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 |
| Molecular Weight | Ledipasvir: 1052.1 Da; Sofosbuvir: 529.4 Da |
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 | No adequate human data; animal studies show no evidence of fetal harm at clinically relevant exposures. Use only if clearly needed. |
| 2nd trimester | Limited human data; no increased risk of major malformations reported in small cohort studies. Use if benefit outweighs risk. |
| 3rd trimester | No adverse fetal effects observed in small studies; consider use if maternal benefit outweighs potential risks. |
Clinical note
Comprehensive clinical and safety monograph for HARVONI (HARVONI).
| Placental transfer | Ledipasvir is >99% protein bound with placental transfer likely minimal; sofosbuvir is 61% protein bound and its metabolite GS-331007 crosses placenta in animal studies. Human data on placental transfer are lacking. |
| Breastfeeding | Ledipasvir and sofosbuvir are excreted into rat milk, but no human data are available. The combination is not recommended during breastfeeding due to potential adverse effects in the infant. Consider alternative agents with more safety data. |
■ 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 |
Hypersensitivity to ledipasvir, sofosbuvir, or any excipientsCoadministration with strong P-gp inducers (e.g., rifampin, St. John's wort)Severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease requiring dialysis
| 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). |
Loading safety data…
| Lactation Rating | L4 - Possibly Hazardous |
| 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. |
| 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. |