SOFOS

Sofosbuvir (tradename Sovaldi) is a direct acting antiviral medication used as part of combination therapy to treat chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV).

HCV is a single-stranded

RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients 14.

Treatment options for chronic Hepatitis

C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as sofosbuvir.

As a prodrug nucleotide analog, Sofosbuvir is metabolized into its active form as the antiviral agent 2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-triphosphate (also known as GS-461203), which acts as a defective substrate for NS5B (non-structural protein 5B) Synthesis.

NS5B, an RNA-dependent RNA polymerase, is essential for the transcription of Hepatitis C viral RNA and for its high replicative rate and genetic diversity 4.

Sofosbuvir and other direct acting antivirals are therefore very potent options for the treatment of Hepatitis C, as they exhibit a high barrier to the development of resistance 5.

This is an important advantage relative to HCV drugs that target other viral enzymes such as the protease, for which rapid development of resistance has proven to be an important cause of therapeutic failure.

In a joint recommendation published in 2016, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommend Sofosbuvir as first line therapy in combination with other antivirals for all six genotypes of Hepatitis C 14.

Depending on the genotype, sofosbuvir is often used in combination with other antivirals such as Ledipasvir, Velpatasvir, Daclatasvir, Simeprevir, Elbasvir, Grazoprevir, Ribavirin, Peginterferon alfa-2a, or Peginterferon alfa-2b with the intent to cure, or achieve a sustained virologic response (SVR), after 12 weeks of daily therapy.

SVR and eradication of

HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality 6.

Treatment with direct acting antivirals such as sofosbuvir is associated with very minimal side effects, with the most common being headache and fatigue Label.

Lack of significant side effects and short duration of therapy is a considerable advantage over older interferon.

• and ribavirin-based regimens, which were limited by infusion site reactions, reduced blood count, and neuropsychiatric effects 11.

Since 2014, sofosbuvir has been available as a fixed dose with Ledipasvir (tradename Harvoni) used for the treatment of chronic Hepatitis C. Approved in October by the FDA, Harvoni is indicated for the treatment of HCV genotypes 1, 4, 5, and with or without Ribavirin depending on the level of liver damage or cirrhosis Label.

When combined together, ledipasvir and sofosbuvir as the Harvoni has been shown to achieve a SVR between and 99% after 12 weeks of treatment 3.

Its use has also proven successful in the treatment of HCV in patients co-infected with HIV 7.

Sofosbuvir is also available as a fixed dose with Velpatasvir as the commercially available product Epclusa.

First approved in

June 2016, Epclusa is the first combination HCV product indicated for the treatment of all genotypes of Hepatitis C with or without cirrhosis.

Epclusa is also currently the most potent HCV antiviral medication on the market with a sustained virologic response (SVR) after 12 weeks of therapy of 93-99% depending on genotype and level of cirrhosis 14.

Both Canadian and American guidelines list

Epclusa as a first line recommendation for all genotypes of HCV 14, 6.

Notably, sofosbuvir has come under intense scrutiny since its release to market in 2013.

With the price per pill set at $1000, a 12-week treatment can cost upwards of $84,000 per patient 12.

Sofosbuvir is used in combination therapy with other antiviral medications to treat chronic hepatitis C virus (HCV) infected patients with HCV genoptypes 1-6, and to treat HCV and HIV co-infected patients.

Depending on the level of cirrhosis or decompensation, combination therapy can also include either ribavirin alone or ribavirin and peg-interferon alfa.

When used in combination with

Ledipasvir, sofosbuvir has the following indications: treatment of genotypes 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis; in combination with Ribavirin for genotype 1 infection with decompensated cirrhosis; or in combination with Ribavirin for the treatment of genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis.

When used in combination with Velpatasvir as the Epclusa, sofosbuvir is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) genotypes 1, 2, 3, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis, or in combination with Ribavirin if associated with decompensated cirrhosis.

Reduced susceptibility to sofosbuvir has been associated with the NS5B substitution mutation S282T 10.

Sofosbuvir acts against

HCV and is categorized as a direct-acting antiviral agent (DAA).

At a dose 3 times the recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent Label.

When given

Oral, sofosbuvir reaches its maximum plasma concentration in about 0.5-2 hours with a maximal concentration (Cmax) of 567 ng/mL Label.

The volume of distribution for sofosbuvir has yet to be determined Label.

In vitro studies in human liver microsomes showed that sofosbuvir was an efficient substrate for Cathepsin A (Cat A) and carboxyl esterase 1 (CES1).

Sofosbuvir was cleaved by CatA and

CES1 and subsequent activation steps included amino acid removal by histidine triad nucleotide-binding protein 1 (HINT1) and phosphorylation by uridine monophosphate-cytidine monophosphate (UMP-CMP) kinase and nucleoside diphosphate (NDP) kinase.

In vitro data indicated that Cat

A preferentially hydrolysed sofosbuvir (the S-diastereomer) while CES1 did not exhibit stereoselectivity 8, 9.

Hover over products below to view reaction partners Sofosbuvir GS-56650 GS-606965 GS-461203.

Sofosbuvir is eliminated by three routes: urine ( 80%), feces (14%), and respiration (2.5%); however, elimination through the kidneys is the major route Label.

Sofosbuvir has a terminal half life of 0.4 hours Label.

The clearance of sofosbuvir has yet to be determined Label.

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Sofosbuvir, as a single agent, has very mild toxicity.

The most common adverse reactions are headache and fatigue.

The FDA Label currently warns of a risk of symptomatic bradycardia when Epclusa is used in combination with amiodarone Label.

is contraindicated with rifampin.

Coadministration with rifampin.

Prior to initiating

VOSEVI, test all patients for HBV infection by measuring HBsAg and anti-HBc.

Recommended dosage

One tablet (400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir) taken orally once daily with food.

See recommended treatment regimen and duration in table below: Genotype Patients Previously Treated with an HCV Regimen Containing: VOSEVI Duration 1, 2, 3, 4, 5, or 6 An NS5A inhibitor In clinical trials, prior NS5A inhibitor experience included daclatasvir, elbasvir, ledipasvir, ombitasvir, or velpatasvir. 12 weeks 1a or 3 Sofosbuvir without an NS5A inhibitor In clinical trials, prior treatment experience included sofosbuvir with or without any of the following: peginterferon alfa/ribavirin, ribavirin, HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir). 12 weeks For patients with renal impairment including end stage renal disease on dialysis, follow the dosage recommendations in the table above.

VOSEVI is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C). 2.1 Testing Prior to the Initiation of Therapy Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with VOSEVI. 2.2 Recommended Dosage The recommended dosage of VOSEVI is one tablet, taken orally, once daily with food.

One tablet of

VOSEVI contains 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir.

Table 1 shows the recommended treatment regimen and duration based on patient population.

Table 1 Recommended Treatment Regimen and Duration in Adults Without Cirrhosis or With Compensated Cirrhosis (Child-Pugh A) Genotype Patients Previously Treated with an HCV Regimen Containing: VOSEVI Duration 1, 2, 3, 4, 5, or 6 An NS5A inhibitor In clinical trials, prior NS5A inhibitor experience included daclatasvir, elbasvir, ledipasvir, ombitasvir, or velpatasvir. 12 weeks 1a or 3 Sofosbuvir without an NS5A inhibitor In clinical trials, prior treatment experience included sofosbuvir with or without any of the following: peginterferon alfa/ribavirin, ribavirin, HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir). 12 weeks 2.3 Renal Impairment No dosage adjustment of VOSEVI is recommended in patients with any degree of renal impairment including patients on dialysis. 2.4 Moderate or Severe Hepatic Impairment VOSEVI is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C) due to higher exposures of voxilaprevir in these patients.

VOSEVI tablet contains 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir.

The tablets are beige, capsule-shaped, film-coated, and debossed with "GSI" on one side and " " on the other side.

Each bottle contains 28 tablets (NDC 61958-2401-1), polyester coil, silica gel desiccant, and is closed with a child-resistant closure.

Store below 30 °C (86 °F).

Dispense only in original container.

Store below 30 °C (86 °F).

Dispense only in original container.

No adequate human data are available to establish whether or not VOSEVI poses a risk to pregnancy outcomes.

In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of VOSEVI (sofosbuvir, velpatasvir, or voxilaprevir) at exposures greater than those in humans at the recommended human dose (RHD) .

During organogenesis in the mouse, rat, and rabbit, systemic exposures (AUC) of velpatasvir were approximately 23 (mice), 4 (rats), and 0.5 (rabbits) times the exposure in humans at the RHD, while exposures of voxilaprevir were approximately 141 (rats) and 4 (rabbits) times the exposure in humans at the RHD.

Exposures of the predominant circulating metabolite of sofosbuvir (GS-331007) were approximately 6 (rats) and 16 (rabbits) times the exposure in humans at the RHD.

In rat pre/postnatal development studies, maternal systemic exposures (AUC) for each component of VOSEVI were approximately 7 (sofosbuvir metabolite GS-331007), 3 (velpatasvir), and 238 (voxilaprevir) times the exposure in humans at the RHD.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Sofosbuvir was administered orally to pregnant rats (up to 500 mg/kg/day) and rabbits (up to 300 mg/kg/day) on gestation days to 18 and to 19, respectively, and also to rats (oral doses up to 500 mg/kg/day) from gestation day to lactation/post-partum day 20.

No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested.

The systemic exposures (AUC) of the predominant circulating metabolite of sofosbuvir (GS-331007) during gestation were approximately 6 (rats) and 16 (rabbits) times the exposure in humans at the RHD.

Velpatasvir was administered orally to pregnant mice (up to 1000 mg/kg/day), rats (up to 200 mg/kg/day) and rabbits (up to 300 mg/kg/day) from gestation days to 15, 6 to 17, and to 20, respectively, and also to rats (oral doses up to 200 mg/kg) on gestation day to lactation/post-partum day 20.

No significant effects on embryo-fetal (mice, rats, and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested.

The systemic exposures (AUC) of velpatasvir during gestation were approximately 23 (mice), 4 (rats), and 0.5 (rabbits) times the exposure in humans at the RHD.

Voxilaprevir was administered orally to pregnant rats (up to 100 mg/kg/day) and rabbits (up to 600 mg/kg/day) from gestation days to 17, and to 19, respectively, and also to rats (oral doses up to 100 mg/kg) on gestation day to lactation/post-partum day 20.

The systemic exposures (AUC) of voxilaprevir during gestation were approximately 141 (rats) and 4 (rabbits) times the exposure in humans at the RHD.

Safety and effectiveness of

VOSEVI have not been established in pediatric patients.

Clinical trials of

VOSEVI included 74 subjects aged and over (17% of total number of subjects in the POLARIS-1 and POLARIS-4 Phase 3 clinical trials).

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

No dosage adjustment of

VOSEVI is warranted in geriatric patients.