Harvoni (Oral)

Uses

Ledipasvir and Sofosbuvir combination is used for the treatment of chronic hepatitis C (CHC) genotype 1, 4 & 6 infection in adults.

Harvoni (Oral) is also used to associated treatment for these conditions: Chronic Hepatitis C Genotype 1, Chronic hepatitis C genotype 4, Chronic hepatitis C genotype 5, Genotype 6 chronic hepatitis C infectionChronic Hepatitis C Genotype 1, Chronic hepatitis C genotype 2, Chronic hepatitis C genotype 3, Chronic hepatitis C genotype 4, Chronic hepatitis C genotype 5, Genotype 6 chronic hepatitis C infection

How Harvoni (Oral) works

Ledipasvir is an inhibitor of the Hepatitis C Virus (HCV) NS5A protein required for viral RNA replication and assembly of HCV virions. Although its exact mechanism of action is unknown, it is postulated to prevent hyperphosphorylation of NS5A which is required for viral production.

Sofosbuvir is nucleotide analog inhibitor, which specifically inhibits HCV NS5B (non-structural protein 5B) RNA-dependent RNA polymerase. Following intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), sofosbuvir incorporates into HCV RNA by the NS5B polymerase and acts as a chain terminator . More specifically, Sofosbuvir prevents HCV viral replication by binding to the two Mg2+ ions present in HCV NS5B polymerase's GDD active site motif and preventing further replication of HCV genetic material .

Dosage

Harvoni (Oral) dosage

Recommended dosage: One tablet (90 mg of Ledipasvir and 400 mg of Sofosbuvir) taken orally once daily with or without food

Recommended treatment duration:

• Treatment-naive with or without cirrhosis: 12 weeks
• Treatment-experienced without cirrhosis: 12 weeks
• Treatment-experienced with cirrhosis: 24 weeks

A dose recommendation cannot be made for patients with severe renal impairment or end stage renal disease.

Side Effects

The most common adverse reactions with treatment with Ledipasvir and Sofosbuvir combination for 8, 12, or 24 weeks are fatigue and headache.

Toxicity

There is very little toxicity associated with the use of ledipasvir in combination products. The most common adverse reactions are headache and fatigue.

Sofosbuvir, as a single agent, has very mild toxicity. The most common adverse reactions are headache and fatigue. The FDA Label currently warns of a risk of symptomatic bradycardia when Epclusa is used in combination with amiodarone .

Precaution

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.

Use with other drugs containing sofosbuvir, is not recommended

Interaction

• Coadministration with amiodarone may result in serious symptomatic bradycardia. Use of Ledipasvir and Sofosbuvir combination with Amiodarone is not recommended
• P-gp inducers (e.g., Rifampin, St. John’s wort): May alter concentrations of Ledipasvir and Sofosbuvir. Use of Ledipasvir and Sofosbuvir combination with P-gp inducers is not recommended

Volume of Distribution

The volume of distribution for sofosbuvir has yet to be determined .

Elimination Route

When given orally, ledipasvir reaches its maximum plasma concentration in about 4 to 4.5 hours with a maximum concentration (Cmax) of 323 ng/mL .

When given orally, sofosbuvir reaches its maximum plasma concentration in about 0.5 to 2 hours with a maximal concentration (Cmax) of 567 ng/mL .

Half Life

The median terminal half-life of ledipasvir is 47 hours .

Sofosbuvir has a terminal half life of 0.4 hours .

Clearance

The clearance of sofosbuvir has yet to be determined .

Elimination Route

Following a single 90 mg oral dose of [14C]-ledipasvir, mean total recovery of the [14C]-radioactivity in feces and urine was approximately 87%, with most of the radioactive dose recovered from feces (approximately 86%). Unchanged ledipasvir excreted in feces accounted for a mean of 70% of the administered dose and the oxidative metabolite M19 accounted for 2.2% of the dose. These data indicate that biliary excretion of unchanged ledipasvir is a major route of elimination, with renal excretion being a minor pathway (approximately 1%) .

Sofosbuvir is eliminated by three routes: urine ( 80%), feces (14%), and respiration (2.5%); however, elimination through the kidneys is the major route .

Pregnancy & Breastfeeding use

Pregnancy Category B. There are no adequate and well-controlled studies with Ledipasvir and Sofosbuvir in pregnant women. Because animal reproduction studies are not always predictive of human response, this should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation: It is not known whether Ledipasvir and Sofosbuvir and its metabolites are present in human breast milk.

Contraindication

This combination is contraindicated in patients with Known hypersensitivity to Ledipasvir, Sofosbuvir or any other ingredient in the product.

Special Warning

Pediatric Use: Safety and effectiveness of Ledipasvir and Sofosbuvir have not been established in pediatric patients.

Geriatric Use: No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. No dosage adjustment of Ledipasvir and Sofosbuvir is warranted in geriatric patients.

Acute Overdose

No specific antidote is available for overdose

Storage Condition

Keep out of the reach of children. Keep in a cool & dry place. Protect from light.

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