Dosing and uses of Harvoni (ledipasvir/sofosbuvir)
Adult dosage forms and strengths
ledipasvir/sofosbuvir
tablet
- 90mg/400mg
Hepatitis C
Indicated for adults with chronic hepatitis C virus (HCV) genotypes 1, 4, 5, or 6 infection
1 tablet (90 mg/400 mg) PO qDay
Treatment duration
- The following regimens also apply to HCV/HIV-1 coinfection
- Genotype 1
- Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A): 12 weeks
- Treatment-experienced without cirrhosis: 12 weeks
- Treatment-experienced with compensated cirrhosis (Child-Pugh A): 24 weeks; may also consider adding daily weight-based ribavirin
- Treatment-naïve and treatment-experienced with decompensated cirrhosis (Child-Pugh B or C), including those who have undergone liver transplantation: 12 weeks in combination with ribavirin
- Note:
- 8 weeks can be considered in treatment-naïve patients without cirrhosis who have pretreatment HCV RNA <6 million IU/mL
- Treatment –experienced patients include those who have failed a peginterferon alfa + ribavirin based regimen with or without an HCV protease inhibitor
- Ledipasvir/sofosbuvir + ribavirin for 12 weeks can be considered in treatment-experienced genotype 1 patients with cirrhosis who are eligible for ribavirin; see ribavirin dosage recommendations below
- In patients with decompensated cirrhosis, the starting dosage of ribavirin is 600 mg and can be titrated up to 1000 mg for patients <75 kg and 1200 mg for those ≥75 kg in two divided doses with food; if starting dosage of ribavirin is not well tolerated, reduce dosage as clinically indicated based on hemoglobin levels
- Ribavirin dosage recommendations: The daily dosage of ribavirin is weight-based (1000 mg for patients <75 kg and 1200 mg for those ≥75 kg) administered orally in two divided doses with food
- For further information on ribavirin dosing and dosage modifications, refer to the ribavirin prescribing information
- Genotypes 1 or 4
- Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A), including those who have undergone liver transplantation: 12 weeks in combination with ribavirin
- Genotypes 4, 5, or 6
- Treatment-naïve and treatment-experienced, without cirrhosis or with compensated cirrhosis (Child-Pugh A): 12 weeks
Dosage modifications
Renal impairment
- Mild or moderate: No dosage adjustment required
- Severe (eGFR <30 mL/min/1.73 m²) or ESRD: No dosage recommendation can be given
Hepatic impairment
- Mild, moderate, or severe: No dosage adjustment required
- Decompensated cirrhosis: Safety and efficacy not established
Pediatric dosage forms and strengths
Safety and efficacy not established
Hepatitis C Virus Infection (Orphan)
Orphan designation for treatment of chronic hepatitis C virus (HCV) infection in pediatric patients
Sponsor
- Gilead Sciences, Inc; 333 Lakeside Drive; Foster City, California 94404
Harvoni (ledipasvir/sofosbuvir) adverse (side) effects
>10%
Asthenia (31-36%)
Fatigue (4-18%)
Headache (13-29%)
Cough (5-11%)
1-10%
Nausea (6-9%)
Diarrhea (3-7%)
Dizziness (1-5%)
Dyspnea (3-9%)
Insomnia (3-6%)
Increased bilirubin >1.5 x ULN (<1 to 3%)
Increased lipase >3 x ULN (<1 to 3%)
Myalgia (4-9%)
Irritability (7-8%)
Frequency not defined
Asymptomatic creatine kinase elevation, Grades 3/4
Postmarketing Reports
Bradycardia in patients taking amiodarone who initiate ledipasvir/sofosbuvir therapy
Skin rash, sometimes with blisters or angioedema-like swelling
Warnings
Black box warnings
Direct-acting antivirals (DDAs) may reactivate hepatitis B virus (HBV) in patients who have a current or previous HBV infection while being treated for hepatitis C virus
In a few cases, HBV reactivation in patients treated with DAA medicines resulted in serious liver problems or death
Patients should be screened for evidence of current or prior HBV infection before starting treatment with DAAs, and monitored for HBV flare-ups or reactivation during DAA treatment and posttreatment follow-up
Contraindications
If coadministered with ribavirin, the contraindications to ribavirin also apply to this combination regimen
Cautions
Do not use with other products that contain sofosbuvir (Sovaldi); duplicate therapy and increased risk for adverse effects
Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with sofosbuvir in combination with an investigational agent (daclatasvir, an investigational NS5A inhibitor) or simeprevir; coadministration is not recommended, if no alternative exists, inpatient cardiac monitoring is recommended for the first 48 hr and then daily home monitoring for at least the first 2 weeks
Due to amiodarone’s long half-life, patients discontinuing amiodarone just prior to starting ledipasvir/sofosbuvir therapy should undergo cardiac monitoring; patients who develop signs or symptoms of bradycardia, including near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or memory problems should seek medical evaluation immediately
Ledipasvir and sofosbuvir are substrates of P-gp and BCRP; coadministration with P-gp inducers (eg, rifampin, St. John’s wort) is not recommended; may significantly decrease ledipasvir and sofosbuvir plasma concentrations and reduce therapeutic effect
Ledipasvir is an inhibitor of P-gp and BCRP; may increase intestinal absorption of coadministered substrates for these transporters
Coadministration of ledipasvir with acid-reducing agents may decrease ledipasvir solubility, resulting in decreased serum concentrations
If coadministered with ribavirin, the warnings and precautions for ribavirin also apply to this combination regimen
Pregnancy and lactation
Pregnancy category: B
Lactation: Unknown if distributed in human breast milk
Ledipasvir was detected in the plasma of suckling rats, likely due to the presence of ledipasvir in milk; had no clear effects on the nursing pups
The predominant circulating metabolite of sofosbuvir (GS-331007) was the primary component observed in the milk of lactating rats, without effect on nursing pups
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Harvoni (ledipasvir/sofosbuvir)
Mechanism of action
Ledipasvir: Inhibits HCV NS5A protein, which is required for viral replication; resistance selection in cell culture and cross-resistance studies indicate ledipasvir targets NS5A as its mode of action
Sofosbuvir: Nucleotide prodrug that undergoes metabolism to the active uridine analog triphosphate, an inhibitor of HCV NS5B RNA-dependent polymerase; its inhibition, in turn, suppresses viral replication
Absorption
Peak plasma concentration
- ledipasvir: 4-4.5 hr
- sofosbuvir: 0.8-1 hr
- GS-331007: 3.5-4 hr
Peak plasma leveL
- ledipasvir: 323 ng/mL
- sofosbuvir: 618 ng/mL
- GS-331007: 707 ng/mL
AUC
- ledipasvir: 7,290 ng•hr/mL
- sofosbuvir: 1,320 ng•hr/mL
- GS-331007: 12,000 ng•hr/mL
Distribution
Protein bound
- ledipasvir: >99.8%
- sofosbuvir: 61-65%
- GS-331007: minimal
Metabolism
ledipasvir: No detectable metabolism
sofosbuvir: Extensively metabolized in liver to form the pharmacologically active nucleoside analog triphosphate GS-461203; dephosphorylation results in formation of GS331007 (accounts for <90% of total systemic exposure of sofosbuvir)
Elimination
Half-life, terminaL
- ledipasvir: 47 hr
- sofosbuvir: 0.5 hr
- GS-331007: 27 hr
Excretion
- ledipasvir: >98% feces (mostly unchanged); <1% urine
- GS-331007: 14% feces; 80% urine; 2.5% expired air
Administration
Instructions
May take with or without food
