Harvoni is a combination of two direct-acting antiviral drugs (Ledipasvir and sofosbuvir).

It is used to treat chronic hepatitis C infection (Genotypes 1, 4, 5, and 6) with cure rates exceeding 94%.

Harvoni (Ledipasvir and sofosbuvir) Uses:

• Chronic hepatitis C infection:

  • Treatment of chronic hepatitis C virus genotype 1, 4, 5, or 6 infections in adult and pediatric patients ≥3 years of age, without cirrhosis or with compensated cirrhosis:
    • genotype 1 in adult patients with decompensated cirrhosis, in combination with ribavirin
    • & genotype 1 or 4 in adult liver transplant patients without cirrhosis or with compensated cirrhosis, in combination with ribavirin.

• Off Label Use of Harvoni (Ledipasvir and sofosbuvir) in Adults:

  • Chronic hepatitis C, genotype 1 or 4 (kidney transplant recipients)
  • Chronic hepatitis C, genotype 4, 5,

Harvoni (Ledipasvir and sofosbuvir) Dose in Adults:

Harvoni (Ledipasvir and sofosbuvir) Dose in the treatment of chronic hepatitis C infection (mono-infection or coinfected with HIV-1) : Oral:

• Genotype 1:

  • Treatment-naive patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A) or peginterferon/ribavirin treatment-experienced patients without cirrhosis:
    • One tablet OD for 12 weeks.
    • Note: Treatment-naive patients without cirrhosis who have hepatitis C virus RNA <6 million units/mL, are HIV uninfected, and non-black may be considered for therapy of 8 weeks duration.

• • Peginterferon/ribavirin treatment-experienced patients with compensated cirrhosis (Child-Pugh class A) (alternative regimen):
    • One tablet OD with concomitant ribavirin for 12 weeks.
  • NS3 protease inhibitor + peginterferon/ribavirin treatment-experienced patients:
    • Without cirrhosis: One tablet OD for 12 weeks.
    • With compensated cirrhosis (Child-Pugh class A) (alternative regimen):
      • One tablet OD once daily with concomitant ribavirin for 12 weeks.
  • Non-NS5A inhibitor, sofosbuvir-containing regimen-experienced patients without cirrhosis (except in cases of simeprevir failure) (alternative regimen):
    • One tablet OD with concomitant ribavirin for 12 weeks.
  • Decompensated cirrhosis (Child-Pugh class B or C):
    • One tablet OD with concomitant ribavirin for 12 weeks; if ribavirin ineligible, one tablet OD for 24 weeks.
  • Decompensated cirrhosis (Child-Pugh class B or C) in patients with prior sofosbuvir treatment failure:
    • One tablet OD with concomitant ribavirin for 24 weeks.
  • Liver transplant recipients (treatment-naive and treatment-experienced) without cirrhosis or with compensated cirrhosis (Child-Pugh class A) :
    • One tablet OD with concomitant ribavirin for 12 weeks.
  • Liver transplant recipients with decompensated cirrhosis (Child-Pugh class B or C) (off label use):
    • One tablet OD with concomitant ribavirin for 12 weeks.
  • Kidney transplant recipients (treatment-naive and treatment-experienced) without cirrhosis or with compensated (Child-Pugh class A) cirrhosis (off-label use):
    • One tablet OD for 12 weeks.

• Genotype 4:

  • Treatment-naive patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A) and peginterferon/ribavirin treatment-experienced patients without cirrhosis:
    • One tablet OD for 12 weeks.
  • Peginterferon/ribavirin treatment-experienced patients with compensated cirrhosis (Child-Pugh class A) (alternative regimen):
    • One tablet OD with concomitant ribavirin for 12 weeks.
  • Decompensated cirrhosis (Child-Pugh class B or C) (off-label use):
    • One tablet OD with concomitant ribavirin for 12 weeks; if ribavirin ineligible, one tablet OD for 24 weeks.
  • Decompensated cirrhosis (Child-Pugh class B or C) in patients with sofosbuvir treatment failure (off-label use):
    • One tablet OD with concomitant ribavirin for 24 weeks.
  • Liver transplant recipients (treatment-naive and treatment-experienced) with compensated (Child-Pugh class A) cirrhosis or without cirrhosis:
    • One tablet OD with concomitant ribavirin for 12 weeks.
  • Liver transplant recipients (treatment-naive and treatment-experienced) with decompensated cirrhosis (Child-Pugh class B or C) (off-label use):
    • One tablet once daily with concomitant ribavirin for 12 weeks.
  • Kidney transplant recipients (treatment-naive and treatment-experienced) without cirrhosis or with compensated (Child-Pugh class A) cirrhosis (off-label use):
    • One tablet OD for 12 weeks.

• Genotype 5 or 6:

  • Treatment-naive and peginterferon/ribavirin treatment-experienced patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A):
    • One tablet OD for 12 weeks.
  • Decompensated cirrhosis (Child-Pugh class B or C) (off-label use):
    • One tablet OD with concomitant ribavirin for 12 weeks; if ribavirin ineligible, one tablet OD for 24 weeks.
  • Decompensated cirrhosis (Child-Pugh class B or C) in patients with sofosbuvir treatment failure:
    • One tablet OD with concomitant ribavirin for 24 weeks.
  • Liver transplant recipients (treatment-naive and treatment-experienced) with or without cirrhosis, including decompensated cirrhosis (off-label use):
    • One tablet OD with concomitant ribavirin for 12 weeks.

Harvoni (Ledipasvir and sofosbuvir) Dose in Children:

Note: Prior to initiating therapy, test patient for evidence of hepatitis B infection (current or prior).

Harvoni (Ledipasvir and sofosbuvir) dose and duration of treatment in patients with chronic hepatitis C infection (mono-infection or co-infected with HIV-1):

• Children ≥3 years and Adolescents:

  • Patient weight:

    • <17 kg:

      • Pellets: Oral: 33.75 mg ledipasvir/150 mg sofosbuvir once a day.

    • 17 to <35 kg:

      • Pellets, tablets: Oral: 45 mg ledipasvir/200 mg sofosbuvir once  a day.

    • ≥35 kg:

      • Pellets, tablets: Oral: 90 mg ledipasvir/400 mg sofosbuvir once a day.

Duration of Treatment:

• Duration of therapy depends upon multiple factors (eg, genotype, hepatic function [cirrhosis/compensation], previous treatment, and response).

Note: Treatment-experienced patients are defined as those who have failed an interferon-based regimen.

• Genotype 1:

  • Treatment-naive patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A) or treatment-experienced patients without cirrhosis:
    • 12 weeks.
  • Treatment-experienced patients with compensated cirrhosis (Child-Pugh class A):
    • 24 weeks.
  • Treatment-naive or treatment-experienced with decompensated cirrhosis (Child-Pugh class B or C):
    • 12 weeks in combination with ribavirin.

• Genotype 1 or 4:

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  • Treatment-naive or treatment-experienced liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh class A):
    • 12 weeks in combination with ribavirin.

• Genotype 4, 5, or 6:

  • Treatment-naive and treatment-experienced patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A):
    • 12 weeks.

Pregnancy Risk Category: B

• In animal reproduction studies, there were no adverse effects from using sofosbuvir or ledipasvir.
• Hepatitis C treatment is not recommended for the treatment of maternal infections or to reduce the chance of mother-to child transmission.
• To reduce the risk of HCV transmission, HCV-infected women with childbearing potential may want to postpone pregnancy until treatment is completed.
• Treatment should be delayed until after birth if HCV infection is discovered during pregnancy.
• Until safety and efficacy data is available, direct-acting antiviral medication should not be administered to pregnant women.
• All warnings regarding ribavirin use in combination with other contraceptives and pregnancy should be observed.
• For more information, refer to the ribavirin monograph.

Use of sofosbuvir and ledipasvir during breastfeeding

• It is unknown if breast milk contains either ledipasvir nor sofosbuvir.
• When deciding whether to discontinue or continue breastfeeding during therapy, it is important to 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.
• HIV co-infection means that breastfeeding is not advised.

Harvoni (Ledipasvir and sofosbuvir) Dose in Kidney Disease:

• Mild, moderate, or severe impairment:

  • Dosage adjustment is not necessary.

• End-stage renal disease requiring hemodialysis:

  • Dosage adjustment is not necessary.

Harvoni (Ledipasvir and sofosbuvir) Dose in Liver disease:

• Mild, moderate, or severe impairment (Child-Pugh class A, B, or C):
  • Dosage adjustment not necessary.

Common Side Effects of Harvoni (Ledipasvir and sofosbuvir):

• Central nervous system:

  • Headache
  • Fatigue

• Neuromuscular & skeletal:

  • Weakness

Less Common Side Effects of Harvoni (Ledipasvir and sofosbuvir):

• Central Nervous System:

  • Irritability
  • Insomnia
  • Dizziness
  • Depression

• Gastrointestinal:

  • Nausea
  • Increased Serum Lipase
  • Diarrhea

• Hepatic:

  • Hyperbilirubinemia

• Neuromuscular & Skeletal:

  • Myalgia
  • Increased Creatine Phosphokinase

• Respiratory:

  • Cough
  • Dyspnea

Contraindication to Harvoni (Ledipasvir and sofosbuvir):

• The US manufacturer's labeling does not list any contraindications.
• If ledipasvir/sofosbuvir is administered with ribavirin, the contraindications to ribavirin also apply.
• Information about ribavirin manufacturers.

Canadian labeling:

• Hypersensitivity to any ingredient of the formulation

Warnings and precautions

• Diabetes:

  • Patients with diabetes may experience rapid reductions in viral load due to direct-acting antiviral therapy (DAA).
  • If antidiabetic drugs are given at the same dosage, this could lead to symptomatic hypoglycemia.
  • Patients should be closely monitored for any changes in glucose tolerance.
  • Modifications to anti-diabetic therapy might be required.

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

  • Reactivation of the hepatitis B virus has been observed in HCV-infected patients.
  • Some cases can lead to hepatic failure and fulminant liver disease.
  • 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 and post-treatment follow-up.
  • As soon as HBV infection is diagnosed, initiate treatment.
  • HBV reactivation was reported in HBsAg-positive patients and in those with serologic evidence that resolved HBV infections (i.e. HBsAg nil and anti-HBc p). It is characterized as an abrupt increase of HBV replication and a rapid rise in serum HBV DNA levels. Patients with resolved HBV infection may experience a recurrence of HBsAg.
  • Patients who are taking immunosuppressants and chemotherapeutics may have a higher risk of HBV reactivation.

Latanoprostene bunod: Drug Interaction

Monitoring parameters:

• Baseline (within 12 weeks prior to treatment initiation) CBC, INR, hepatic function (albumin, total and direct bilirubin, ALT, AST, alkaline phosphatase), calculated GFR
• Baseline (obtain any time prior to treatment initiation) hepatitis C virus (HCV) genotype and subtype, quantitative HCV viral load.

• During treatment;

  •  Monitor CBC, serum creatinine, calculated GFR, hepatic function panel (after 4 weeks of therapy and as clinically indicated)
  • 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).
• If used in combination with amiodarone (or in patients who discontinued amiodarone just prior to initiating ledipasvir/sofosbuvir), inpatient cardiac monitoring for the first 48 hours of coadministration, then outpatient or self-monitoring of heart rate daily through at least the first 2 weeks of treatment.
• Hepatitis B surface antigen and hepatitis B core antibody 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.

How to administer Harvoni (Ledipasvir and sofosbuvir)?

• Oral:
  • Tablets:
    • Administer with or without food.
  • Pellets:
    • Administer with or without food. May be sprinkled on 1 or more spoonfuls of nonacidic soft foods (eg, pudding, chocolate syrup, mashed potatoes, ice cream) at or below room temperature; mix gently.
    • Swallow entire contents within 30 minutes of mixing
    • Do not chew to avoid bitter aftertaste.

Mechanism of action of Harvoni (Ledipasvir and sofosbuvir):

• Ledipasvir blocks the HCV NS5A protein, which is necessary for viral replication
• Sofosbuvir is a prodrug converted to its pharmacologically active form (GS-461203), inhibits NS5B RNA-dependent RNA polymerase, also essential for viral replication, and acts as a chain terminator.

Notification:

• • Pediatric patients aged >=3 years are similar to adults in terms of pharmacokinetic profiles.

Absorption:

• Ledipasvir and sofosbuvir are well absorbed

Protein binding:

• Ledipasvir: >99.8%
• Sofosbuvir: ~61% to 65%

Metabolism:

• Ledipasvir: Slow oxidative metabolism via an unknown mechanism
• 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:

• Ledipasvir: 47 hours
• Sofosbuvir: ~0.5 hours

Time to peak:

• Ledipasvir: 4 to 4.5 hours
• Sofosbuvir: ~0.8 to 1 hour

Excretion:

• Ledipasvir:
  • Feces (~86%)
  • urine (1%)
• Sofosbuvir:
  • Urine (80%)
  • feces (14%)

International Brands of Ledipasvir and sofosbuvir:

• Harvoni
• Atcosodivir
• Harvocee
• Harvoni
• Ledisbuvir
• Ledvir
• Lesovir
• Lesovir-C
• Napcovir
• Twinvir

Ledipasvir and sofosbuvir Brand Names in Pakistan:

No Brands Available in Pakistan.