Epclusa (Gilead Sciences) is a combination of two direct antiviral medicines (Sofosbuvir and Velpatasvir). It is considered as a pan-genotypic antiviral drug with efficacy exceeding 90% for the treatment of chronic active hepatitis C.

Epclusa (Sofosbuvir and velpatasvir) Uses:

• Chronic hepatitis C:

  • Used for treatment of chronic hepatitis C (CHC) genotype 1, 2, 3, 4, 5, or 6 infections in adults without cirrhosis or with compensated cirrhosis or in combination with ribavirin in patients with decompensated cirrhosis.

Epclusa (Velpatasvir + Sofosbuvir) dose in Adults

Epclusa (Velpatasvir + Sofosbuvir) dose in the treatment of chronic hepatitis C (HCV monoinfected or HCV/HIV co-infected) (AASLD/IDSA 2017): Oral:

• Genotype 1a:

  • Treatment-naive or peginterferon/ribavirin experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A):

    • 1 tablet OD for 12 weeks

  • NS3 protease inhibitor + peginterferon/ribavirin experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A):

    • 1 tablet OD for 12 weeks

  • With decompensated cirrhosis:

    • 1 tablet OD with concomitant ribavirin for 12 weeks (if ribavirin-ineligible, 1 tablet OD for 24 weeks)

  • Prior treatment failure with sofosbuvir- or NS5A-based regimens:

    • 1 tablet OD with concomitant ribavirin for 24 weeks

• Genotype 1b:

  • Treatment-naive or peginterferon/ribavirin experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A):

    • 1 tablet OD for 12 weeks

  • NS3 protease inhibitor + peginterferon/ribavirin experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A):

    •  1 tablet OD for 12 weeks

  • Non-NS5A inhibitor, sofosbuvir-containing regimen-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A):

    • 1 tablet OD for 12 weeks

  • With decompensated cirrhosis:

    • 1 tablet OD with concomitant ribavirin for 12 weeks (if ribavirin-ineligible, one tablet once daily for 24 weeks)

  • Prior treatment failure with sofosbuvir- or NS5A-based regimens:

    •  1 tablet OD with concomitant ribavirin for 24 weeks

• Genotype 2:

  • Treatment-naive or peginterferon/ribavirin experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A):

    • 1 tablet OD for 12 weeks

  • Sofosbuvir + ribavirin-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A):

    • 1 tablet OD for 12 weeks

  • With decompensated cirrhosis:

    • 1 tablet OD with concomitant ribavirin for 12 weeks (if ribavirin-ineligible, one tablet once daily for 24 weeks)

  • Prior treatment failure with sofosbuvir- or NS5A-based regimens:

    • 1 tablet OD with concomitant ribavirin for 24 weeks

  • Liver transplant recipients with compensated cirrhosis (Child-Pugh class A) (alternative regimen ):

    • 1 tablet OD with concomitant ribavirin for 12 weeks

  • Liver transplant recipients with decompensated cirrhosis (Child-Pugh class B or C):

    • 1 tablet OD with concomitant ribavirin for 12 weeks

• Genotype 3:

  • Treatment-naive without cirrhosis or with compensated cirrhosis (Child-Pugh class A):

    • 1 tablet OD for 12 weeks

  • Peginterferon/ribavirin experienced without cirrhosis:

    • 1 tablet OD for 12 weeks

  • Peginterferon/ribavirin experienced with compensated cirrhosis (Child-Pugh class A) (alternative regimen):

    • 1 tablet OD, with concomitant ribavirin, for 12 weeks

  • With decompensated cirrhosis:

    • 1 tablet OD with concomitant ribavirin for 12 weeks (if ribavirin-ineligible, one tablet once daily for 24 weeks)

  • Prior treatment failure with sofosbuvir- or NS5A-based regimens:

    • 1 tablet OD with concomitant ribavirin for 24 weeks

  • Liver transplant recipients with compensated cirrhosis (Child-Pugh class A) (alternative regimen):

    • 1 tablet OD with concomitant ribavirin for 12 weeks

  • Liver transplant recipients with decompensated cirrhosis (Child-Pugh class B or C):

    • 1 tablet OD with concomitant ribavirin for 12 weeks

• Genotype 4, 5, or 6:

  • Treatment-naive or peginterferon/ribavirin experienced without cirrhosis or with compensated cirrhosis (Child-Pugh class A):

    • 1 tablet OD for 12 weeks

  • With decompensated cirrhosis:

    • 1 tablet OD with concomitant ribavirin for 12 weeks (if ribavirin-ineligible, 1 tablet OD daily for 24 weeks)

  • Prior treatment failure with sofosbuvir- or NS5A-based regimens:

    • 1 tablet OD with concomitant ribavirin for 24 weeks

Use in Children:

The safety and efficacy of the drug have not been established in pediatric patients.

Epclusa Pregnancy Risk Category: N (Not assigned)

• In animal reproduction studies with sofosbuvir and velpatasvir, there were no adverse reactions.
• Also, refer to the sofosbuvir monograph for additional information.
• Hepatitis C treatment for pregnant women is not recommended.
• HIV-infected women with childbearing potential who are at high risk of HCV transmission should postpone pregnancy until treatment is completed.
• If HCV infection has been detected in pregnancy, treatment should be delayed until after delivery.
• Pregnant females should not receive antiviral medication that is directly effective in the absence of safety and efficacy data.
• All warnings regarding ribavirin use in combination with ribavirin should be observed.
• For more information, refer to the ribavirin monograph.

Use of velpatasvir and sofosbuvir during breastfeeding

• It is unknown if sofosbuvir and velpatasvir are secreted into breast milk.
• According to the manufacturer, when deciding whether to continue or stop breastfeeding during therapy, it should consider the risks to infants, the benefits to the infant and the benefits to the mother.
• The spread of the hepatitis C viruses is not associated with breastfeeding
• Breastfeeding is not recommended if the nipples become cracked or bleeding.
• Breastfeeding is not recommended in the case of HIV co-infection.

Epclusa Dose in Kidney Disease:

eGFR ≥30 mL/minute/1.73 m2:

• Dosage adjustment not necessary.

eGFR <30 mL/minute/1.73 m2:

• No dosage adjustments provided in the manufacturer's labeling.
• However, sofosbuvir and metabolite accumulate in patients with severe renal impairment.

End-stage renal disease (ESRD), including hemodialysis:

• No dosage adjustments provided in the manufacturer's labeling.
• However, sofosbuvir and metabolite accumulate in patients with severe renal impairment.

Epclusa Dose in Liver disease:

Mild, moderate, or severe impairment (Child-Pugh class A, B, or C):

• Dosage adjustment is not necessary.

Common Side Effects of Epclusa (Sofosbuvir and velpatasvir):

• Central nervous system:

  • Headache
  • Fatigue

Less Common Side Effects of Epclusa (Sofosbuvir and velpatasvir):

• Central Nervous System:

  • Irritability
  • Insomnia
  • Depression

• Dermatologic:

  • Skin Rash

• Gastrointestinal:

  • Nausea
  • Increased Serum Lipase

• Neuromuscular & Skeletal:

  • Weakness
  • Increased Creatine Phosphokinase

Side effects of Epclusa (Frequency not defined):

• Infection:

  • Reactivation of HBV

Contraindications to Epclusa (Sofosbuvir and velpatasvir):

• There are no contraindications in the labeling.
• If sofosbuvir/velpatasvir is administered with ribavirin, the contraindications to ribavirin also apply. Refer to the labeling information for ribavirin manufacturers.

Canadian labeling:

• Hypersensitivity to sofosbuvir or velpatasvir or any other component of the formulation
• If sofosbuvir/velpatasvir is administered with ribavirin, the contraindications to ribavirin also apply.
• Refer to the labeling information for ribavirin manufacturers.

Warnings and precautions

• Diabetes:

  • A rapid reduction in the viral load of hepatitis C during direct-acting antiviral therapy (DAA) for hepatitis C could lead to an improvement of glucose metabolism in diabetics, possibly leading to symptomatic hypoglycemia.
  • Monitor glucose tolerance changes and inform patients about the possibility of hypoglycemia while on DAA therapy, especially in the first three months. Modifications to anti-diabetic therapy might be necessary.

• Hepatitis B virus activation: [US-Boxed Warning]

  • Hepatitis B virus reactivation has been observed in HCV co-infected patients. These patients were receiving or having completed treatment with HCV direct acting antivirals. Some cases have led to hepatic failure and death.
  • Test all patients for evidence of current or prior HBV infection prior to initiation of ledipasvir/sofosbuvir; monitor HCV/HBV co-infected patients for hepatitis flare or HBV reactivation during treatment & post-treatment follow-up.
  • As soon as HBV infection is diagnosed, initiate treatment.
  • HBV reactivation was reported in HBsAg-positive patients and in patients with serologic evidence that resolved HBV infections (i.e. HBsAg & anti HBc positive). It is characterized as an abrupt increase of HBV replication, manifested by a rapid rise in serum HBV DNA levels. Patients with resolved HBV infections may experience a reappearance.
  • Patients who are taking immunosuppressants and chemotherapeutic drugs may have a higher risk of HBV reactivation.

Sofosbuvir and velpatasvir: Drug Interactions

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Baseline (within 12 weeks prior to starting antiviral therapy) CBC, INR, hepatic function panel (albumin, total and direct bilirubin, ALT, AST, and alkaline phosphatase), and calculated GFR
• Repeat CBC, serum creatinine, calculated GFR, and hepatic function panel after 4 weeks of therapy and as clinically indicated
• Baseline (at any time prior to starting therapy) HCV genotype and subtype and quantitative HCV viral load
• Repeat quantitative HCV viral load testing (after 4 weeks of therapy and at 12 weeks after completion of therapy).
• If quantitative HCV viral load is detectable at treatment week 4, repeat testing is recommended after 2 additional weeks of treatment (treatment week 6) (AASLD/IDSA 2017).
• Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) prior to initiation; in patients with serologic evidence of hepatitis B virus (HBV) infection
• Monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during treatment and during post-treatment follow-up.
• In patients with diabetes, monitor blood glucose and for signs/symptoms of hypoglycemia.
• If used in combination with amiodarone (or in patients who discontinued amiodarone just prior to initiating sofosbuvir/velpatasvir), inpatient cardiac monitoring for the first 48 hours of coadministration, then outpatient or self-monitoring of heart rate daily through at least the 1st two weeks of treatment.

How to administer Epclusa (Sofosbuvir and velpatasvir)?

P/O:

• Administer with or without food.

Mechanism of action of Epclusa (Sofosbuvir and velpatasvir):

• Velpatasvir blocks the HCV NS5A protein that is necessary for viral replication
• Sofosbuvir, a drug that has been converted to its pharmacologically effective form (GS-461203), causes inhibition of NS5B RNA dependent RNA polymerase. This is essential for viral replication and acts as a chain terminator.

Protein binding:

• Velpatasvir: >99.5%
• Sofosbuvir: 61% to 65%

Metabolism: Velpatasvir:

• Hepatic; substrate of P-gp, organic anion-transporting polypeptides (OATPs) and CYP 2B6, CYP 2C8, and CYP 3A4 (Smolders 2016)

Sofosbuvir:

• Hepatic; forms pharmacologically active nucleoside (uridine) analog triphosphate GS-461203; dephosphorylation results in the formation of nucleoside inactive metabolite GS-331007

Half-life elimination:

• Velpatasvir: 15 hours
• Sofosbuvir: 0.5 hours

Time to peak:

• Velpatasvir: 3 hours
• Sofosbuvir: 0.5 to 1 hour

Excretion: Velpatasvir:

• Urine: 0.4%
• feces: 94%

Sofosbuvir:

• Urine: 80%
• feces: 14%

International Brands of Sofosbuvir and velpatasvir (400/100 mg):

• Epclusa
• Panovir
• Sofosvel
• Velpacee

Sofosbuvir and velpatasvir (400/100 mg) Brand Names in Pakistan:

MyHep ALL - AGP Pharma Maclusa - Macter Pharma Hilvel - Hilton Pharma Velso - Genix Pharma OCVIR-V - Sami Pharma Velpaget - Getz Pharma