Ledipasvir + Sofosbuvir

Usage

• Ledipasvir + Sofosbuvir is prescribed for chronic hepatitis C virus (HCV) infection in adults and children 3 years and older. It is effective against HCV genotypes 1, 4, 5, and 6. It can be used in patients without cirrhosis, with compensated cirrhosis, and with decompensated cirrhosis (in combination with ribavirin). It is also used in patients who have had a liver transplant.
• Pharmacological classification: Direct-acting antiviral agent (DAA). This combination includes a NS5A inhibitor (Ledipasvir) and a nucleotide polymerase inhibitor (Sofosbuvir).
• Mechanism of Action: Ledipasvir inhibits NS5A, a viral protein essential for HCV replication. Sofosbuvir inhibits NS5B, the viral RNA polymerase, another protein crucial for HCV replication. Together, these drugs block viral replication at multiple steps.

Alternate Names

• The combination of Ledipasvir and Sofosbuvir is commonly known by the brand name Harvoni.

How It Works

• Pharmacodynamics: Ledipasvir and Sofosbuvir work synergistically to suppress HCV RNA levels, leading to a sustained virologic response (SVR), indicating viral eradication.
• Pharmacokinetics:
  • Absorption: Both drugs are orally absorbed. Food can affect the absorption of Sofosbuvir.
  • Metabolism: Ledipasvir undergoes slow oxidative metabolism. Sofosbuvir is metabolized intracellularly by hydrolase and nucleotide phosphorylation pathways to its active triphosphate form.
  • Elimination: Both drugs are primarily eliminated via hepatic routes, with a small fraction eliminated renally. Ledipasvir is an inhibitor of P-gp and BCRP transporters. Sofosbuvir is a substrate of P-gp and BCRP.
• Mode of Action: Ledipasvir directly inhibits the NS5A protein, disrupting viral assembly and replication. Sofosbuvir, as a prodrug, is metabolized to its active triphosphate form, which acts as a chain terminator, inhibiting the NS5B RNA polymerase and halting viral RNA synthesis.
• Receptor Binding/Enzyme Inhibition: Ledipasvir acts by binding to the NS5A protein. The active metabolite of Sofosbuvir inhibits the NS5B RNA polymerase.
• Elimination Pathways: Primarily hepatic excretion.

Dosage

Standard Dosage

Adults:

• One tablet of Ledipasvir 90 mg/Sofosbuvir 400 mg once daily, with or without food. Treatment duration is typically 12 or 24 weeks, depending on the patient’s HCV genotype, cirrhosis status, and prior treatment history.

Children (3 years and older):

• Dosing is weight-based and should be determined by the physician. Available formulations allow for flexibility in dosing. Treatment duration is typically 12 or 24 weeks, depending on individual factors. Safety and efficacy have not been established in children younger than 3 years.

Special Cases:

• Elderly Patients: No specific dose adjustment is generally required.
• Patients with Renal Impairment: No dose adjustment is needed for mild or moderate renal impairment. Safety has not been fully assessed in patients with severe renal impairment or end-stage renal disease.
• Patients with Hepatic Dysfunction: No dose adjustment is required for mild, moderate, or severe hepatic impairment. Dosage adjustments may be needed for patients with decompensated cirrhosis, particularly when ribavirin is added.
• Patients with Comorbid Conditions: Close monitoring for bradycardia is crucial in patients also taking amiodarone. Dosage adjustment may be required for ribavirin in patients with comorbid conditions, like anemia or cardiac problems.

Clinical Use Cases

• Ledipasvir + Sofosbuvir is specifically indicated for chronic HCV infection and is not typically used in settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.

Dosage Adjustments

• Dose adjustments are not generally required based on age, renal function, or hepatic function (except for decompensated cirrhosis). However, close monitoring is needed in patients with comorbid conditions, particularly cardiac conditions if amiodarone is co-administered.

Side Effects

Common Side Effects:

• Fatigue
• Headache
• Nausea
• Diarrhea
• Insomnia

Rare but Serious Side Effects:

• Hepatitis B reactivation in patients co-infected with HBV
• Severe allergic reactions (skin rash, hives, difficulty breathing, swelling)
• Symptomatic bradycardia (especially with amiodarone)

Long-Term Effects:

• Limited data is available on long-term effects, but SVR generally signifies a favorable long-term prognosis.

Adverse Drug Reactions (ADR):

• HBV reactivation
• Symptomatic bradycardia
• Angioedema

Contraindications

• Co-administration with amiodarone is generally contraindicated unless no other options are available due to the risk of severe bradycardia.
• Use with strong P-gp inducers (e.g., rifampin) can significantly reduce drug efficacy.
• Ribavirin is contraindicated in pregnancy.

Drug Interactions

• Amiodarone: Risk of symptomatic bradycardia.
• P-gp inducers (e.g., rifampin, St. John’s Wort): Reduced Ledipasvir and Sofosbuvir concentrations.
• Rosuvastatin: Ledipasvir inhibits P-gp, increasing rosuvastatin levels.
• HIV medications (especially protease inhibitors and some integrase inhibitors): Requires careful monitoring and potential dose adjustments.
• Other drugs: Consult a drug interaction database for a comprehensive list of potential interactions.

Pregnancy and Breastfeeding

• Pregnancy: Ledipasvir + Sofosbuvir should be used with caution during pregnancy only if the benefit outweighs the risk to the fetus. Ribavirin is contraindicated during pregnancy. Effective contraception is essential.
• Breastfeeding: Limited information is available. While both drugs are likely present in breast milk at low levels, it is generally recommended to avoid breastfeeding while on Ledipasvir/Sofosbuvir, particularly when used with ribavirin.

Drug Profile Summary

• Mechanism of Action: Dual mechanism: NS5A inhibition (Ledipasvir) and NS5B inhibition (Sofosbuvir).
• Side Effects: Fatigue, headache, nausea, HBV reactivation (rare), bradycardia (rare, especially with amiodarone).
• Contraindications: Co-administration with amiodarone (generally), strong P-gp inducers, ribavirin in pregnancy.
• Drug Interactions: Amiodarone, P-gp inducers, rosuvastatin, certain HIV medications.
• Pregnancy & Breastfeeding: Caution advised. Ribavirin contraindicated in pregnancy.
• Dosage: One tablet of Ledipasvir 90 mg/Sofosbuvir 400 mg daily for 12-24 weeks (adult dose). Pediatric dose is weight-based.
• Monitoring Parameters: HCV RNA levels, liver function tests, ECG (if taking amiodarone), hemoglobin levels (if on ribavirin), HBV DNA (if co-infected).

Popular Combinations

• Ribavirin is commonly used in combination with Ledipasvir + Sofosbuvir in certain patient populations (e.g., patients with decompensated cirrhosis, post-liver transplant).

Precautions

• General Precautions: Screen for HBV infection before starting therapy. Monitor for HBV reactivation during and after treatment. Assess cardiac history and monitor ECG if using amiodarone concomitantly.
• Specific Populations: Caution in pregnant women and breastfeeding mothers. Ribavirin is strictly contraindicated during pregnancy and should be avoided while breastfeeding. Weight-based dosing for children. Monitor carefully in patients with decompensated cirrhosis.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Ledipasvir + Sofosbuvir?

A: For adults, the standard dose is one tablet of Ledipasvir 90 mg/Sofosbuvir 400 mg once daily. Pediatric doses are weight-based.

Q2: How long is the typical treatment duration?

A: Treatment typically lasts 12 or 24 weeks, depending on several factors including HCV genotype, presence of cirrhosis, and prior treatment history.

Q3: What are the most common side effects?

A: Common side effects include fatigue, headache, nausea, and insomnia.

Q4: What are the serious side effects to watch for?

A: Serious side effects include HBV reactivation in co-infected patients and symptomatic bradycardia, particularly in patients also taking amiodarone.

Q5: What are the contraindications for this drug combination?

A: Co-administration with amiodarone is generally contraindicated unless there are no other treatment options available. The use of strong P-gp inducers like rifampin is also contraindicated, as is ribavirin during pregnancy.

Q6: What are the key drug interactions?

A: Significant interactions occur with amiodarone, P-gp inducers (e.g., rifampin), rosuvastatin, and certain HIV medications.

Q7: Can Ledipasvir + Sofosbuvir be used during pregnancy?

A: It should be used with caution during pregnancy and only if the potential benefit outweighs the risk to the fetus. Ribavirin is strictly contraindicated in pregnancy.

Q8: Can Ledipasvir + Sofosbuvir be used while breastfeeding?

A: Limited data is available, but it is generally recommended to avoid breastfeeding while on Ledipasvir + Sofosbuvir, especially when combined with ribavirin.

Q9: What should I monitor in patients taking Ledipasvir + Sofosbuvir?

A: Monitor HCV RNA levels, liver function tests, ECG (if co-administered with amiodarone), and hemoglobin levels (if on ribavirin). In HBV co-infected patients, monitor for reactivation by checking HBV DNA levels.