Harvoni, Epclusa, and Vosevi: severe renal impairment label updates

November 18, 2019

FDA recently approved changes to the HARVONI (ledipasvir and sofosbuvir), EPCLUSA (sofosbuvir and velpatasvir) and VOSEVI (sofosbuvir, velpatasvir, and voxilaprevir) product labeling to include new efficacy and safety data from completed studies in HCV-infected adults with severe renal impairment, including those requiring dialysis. A summary of the changes for each label is as follows.

HARVONI Section 2 DOSAGE AND ADMINISTRATION 2.6 Renal Impairment No dosage adjustment of HARVONI is recommended in patients with any degree of renal impairment, including end stage renal disease (ESRD) on dialysis. Take HARVONI with or without ribavirin according to the recommendations (see Table below).  Refer to ribavirin tablet prescribing information for ribavirin dosage modification for patients with CrCl less than or equal to 50 mL per minute.

Section 6: ADVERSE REACTIONS 6.1 Clinical Trials Experience Adverse Reactions in Adults with Severe Renal Impairment, Including those on Dialysis In an open-label trial (Trial 0154) in which adults with HCV with compensated liver disease (with or without cirrhosis) and severe renal impairment received HARVONI for 12 weeks (N=18), the most common adverse reaction was fatigue (17%). In an open-label clinical trial, Trial 4063, a total of 95 adults with HCV with compensated liver disease (with or without cirrhosis) and ESRD requiring dialysis received HARVONI for 8 (n=45), 12 (n=31), or 24 (n=19) weeks. The most common adverse reactions were insomnia and headache (each reported in 4% of subjects overall). Section 8: USE IN SPECIFIC POPULATIONS 8.4 Pediatric Use In patients with severe renal impairment, including those requiring dialysis, exposures of GS-331007, the inactive metabolite of sofosbuvir, are increased.  No data are available regarding the safety of HARVONI in pediatric patients with renal impairment. 8.6 Renal Impairment No dosage adjustment of HARVONI is recommended for patients with mild, moderate, or severe renal impairment, including ESRD requiring. No safety data are available in subjects with both decompensated cirrhosis and severe renal impairment, including those on dialysis. Additionally, no safety data are available in pediatric patients with renal impairment. Refer to ribavirin tablet prescribing information regarding use in patients with renal impairment. Section 12: CLINICAL PHARMACOLOGY 12.3 Pharmacokinetics, Specific Populations, Patients with Renal Impairment The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were studied in HCV-infected subjects with severe renal impairment or ESRD requiring dialysis treated with HARVONI for 8, 12, or 24 weeks. The results were generally consistent with those observed in HCV-negative subjects with ESRD requiring dialysis. Section 14: CLINICAL STUDIES 14.6 Clinical Trials in Adults with Severe Renal Impairment, Including those Requiring Dialysis Trial 0154 was an open-label clinical trial that evaluated 12 weeks of treatment with HARVONI in 18 treatment-naïve and treatment-experienced (subjects with prior exposure to an HCV NS5B polymerase inhibitor were excluded) genotype 1 HCV-infected adults with severe renal impairment not requiring dialysis. At baseline, two subjects (11%) had cirrhosis and the mean eGFR was 24.9 mL/min (range: 9.0 to 39.6). The SVR rate was 100% (18/18). As shown in the table below, Trial 4063 was an open-label three-arm clinical trial that evaluated 8, 12, and 24 weeks of treatment with HARVONI in a total of 63 adults with chronic HCV infection and ESRD requiring dialysis. Of the 63 subjects, 10% had cirrhosis, 24% were treatment-experienced, 95% were on hemodialysis, and 5% were on peritoneal dialysis; mean duration on dialysis was 12 years (range: 0.2 to 43 years). The SVR rates for the 8, 12, and 24 week HARVONI treatment groups are shown in the table below.

EPCLUSA Section 2: DOSAGE AND ADMINISTRATION 2.3 Renal Impairment No dosage adjustment of EPCLUSA is recommended in patients with any degree of renal impairment, including patients requiring dialysis. Administer EPCLUSA with or without ribavirin according to the recommendations in Table. Refer to ribavirin tablet prescribing information for ribavirin dosage modification for patients with CrCl less than or equal to 50 mL per minute.

Section 6: ADVERSE REACTIONS 6.1 Clinical Trials Experience Adverse Reactions in Adults with Severe Renal Impairment Requiring Dialysis In an open-label trial (Trial 4062), in which a total of 59 adults with HCV with compensated liver disease (with or without cirrhosis) and ESRD requiring dialysis received EPCLUSA for 12 weeks, the most common adverse reaction was nausea (7%). Section 8: USE IN SPECIFIC POPULATIONS 8.6 Renal Impairment No dosage adjustment of EPCLUSA is recommended for patients with mild, moderate, or severe renal impairment, including ESRD requiring dialysis. No safety data are available in subjects with both decompensated cirrhosis and severe renal impairment, including ESRD requiring dialysis. Refer to ribavirin tablet prescribing information regarding use of ribavirin in patients with renal impairment. Section 12: CLINICAL PHARMACOLOGY 12.3 Pharmacokinetics, Specific Populations, Patients with Renal Impairment The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were studied in HCV-infected subjects with ESRD requiring dialysis treated with EPCLUSA for 12 weeks. The results were generally consistent with those in HCV negative subjects with ESRD requiring dialysis. 12.4 Microbiology In a pooled analysis of clinical trials in subjects with HCV genotype 3 infection, the prevalence of the baseline NS5A Y93H polymorphism was 6% (104/1842). Among HCV genotype 3 infected subjects with the Y93H polymorphism who were treated with EPCLUSA for 12 weeks, 7% (2/28) of subjects without cirrhosis relapsed, and 40% (6/15) of subjects with compensated cirrhosis experienced virologic failure (5 relapse, 1 on-treatment).  Section 13: NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Velpatasvir was not carcinogenic in a 6-month rasH2 transgenic mouse study (up to 1000 mg/kg/day) and a 2-year rat carcinogenicity study (up to 200 mg/kg/day). The exposure of VEL in the 2-year rat study was approximately 6 times the exposure in humans at the RHD. Section 14: CLINICAL STUDIES 14.5 Clinical Trial in Subjects with Severe Renal Impairment Requiring Dialysis Trial 4062 was an open-label clinical trial that evaluated 12 weeks of treatment with EPCLUSA in 59 HCV-infected adults with ESRD requiring dialysis. The proportions of subjects with genotype 1, 2, 3, 4, 6 or indeterminate HCV infection were 42%,12%, 27%, 7%, 3%, and 8%, respectively. At baseline, 29% of subjects had cirrhosis, 22% were treatment-experienced (subjects with prior exposure to any HCV NS5A inhibitor were excluded), 92% were on hemodialysis, and 8% were on peritoneal dialysis; mean duration on dialysis was 7 years (range: 0 to 40 years). The overall SVR rate was 95% (56/59). Of the subjects completing 12 weeks of EPCLUSA, 1 subject experienced virologic relapse.

VOSEVI Section 2: DOSAGE AND ADMINISTRATION 2.3 Renal Impairment No dosage adjustment of VOSEVI is recommended in patients with any degree of renal impairment including patients on dialysis.

Section 8: USE IN SPECIFIC POPULATIONS 8.6 Renal Impairment No dosage adjustment of VOSEVI is recommended for patients with mild, moderate, or severe renal impairment, including ESRD requiring dialysis. Section 12: CLINICAL PHARMACOLOGY 12.3 Pharmacokinetics, Specific Populations, Patients with Renal Impairment The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were studied in HCV-infected subjects with ESRD requiring dialysis treated with once daily sofosbuvir/velpatasvir 400/100 mg for 12 weeks. The results were consistent with those observed in HCV negative subjects with ESRD requiring dialysis. The pharmacokinetics of voxilaprevir have not been studied in subjects with ESRD. However, voxilaprevir exposure following administration of VOSEVI is not expected to be meaningfully altered in HCV-infected subjects with ESRD requiring dialysis compared to subjects with normal renal function.

The updated labels will soon be available at Drugs@FDA or DailyMed Kimberly Struble Division of Antivirals Food and Drug Administration Elizabeth Thompson Division of Antivirals Food and Drug Administration Michael Stanfield Jr. Division of Antivirals Food and Drug Administration