Immunodeficiency Clinic > Drug Information
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Other Names
VEL, GS-5816
Epclusa: fixed dose tablet of sofosbuvir 400 mg/velpatasvir 100 mg
Vosevi: fixed-dose tablet of sofosbuvir 400 mg/velpatasvir 100 mg/voxilaprevir 100mg
NS5A inhibitor
Activity
Picomolar potency against HCV genotypes 1-6
Velpatasvir is commercially available as Epclusa, as pink-colored, diamond-shaped, film-coated tablet debossed with
“GSI” on one side and “7916” on the other side of the tablet and contains velpatasvir 100mg and sofosbuvir 400 mg.
Epclusa®:
Manufacturer states that Epclusa® tablets are not enteric-coated and are not sustained-release. Tablets can be disintegrated in water, juice, or milk with minor stirring and pressure with a spoon. A disintegrated, crushed or split tablet may have an unpleasant taste and there are no studies evaluating the pharmacokinetics of these methods of administration. (Gilead Sciences Canada, Data on File, Nov 11, 2018).
A case report of a 70 year-old female with an oropharyngectomy and chronic HCV genotype 1b studied drug absorption and exposure of crushed sofosbuvir/velpatasvir 400/100 mg tablet daily taken with an acidic beverage and meal (to enhance absorption). TDM showed that the absorption of both was increased compared to historical controls and the steady-state trough concentration (Css) of velpatasvir at weeks 1 and 10 showed concentrations above historical reference with no accumulation. Although the trough Css of sofosbuvir was below the limit of quantification, this was anticipated/expected given the short half-life of the drug (30 minutes). The drugs were well tolerated with improved liver parameters. The HCV viral load became undetectable after 4 weeks and remained undetectable 12 weeks post-treatment.3303
A case report of a 62 year-old female with dysphagia and hepatitis C genotype 4 infection (non-cirrhotic, treatment naïve) was treated with sofosbuvir/velpatasvir given mixed with soft foods (e.g. apple sauce). The patient was adherent to therapy and it was well tolerated. The viral load was undetectable at weeks 4 and 12 of therapy and a 12 week sustained virologic response was achieved. Liver transaminases normalized during treatment.3304
A case report of a 54 year-old male with hepatitis genotype 2b infection requiring PEG tube administration of medications due to left-sided hemiparesis post-stroke. Sofosbuvir/velpatasvir was crushed, dissolved in water and administered via PEG tube. Rinsing of tablet crusher and syringe to get residual drug was recommended. Steady-state pharmacokinetics (24 hour curve) of SOF-VEL via PEG tube was done on day 15 and on day 16 a second shorter 4- hour curve was done after the patient took the tablet whole under medical observation. SOF exposure was similar for crushed vs whole tablet. Crushed VEL Cmax was decreased by 35% and AUC decreased by 25% compared to whole tablet. However, the crushed concentrations were comparable or higher than whole tablet values in population-based references. The HCV viral load decreased to 49.6 IU/mL after 2 weeks, therefore treatment was continued for the full 12 weeks and a 12-week sustained virological response was achieved.3362
A case series of 19 patients who received crushed SOF/VEL administered via oral = 8, NG tube = 3, PEG tube = 7, J-tube =1) demonstrated high HCV cure rates and safety.3547
In a retrospective case series of 10 patients (60% HCV GT1a) on SOF/VEL (50%), LED/SOF (30%) and GLE/PIB (20%), patients either crushed (70%) or split (30%) their DAA tablets. All patients were prescribed 12 weeks of DAA therapy and had undetectable HCV viral loads by day 56. All patients with available data (7/7) had SVR12; 3 patients had undetectable viral loads at end of treatment but no follow-up data were available. No patients experienced severe adverse events.3560
Vosevi®:
Manufacturer states that Vosevi® tablets are not enteric-coated and are not sustained-release. Tablets can be disintegrated in water, juice, or milk with minor stirring and pressure with a spoon. A disintegrated, crushed or split tablet may have an unpleasant taste and there are no studies evaluating the pharmacokinetics of these methods of administration. (Gilead Sciences Canada, Data on File, Nov 19, 2018).
100 mg velpatasvir daily plus sofosbuvir 400 mg daily (coformulated in a fixed dose tablet).
For patients with genotypes 1 to 6:
a) Treatment-naive and treatment-experienced*, without cirrhosis or with compensated cirrhosis (Child-Pugh A), treat with sofosbuvir/velpatasvir for 12 weeks.
b) Treatment-naive and treatment-experienced*, with decompensated cirrhosis (Child-Pugh B or C), treat with sofosbuvir/velpatasvir plus ribavirin for 12 weeks
*prior regimens containing pegylated interferon/ribavirin with or without an HCV NS3/4A protease inhibitors (boceprevir, simeprevir, telaprevir)
Safety has not been established in pediatric patients [Epclusa Product monograph, 2016].
Dose adjustment in geriatric patients is not required.[Epclusa Product monograph, 2016]
Dose adjustment in patients with mild or moderate renal impairment is not required.
The safety of sofosbuvir/velpatasvir in patients with severe renal impairment (eGFR<30 mL/min/1.73m2) or endstage renal disease requiring hemodialysis is unknown, and thus dose recommendations are not available for this population. [Epclusa product monograph 2016]
Dose adjustment in mild, moderate or severe hepatic impairment is not required. Clinical and hepatic lab monitoring is recommended in patients with decompensated cirrhosis. [Epclusa Product monograph, 2016]
Sofosbuvir/velpatasvir may be given with or without food.
When administered with a moderate meal (600 kcal, 30% fat), sofosbuvir AUC increased 60% and velpatasvir AUC increased 34% relative to fasting. When administered with a high fat meal (800 kcal, 50% fat), sofosbuvir AUC increased 78% and velpatasvir AUC increased 21% relative to fasting. 2865
Substrate of P-gp, BCRP, OATP1B1 and OATP1B3, as well as CYP3A4, 2C8 and 2B6. No inhibition or induction of CYP enzymes. Velpatasvir inhibits P-gp, BCRP, OATP1B1, OATP1B3 and OATP2B1.2802
Sofosbuvir/velpatasvir may be used with P-gp, BCRP, OATP and CYP inhibitors without dose adjustment. Coadministration with potent P-gp or moderate/potent inducers of CYP2B6, 2C8 or 3A4 is not recommended.2793 2802
Oral Bioavailability:
25-30%
Protein Binding:
> 99.5%
Vd:
1.4-1.6 L/kg
Tmax:
3-4 h
Serum T½:
15h
Metabolism:
Substrate of CYP3A4, 2C8 and 2B6 as well as OATP and P-gp. No inhibition or induction of CYP enzymes. Inhibits OATP (weak), P-gp (weak) and BCRP (moderate).
94% excreted in feces with 77% as parent compound. 0.4% excreted in urine.
Excretion:
Biliary excretion of parent drug was the major route of elimination for velpatasvir.
0.4% is excreted in urine.
In HCV-infected patients (ranges in bracket)
AUC: 2967 ng·h/mL (603, 11503)
Cmax: 259 ng/mL (39, 977)
Cmin: 41 ng/mL (5, 236)
Pregnancy should be avoided while taking sofosbuvir/velpatasvir as there are no data on the use of sofosbuvir/velpatasvir in pregnant women. sofosbuvir/velpatasvir should not be used during pregnancy unless thepotential benefit justifies the potential risk to the fetus. Patients should be advised to notify theirhealth care provider immediately in the event of a pregnancy.No effects on pre- or post-natal development were observed in animal reproduction studies at the highest doses of sofosbuvir tested. In the rat and rabbit embryo fetal studies, and the rat pre/postnatal study, exposure to the predominant circulating metabolite GS-331007 at the highest dose was approximately 5-fold, 14-fold, and 6-fold the exposure in humans at the recommended clinical dose, respectively. No effects on pre- or post-natal development have been observed in animal reproduction studies at the highest doses of velpatasvir tested. In the mouse, rat, and rabbit embryo fetal studies, and
rat pre/post-natal study, velpatasvir exposure was approximately 31-fold, 6-fold, 0.7-fold, and 5-fold the exposure in humans at the recommended clinical dose, respectively.2802
Lactation
No information is available on velpatasvir excretion into milk in humans. Breastfeeding is not recommended.
After oral dosing of [14C] VEL to lactating rats, [14C]VEL-derived radioactivity was transferred into milk with a Tmax of 4 hours and was not detectable by 24 hours post dose. The mean milk:plasma exposure (AUC) ratio was 1.74.
Phenotypic analysis of site-directed mutant replicons of the selected NS5A substitutions showed that single and double combinations of L31V and Y93H/N in genotype 1a, the combination of L31V + Y93H in genotype 1b, Y93H/S in genotype 3a, and L31V and P32A/L/Q/R in genotype 6 conferred greater than 100-fold reduction in velpatasvir susceptibility. In the genotype 2a replicon, the single mutants F28S and Y93H showed 91-fold and 46-fold reduced susceptibility to velpatasvir, respectively. The single mutant Y93H conferred 3-fold reduced susceptibility to velpatasvir in genotype 4a replicons. Combinations of these NS5A substitutions often showed greater reductions in susceptibility to velpatasvir than single substitutions alone.2802
Both sofosbuvir and velpatasvir were fully active against substitutions associated with resistance to other classes of direct-acting antivirals with different mechanisms of action, such as NS5B non-nucleoside inhibitors and NS3 protease inhibitors. The efficacy of sofosbuvir/velpatasvir has not been established in patients who have previously failed treatment with other regimens that include an NS5A inhibitor.
Grade 2-4 adverse reactions from pooled phase 3 sudies include headache (4%) and fatigue (3%).
Routine Labs
If sofosbuvir/velpatasvir is administered with amiodarone, close monitoring for bradycardia isrecommended.
Monitoring of liver function including direct bilirubin is recommended in patients with decompensated cirrhosis.
Store below 30 degrees C (86 degrees F)
Gilead Sciences