led-i-PAS-vir/soe-FOS-bue-vir

Therapeutic Classification: antivirals

Pharmacologic Classification: NS5A inhibitors, polymerase inhibitors

• Chronic hepatitis C virus (HCV) infection (genotypes 1, 4, 5, or 6) in patients without cirrhosis or with compensated cirrhosis.
• Chronic HCV infection (genotype 1) in patients with decompensated cirrhosis (in combination with ribavirin).
• Chronic HCV infection (genotypes 1 or 4) in patients who are liver transplant recipients without cirrhosis or with compensated cirrhosis (in combination with ribavirin).

• Ledipasvir: inhibits NS5A, a protein required for viral replication.
• Sofosbuvir: inhibits RNA-dependent RNA polymerase, resulting in inhibition of viral replication.

• Decreased HCV RNA levels with decreased severity and sequelae of chronic HCV.

Ledipasvir

Absorption: Well absorbed following oral administration.

Distribution: Unknown.

Protein Binding: >99.8%.

Metabolism/Excretion: Minimal metabolism, undergoes biliary excretion. Mostly excreted unchanged in feces (86%), 1% eliminated in urine.

Half-life: 47 hr.

Sofosbuvir

Absorption: Rapidly metabolized following absorption (extensive first-pass effect).

Distribution: Unknown.

Protein Binding: 61–65%.

Metabolism/Excretion: Extensively metabolized with much conversion to GS-461203, an active antiviral moiety, then converted GS-331007, which does not have antiviral activity. 80% excreted in urine mostly as GS-331007 (3.5% as unchanged drug), 14% excreted in feces, 2.5% excreted in expired air.

Half-life: Sofosbuvir: 0.4 hr; GS-331007: 27 hr.

(blood levels)

†Sofosbuvir (2–4 hr for GS-331007).

Contraindicated in:

• Should not be used with other drugs/regimens that already containing sofosbuvir
• Concurrent use of P-gp inducers, some anticonvulsants, some antivirals and rosuvastatin
• Any condition in which ribavirin is contraindicated.

Use Cautiously in:

• Receiving immunosuppressant or chemotherapy medications (↑ risk of hepatitis B virus reactivation)
• OB: Use during pregnancy only if potential maternal benefit justifies potential fetal risk
• Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant
• Pedi: Children <3 yr (safety and effectiveness not established)
• Geri: May be more sensitive to drug effects.

GI: diarrhea, hepatitis B virus reactivation, nausea.

Neuro: fatigue, headache, insomnia.

Drug-Drug:

• Concurrent use of P-gp inducers including rifampin↓ levels and effectiveness of both ledipasvir and sofosbuvir; concurrent use contraindicated.
• Ledipasvir inhibits P-gp and may ↑ levels of substrates of P-gp.
• Amiodarone may ↑ risk of symptomatic bradycardia; concurrent use not recommended; if amiodarone necessary, monitor patients in inpatient setting for first 48 hr of concomitant use and then monitor heart rate on outpatient basis for at least the first 2 wk of treatment (follow same monitoring procedure if discontinuing amiodarone immediately before initiation of ledipasvir/sofosbuvir therapy)
• Acid-reducing agents may ↓ levels of ledipasvir; separate antacids including magnesium and aluminum hydroxide by 4 hr, administer H₂-receptor antagonists, including famotidine, simultaneously or 12 hr apart (dose of antagonist should not exceed famotidine 40 mg twice daily or equivalent), proton-pump inhibitors including omeprazole 20 mg daily or equivalent may be given simultaneously.
• May ↑ levels/effects/risk of toxicity with digoxin (therapeutic monitoring recommended).
• Level and effectiveness ↓ by carbamazepine, phenytoin, phenobarbital, and oxcarbazepine concurrent use is not recommended.
• Levels and effectiveness may be ↓ by concurrent use of rifabutin and rifapentine; concurrent use not recommended.
• ↑levels and risk of adverse reactions from tenofovir and tenofovir-containing combinations (dosage adjustments may be necessary, consider alternative regimens).
• Levels and effectiveness are ↓ by tipranavir/ritonavir; concurrent use not recommended.
• May ↑ levels/toxicity of rosuvastatin and atorvastatin; concurrent use with rosuvastatin not recommended; monitor closely for atorvastatin-induced myopathy or rhabdomyolysis.
• May cause fluctuations in INR when used with warfarin; closely monitor INR.
• May ↑ risk of hypoglycemia when used with certain antidiabetic agents.

Drug-Natural Products:

• Concurrent use with St. John's wort↓ blood levels and effectiveness; concurrent use contraindicated.

• PO (Adults): Genotype 1 (treatment-nave without cirrhosis or with compensated cirrhosis [Child-Pugh A]): Ledipasvir 90 mg/sofosbuvir 400 mg (one tablet) once daily for 12 wk; Genotype 1 (treatment-experienced without cirrhosis): Ledipasvir 90 mg/sofosbuvir 400 mg (one tablet) once daily for 12 wk; Genotype 1 (treatment-experienced with compensated cirrhosis [Child-Pugh A]): Ledipasvir 90 mg/sofosbuvir 400 mg (one tablet) once daily for 24 wk; Genotype 1 (treatment-nave or treatment-experienced with decompensated cirrhosis [Child-Pugh B or C]): Ledipasvir 90 mg/sofosbuvir 400 mg (one tablet) once daily with ribavirin for 12 wk; Genotype 1 or 4 (treatment-nave or treatment-experienced liver transplant recipients without cirrhosis or with compensated cirrhosis [Child-Pugh A]): Ledipasvir 90 mg/sofosbuvir 400 mg (one tablet) once daily with ribavirin for 12 wk; Genotype 4, 5, or 6 (treatment-nave or treatment-experienced without cirrhosis or with compensated cirrhosis [Child-Pugh A]): Ledipasvir 90 mg/sofosbuvir 400 mg (one tablet) once daily for 12 wk.
• PO (Children 3 yr and 35 kg): Genotype 1 (treatment-nave without cirrhosis or with compensated cirrhosis [Child-Pugh A]): Ledipasvir 90 mg/sofosbuvir 400 mg (as one 90 mg/400 mg tablet, two 45 mg/200 mg tablets, or two 45 mg/200 mg packets of oral pellets) once daily for 12 wk; Genotype 1 (treatment-experienced without cirrhosis): Ledipasvir 90 mg/sofosbuvir 400 mg (as one 90 mg/400 mg tablet, two 45 mg/200 mg tablets, or two 45 mg/200 mg packets of oral pellets) once daily for 12 wk; Genotype 1 (treatment-experienced with compensated cirrhosis [Child-Pugh A]): Ledipasvir 90 mg/sofosbuvir 400 mg (as one 90 mg/400 mg tablet, two 45 mg/200 mg tablets, or two 45 mg/200 mg packets of oral pellets) once daily for 24 wk; Genotype 1 (treatment-nave or treatment-experienced with decompensated cirrhosis [Child-Pugh B or C]): Ledipasvir 90 mg/sofosbuvir 400 mg (as one 90 mg/400 mg tablet, two 45 mg/200 mg tablets, or two 45 mg/200 mg packets of oral pellets) once daily with ribavirin for 12 wk; Genotype 1 or 4 (treatment-nave or treatment-experienced liver transplant recipients without cirrhosis or with compensated cirrhosis [Child-Pugh A]): Ledipasvir 90 mg/sofosbuvir 400 mg (as one 90 mg/400 mg tablet, two 45 mg/200 mg tablets, or two 45 mg/200 mg packets of oral pellets) once daily with ribavirin for 12 wk; Genotype 4, 5, or 6 (treatment-nave or treatment-experienced without cirrhosis or with compensated cirrhosis [Child-Pugh A]): Ledipasvir 90 mg/sofosbuvir 400 mg (as one 90 mg/400 mg tablet, two 45 mg/200 mg tablets, or two 45 mg/200 mg packets of oral pellets) once daily for 12 wk.
• PO (Children 3 yr and 17–<35 kg): Genotype 1 (treatment-nave without cirrhosis or with compensated cirrhosis [Child-Pugh A]): Ledipasvir 45 mg/sofosbuvir 200 mg (as one 45 mg/200 mg tablet or one 45 mg/200 mg packet of oral pellets) once daily for 12 wk; Genotype 1 (treatment-experienced without cirrhosis): Ledipasvir 45 mg/sofosbuvir 200 mg (as one 45 mg/200 mg tablet or one 45 mg/200 mg packet of oral pellets) once daily for 12 wk; Genotype 1 (treatment-experienced with compensated cirrhosis [Child-Pugh A]): Ledipasvir 45 mg/sofosbuvir 200 mg (as one 45 mg/200 mg tablet or one 45 mg/200 mg packet of oral pellets) once daily for 24 wk; Genotype 1 (treatment-nave or treatment-experienced with decompensated cirrhosis [Child-Pugh B or C]): Ledipasvir 45 mg/sofosbuvir 200 mg (as one 45 mg/200 mg tablet or one 45 mg/200 mg packet of oral pellets) once daily with ribavirin for 12 wk; Genotype 1 or 4 (treatment-nave or treatment-experienced liver transplant recipients without cirrhosis or with compensated cirrhosis [Child-Pugh A]): Ledipasvir 45 mg/sofosbuvir 200 mg (as one 45 mg/200 mg tablet or one 45 mg/200 mg packet of oral pellets) once daily with ribavirin for 12 wk; Genotype 4, 5, or 6 (treatment-nave or treatment-experienced without cirrhosis or with compensated cirrhosis [Child-Pugh A]): Ledipasvir 45 mg/sofosbuvir 200 mg (as one 45 mg/200 mg tablet or one 45 mg/200 mg packet of oral pellets) once daily for 12 wk.
• PO (Children 3 yr and <17 kg): Genotype 1 (treatment-nave without cirrhosis or with compensated cirrhosis [Child-Pugh A]): Ledipasvir 33.75 mg/sofosbuvir 150 mg (as one 33.75 mg/150 mg packet of oral pellets) once daily for 12 wk; Genotype 1 (treatment-experienced without cirrhosis): Ledipasvir 45 mg/sofosbuvir 200 mg (as one 33.75 mg/150 mg packet of oral pellets) once daily for 12 wk; Genotype 1 (treatment-experienced with compensated cirrhosis [Child-Pugh A]): Ledipasvir 45 mg/sofosbuvir 200 mg (as one 33.75 mg/150 mg packet of oral pellets) once daily for 24 wk; Genotype 1 (treatment-nave or treatment-experienced with decompensated cirrhosis [Child-Pugh B or C]): Ledipasvir 45 mg/sofosbuvir 200 mg (as one 33.75 mg/150 mg packet of oral pellets) once daily with ribavirin for 12 wk; Genotype 1 or 4 (treatment-nave or treatment-experienced liver transplant recipients without cirrhosis or with compensated cirrhosis [Child-Pugh A]): Ledipasvir 45 mg/sofosbuvir 200 mg (as one 33.75 mg/150 mg packet of oral pellets) once daily with ribavirin for 12 wk; Genotype 4, 5, or 6 (treatment-nave or treatment-experienced without cirrhosis or with compensated cirrhosis [Child-Pugh A]): Ledipasvir 45 mg/sofosbuvir 200 mg (as one 33.75 mg/150 mg packet of oral pellets) once daily for 12 wk.

• Tablets: ledipasvir 45 mg/sofosbuvir 200 mg; ledipasvir 90 mg/sofosbuvir 400 mg;
• Oral pellets: ledipasvir 33.75 mg/sofosbuvir 150 mg/pkt; ledipasvir 45 mg/sofosbuvir 200 mg/pkt;

• Monitor for signs and symptoms of hepatitis during therapy.

• Determine current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV therapy.
  • May cause ↑ serum bilirubin and lipase levels.

• PO: Administer once daily with or without food.
  • Administer pellets within 30 min of gently mixing with food and swallow entire contents without chewing to avoid a bitter aftertaste. If pellets are administered with food, sprinkle the pellets on one or more spoonfuls of non-acidic soft food (pudding, chocolate syrup, mashed potato, ice cream) at or below room temperature.

• Instruct patient to take ledipasvir/sofosbuvir at the same time each day for the full course of therapy. Take missed doses as soon as remembered on same day; do not take more than 1 tablet in a day. Do not stop taking ledipasvir/sofosbuvir without consulting health care professional. Advise patient to read Patient Information prior to starting therapy and with each Rx refill in case of changes.
• Inform patient that ledipasvir/sofosbuvir may not reduce the risk of transmission of HCV to others; use appropriate precautions to prevent transmission.
• Instruct patient that ledipasvir/sofosbuvir should not be shared with others; may be harmful.
• Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. John's wort.
• Instruct patient to take antacids containing aluminum or magnesium 4 hrs before or 4 hrs after ledipasvir/sofosbuvir.
• Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected and to avoid breast feeding during therapy.

• Decreased HCV RNA levels with decreased severity and sequelae of CHC.

Harvoni