Usage
- Daclatasvir + Sofosbuvir is prescribed for the treatment of chronic hepatitis C (HCV) infection genotypes 1, 2, 3, 4, 5, and 6 in adults and children weighing at least 14 kg. It is a direct-acting antiviral (DAA) regimen.
- Pharmacological Classification: Direct-acting antiviral (DAA).
- Mechanism of Action: Daclatasvir is an NS5A inhibitor, while Sofosbuvir is an NS5B nucleotide polymerase inhibitor. Together, they target different stages of the HCV lifecycle, blocking viral replication and reducing the viral load.
Alternate Names
- Daclatasvir/Sofosbuvir, Sofosbuvir/Daclatasvir
- Brand Names: Daklinza/Sovaldi, Darvoni, Sovodak
How It Works
- Pharmacodynamics: Daclatasvir and Sofosbuvir act synergistically to inhibit HCV replication. Daclatasvir targets the NS5A protein, which is essential for viral replication and assembly, while Sofosbuvir, a prodrug, is metabolized into its active form (GS-461203), which inhibits the NS5B RNA polymerase, another key enzyme required for HCV replication. This combined action disrupts multiple steps in the HCV lifecycle, leading to a significant reduction in viral load.
- Pharmacokinetics: Daclatasvir is absorbed orally, reaching peak plasma concentrations within 1-2 hours. It has a terminal half-life of 12–15 hours and is primarily excreted in feces. Sofosbuvir is also absorbed orally and undergoes intracellular metabolism by hydrolase and nucleotide phosphorylation pathways to its active metabolite. It is eliminated through renal and biliary routes.
- Mode of Action: Daclatasvir binds to the NS5A protein, disrupting its function in viral replication. Sofosbuvir’s active metabolite acts as a chain terminator of RNA synthesis by the NS5B polymerase.
- Elimination Pathways: Daclatasvir is primarily eliminated via fecal excretion, while Sofosbuvir undergoes both renal and hepatic elimination.
Dosage
Standard Dosage
Adults:
- 60 mg daclatasvir + 400 mg sofosbuvir once daily, taken orally with or without food, usually for 12 weeks. Duration of therapy can be extended to 24 weeks depending on HCV genotype and presence of cirrhosis.
Children (weighing at least 14 kg):
- Dosing is weight-based and determined by the physician.
Special Cases:
- Elderly Patients: No dose adjustment is generally required unless there is significant renal or hepatic impairment.
- Patients with Renal Impairment: No dose adjustment is required for daclatasvir. Sofosbuvir dose adjustments may be needed in severe renal impairment.
- Patients with Hepatic Dysfunction: No dose adjustment of daclatasvir or sofosbuvir is required for mild to moderate liver disease. Close monitoring is recommended for patients with decompensated cirrhosis.
- Patients with Comorbid Conditions: Close monitoring is recommended, particularly for patients with diabetes (risk of hypoglycemia) or cardiovascular disease.
Clinical Use Cases
Daclatasvir + Sofosbuvir is specifically indicated for chronic HCV infection. It is not indicated for the listed use cases like Intubation, Surgical procedures, Mechanical ventilation, ICU use, or emergency situations like status epilepticus or cardiac arrest.
Dosage Adjustments
- Patients receiving strong CYP3A4 inhibitors or certain HIV antiviral agents: Daclatasvir dose reduced to 30 mg once daily.
- Patients receiving moderate CYP3A4 inducers or nevirapine: Daclatasvir dose increased to 90 mg once daily.
- Strong CYP3A4 inducers are contraindicated with daclatasvir.
Side Effects
Common Side Effects:
- Headache
- Fatigue
- Nausea
- Diarrhea
- Insomnia
Rare but Serious Side Effects:
- Severe allergic reactions (rash, itching/swelling, dizziness, trouble breathing)
- Reactivation of hepatitis B virus (HBV) in co-infected patients
- Liver failure (in patients with advanced cirrhosis)
- Severe bradycardia (especially when co-administered with amiodarone and sofosbuvir)
Long-Term Effects:
Limited data available on long-term effects, but monitoring for late-onset adverse events is recommended.
Adverse Drug Reactions (ADR):
- Stevens-Johnson syndrome
- Toxic epidermal necrolysis
Contraindications
- Hypersensitivity to daclatasvir or sofosbuvir.
- Co-administration with strong CYP3A4 inducers (e.g., rifampin, St. John’s wort).
- Co-administration with sofosbuvir and amiodarone (unless no alternatives exist, then close cardiac monitoring is mandatory).
- Pregnancy (especially when combined with ribavirin).
Drug Interactions
- CYP450 Interactions: Daclatasvir is a substrate of CYP3A4 and an inhibitor of P-gp. Sofosbuvir is a substrate of P-gp.
- Drug Interactions:
- Strong CYP3A4 inducers (e.g., rifampin, St. John’s wort): Contraindicated.
- Moderate CYP3A4 inducers (e.g., efavirenz, etravirine, nevirapine): Daclatasvir dose adjustment required.
- Certain HIV antiviral agents: Dose adjustment of daclatasvir may be necessary.
- Amiodarone: Contraindicated with daclatasvir + sofosbuvir.
- Other medications (e.g., carvedilol, certain immunosuppressants): Close monitoring required.
- OTC Drugs and Supplements: St. John’s wort is contraindicated.
- Food and Lifestyle Factors: No specific interactions with food or alcohol, but close monitoring of blood glucose is recommended in diabetic patients.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Category B for sofosbuvir and daclatasvir when used alone. Category X when combined with ribavirin.
- Contraindicated during pregnancy, especially with ribavirin, due to potential fetal harm.
- Effective contraception is essential during treatment and for 6 months after treatment discontinuation (9 months for women receiving ribavirin).
- Breastfeeding: Daclatasvir and sofosbuvir use during breastfeeding is not recommended when combined with ribavirin. If daclatasvir is used alone or with sofosbuvir, breastfeeding may be considered after a careful risk-benefit assessment.
Drug Profile Summary
- Mechanism of Action: Daclatasvir (NS5A inhibitor) and Sofosbuvir (NS5B polymerase inhibitor) synergistically inhibit HCV replication.
- Side Effects: Headache, fatigue, nausea, diarrhea, insomnia. Rare but serious side effects include severe allergic reactions, HBV reactivation, liver failure, bradycardia.
- Contraindications: Hypersensitivity, strong CYP3A4 inducers, concomitant use of sofosbuvir and amiodarone, pregnancy (especially with ribavirin).
- Drug Interactions: CYP3A4 inducers/inhibitors, certain HIV medications, amiodarone.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy, especially with ribavirin. Caution advised during breastfeeding.
- Dosage: 60 mg daclatasvir + 400 mg sofosbuvir once daily, usually for 12 weeks. Dose adjustments needed for specific drug interactions and patient populations.
- Monitoring Parameters: Liver function tests (ALT, AST, bilirubin), renal function, CBC, HCV RNA levels, cardiac monitoring (if amiodarone is co-administered).
Popular Combinations
- Daclatasvir + Sofosbuvir
- Daclatasvir + Sofosbuvir + Ribavirin (for specific genotypes and patient populations)
Precautions
- General Precautions: Assess liver and renal function, screen for HBV and HIV co-infection, monitor for adverse events.
- Specific Populations: Contraindicated in pregnancy (especially with ribavirin). Caution advised during breastfeeding. Use with caution in patients with decompensated cirrhosis.
- Lifestyle Considerations: No specific restrictions regarding alcohol or diet, but patients with diabetes require careful blood glucose monitoring.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Daclatasvir + Sofosbuvir?
A: 60 mg daclatasvir + 400 mg sofosbuvir once daily, taken orally with or without food. Dosage adjustments are necessary for specific drug interactions and patient populations.
Q2: What are the common side effects of Daclatasvir + Sofosbuvir?
A: Headache, fatigue, nausea, diarrhea, and insomnia are common side effects.
Q3: What are the contraindications for Daclatasvir + Sofosbuvir?
A: Contraindications include hypersensitivity, co-administration with strong CYP3A4 inducers or amiodarone (with sofosbuvir), and pregnancy (especially with ribavirin).
Q4: Can Daclatasvir + Sofosbuvir be used in patients with cirrhosis?
A: Yes, but caution and close monitoring are necessary, especially in patients with decompensated cirrhosis. Treatment duration may be extended to 24 weeks, and ribavirin may be added to the regimen.
Q5: How does Daclatasvir + Sofosbuvir interact with other medications?
A: Daclatasvir is primarily metabolized by CYP3A4 and is also a P-gp inhibitor. Sofosbuvir is a substrate of P-gp. Co-administration with CYP3A4 inducers or inhibitors, certain HIV medications, or amiodarone can lead to clinically significant drug interactions.
Q6: Can Daclatasvir + Sofosbuvir be used in pregnant or breastfeeding women?
A: Contraindicated in pregnancy, particularly with ribavirin, due to potential for fetal harm. Caution advised during breastfeeding, with ribavirin contraindicated.
Q7: What is the duration of therapy for Daclatasvir + Sofosbuvir?
A: Usually 12 weeks, but can be extended to 24 weeks depending on HCV genotype and the presence of cirrhosis.
Q8: What are the monitoring parameters for patients on Daclatasvir + Sofosbuvir?
A: Monitor liver function tests, renal function, CBC, HCV RNA levels, and perform cardiac monitoring if amiodarone is co-administered.
Q9: What is the mechanism of action of Daclatasvir + Sofosbuvir?
A: Daclatasvir inhibits NS5A, while Sofosbuvir inhibits NS5B polymerase, both crucial for HCV replication. This dual action disrupts the HCV lifecycle.
