VOSEVI FILM-COATED TABLETS 400MG/100MG/100MG

Sofosbuvir
Velpatasvir
Voxilaprevir

Source of information: Drugbank (External Link). Last updated on: 3rd July 18
*Trade Name used in the content below may not be the same as the HSA-registered product.

Active Ingredient / Synonyms

S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)- (phenoxy)phosphorylamino)propanoate | Sofosbuvir |

Description

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 [L852]. 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 [A19594]. 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 [A19593]. 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 [L852]. Depending on the genotype, sofosbuvir is often used in combination with other antivirals such as [DB09027], [DB11613], [DB09102], [DB06290], [DB11574], [DB11575], [DB00811], [DB00008], or [DB00022] 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 [A19626]. Treatment with direct acting antivirals such as sofosbuvir is associated with very minimal side effects, with the most common being headache and fatigue [FDA 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 [A19635]. Since 2014, sofosbuvir has been available as a fixed dose combination product with [DB09027] (tradename Harvoni) used for the treatment of chronic Hepatitis C. Approved in October 2014 by the FDA, Harvoni is indicated for the treatment of HCV genotypes 1, 4, 5, and 6 with or without [DB00811] depending on the level of liver damage or cirrhosis [FDA Label]. When combined together, ledipasvir and sofosbuvir as the combination product Harvoni has been shown to achieve a SVR between 93 and 99% after 12 weeks of treatment [A7535]. Its use has also proven successful in the treatment of HCV in patients co-infected with HIV [A19627]. Sofosbuvir is also available as a fixed dose combination product with [DB11613] 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 [L852]. Both Canadian and American guidelines list Epclusa as a first line recommendation for all genotypes of HCV [L852, A19626]. 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 [A19636].

Indication

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 [DB09027] as the combination product Harvoni, sofosbuvir has the following indications: treatment of genotypes 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis; in combination with [DB00811] for genotype 1 infection with decompensated cirrhosis; or in combination with [DB00811] 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 [DB11613] as the combination product 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 [DB00811] if associated with decompensated cirrhosis. Resistance: Reduced susceptibility to sofosbuvir has been associated with the NS5B substitution mutation S282T [A19634].

Mechanism of Action

Sofosbuvir is nucleotide analog inhibitor, which specifically inhibits HCV NS5B (non-structural protein 5B) RNA-dependent RNA polymerase. Following intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), sofosbuvir incorporates into HCV RNA by the NS5B polymerase and acts as a chain terminator [synthesis, A7533]. More specifically, Sofosbuvir prevents HCV viral replication by binding to the two Mg2+ ions present in HCV NS5B polymerase's GDD active site motif and preventing further replication of HCV genetic material [A19638, FDA Label].

Pharmacodynamics

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 [FDA Label].

Pharmacokinetics

Absorption:

When given orally, sofosbuvir reaches its maximum plasma concentration in about 0.5 to 2 hours with a maximal concentration (Cmax) of 567 ng/mL [FDA Label].

Distribution:

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

Metabolism:

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 [A19628, A19631].

Elimination:

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

Half-life

Sofosbuvir has a terminal half life of 0.4 hours [FDA Label].

Clearance

The clearance of sofosbuvir has yet to be determined [FDA Label].

Toxicity

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 [FDA Label].

Source of information: Drugbank (External Link). Last updated on: 3rd July 18
*Trade Name used in the content below may not be the same as the HSA-registered product.

Active Ingredient / Synonyms

methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-4-yl}-1,11-dihydro[2]benzopyrano[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate | Velpatasvir |

Description

Velpatasvir is a Direct-Acting Antiviral (DAA) 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 [L852]. Velpatasvir acts as a defective substrate for NS5A (Non-Structural Protein 5A), a non-enzymatic viral protein that plays a key role in Hepatitis C Virus replication, assembly, and modulation of host immune responses [A19175]. Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as velpatasvir. Notably, velpatasvir has a significantly higher barrier to resistance than the first generation NS5A inhibitors, such as [DB09027] and [DB09102], making it a highly potent and reliable alternative for treatment of chronic Hepatitis C [A19637]. 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 Velpatasvir as first line therapy in combination with sofosbuvir for all six genotypes of Hepatitis C [L852]. Velpatasvir is currently only available within a fixed dose combination product as Epclusa with [DB08934], another direct acting antiviral. Goals of therapy for Epclusa include 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 and risk of requiring a liver transplant [A19626]. Since June 2016, Velpatasvir has been available as a fixed dose combination product with [DB08934], as the commercially available product Epclusa. Epclusa is the first combination HCV product indicated for the treatment of all genotypes of Hepatitis C with or without cirrhosis. It 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 and a high barrier to resistance [L852]. Both Canadian and American guidelines list Epclusa as a first line recommendation for all genotypes of HCV [L852, A19626].

Indication

Velpatasvir 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 therapy with [DB00811]. When used in combination with [DB08934] as the combination product Epclusa, Velpatasvir is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis, or in combination with [DB00811] if associated with decompensated cirrhosis [FDA Label].

Mechanism of Action

Velpatasvir's mechanism of action is likely similar to other selective NS5A inhibitors which bind domain I of NS5A consisting of amino acids 33-202 [A19172]. NS5A inhibitors compete with RNA for binding at this site. It is also thought that NS5A inhibitors bind the target during its action in replication when the binding site is exposed [A19173]. Inhibition of NS5A is also known to produce redistribution of the protein to lipid droplets. The exact role of NS5A in RNA replication is not yet understood although it is known to be an important component.

Pharmacodynamics

Velpatasvir is a small molecule direct-acting antiviral used in the treatment of hepatitis C in combination with sofosbuvir. Velpatasvir prevents viral replication by inhibiting non-structural protein 5A (NS5A) [A19177]. At a dose 5 times the recommended dose, velpatasvir does not prolong QTc interval to any clinically relevant extent [FDA Label].

Pharmacokinetics

Absorption:

Oral bioavailability of 25-30% [A19175].

Distribution:

1.4-1.6 L/kg [A19175].

Metabolism:

Some metabolism by CYP2B6, CYP2C8, and CYP3A4 [A19175].

Elimination:

94% excreted in feces with 77% as parent compound. 0.4% excreted in urine [FDA Label].

Half-life

15h [FDA Label].

Clearance

Estimated 0.12 L/h/kg [A19175.

Toxicity

No indication of carcinogenicity or impairment of fertility/fetal viability [FDA Label].

Source of information: Drugbank (External Link). Last updated on: 3rd July 18
*Trade Name used in the content below may not be the same as the HSA-registered product.

Active Ingredient / Synonyms

Voxilaprevir | Voxilaprevir |

Description

Voxilaprevir is a Direct-Acting Antiviral (DAA) 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 [L852]. Voxilaprevir exerts its antiviral action by reversibley binding and inhibiting the NS3/4A serine protease of Hepatitis C Virus (HCV) [FDA Label]. Following viral replication of HCV genetic material and translation into a single polypeptide, Nonstructural Protein 3 (NS3) and its activating cofactor Nonstructural Protein 4A (NS4A) are responsible for cleaving genetic material into the following structural and nonstructural proteins required for assembly into mature virus: NS3, NS4A, NS4B, NS5A, and NS5B [A19643]. By inhibiting viral protease NS3/4A, voxilaprevir therefore prevents viral replication and function. Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as voxilaprevir. Voxilaprevir has been available since July 2017 in a fixed dose combination product with [DB08934] and [DB11613] as the commercially available product Vosevi. Vosevi is approved for the treatment of adult patients with chronic HCV infection with genotype 1, 2, 3, 4, 5, or 6 infection [FDA Label]. Notably, Vosevi is approved for use in patients with genotypes 1-6 who have been previously treated with an NS5A inhibitor, or patients with genotypes 1a or 3 infection and have previously been treated with an HCV regimen containing [DB08934] without an NS5A inhibitor [L935]. Prior to Vosevi, there were no approved retreatment options for patients who have previously received, and failed, a regimen containing an NS5A inhibitor for treatment of chronic HCV infection.

Indication

Vosevi (Voxilaprevir/[DB08934]/[DB11613]) is approved for use in patients with genotypes 1-6 who have been previously treated with an NS5A inhibitor, or patients with genotypes 1a or 3 infection who have previously been treated with an HCV regimen containing [DB08934] without an NS5A inhibitor [L935].

Mechanism of Action

Voxilaprevir exerts its antiviral action by reversibley binding and inhibiting the NS3/4A serine protease of Hepatitis C Virus (HCV) [FDA Label]. Following viral replication of HCV genetic material and translation into a single polypeptide, Nonstructural Protein 3 (NS3) and its activating cofactor Nonstructural Protein 4A (NS4A) are responsible for cleaving genetic material into the following structural and nonstructural proteins required for assembly into mature virus: NS3, NS4A, NS4B, NS5A, and NS5B [A19643]. By inhibiting viral protease NS3/4A, voxilaprevir therefore prevents viral replication and function.

Pharmacodynamics

Voxilaprevir is a direct-acting antiviral agent that targets viral NS3/4A protein and causes a decrease in serum HCV RNA levels. It disrupts HCV replication by specifically inhibiting the critical functions of NS3/4A protein in the replication complex. It does not appear to prolong the QT interval even when given at 9 times the maximum recommended dose [FDA Label].

Pharmacokinetics

Absorption:

When provided as the fixed dose combination product Vosevi with [DB08934] and [DB11613], voxilaprevir reaches a maximum concentration (Cmax) of 192 ng/mL at a maximum time (Tmax) of 4 hours post-dose [FDA Label].

Distribution:

Not Available

Metabolism:

Voxilaprevir is primarily metabolized by Cytochrome P450 3A4 (CYP3A4) and to a lesser extent by CYP2C8 and CYP1A2[FDA Label].

Elimination:

Voxilaprevir is primarily eliminated via biliary excretion [FDA Label].

Half-life

33 hr [FDA Label]

Clearance

Not Available

Toxicity

Not Available

References

  1. Health Science Authority of Singapore - Reclassified POM
  2. Drugbank

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Approval Information

VOSEVI FILM-COATED TABLETS 400MG/100MG/100MG was registered with Health Science Authority of Singapore by GILEAD SCIENCES SINGAPORE PTE LTD. It is marketed with the registration number of SIN15705P with effective from 2019-05-31.

This product contains 400 mg of Sofosbuvir, 100 MG of Velpatasvir, and 100 MG of Voxilaprevir in the form of TABLET, FILM COATED.

The medicine was manufactured by Gilead Sciences Ireland UC in IRELAND, Hovione FarmaCiencia in PORTUGAL, and S.A. (Drug product intermediate) in IRELAND

It is a Presciption Only Medicine which can only be obtained from a doctor or a dentist, or from a pharmacist with a prescription from a Singapore-registered doctor or dentist.

Anatomical Therapeutic Chemical (ATC) Classification

ATC Code: J05AP56

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