HARVONI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for HARVONI (HARVONI).
Fixed-dose combination of ledipasvir, an HCV NS5A inhibitor, and sofosbuvir, an HCV NS5B nucleotide polymerase inhibitor. Ledipasvir inhibits HCV NS5A protein essential for viral replication and assembly; sofosbuvir is a prodrug that after intracellular metabolism acts as a chain terminator by inhibiting NS5B RNA-dependent RNA polymerase.
| Metabolism | Ledipasvir: primarily metabolized by CYP3A; sofosbuvir: cathepsin A and CES1 hydrolysis, followed by HINT1 phosphorylation to active triphosphate. Sofosbuvir is primarily excreted renally (80%). |
| Excretion | Ledipasvir: 86% fecal, 1% renal; Sofosbuvir: 80% renal (as inactive metabolite GS-331007), 14% fecal; GS-331007: 78% renal |
| Half-life | Ledipasvir: 47 hours; Sofosbuvir: 0.5 hours; GS-331007 (predominant circulating metabolite): 27 hours; clinical context: supports once-daily dosing with no accumulation beyond steady state by day 7 |
| Protein binding | Ledipasvir: >99.8% bound (primarily albumin); Sofosbuvir: 61-65% bound (albumin); GS-331007: minimal binding |
| Volume of Distribution | Ledipasvir: 47.5 L (0.68 L/kg for 70 kg); Sofosbuvir: 127 L (1.81 L/kg for 70 kg); GS-331007: 260 L (3.71 L/kg); meaning: extensive extravascular distribution for metabolites |
| Bioavailability | Oral: Ledipasvir 92% (fed/fasted); Sofosbuvir 90% (fed/fasted); GS-331007 90% (fed/fasted) |
| Onset of Action | Oral: 1-2 hours to first decline in HCV RNA, with maximal viral suppression within 2-4 weeks |
| Duration of Action | 24 hours; clinical note: sustained virologic response at 12 weeks post-treatment is the primary endpoint; drug levels remain above EC90 for 24 hours with daily dosing |
One tablet (90 mg ledipasvir/400 mg sofosbuvir) orally once daily with or without food for 12 weeks. For treatment-naïve patients with genotype 1 and cirrhosis, 24 weeks may be considered. For genotype 4, 12 weeks recommended.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (eGFR >=30 mL/min/1.73 m2). Safety and efficacy not established in severe renal impairment (eGFR <30 mL/min/1.73 m2) or hemodialysis; use is not recommended. |
| Liver impairment | No dose adjustment required for mild, moderate, or severe hepatic impairment (Child-Pugh A, B, or C). |
| Pediatric use | Approved for children 3 years and older. Weight-based dosing: <17 kg: not recommended; 17 to <35 kg: one tablet of 45 mg/200 mg (ledipasvir/sofosbuvir) orally once daily; >=35 kg: one tablet of 90 mg/400 mg orally once daily. Duration typically 12 weeks. |
| Geriatric use | No specific dose adjustment required. Older patients may have higher risk of adverse events; monitor renal function and drug interactions, especially with medications affecting gastric pH. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for HARVONI (HARVONI).
| Breastfeeding | No data on presence in human milk; M/P ratio unknown. Consider risk of HCV transmission vs. infant exposure; use caution. |
| Teratogenic Risk | Insufficient human data; animal studies show no teratogenicity at clinically relevant doses. Risk cannot be excluded. First trimester: limited data; second and third trimesters: no known fetal harm. |
| Fetal Monitoring | Monitor HCV RNA levels and liver function tests; ultrasonography for fetal growth if used during pregnancy. |
■ FDA Black Box Warning
Hepatitis B virus (HBV) reactivation: Test all patients for evidence of current or prior HBV infection before initiating treatment. HBV reactivation has been reported in HCV/HBV coinfected patients, some resulting in fulminant hepatitis, hepatic failure, and death.
| Serious Effects |
["Coadministration with amiodarone (risk of symptomatic bradycardia)","Coadministration with P-gp inducers (e.g., rifampin) or strong CYP3A inducers (e.g., carbamazepine, phenytoin)","Coadministration with rosuvastatin (increased statin levels and risk of myopathy/rhabdomyolysis)","Severe hypersensitivity to ledipasvir or sofosbuvir"]
| Precautions | ["Risk of HBV reactivation","Risk of symptomatic bradycardia when used with amiodarone","Potential for decreased therapeutic effect when coadministered with P-gp inducers (e.g., rifampin, St. John's wort)","Use with caution in patients with severe renal impairment (eGFR <30 mL/min) or ESRD requiring hemodialysis","Monitor hepatic function in patients with decompensated cirrhosis"] |
| Food/Dietary | No significant food interactions. Administer with or without food. Avoid grapefruit juice? Not specifically contraindicated; no known interaction. Ensure consistent intake pattern if using with antacids: separate by at least 4 hours if taking H2 blockers or proton pump inhibitors (reduce absorption). |
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| Fertility Effects | No evidence of impaired fertility in animal studies; no human data on fertility effects. |
| Clinical Pearls | HARVONI is a fixed-dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg), a direct-acting antiviral for chronic hepatitis C genotype 1,4,5,6. Dose adjustment with rifampin or St. John's wort coadministration is contraindicated. Check renal function: no dose adjustment needed for mild/moderate impairment (eGFR >30 mL/min); not recommended in severe renal impairment (eGFR <30 mL/min) or dialysis. Monitor for hepatitis B reactivation in coinfected patients. Treatment duration: 12 weeks for treatment-naïve without cirrhosis or with compensated cirrhosis; 24 weeks for treatment-experienced with cirrhosis or prior protease inhibitor failure. Administer with or without food. SVR rates >95% in most populations. |
| Patient Advice | Take one tablet (ledipasvir/sofosbuvir) orally once daily with or without food. · Do not miss doses; if missed within 18 hours, take as soon as possible; if only discovered after 18 hours, skip and take next dose at regular time. · Avoid taking HARVONI with rifampin, St. John's wort, or medications containing tenofovir disoproxil fumarate (unless HIV coinfection). · Inform your doctor about all medications, including over-the-counter drugs and supplements. · Report symptoms of hepatitis B reactivation (jaundice, dark urine, right upper quadrant pain) if you have prior HBV infection. · Continue treatment as prescribed; do not stop without consulting your doctor. |