- ACRONYMS AND DEFINITIONS
- AASLD - American Association for the Study of Liver Diseases
- CP - Child-Pugh liver failure classification
- GT - Genotype
- HBV - Hepatitis B virus
- HCV - Hepatitis C virus
- IDSA - Infectious Diseases Society of America
- ULN - Upper limit of normal
- DRUGS IN CLASS
- Vosevi®
- Vosevi is part of a new generation of antiviral medications that are highly effective against hepatitis C
- Vosevi is a combination pill that contains 3 medications - sofosbuvir, velpatasvir, and voxilaprevir
- See Hepatitis C treatment for a list of other HCV drugs
- MECHANISM OF ACTION
- Sofosbuvir
- Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication
- Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator
- Velpatasvir
- Velpatasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication and virion assembly
- Voxilaprevir
- Voxilaprevir is a NS3/4A protease inhibitor
- HCV NS3/4A protease cleaves HCV-encoded polyprotein into the individual proteins NS3, NS4A, NS4B, NS5A, and NS5B. These proteins form a complex that is necessary for viral replication.
- FDA-APPROVED INDICATIONS
- Retreatment of HCV in adult patients without cirrhosis or with Child-Pugh A who meet the following criteria:
- HCV genotypes 1, 2, 3, 4, 5, and 6 in patients previously treated with an HCV regimen containing an NS5A inhibitor
- HCV genotypes 1a or 3 in patients previously treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor
- NS5A inhibitors include the following drugs:
- Daclatasvir
- Elbasvir
- Ledipasvir
- Ombitasvir
- Pibrentasvir
- Velpatasvir
- HEPATITIS C TREATMENT
- In trials, Vosevi was > 90% effective in eradicating HCV in all subtypes of disease for which it is indicated
- SIDE EFFECTS
- Common
- In trials, Vosevi was well tolerated with only 0.2% of subjects discontinuing treatment because of side effects
- The table below details side effects from the POLARIS-1 trial where Vosevi was compared to placebo in patients with HCV GN 1, 2, 3, 4, 5, and 6
| Side effect | Vosevi™ for 12 weeks (N=263) |
Placebo for 12 weeks (N=152) |
|---|---|---|
| Headache | 21% | 14% |
| Fatigue | 17% | 15% |
| Diarrhea | 13% | 9% |
| Nausea | 13% | 7% |
| Asthenia | 6% | 4% |
| Insomnia | 6% | 3% |
- Elevated bilirubin
- Bilirubin is transported by OATP1B1/B3, and voxilaprevir is an OATP1B1/B3 inhibitor. Because of this, bilirubin elevations may occur in patients receiving Vosevi.
- In trials, up to 6% of patients without cirrhosis and up to 13% of patients with Child-Pugh A had total bilirubin elevations that were ≤ 1.5 X ULN
- No patients experienced jaundice and bilirubin levels decreased after stopping Vosevi
- CONTRAINDICATIONS
- Concomitant therapy with rifampin
- PRECAUTIONS
- Kidney disease
- No dosage adjustment is recommended in patients with any degree of renal impairment
- Liver disease
- Child-Pugh A: No dose adjustment necessary
- Child-Pugh B or C: DO NOT USE
- History of hepatic decompensation: DO NOT USE
- Rare cases of worsening liver function or liver failure have occurred in patients with moderate to severe liver disease who took Vosevi. Vosevi should also not be used in patients with a history of hepatic decompensation.
- In patients with compensated cirrhosis (Child Pugh A) or evidence of advanced liver disease such as portal hypertension, perform hepatic laboratory testing as clinically indicated; and monitor for signs and symptoms of hepatic decompensation such as the presence of jaundice, ascites, hepatic encephalopathy, and variceal hemorrhage. Discontinue Vosevi in patients who develop evidence of hepatic decompensation.
- Hepatitis B coinfection
- In October 2016, the FDA placed a boxed warning on all new hepatitis C drugs about the possible reactivation of hepatitis B infection in coinfected patients who are taking direct-acting antiviral hepatitis C drugs
- At the time of the warning, the FDA had identified 24 cases of hepatitis B reactivation in patients taking these drugs. Reactivation occurred in patients who were HBsAg positive and in those who were HBsAg negative and anti-HBc positive (see interpreting HBV screening results for more).
- The FDA recommends that providers check all patients for hepatitis B coinfection (HBsAg and anti-HBc) before starting therapy and that they monitor patients for reactivation during and after therapy
- See AASLD guidelines for HBV coinfected patients for more
- MONITORING THERAPY
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- Vosevi
- See the Vosevi PI for a complete list of potential drug interactions
- Clearance of HCV and liver function - Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. Examples of drugs that may need to be adjusted after liver function improves include diabetes medications, drugs with narrow therapeutic index, warfarin, immunosuppressants, and others.
- Amiodarone (Cordarone®)
- Serious cases of bradycardia have been reported in patients taking amiodarone in combination with sofosbuvir. Bradycardia typically occurs within hours to days, but has been observed as late as 2 weeks after initiating therapy.
- The combination of Vosevi and amiodarone is not recommended
- In cases where no other options are available, inpatient cardiac monitoring should be performed for the first 48 hours of concomitant therapy, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment
- BCRP substrates - Velpatasvir and voxilaprevir are inhibitors of the BCRP drug transporter. Coadministration of Vosevi with BCRP substrates is not recommended.
- Examples of BCRP substrates include:
- Methotrexate
- Mitoxantrone
- Imatinib
- Irinotecan
- Lapatinib
- Rosuvastatin
- Sulfasalazine
- Topotecan
- Cyclosporine - DO NOT COMBINE. Cyclosporine may raise Voxilaprevir exposure.
- CYP3A4 strong and moderate inducers - CYP3A4 inducers may decrease the effectiveness of Vosevi. Concomitant use is not recommended.
- CYP2C8 strong and moderate inducers = CYP2C8 inducers may decrease the effectiveness of Vosevi. Concomitant use is not recommended.
- CYP2B6 strong and moderate inducers - CYP2B6 inducers may decrease the effectiveness of Vosevi. Concomitant use is not recommended.
- Dabigatran (Pradaxa®) - Vosevi may raise dabigatran levels. See dabigatran drug interactions for information on dosing dabigatran with p-glycoprotein inhibitors.
- Digoxin - Vosevi may increase digoxin levels. Monitor digoxin levels closely when combining.
- HIV medications
- Atazanavir/lopinavir - Atazanavir/lopinavir may increase voxilaprevir levels. Coadministration is not recommended.
- Tipranavir/ritonavir - Tipranavir/ritonavir may decrease levels of sofosbuvir/velpatasvir. Coadministration is not recommended.
- Efavirenz - Efavirenz may decrease velpatasvir/voxilaprevir levels. Coadministration is not recommended.
- Tenofovir (Viread®, etc.) - Vosevi may increase levels of tenofovir. Monitor for tenofovir-associated adverse reactions during coadministration.
- P-glycoprotein inducers
- Velpatasvir, sofosbuvir, and voxilaprevir are p-glycoprotein substrates
- Drugs that induce P-glycoprotein may decrease the effectiveness of Vosevi
- Vosevi should not be given with with p-glycoprotein inducers
- NOTE: Vosevi® may be given with P-glycoprotein inhibitors
- Examples of common P-glycoprotein inducers include:
- Carbamazepine (Tegretol®)
- Oxcarbazepine (Trileptal®) (decreases sofosbuvir levels probably through P-glycoprotein induction)
- Phenobarbital
- Phenytoin (Dilantin®)
- Rifabutin
- Rifampin
- Rifapentine (Priftin®)
- St John's Wort
- Tipranavir (Aptivus®)
- Ritonavir (Norvir®)
- Statins
- Atorvastatin (Lipitor®) - Atorvastatin exposure is increased raising the risk of myopathy. Use lowest approved dose of atorvastatin.
- Fluvastatin (Lescol®) - Fluvastatin exposure is increased raising the risk of myopathy. Use lowest approved dose of fluvastatin.
- Lovastatin (Mevacor®) - Lovastatin exposure is increased raising the risk of myopathy. Use lowest approved dose of lovastatin.
- Pitavastatin (Livalo®) - DO NOT COMBINE. Pitavastatin exposure is increased raising the risk of myopathy.
- Pravastatin (Pravachol®) - Pravastatin exposure is increased raising the risk of myopathy. Pravastatin dose should not exceed 40 mg/day.
- Rosuvastatin (Crestor®) - DO NOT COMBINE. Rosuvastatin exposure is increased raising the risk of myopathy.
- Simvastatin (Zocor®) - Simvastatin exposure is increased raising the risk of myopathy. Use lowest approved dose of simvastatin.
- Warfarin (Coumadin®) - Fluctuations in INR levels may occur when Vosavi is taken with warfarin. Monitor INR levels closely.
- Velpatasvir
- Drugs that raise stomach pH - The solubility of velpatasvir decreases as stomach pH increases. Medications that raise stomach pH can lead to decreased absorption and effectiveness of velpatasvir
- Common acid-reducing agents include
- Antacids (aluminum and magnesium hydroxide) - separate antacid and Vosevi administration by 4 hours
- H2-receptor blockers (Pepcid®, Tagamet®, famotidine, etc.) - H2-receptor antagonists may be administered with Vosevi at doses that do not exceed doses comparable to famotidine 40 mg twice daily.
- Proton pump inhibitors (Nexium®, Prilosec®, Prevacid®) - omeprazole 20 mg once daily may be administered with Vosevi. Other PPIs have not been studied.
- Metabolism and clearance
- Sofosbuvir
- Sofosbuvir does not undergo CYP450 metabolism
- The metabolic activation pathway of sofosbuvir involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway.
- P-glycoprotein - substrate
- BCRP - substrate
- Velpatasvir
- CYP3A4 - substrate
- CYP2C8 - substrate
- CYP2B6 - substrate
- P-glycoprotein - substrate and inhibitor
- OATP1B1/P1B3 - substrate and inhibitor
- OATP2B1 - inhibitor
- BCRP - substrate and inhibitor
- Voxilaprevir
- CYP3A4 - sensitive substrate
- CYP2C8 - minor substrate
- CYP1A2 - minor substrate
- P-glycoprotein - substrate and inhibitor
- OATP1B1/B3 - substrate and inhibitor
- BCRP - substrate and inhibitor
- DOSING
- Dosage form
- Each tablet contains sofosbuvir 400 mg, velpatasvir 100 mg, and voxilaprevir 100 mg
- Vosevi comes in bottles that contain 28 tablets. Vosevi should be dispensed in its original container.
- Dosing
- One tablet once daily with food. Food increases absorption.
- Treatment regimens
- Vosevi is given once daily for 12 weeks for all indications
- Retreatment of HCV in adult patients without cirrhosis or with Child-Pugh A who meet the following criteria:
- HCV genotypes 1, 2, 3, 4, 5, and 6 in patients previously treated with an HCV regimen containing an NS5A inhibitor
- HCV genotypes 1a or 3 in patients previously treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor
- NS5A inhibitors include the following drugs:
- Daclatasvir
- Elbasvir
- Ledipasvir
- Ombitasvir
- Pibrentasvir
- Velpatasvir
- LONG TERM SAFETY
- Vosevi was FDA-approved in 2017
- There is no long-term safety data available
- BIBLIOGRAPHY
- 1 - Vosevi™ PI