- 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
- RBV - Ribavirin
- ULN - Upper limit of normal
- DRUGS IN CLASS
- Epclusa is part of a new generation of antiviral medications that are highly effective against hepatitis C
- Epclusa is a combination pill that contains 2 medications - sofosbuvir and velpatasvir
- 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
- FDA-APPROVED INDICATIONS
- Treatment of adults and pediatric patients ≥ 3 years of age with HCV genotypes 1, 2, 3, 4, 5, and 6
- No cirrhosis and Child-Pugh A: Epclusa only
- Child-Pugh B/C: Epclusa + ribavirin
- EFFECTIVENESS
| HCV cure rates for Epclusa | ||
|---|---|---|
| Genotype | No cirrhosis or Child-Pugh A | Child-Pugh B/C |
| 1 | > 90% | > 90% |
| 2 | > 90% | > 90% |
| 3 | > 90% | > 90% |
| 4 | > 90% | > 90% |
| 5 | > 90% | N/A |
| 6 | > 90% | N/A |
- SIDE EFFECTS
- Overview
- In trials, the incidence of side effects with Epclusa was similar to placebo
- Side effects from the ASTRAL-1 trial are listed below
| Side effect | Epclusa® for 12 weeks (N=624) |
Placebo for 12 weeks (N=116) |
|---|---|---|
| Headache | 29% | 28% |
| Fatigue | 20% | 20% |
| Nasopharyngitis | 13% | 10% |
| Nausea | 12% | 11% |
| Insomnia | 8% | 9% |
| Diarrhea | 8% | 7% |
| Asthenia | 7% | 8% |
| Arthralgia | 6% | 8% |
| Cough | 6% | 3% |
| Lipase elevations > 3 X ULN |
3% | 1% |
| Rash | 2% | 1% |
| Depression | 1% | 0% |
| CK elevations > 10 X ULN |
1% | 0% |
- CONTRAINDICATIONS
- None known
- See ribavirin contraindications if Epclusa is to be given with ribavirin
- PRECAUTIONS
- Kidney disease
- No dosage adjustment of Epclusa is recommended for patients with mild, moderate, or severe renal impairment, including end-stage renal disease requiring dialysis
- No safety data are available in subjects with both decompensated cirrhosis and severe renal impairment, including end-stage renal disease requiring dialysis.
- Liver disease
- No dose adjustment of Epclusa is required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B or C)
- 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.
- Velpatasvir and sofosbuvir
- See the Epclusa 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 (slow heart rate) 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 Epclusa 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
- Atorvastatin (Lipitor®) - Epclusa may increase blood levels of atorvastatin. Monitor closely for muscle toxicity during coadministration.
- Digoxin - Epclusa may increase digoxin levels. Monitor levels closely when given together.
- HIV antiretrovirals - See the [Epclusa PI [sec 7] for recommendations on concomitant HIV antiretroviral medications
- P-glycoprotein inducers
- Velpatasvir and sofosbuvir are p-glycoprotein substrates
- Drugs that induce P-glycoprotein may decrease the effectiveness of velpatasvir and sofosbuvir
- Epclusa should not be given with with p-glycoprotein inducers
- NOTE: Epclusa® 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®)
- Rosuvastatin (Crestor®) - Epclusa may increase blood levels of rosuvastatin. Rosuvastatin doses should not exceed 10 mg when given with Epclusa.
- Topotecan - Epclusa may increase topotecan levels. Coadministration is not recommended.
- Warfarin (Coumadin®) - Fluctuations in INR levels may occur when Epclusa 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 Epclusa administration by 4 hours
- H₂-receptor blockers (Pepcid®, Tagamet®, famotidine, etc.) - H2-receptor antagonists may be administered simultaneously with or 12 hours apart from Epclusa at a dose that does not exceed doses comparable to famotidine 40 mg twice daily.
- Proton pump inhibitors (Nexium®, Prilosec®, Prevacid®) - PPIs are not recommended with Epclusa. If concomitant use is unavoidable, Epclusa should be administered with food and taken 4 hours before omeprazole 20 mg. Other PPIs have not been studied.
- CYP3A4 strong and moderate inducers -Velpatasvir is a CYP3A4 substrate. CYP3A4 inducers may decrease blood levels of velpatasvir. Concomitant use is not recommended.
- CYP2C8 strong and moderate inducers - Velpatasvir is a CYP2C8 substrate. CYP2C8 inducers may decrease blood levels of velpatasvir. Concomitant use is not recommended.
- CYP2B6 strong and moderate inducers - Velpatasvir is a CYP2B6 substrate. CYP2B6 inducers may decrease blood levels of velpatasvir. Concomitant use is not recommended.
- Metabolism and clearance
- Velpatasvir
- CYP3A4 - substrate
- CYP2C8 - substrate
- CYP2B6 - substrate
- P-glycoprotein - substrate and inhibitor
- OATP1B1/P1B3 - substrate and inhibitor
- OATP2B1 - inhibitor
- BCRP - substrate and inhibitor
- 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
- DOSING
- Dosage form
- Tablet
- Sofosbuvir : Velpatasvir
- 200 mg : 50 mg
- 400 mg : 100 mg
- Comes in bottles of 28 tablets
- Dispense in original container
- Oral pellets
- Sofosbuvir : Velpatasvir
- 150 mg : 37.5 mg
- 200 mg : 50 mg
- Comes in carton with 28 packets
- Dosing
- Adults: One 400/100 mg tablet once daily. May take without regard to food.
- See Epclusa PI [sec 2] for dosing in pediatric patients
| Epclusa treatment regimens for GT 1, 2, 3, 4, 5, and 6 | |
|---|---|
| Patient population | Treatment |
| Treatment-naïve and treatment-experienced✝ with no cirrhosis or Child-Pugh A | Epclusa for 12 weeks |
| Treatment-naïve and treatment-experienced✝ with Child-Pugh B or C | Epclusa + weight-based ribavirin for 12 weeks |
| Liver transplant recipients who are treatment-naïve or treatment-experienced✝ with no cirrhosis or Child-Pugh A | Epclusa for 12 weeks |
- LONG TERM SAFETY
- Epclusa® was FDA-approved in 2016
- There is no long-term safety data available
- BIBLIOGRAPHY
- 1 - Epclusa® PI
- 2 - PMID 26571066 - Astral-1