Ledipasvir + Sofosbuvir

Indications

Ledipasvir + Sofosbuvir is used for: Chronic hepatitis C (CHC), genotype 1, 4 & 6 infection in adults.

Adult Dose

Oral Hepatitis C Indicated for adults with chronic hepatitis C virus (HCV) genotypes 1, 4, 5, or 6 infection Recommended dosage: One tablet (90 mg of Ledipasvir and 400 mg of Sofosbuvir) taken once daily. Recommended treatment duration: Treatment-naive with or without cirrhosis: 12 weeks Treatment-experienced without cirrhosis: 12 weeks Treatment-experienced with cirrhosis: 24 weeks Hepatic impairment Mild, moderate, or severe: No dosage adjustment required Decompensated cirrhosis: Safety and efficacy not established

Child Dose

Safety and efficacy not established

Renal Dose

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

Administration

Can be taken with or without food.

Contra Indications

Hypersensitivity.

Precautions

Bradycardia with Amiodarone coadministration: Serious symptomatic bradycardia may occur in patients taking Amiodarone, particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. Coadministration of Amiodarone with Ledipasvir and Sofosbuvir combination is not recommended. In patients without viable treatment options, cardiac monitoring is recommended. Lactation: Unknown if distributed in human breast milk

Pregnancy-Lactation

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

Interactions

Reduced therapeutic effect w/ drugs that are potent P-gp inducers in the intestine (eg rifampicin, St. John's wort, carbamazepine & phenytoin), modafinil, phenobarb/oxcarbazepine, rifabutin/rifapentine. P-gp &/or BCRP inhibitors. May result in serious symptomatic bradycardia when co-administered w/ amiodarone in combination w/ another direct acting antiviral.

Side Effects

Side effects of Ledipasvir + Sofosbuvir : >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

Mode of Action

Ledipasvir is an HCV NS5A inhibitor and Sofosbuvir is a nucleotide analog inhibitor of HCV NS5B polymerase. Ledipasvir is a potent inhibitor of HCV NS5A, a viral phosphoprotein that plays an important role in viral replication, assembly, and secretion. Sofosbuvir is a nucleotide analog inhibitor of hepatitis C virus NS5B polymerase—the key enzyme mediating HCV RNA replication. The triphosphate form of sofosbuvir (GS-461203) mimics the natural cellular uridine nucleotide and is incorporated by the HCV RNA polymerase into the elongating RNA primer strand, resulting in chain termination.