Ledipasvir

Usage

• Ledipasvir is prescribed in combination with sofosbuvir for the treatment of chronic hepatitis C virus (HCV) genotypes 1, 4, 5, and 6 infections. It is sometimes used in combination with ribavirin.
• Pharmacological Classification: Antiviral (direct-acting antiviral agent, or DAA) specifically, an HCV NS5A inhibitor.
• Mechanism of Action: Ledipasvir targets and inhibits NS5A, a nonstructural protein essential for HCV replication. By blocking NS5A, ledipasvir disrupts the virus’s life cycle and prevents it from multiplying. It is often used in combination with other DAAs like sofosbuvir, which targets a different part of the HCV life cycle, for a more effective treatment.

Alternate Names

• Ledipasvir is primarily known by its generic name.
• Brand Names: Harvoni (in combination with sofosbuvir)

How It Works

• Pharmacodynamics: Ledipasvir exerts its antiviral effect by binding to NS5A, a protein crucial for HCV replication. This binding inhibits both RNA replication and virion assembly, effectively reducing the viral load in the patient’s body.
• Pharmacokinetics:
  • Absorption: Ledipasvir is absorbed orally and reaches peak plasma concentrations within 4-4.5 hours when taken with sofosbuvir. Food can increase absorption.
  • Metabolism: Primarily undergoes hepatic metabolism, likely involving oxidative pathways though specific enzymes haven’t been fully identified. It’s a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters but doesn’t significantly interact with CYP450 enzymes.
  • Elimination: Primarily eliminated through the feces (about 86%), with only a small amount excreted in urine (around 1%).
• Mode of Action: Ledipasvir specifically binds to domain I of the NS5A protein, disrupting the necessary conformational changes for viral replication and assembly. This specific targeting of NS5A inhibits viral production, leading to a reduced viral load. In particular, it seems to prevent NS5A hyperphosphorylation.
• Receptor Binding/Enzyme Inhibition: Ledipasvir acts as an inhibitor of NS5A, not a receptor binder. It doesn’t seem to have significant direct effects on major CYP450 enzymes, though it does inhibit P-gp and BCRP which can have significant implications for drug interactions. This inhibition can result in an increased plasma concentration of drugs that are substrates for these transporters, necessitating careful monitoring for toxicity.

Dosage

Standard Dosage

Adults:

• One tablet of Harvoni (90 mg ledipasvir/400 mg sofosbuvir) orally once daily, with or without food. Treatment duration is typically 12 weeks but can be extended to 24 weeks in certain cases (e.g., patients with cirrhosis, previous treatment experience).

Children:

• 3 years and older weighing at least 35 kg: One tablet of Harvoni (90 mg ledipasvir/400 mg sofosbuvir) once a day.
• 3 years and older weighing 17 kg to less than 35 kg: One tablet containing 45 mg ledipasvir/200 mg sofosbuvir or two packets of pellets with the same dose once a day.
• 3 years and older weighing less than 17 kg: One packet of pellets containing 33.75 mg ledipasvir/150 mg sofosbuvir once a day.
• Treatment duration is typically 12 to 24 weeks.

Special Cases:

• Elderly Patients: No specific dose adjustments are required based on age. However, closely monitor patients for potential side effects or drug interactions, as they might be more susceptible due to age-related changes in physiology.
• Patients with Renal Impairment: No dose adjustment is necessary for mild to severe renal impairment, including those on dialysis. However, the safety of Ledipasvir has not been thoroughly studied in patients with both decompensated cirrhosis and severe renal impairment.
• Patients with Hepatic Dysfunction: No dose adjustment is necessary for mild, moderate, or severe hepatic impairment.
• Patients with Comorbid Conditions: Monitor patients with diabetes closely for hypoglycemia. For patients with a history of Hepatitis B Virus (HBV) infection, monitor for HBV reactivation. For patients taking vitamin K antagonists, monitor INR closely.

Clinical Use Cases

Ledipasvir/sofosbuvir is specifically indicated for treating chronic HCV infection and isn’t typically used in clinical settings like intubation, surgical procedures, mechanical ventilation, or ICU care for reasons other than managing an underlying HCV infection. In emergency situations (e.g., cardiac arrest, status epilepticus), Ledipasvir’s antiviral effects would not be relevant.

Dosage Adjustments

Refer to “Special Cases” in the previous sections. Dose adjustment of ribavirin might be necessary if used in combination with ledipasvir/sofosbuvir, particularly based on hemoglobin levels.

Side Effects

Common Side Effects:

• Fatigue
• Headache
• Nausea
• Diarrhea
• Difficulty sleeping
• Irritability
• Muscle pain
• Dizziness
• Cough

Rare but Serious Side Effects:

• Severe allergic reactions (e.g., skin rash, itching/swelling, hives, difficulty breathing, swelling of the face, lips, tongue, or throat)
• Reactivation of hepatitis B virus (HBV) in patients with prior HBV infection
• Symptomatic bradycardia (especially in patients also taking amiodarone)
• Signs of liver decompensation (e.g., jaundice, loss of appetite, right-sided upper stomach pain, vomiting, general feeling of unwellness, light-colored stools)

Long-Term Effects:

Data on the long-term side effects of Ledipasvir are still limited. Monitoring for liver health and potential delayed adverse events is important.

Adverse Drug Reactions (ADR):

Refer to “Rare but Serious Side Effects”. Any ADRs should be promptly reported to relevant pharmacovigilance authorities.

Contraindications

• Coadministration with strong P-gp inducers like rifampin, rifabutin, St. John’s wort, carbamazepine, phenobarbital, phenytoin, and tipranavir/ritonavir is contraindicated as they substantially decrease ledipasvir and sofosbuvir plasma concentrations and reduce therapeutic efficacy.
• Hypersensitivity to Ledipasvir or Sofosbuvir.

Drug Interactions

• Strong P-gp inducers: Rifampin, Rifabutin, St. John’s Wort, carbamazepine, phenobarbital, phenytoin, tipranavir/ritonavir (Contraindicated - see Contraindications section.)
• Moderate to Serious Interactions: Amiodarone (can cause bradycardia), certain HIV medications, antacids (containing aluminum or magnesium hydroxide – take 4 hours before or after Ledipasvir/Sofosbuvir).
• Other Interactions: Many other drug interactions exist. Refer to a comprehensive drug interaction database before co-prescribing.
• CYP450 Interactions: Ledipasvir is not a significant CYP450 inhibitor or inducer, though its inhibition of P-gp and BCRP can affect drugs that are transported by these proteins.
• Food and Lifestyle Factors: No specific restrictions other than the potential interaction with grapefruit juice (due to CYP3A4 interaction with sofosbuvir). Alcohol should be limited due to its potential impact on liver health.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: When used with Ribavirin: Contraindicated in pregnancy and in males whose partners are pregnant. When used alone: Benefit should outweigh the risk to the fetus.
• Fetal Risks/Teratogenicity: Ribavirin is teratogenic. Ledipasvir/sofosbuvir combination without ribavirin is not recommended during pregnancy unless clearly necessary.
• Breastfeeding: Ledipasvir levels in breast milk are expected to be low. While some sources suggest it may be acceptable to breastfeed when using ledipasvir alone or with sofosbuvir, it is generally recommended against when used with ribavirin.

Drug Profile Summary

• Mechanism of Action: NS5A inhibitor that disrupts HCV replication.
• Side Effects: Fatigue, headache, nausea, diarrhea, and insomnia. Serious but rare side effects: HBV reactivation, severe allergic reactions, and symptomatic bradycardia (especially with amiodarone).
• Contraindications: Strong P-gp inducers.
• Drug Interactions: Many. Especially note amiodarone, P-gp inducers, some HIV medications, and antacids.
• Pregnancy & Breastfeeding: Contraindicated with ribavirin. Without ribavirin: Use with caution and only if the benefits outweigh the risks.
• Dosage: One tablet of Harvoni (90 mg/400 mg) daily. Adjust based on age/weight for children. No adjustments needed for renal/hepatic impairment.
• Monitoring Parameters: Liver function tests, HBV DNA (if applicable), INR (if on vitamin K antagonists), blood glucose (in diabetic patients).

Popular Combinations

• Ledipasvir/Sofosbuvir
• Ledipasvir/Sofosbuvir/Ribavirin (for certain patient populations)

Precautions

• General Precautions: Screen for HBV and other liver diseases before and during treatment. Monitor liver function tests regularly. Assess for drug interactions. Be cautious of hypoglycemia in diabetic patients.
• Specific Populations: See “Dosage - Special Cases.”
• Lifestyle Considerations: Limit alcohol.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Ledipasvir?

A: Ledipasvir is always given in combination with sofosbuvir as Harvoni. For adults and children weighing at least 35 kg, the standard dose is one tablet (90mg ledipasvir/400mg sofosbuvir) once daily. Dosage adjustments are needed for children under 35 kg.

Q2: How does Ledipasvir work against HCV?

A: Ledipasvir is an NS5A inhibitor. NS5A is a viral protein critical for HCV replication. By inhibiting its function, Ledipasvir prevents the virus from multiplying.

Q3: What are the most common side effects of Ledipasvir/Sofosbuvir?

A: Common side effects include fatigue, headache, nausea, diarrhea, and difficulty sleeping.

Q4: Are there any serious side effects I should be aware of?

A: Yes. Though rare, serious side effects can include severe allergic reactions, reactivation of HBV, and symptomatic bradycardia (especially if taken with amiodarone). Liver decompensation is also possible.

Q5: Can Ledipasvir/Sofosbuvir be used in patients with kidney disease?

A: Yes, no dose adjustment is needed for patients with mild to severe renal impairment. However, safety in patients with both decompensated cirrhosis and severe renal impairment has not been fully assessed.

Q6: What are the contraindications for Ledipasvir/Sofosbuvir?

A: Concomitant use with strong P-gp inducers (e.g., rifampin, St. John’s wort, carbamazepine, phenobarbital) is contraindicated.

Q7: Does Ledipasvir interact with other medications?

A: Yes, many drug interactions are possible. It is vital to check for interactions before co-prescribing. Of particular concern are amiodarone, certain HIV medications, antacids, and P-gp inducers.

Q8: Can Ledipasvir/Sofosbuvir be used during pregnancy or breastfeeding?

A: It is contraindicated during pregnancy when combined with ribavirin. Without ribavirin, it is recommended to avoid use during pregnancy unless the benefit clearly outweighs the risk to the fetus. If the mother requires this drug during breastfeeding, consult guidelines from LactMed and consider the risks and benefits.

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

A: Monitor liver function tests, HBV DNA (if the patient has a history of HBV infection), INR (if on vitamin K antagonists), and blood glucose levels (if diabetic).

Q10: How long is the typical treatment duration for Ledipasvir/Sofosbuvir?

A: The typical duration is 12 weeks, but it may be extended to 24 weeks for certain patient populations (e.g., those with cirrhosis, those with prior treatment experience).