ledipasvir/sofosbuvir (Rx)

>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

Contraindications

If coadministered with ribavirin, the contraindications to ribavirin also apply to this combination regimen

Cautions

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV DDAs, and who were not receiving HBV antiviral therapy; HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level (see Black Box Warnings and Dosing Considerations)

Do not use with other products that contain sofosbuvir (Sovaldi, Epclusa); 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

If the drug combination is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant; refer to ribavirin prescribing information for more information on ribavirin-associated risks of use during pregnancy

No adequate human data are available to establish whether or not the drug combination poses a risk to pregnancy outcomes; in animal reproduction studies, no evidence of adverse developmental outcomes was observed with the drug combination ledipasvir or sofosbuvir at exposures greater than those in humans at the recommended human dose (RHD)

Lactation

It is not known whether ledipasvir or sofosbuvir, the drug combination, or their metabolites are present in human breast milk, affect human milk production or have effects on the breastfed infant.

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for the drug combination and any potential adverse effects on the breastfed child from the drug combination or from the underlying maternal condition

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.

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

Oral Preparation (Oral Pellets)

Do not chew pellets

If pellets are administered with food, sprinkle on ≥1 spoonfuls of nonacidic soft food (eg, pudding, chocolate syrup, mashed potato, ice cream) at or below room temperature

Take pellets within 30 min of gently mixing with food and swallow entire contents without chewing to avoid a bitter aftertaste

Oral Administration

Take with or without food

Storage

Tablets and oral pellets: Store <30ºC; dispense in original bottle