Ledihep

Ledihep Uses, Dosage, Side Effects, Food Interaction and all others data.

Ledipasvir is a direct acting antiviral (DAA) medication used as part of combination therapy to treat chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV). HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients . Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as ledipasvir. More specifically, ledipasvir is an inhibitor of the Hepatitis C Virus (HCV) Non-Structural Protein 5A (NS5A), which is 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 protein production. It is effective against genotypes 1a, 1b, 4a, and 5a and with a lesser activity against genotypes 2a and 3a of HCV. Ledipasvir and other direct acting antivirals are very potent options for the treatment of Hepatitis C, as they exhibit a high barrier to the development of resistance . This is an important advantage relative to HCV drugs that target other viral enzymes such as the protease, for which rapid development of resistance has proven to be an important cause of therapeutic failure.

In a joint recommendation published in 2016, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommend ledipasvir as a first line therapy option in combination with sofosbuvir for the treatment of HCV genotypes 1a, 1b, 4, 5, and 6 . Treatment with ledipasvir is used with the intent to cure, or achieve a sustained virologic response (SVR), after 12 weeks of daily therapy. SVR and eradication of HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality . Treatment with direct acting antivirals such as ledipasvir is associated with very minimal side effects, with the most common being headache and fatigue . Lack of significant side effects and short duration of therapy is a considerable advantage over older interferon- and ribavirin-based regimens, which were limited by infusion site reactions, reduced blood count, and neuropsychiatric effects .

Since 2014, ledipasvir has been available as a fixed dose combination product with sofosbuvir (tradename Harvoni) used for the treatment of chronic Hepatitis C. Approved in October 2014 by the FDA, Harvoni is indicated for the treatment of HCV genotypes 1, 4, 5, and 6 with or without ribavirin depending on the level of liver damage or cirrhosis . When combined together, ledipasvir and sofosbuvir as the combination product Harvoni has been shown to achieve a SVR between 93 and 99% after 12 weeks of treatment . Its use has also proven successful in the treatment of HCV in patients co-infected with HIV .

Sofosbuvir is an inhibitor of the hepatitis C virus (HCV) NS5B ribonucleic acid (RNA)-dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a, 3a and 4a with a 50% inhibitory concentration (IC50) value ranging from 0.7-2.6 micrometer. GS-461203 (the active metabolite of sofosbuvir) is not an inhibitor of human deoxyribonucleic acid (DNA) and RNA polymerases, nor an inhibitor of mitochondrial RNA polymerase.

Sofosbuvir acts against HCV and is categorized as a direct-acting antiviral agent (DAA).

At a dose 3 times the recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent .

Ledihep
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Ledihep
Generic	Sofosbuvir + Ledipasvir
Weight	400mg
Type	Tablet
Therapeutic Class
Manufacturer	Zydus Cadila Healthcare Ltd
Available Country	India
Last Updated:	September 19, 2023 at 7:00 am

Uses

Ledipasvir is a direct-acting antiviral agent used to treat specific hepatitis C virus (HCV) infections in combination with other antiviral agents.

When used in combination with the antiviral medication sofosbuvir as the commercially available product Harvoni, ledipasvir is indicated for the treatment of HCV genotypes 1, 4, 5, and 6 with or without ribavirin depending on the level of liver damage or cirrhosis . Its use has also proven successful in the treatment of HCV in patients co-infected with HIV .

Sofosbuvir is used for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen. Sofosbuvir efficacy has been established in subjects with MCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection.

Ledihep 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 Ledihep 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

Ledihep dosage

One 400 mg tablet taken once daily with or without food. Should be used in combination with Ribavirin or in combination with Pegylated Interferon and Ribavirin for the treatment of CHC.

Recommended combination therapy: (HCV Mono-infected and HCV/HIV-1 Co-infected)-

Genotype 1 or 4: Sofosbuvir + Peginterferon alfa + Ribavirin for 12 weeks
Genotype 2: Sofosbuvir + Ribavirin for 12 weeks
Genotype 3: Sofosbuvir + Ribavirin for 24 weeks

Sofosbuvir in combination with Ribavirin for 24 weeks can be considered for CHC patients with genotype 1 infection who are Interferon ineligible

Should be used in combination with Ribavirin for treatment of CHC in patients with hepatocellular carcinoma awaiting liver transplantation for up to 48 weeks or until liver transplantation whichever occurs first

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

Side Effects

The most common adverse events observed with Sofosbuvir in combination with ribavirin were fatigue and headache.

The most common adverse events for Sofosbuvir, peginterferon alfa and Ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia.

The following ADRs occured in <1% of subjects receiving Sofosbuvir in combination regimen.

Hematologic effects: pancytopenia (particularly in subjects receiving concomitant Pegylated Interferon).

Psychiatric disorders: severe depression (particularly in subjects with pre-existing history of psychiatric illness), including suicidal ideation and suicide.

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 co-administration: Serious symptomatic bradycardia may occur in patients taking amiodarone and Sofosbuvir in combination with another direct acting antiviral (DAA), particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. Co-administration of amiodarone with Sofosbuvir in combination with another DAA is not recommended. In patients without alternative, viable treatment options, cardiac monitoring is recommended.

Interaction

Reduced therapeutic effect with 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 with amiodarone in combination with another direct acting antiviral.

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. Ribavirin may cause birth defects and fetal death and animal studies have shown interferons have abortifacient effects; avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to initiating therapy, use at least 2 effective methods of contraception and have monthly pregnancy tests.

Lactation: Unknown if distributed in human breast milk; take into account the importance of therapy to the mother when administered combination with ribavirin and/or peg-interferon alfa; because of the potential for adverse reaction, breastfeeding is not recommended

Contraindication

When Sofosbivur is used in combination with Ribavirin or Peginterferon alfa/ Ribavirin, the contraindications applicable to those agents are applicable to combination therapies. Sofosbuvir combination treatment with Ribavirin or Peginterferon alfa/Ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant, because of the risks for birth defects and fetal death associated with Ribavirin.

Special Warning

Geriatric Use: No dose adjustment of Sofosbuvir is warranted in geriatric patients.

Acute Overdose

The highest dose of Sofosbuvir is a single dose of Sofosbuvir 1200 mg. No specific antidote is available for overdose treatment. Treatment of overdose with Sofosbuvir consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.