 weeks |
|
|
Treatment-experienced** with compensated cirrhosis (Child-Pugh A) |
HARVONI 24 weeks† |
|
|
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) |
HARVONI 12 weeks |
* HARVONI for 8 weeks can be considered in treatment-naïve genotype 1 patients without cirrhosis who have pre‑treatment HCV RNA less than 6 million IU/mL [see Clinical Studies (14.2)].
** Treatment-experienced patients include those who have failed a peginterferon alfa + ribavirin based regimen with or without an HCV protease inhibitor.
† HARVONI+ribavirin for 12 weeks can be considered in treatment-experienced genotype 1 patients with cirrhosis who are eligible for ribavirin [see Clinical Studies (14.2)]. See footnote § for ribavirin dosage recommendations.
‡ In patients with decompensated cirrhosis, the starting dosage of ribavirin is 600 mg and can be titrated up to 1000 mg for patients <75 kg and 1200 mg for those ≥75 kg in two divided doses with food. If the starting dosage of ribavirin is not well tolerated, the dosage should be reduced as clinically indicated based on hemoglobin levels.
- The daily dosage of ribavirin is weight-based (1000 mg for patients <75 kg and 1200 mg for those ≥75 kg) administered orally in two divided doses with food.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Adverse Reactions in Liver Transplant Recipients and/or Subjects with Decompensated Cirrhosis
The safety assessment of HARVONI with ribavirin (RBV) in liver transplant recipients and/or those who had decompensated liver disease was based on pooled data from two Phase 2 open-label clinical trials including 336 subjects who received HARVONI plus RBV for 12 weeks. Subjects with Child-Pugh-Turcotte (CPT) scores greater than 12 were excluded from the trials.
The adverse events observed were consistent with the expected clinical sequelae of liver transplantation and/or decompensated liver disease, or the known safety profile of HARVONI and/or ribavirin.
Decreases in hemoglobin to less than 10 g/dL and 8.5 g/dL during treatment were observed in 38% and 13% of subjects treated with HARVONI plus RBV for 12 weeks, respectively. Ribavirin was permanently discontinued in 11% of subjects treated with HARVONI plus RBV for 12 weeks.
Liver Transplant Recipients with Compensated Liver Disease:
Among the 174 liver transplant recipients with compensated liver disease who received HARVONI with RBV for 12 weeks, 2 (1%) subjects permanently discontinued HARVONI due to an adverse event.
Subjects with Decompensated Liver Disease:
Among the 162 subjects with decompensated liver disease (pre- or post-transplant) who received HARVONI with RBV for 12 weeks, 7 (4%) subjects died, 4 (2%) subjects underwent liver transplantation, and 1 subject (<1%) underwent liver transplantation and died during treatment or within 30 days after discontinuation of treatment. Because these events occurred in patients with advanced liver disease who are at risk of progression of liver disease including liver failure and death, it is not possible to reliably assess the contribution of drug effect to outcomes. A total of 4 (2%) subjects permanently discontinued HARVONI due to an adverse event.
8.7 Hepatic Impairment
Clinical and hepatic laboratory monitoring, as clinically indicated, is recommended for patients with decompensated cirrhosis receiving treatment with HARVONI and ribavirin.
12.4 Microbiology
Clinical Trials - Genotype 1
In the SOLAR-1 and SOLAR-2 trials (liver transplant recipients or subjects with decompensated liver disease), there were 24 virologic failures with genotype 1 infection (20 relapsers and 4 subjects who discontinued treatment prior to achieving HCV RNA <LLOQ). Treatment-emergent NS5A resistance-associated substitutions K24R, M28T, Q30R/H/K, L31V, H58D/P and/or Y93H/C were detected in 14/17 (82%) genotype 1a virologic failure subjects, and R30Q, L31M and/or Y93H/N were detected in 6/7 (86%) genotype 1b virologic failure subjects.
The E237G substitution was detected in 3 subjects infected with HCV GT1a in the SOLAR-1 and SOLAR-2 trials.
Effect of Baseline HCV Polymorphisms on Treatment Response - Genotype 1
In the SOLAR-1 and SOLAR-2 trials (liver transplant recipients or subjects with decompensated liver disease), after 12 weeks of treatment with HARVONI and RBV, relapse rates were 7% (5/71) and 5% (10/217) in genotype 1 subjects with and without baseline NS5A polymorphisms at resistance-associated positions, respectively.
In the Phase 3 trials and SOLAR trials, the specific baseline NS5A resistance-associated polymorphisms observed among subjects who relapsed were M28T/V, Q30H/R, L31M, H58D/P, and Y93H/N in genotype 1a, and L28M, L31M, A92T, and Y93H in genotype 1b. Subjects with multiple NS5A polymorphisms at resistance-associated positions appeared to have higher relapse rates.
14 CLINICAL STUDIES
14.5 Clinical Trials in Liver Transplant Recipients and/or Subjects with Decompensated Cirrhosis
SOLAR-1 and SOLAR-2 were two open-label trials that evaluated 12 and 24 weeks of treatment with HARVONI in combination with ribavirin in HCV treatment-naïve and previously-treated subjects with genotype 1 and 4 infection who had undergone liver transplantation and/or who had decompensated liver disease. The two trials were identical in study design. Subjects were enrolled in one of the seven groups in the trials based on liver transplantation status and severity of hepatic impairment (see Table 16). Subjects with a CPT score greater than 12 were excluded. Within each group, subjects were randomized in a 1:1 ratio to receive HARVONI + RBV for 12 weeks or HARVONI + RBV for 24 weeks. For subjects with decompensated cirrhosis in SOLAR-1 and SOLAR-2 studies, the starting RBV dosage was 600 mg per day regardless of transplantation status. RBV dose adjustments were performed according to the RBV labeling.
Demographics and baseline characteristics were balanced across the treatment groups. Of the 670 treated subjects, the median age was 59 years (range: 21 to 81); 77% of the subjects were male; 91% were White; mean body mass index was 28 kg/m2 (range: 18 to 49 kg/m2); 94% and 6% had genotype 1 and 4 HCV infection, respectively; 78% of the subjects failed a prior HCV therapy.
Table 16 presents the pooled SVR12 rates for SOLAR-1 and SOLAR-2 in subjects with genotype 1 HCV treated with HARVONI+RBV for 12 weeks. The SVR12 rates observed with 24 weeks of HARVONI+RBV were similar to the SVR12 rates observed with 12 weeks of treatment. Therefore, the results for the HARVONI+RBV 24 weeks arm are not presented in Table 16.
Table 16 Studies SOLAR-1 and SOLAR-2: SVR12 and Relapse Rates After 12 Weeks of Treatment with HARVONI and Ribavirin in Subjects with Genotype 1 HCV Who Were Post Liver Transplant and/or Who Had Decompensated Liver Disease
|
|
HARVONI + RBV 12 weeks N=307 | |
|---|---|---|
|
|
SVR12 (N=300)a,b |
Relapse (N=288)a,b,c |
|
Pre-transplant |
|
|
|
CPT B |
87% (45/52) |
12% (6/51) |
|
CPT C |
88% (35/40) |
5% (2/37) |
|
Post-transplant |
|
|
|
Metavir score F0-F3 |
95% (94/99) |
3% (3/97) |
|
CPT A |
98% (55/56) |
0% (0/55) |
|
CPT B |
89% (41/46) |
2% (1/42) |
|
CPT C |
57% (4/7) |
33% (2/6) |
- Five subjects transplanted prior to post-treatment Week 12 with HCV RNA<LLOQ at last measurement prior to transplant were excluded.
- Two subjects were excluded due to failure to meet the inclusion criteria for any of the treatment groups (i.e., did not have decompensated cirrhosis and had also not received a liver transplant).
- Twelve subjects were excluded from relapse analysis because they died (N=11) or withdrew consent (N=1) prior to reaching the 12 week posttreatment follow-up visit.
There were 7 subjects with fibrosing cholestatic hepatitis in the 12 week treatment arm; and all subjects achieved SVR12.
In genotype 4 HCV post-transplant subjects without cirrhosis or with compensated cirrhosis treated with HARVONI+RBV for 12 weeks (N=12), the SVR12 rate was similar to rates reported with genotype 1; no subjects relapsed. Available data in subjects with genotype 4 HCV who had decompensated cirrhosis (pre- and post-liver transplantation) were insufficient for dosing recommendations, therefore these results are not presented.
The updated labeling will be posted soon on Drugs@FDA, and DailyMed.
Harvoni is a product of Gilead Sciences, Inc.
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
| This email was sent to list-fda@xxxxxxxxxxx using GovDelivery, on behalf of: U.S. Food & Drug Administration (FDA) · 10903 New Hampshire Ave · Silver Spring, MD 20993 · 1-888-INFO-FDA (1-888-463-6332) |  |
