ledipasvir/sofosbuvir (Rx)

Brand and Other Names:Harvoni
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

ledipasvir/sofosbuvir

tablet

  • 90mg/400mg

Hepatitis C Virus Infection

Indicated for adults with chronic hepatitis C virus (HCV) genotypes 1, 4, 5, or 6 infection

1 tablet (90 mg/400 mg) PO qDay

Treatment duration

  • The following regimens also apply to HCV/HIV-1 coinfection
  • Genotype 1
    • Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A): 12 weeks; may consider 8 weeks in treatment-naïve patients without cirrhosis who have pretreatment HCV RNA <6 million IU/mL

    • Treatment-experienced (ie, those who have failed a peginterferon alfa + ribavirin based regimen with or without an HCV protease inhibitor) without cirrhosis: 12 weeks

    • Treatment-experienced with compensated cirrhosis (Child-Pugh A): 24 weeks; may also consider adding daily weight-based ribavirin

    • Treatment-naïve and treatment-experienced with decompensated cirrhosis (Child-Pugh B or C), including those who have undergone liver transplantation: 12 weeks in combination with ribavirin

  • Genotypes 1 or 4
    • Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A), including those who have undergone liver transplantation: 12 weeks in combination with ribavirin
  • Genotypes 4, 5, or 6
    • Treatment-naïve and treatment-experienced, without cirrhosis or with compensated cirrhosis (Child-Pugh A): 12 weeks
  • Ribavirin dosing

    • <75 kg with or without decompensated cirrhosis: 1000 mg PO q12hr
    • ≥75 kg with or without decompensated cirrhosis: 1200 mg PO q12hr
    • If initial dose is not well tolerated, reduced dose as clinically indicated based on hemoglobin levels; refer to the ribavirin prescribing information for further information

Dosage Modifications

Renal impairment

  • Mild-to-severe (including ESRD requiring dialysis): No dosage adjustment necessary
  • No safety data are available in subjects with both decompensated cirrhosis and severe renal impairment, including those on dialysis
  • Refer to ribavirin tablet prescribing information regarding use in patients with renal impairment

Hepatic impairment

  • Mild, moderate, or severe: No dosage adjustment required
  • Decompensated cirrhosis: Safety and efficacy not established

Dosing Considerations

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with HCV direct acting antivirals (DDAs)

Dosage Forms & Strengths

ledipasvir/sofosbuvir

tablet

  • 45mg/200mg
  • 90mg/400mg

oral pellets

  • 33.75mg/150mg per packet
  • 45mg/200mg per packet

Hepatitis C Virus Infection

Indicated for pediatric patients aged ≥3 yr with hepatitis C virus (HCV) genotype 1, 4, 5 or 6 infection

<3 years: Safety and efficacy not established

≥3 years

<17 kg: 1 packet (33.75 mg/150 mg) of pellets PO qDay

17 to <35kg: 1 tablet or packet (45 mg/200 mg) PO qDay

≥35 kg: 1 tablet (90 mg/400 mg) PO qDay or 2 tablets or packets (45 mg/200 mg) PO qDay

Treatment duration

  • The following regimens also apply to HCV/HIV-1 coinfection
  • Genotype 1
    • Treatment-naïve without cirrhosis or with compensated cirrhosis (Child-Pugh A): 12 weeks; may consider 8 weeks in treatment-naïve patients without cirrhosis who have pretreatment HCV RNA <6 million IU/mL

    • Treatment-experienced (ie, those who have failed a peginterferon alfa + ribavirin based regimen with or without an HCV protease inhibitor) without cirrhosis: 12 weeks

    • Treatment-experienced with compensated cirrhosis (Child-Pugh A): 24 weeks; may also consider adding daily weight-based ribavirin

    • Treatment-naïve and treatment-experienced with decompensated cirrhosis (Child-Pugh B or C), including those who have undergone liver transplantation: 12 weeks in combination with ribavirin

  • Genotypes 1 or 4
    • Treatment-naïve and treatment-experienced without cirrhosis or with compensated cirrhosis (Child-Pugh A), including those who have undergone liver transplantation: 12 weeks in combination with ribavirin
  • Genotypes 4, 5, or 6
    • Treatment-naïve and treatment-experienced, without cirrhosis or with compensated cirrhosis (Child-Pugh A): 12 weeks

Ribavirin dosing

  • <47 kg: 15 mg/kg/day PO (divided dose AM and PM)
  • 47-49 kg: 600 mg/day PO (ie, 200 mg AM, 400 mg PM)
  • 50-65 kg: 800 mg/day PO (ie, 400 mg AM, 400 mg PM)
  • 66-80 kg: 1000 mg/day PO (ie, 400 mg AM, 600 mg PM)
  • >80 kg: 1200 mg/day PO (ie, 600 mg AM, 600 mg PM)

Dosage Modifications

Renal impairment

  • Mild-to-severe (including ESRD requiring dialysis): No dosage adjustment necessary
  • No safety data are available in subjects with both decompensated cirrhosis and severe renal impairment, including those on dialysis
  • Refer to ribavirin tablet prescribing information regarding use in patients with renal impairment

Dosing Considerations

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with HCV direct acting antivirals (DDAs)

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Interactions

Interaction Checker

and ledipasvir/sofosbuvir

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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Contraindicated (10)

            • carbamazepine

              carbamazepine will decrease the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Contraindicated. P-gp inducers decrease sofosbuvir levels, and therefore decrease conversion to sofosbuvir's active metabolite (GS-331007) responsible for 90% of pharmacologic effect

            • fosphenytoin

              fosphenytoin will decrease the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Contraindicated. P-gp inducers decrease sofosbuvir levels, and therefore decrease conversion to sofosbuvir's active metabolite (GS-331007) responsible for 90% of pharmacologic effect

            • oxcarbazepine

              oxcarbazepine will decrease the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Contraindicated. P-gp inducers decrease sofosbuvir levels, and therefore decrease conversion to sofosbuvir's active metabolite (GS-331007) responsible for 90% of pharmacologic effect

            • phenobarbital

              phenobarbital will decrease the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Contraindicated. P-gp inducers decrease sofosbuvir levels, and therefore decrease conversion to sofosbuvir's active metabolite (GS-331007) responsible for 90% of pharmacologic effect

            • phenytoin

              phenytoin will decrease the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Contraindicated. P-gp inducers decrease sofosbuvir levels, and therefore decrease conversion to sofosbuvir's active metabolite (GS-331007) responsible for 90% of pharmacologic effect

            • rifabutin

              rifabutin will decrease the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Contraindicated. P-gp inducers decrease sofosbuvir levels, and therefore decrease conversion to sofosbuvir's active metabolite (GS-331007) responsible for 90% of pharmacologic effect

            • rifampin

              rifampin will decrease the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Contraindicated. P-gp inducers decrease sofosbuvir levels, and therefore decrease conversion to sofosbuvir's active metabolite (GS-331007) responsible for 90% of pharmacologic effect

            • rifapentine

              rifapentine will decrease the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Contraindicated. P-gp inducers decrease sofosbuvir levels, and therefore decrease conversion to sofosbuvir's active metabolite (GS-331007) responsible for 90% of pharmacologic effect

            • St John's Wort

              St John's Wort will decrease the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Contraindicated. P-gp inducers decrease sofosbuvir levels, and therefore decrease conversion to sofosbuvir's active metabolite (GS-331007) responsible for 90% of pharmacologic effect

            • tipranavir

              tipranavir will decrease the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Contraindicated. P-gp inducers decrease sofosbuvir levels, and therefore decrease conversion to sofosbuvir's active metabolite (GS-331007) responsible for 90% of pharmacologic effect

            Serious - Use Alternative (10)

            • colchicine

              ledipasvir/sofosbuvir will increase the level or effect of colchicine by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Avoid use of colchicine with P-gp inhibitors. If coadministration is necessary, decrease colchicine dose or frequency as recommended in prescribing information. Use of any colchicine product in conjunction with P-gp inhibitors is contraindicated in patients with renal or hepatic impairment.

            • darolutamide

              darolutamide will increase the level or effect of ledipasvir/sofosbuvir by Other (see comment). Avoid or Use Alternate Drug. Darolutamide is a BCRP inhibitor. Avoid coadministration with BCRP inhibitors. If use is unavoidable, closely monitor for adverse reactions and consider dose reduction of BCRP substrate drug (refer BCRP substrate prescribing information).

            • edoxaban

              ledipasvir/sofosbuvir will increase the level or effect of edoxaban by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Dose adjustment may be required with strong P-gp inhibitors. DVT/PE treatment: Decrease dose to 30 mg PO once daily. NVAF: No dose reduction recommended

            • erdafitinib

              erdafitinib will increase the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If coadministration unavoidable, separate administration by at least 6 hr before or after administration of P-gp substrates with narrow therapeutic index.

            • lasmiditan

              lasmiditan increases levels of ledipasvir/sofosbuvir by Other (see comment). Avoid or Use Alternate Drug. Comment: Lasmiditan inhibits BCRP in vitro. Avoid coadministration of lasmiditan with BCRP substrates.

            • rimegepant

              ledipasvir/sofosbuvir will increase the level or effect of rimegepant by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.

            • sotorasib

              sotorasib will decrease the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If use is unavoidable, refer to the prescribing information of the P-gp substrate for dosage modifications.

            • tepotinib

              tepotinib will increase the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If concomitant use unavoidable, reduce the P-gp substrate dosage if recommended in its approved product labeling.

            • topotecan

              ledipasvir/sofosbuvir will increase the level or effect of topotecan by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Product labeling for PO topotecan recommends avoiding concomitant use of P-gp inhibitors; the interaction with IV topotecan may be less severe but is still likely of clinical significance

            • venetoclax

              ledipasvir/sofosbuvir will increase the level or effect of venetoclax by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If a P-gp inhibitor must be used, reduce the venetoclax dose by at least 50%. Monitor more closely for signs of venetoclax toxicities.

            Monitor Closely (47)

            • acalabrutinib

              acalabrutinib increases levels of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Comment: Acalabrutinib may increase exposure to coadministered BCRP substrates by inhibition of intestinal BCRP.

            • aluminum hydroxide

              aluminum hydroxide decreases levels of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Comment: Ledipasvir solubility decreases as pH increases; drugs that increase gastric pH are expected to decrease levels of ledipasvir; separate antacid and ledipasivr/sofosbuvir administration by 4 hr.

            • aluminum hydroxide/magnesium carbonate

              aluminum hydroxide/magnesium carbonate decreases levels of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Comment: Ledipasvir solubility decreases as pH increases; drugs that increase gastric pH are expected to decrease levels of ledipasvir; separate antacid and ledipasivr/sofosbuvir administration by 4 hr.

            • aluminum hydroxide/magnesium trisilicate

              aluminum hydroxide/magnesium trisilicate decreases levels of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Comment: Ledipasvir solubility decreases as pH increases; drugs that increase gastric pH are expected to decrease levels of ledipasvir; separate antacid and ledipasivr/sofosbuvir administration by 4 hr.

            • amiodarone

              ledipasvir/sofosbuvir increases toxicity of amiodarone by unknown mechanism. Modify Therapy/Monitor Closely. Postmarketing reports describe bradycardia resulting in death or pacemaker insertion when amiodarone was coadministered with sofosbuvir in combination with another direct acting antiviral. Patients also taking beta blockers (7 of 9 of the postmarketing reports), or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Cardiac monitoring in an inpatient setting for the first 48 hr of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.

            • apalutamide

              apalutamide will decrease the level or effect of ledipasvir/sofosbuvir by increasing elimination. Use Caution/Monitor. Apalutamide weakly induces BCRP and may decrease systemic exposure of drugs that are BCRP substrates.

            • aspirin/citric acid/sodium bicarbonate

              aspirin/citric acid/sodium bicarbonate decreases levels of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Comment: Ledipasvir solubility decreases as pH increases; drugs that increase gastric pH are expected to decrease levels of ledipasvir; separate antacid and ledipasivr/sofosbuvir administration by 4 hr.

            • atorvastatin

              ledipasvir/sofosbuvir will increase the level or effect of atorvastatin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Coadministration of ledipasvir/sofosbuvir with atorvastatin may be associated withincreased risk of myopathy,including rhabdomyolysis. Monitor closely.

            • berotralstat

              ledipasvir/sofosbuvir increases levels of berotralstat by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Reduced berotralstat dose to 110 mg/day when coadministered with P-gp inhibitors.

              berotralstat will increase the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor or titrate P-gp substrate dose if coadministered.

            • betrixaban

              ledipasvir/sofosbuvir increases levels of betrixaban by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Decrease betrixaban dose to 80 mg PO once, then 40 mg PO qDay if coadministered with a P-gp inhibitor.

            • calcium carbonate

              calcium carbonate decreases levels of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Comment: Ledipasvir solubility decreases as pH increases; drugs that increase gastric pH are expected to decrease levels of ledipasvir; separate antacid and ledipasivr/sofosbuvir administration by 4 hr.

            • cimetidine

              cimetidine decreases levels of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Comment: Ledipasvir solubility decreases as pH increases; drugs that increase gastric pH are expected to decrease levels of ledipasvir; H2-receptor antagonists may be administered simultaneously with or 12 hr apart from ledipasvir/sofosbuvir at a dose that does not exceed doses comparable to famotidine 40 mg BID.

            • citric acid/sodium bicarbonate

              citric acid/sodium bicarbonate decreases levels of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Comment: Ledipasvir solubility decreases as pH increases; drugs that increase gastric pH are expected to decrease levels of ledipasvir; separate antacid and ledipasivr/sofosbuvir administration by 4 hr.

            • dabigatran

              ledipasvir/sofosbuvir will increase the level or effect of dabigatran by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Atrial fibrillation: Avoid coadministering dabigatran with P-gp inhibitors if CrCl <30 mL/min. DVT/PE treatment: Avoid coadministering dabigatran with P-gp inhibitors if CrCl <50 mL/min

            • dexlansoprazole

              dexlansoprazole decreases levels of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Comment: Ledipasvir solubility decreases as pH increases; drugs that increase gastric pH are expected to decrease levels of ledipasvir; proton-pump inhibitor doses comparable to omeprazole <20 mg can be administered simultaneously with ledipasvir/sofosbuvir under fasted conditions.

            • digoxin

              ledipasvir/sofosbuvir will increase the level or effect of digoxin by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely.

            • duvelisib

              ledipasvir/sofosbuvir will increase the level or effect of duvelisib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • elagolix

              elagolix will increase the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • elvitegravir/cobicistat/emtricitabine/tenofovir DF

              ledipasvir/sofosbuvir will increase the level or effect of elvitegravir/cobicistat/emtricitabine/tenofovir DF by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Tenofovir levels increased; alteration of dose regimen may be necessary

              ledipasvir/sofosbuvir will increase the level or effect of elvitegravir/cobicistat/emtricitabine/tenofovir DF by unspecified interaction mechanism. Use Caution/Monitor.

            • esomeprazole

              esomeprazole decreases levels of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Comment: Ledipasvir solubility decreases as pH increases; drugs that increase gastric pH are expected to decrease levels of ledipasvir; proton-pump inhibitor doses comparable to omeprazole <20 mg can be administered simultaneously with ledipasvir/sofosbuvir under fasted conditions.

            • famotidine

              famotidine decreases levels of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Comment: Ledipasvir solubility decreases as pH increases; drugs that increase gastric pH are expected to decrease levels of ledipasvir; H2-receptor antagonists may be administered simultaneously with or 12 hr apart from ledipasvir/sofosbuvir at a dose that does not exceed doses comparable to famotidine 40 mg BID.

            • fostamatinib

              fostamatinib will increase the level or effect of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Concomitant use of fostamatinib may increase concentrations of P-gp/BCRP substrate drugs. Monitor for toxicities of P-gp/BCRP substrate drug that may require dosage reduction when given concurrently with fostamatinib.

            • fostemsavir

              fostemsavir will increase the level or effect of ledipasvir/sofosbuvir by Other (see comment). Modify Therapy/Monitor Closely. Fostemsavir inhibits BCRP transporters. If possible, avoid coadministration or modify dose of BCRP substrate coadministered with fostemsavir.

            • glecaprevir/pibrentasvir

              ledipasvir/sofosbuvir will increase the level or effect of glecaprevir/pibrentasvir by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              glecaprevir/pibrentasvir will increase the level or effect of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Glecaprevir/pibrentasvir may increase plasma concentration of P-gp and BCRP substrates.

            • ibuprofen/famotidine

              ibuprofen/famotidine decreases levels of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Comment: Ledipasvir solubility decreases as pH increases; drugs that increase gastric pH are expected to decrease levels of ledipasvir; H2-receptor antagonists may be administered simultaneously with or 12 hr apart from ledipasvir/sofosbuvir at a dose that does not exceed doses comparable to famotidine 40 mg BID.

            • istradefylline

              istradefylline will increase the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of P-gp substrates in clinical trials. Consider dose reduction of sensitive P-gp substrates.

            • lansoprazole

              lansoprazole decreases levels of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Comment: Ledipasvir solubility decreases as pH increases; drugs that increase gastric pH are expected to decrease levels of ledipasvir; proton-pump inhibitor doses comparable to omeprazole <20 mg can be administered simultaneously with ledipasvir/sofosbuvir under fasted conditions.

            • lonafarnib

              lonafarnib will increase the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Lonafarnib is a weak P-gp inhibitor. Monitor for adverse reactions if coadministered with P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. Reduce P-gp substrate dose if needed.

            • magnesium oxide

              magnesium oxide decreases levels of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Comment: Ledipasvir solubility decreases as pH increases; drugs that increase gastric pH are expected to decrease levels of ledipasvir; separate antacid and ledipasivr/sofosbuvir administration by 4 hr.

            • naldemedine

              ledipasvir/sofosbuvir increases levels of naldemedine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor naldemedine for potential adverse effects if coadministered with P-gp inhibitors.

            • nintedanib

              ledipasvir/sofosbuvir increases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. If nintedanib adverse effects occur, management may require interruption, dose reduction, or discontinuation of therapy .

            • nizatidine

              nizatidine decreases levels of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Comment: Ledipasvir solubility decreases as pH increases; drugs that increase gastric pH are expected to decrease levels of ledipasvir; H2-receptor antagonists may be administered simultaneously with or 12 hr apart from ledipasvir/sofosbuvir at a dose that does not exceed doses comparable to famotidine 40 mg BID.

            • omeprazole

              omeprazole decreases levels of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Comment: Ledipasvir solubility decreases as pH increases; drugs that increase gastric pH are expected to decrease levels of ledipasvir; proton-pump inhibitor doses comparable to omeprazole <20 mg can be administered simultaneously with ledipasvir/sofosbuvir under fasted conditions.

            • pantoprazole

              pantoprazole decreases levels of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Comment: Ledipasvir solubility decreases as pH increases; drugs that increase gastric pH are expected to decrease levels of ledipasvir; proton-pump inhibitor doses comparable to omeprazole <20 mg can be administered simultaneously with ledipasvir/sofosbuvir under fasted conditions.

            • rabeprazole

              rabeprazole decreases levels of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Comment: Ledipasvir solubility decreases as pH increases; drugs that increase gastric pH are expected to decrease levels of ledipasvir; proton-pump inhibitor doses comparable to omeprazole <20 mg can be administered simultaneously with ledipasvir/sofosbuvir under fasted conditions.

            • regorafenib

              regorafenib will increase the level or effect of ledipasvir/sofosbuvir by Other (see comment). Modify Therapy/Monitor Closely. Regorafenib likely inhibits BCRP (ABCG2) transport. Coadministration with a BCRP substrate may increase systemic exposure to the substrate and related toxicity.

            • rosuvastatin

              ledipasvir/sofosbuvir will increase the level or effect of rosuvastatin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Coadministration of ledipasvir/sofosbuvir with rosuvastatin may be associated withincreased risk of myopathy,including rhabdomyolysis. Monitor closely.

            • safinamide

              safinamide will increase the level or effect of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Safinamide and its major metabolite may inhibit intestinal BCRP. Monitor BCRP substrates for increased pharmacologic or adverse effects.

            • sarecycline

              sarecycline will increase the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor for toxicities of P-gp substrates that may require dosage reduction when coadministered with P-gp inhibitors.

            • sodium zirconium cyclosilicate

              sodium zirconium cyclosilicate will decrease the level or effect of ledipasvir/sofosbuvir by increasing gastric pH. Applies only to oral form of both agents. Modify Therapy/Monitor Closely. Check specific recommendations for drugs that exhibit pH-dependent solubility that may affect their systemic exposure and efficacy. In general, administer drugs at least 2 hr before or after sodium zirconium cyclosilicate.

            • stiripentol

              stiripentol will increase the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Consider reducing the dose of P-glycoprotein (P-gp) substrates, if adverse reactions are experienced when administered concomitantly with stiripentol.

              stiripentol will increase the level or effect of ledipasvir/sofosbuvir by Other (see comment). Modify Therapy/Monitor Closely. Stiripentol is a BCRP transport inhibitor. Consider dosage reduction for BCRP substrates if adverse effects are experienced when coadministered.

            • tafamidis

              tafamidis will increase the level or effect of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Tafamidis inhibits breast cancer resistant protein (BCRP) in vitro and may increase exposure of BCRP substrates following tafamidis or tafamidis meglumine administration. Dosage adjustment of these BCRP substrates may be necessary.

            • tafamidis meglumine

              tafamidis meglumine will increase the level or effect of ledipasvir/sofosbuvir by Other (see comment). Use Caution/Monitor. Tafamidis inhibits breast cancer resistant protein (BCRP) in vitro and may increase exposure of BCRP substrates following tafamidis or tafamidis meglumine administration. Dosage adjustment of these BCRP substrates may be necessary.

            • talazoparib

              ledipasvir/sofosbuvir will increase the level or effect of talazoparib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Talazoparib is a P-glycoprotein (P-gp) substrate; coadministration with P-gp inhibitors may increase talazoparib systemic exposure.

            • tenofovir DF

              ledipasvir/sofosbuvir will increase the level or effect of tenofovir DF by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              ledipasvir/sofosbuvir will increase the level or effect of tenofovir DF by unspecified interaction mechanism. Use Caution/Monitor.

            • tucatinib

              tucatinib will increase the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Consider reducing the dosage of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities.

            • warfarin

              ledipasvir/sofosbuvir increases toxicity of warfarin by anticoagulation. Use Caution/Monitor. Fluctuations in INR values may occur in patients receiving warfarin concomitant with HCV treatment; frequent monitoring of INR values recommended during treatment and post-treatment follow-up.

            Minor (0)

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              Adverse Effects

              >10%

              Asthenia (31-36%)

              Fatigue (4-18%)

              Headache (13-29%)

              Cough (5-11%)

              1-10%

              Nausea (6-9%)

              Diarrhea (3-7%)

              Dizziness (1-5%)

              Dyspnea (3-9%)

              Insomnia (3-6%)

              Increased bilirubin >1.5 x ULN (<1 to 3%)

              Increased lipase >3 x ULN (<1 to 3%)

              Myalgia (4-9%)

              Irritability (7-8%)

              Frequency Not Defined

              Asymptomatic creatine kinase elevation, Grades 3/4

              Postmarketing Reports

              Bradycardia in patients taking amiodarone who initiate ledipasvir/sofosbuvir therapy

              Skin rash, sometimes with blisters or angioedema-like swelling

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              Warnings

              Black Box Warnings

              Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with HCV direct acting antivirals (DDAs)

              HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with DDAs and were not receiving HBV antiviral therapy

              Some cases have resulted in fulminant hepatitis, hepatic failure, and death

              Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up

              Initiate appropriate patient management for HBV infection as clinically indicated

              Contraindications

              If coadministered with ribavirin, the contraindications to ribavirin also apply to this combination regimen

              Cautions

              HCV and HBV Coinfection

              • Hepatitis B virus (HBV) reactivation reported in HCV/HBV coinfected patients undergoing or had completed treatment with HCV direct-acting antivirals, and who were not receiving HBV antiviral therapy
              • Some cases have resulted in fulminant hepatitis, hepatic failure, and death; cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (eg, HBsAg negative and anti-HBc positive)
              • HBV reactivation also reported in patients receiving certain immunosuppressants or chemotherapeutic agents
              • Risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients
              • HBV reactivation is characterized as abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level; in patients with resolved HBV infection, reappearance of HBsAg can occur
              • Reactivation of HBV replication may be accompanied by hepatitis, eg, increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur
              • Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV therapy
              • In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment and during post-treatment follow-up; initiate appropriate patient management for HBV infection as clinically indicated

              Drug interaction overview

              • The concomitant use of drug combination and P- gp inducers may significantly decrease ledipasvir and sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect; use of drug combination with P- gp inducers (eg, rifampin, St. John’s wort) not recommended
              • If drug combination administered with ribavirin, the warnings and precautions for ribavirin, in particular, the pregnancy avoidance warning, apply to this combination regimen; refer to ribavirin prescribing information for a full list of warnings and precautions for ribavirin
              • Ledipasvir and sofosbuvir are substrates of P-gp and BCRP; coadministration with P-gp inducers (eg, rifampin, St. John’s wort) is not recommended; may significantly decrease ledipasvir and sofosbuvir plasma concentrations and reduce therapeutic effect
              • Ledipasvir is an inhibitor of P-gp and BCRP; may increase intestinal absorption of coadministered substrates for these transporters
              • Coadministration of ledipasvir with acid-reducing agents may decrease ledipasvir solubility, resulting in decreased serum concentrations
              • Frequent monitoring of relevant laboratory parameters (eg, International Normalized Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as cytochrome P450 substrates with a narrow therapeutic index (eg, certain immunosuppressants) is recommended to ensure safe and effective use; dose adjustments of concomitant medications may be necessary
              • Bradycardia with amiodarone coadministration
                • Postmarketing cases of symptomatic bradycardia, as well as fatal cardiac arrest and cases requiring pacemaker intervention, reported when the drug combination is administered with amiodarone
                • Bradycardia has generally occurred within hours to days, but cases reported up to 2 weeks after initiating HCV treatment; patients also taking beta-blockers, or those with underlying cardiac comorbidities and/or advanced liver disease, may be at increased risk for symptomatic bradycardia with coadministration of amiodarone
                • Bradycardia generally resolved after discontinuation of HCV treatment; the mechanism for this effect is unknown
                • Coadministration of amiodarone not recommended; for patients taking amiodarone with no other alternative, viable treatment options should counsel patients about risk of serious symptomatic bradycardia; cardiac monitoring in an in-patient setting for first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of heart rate should occur on a daily basis through at least first 2 weeks of treatment; patients on the drug combination who need to take amiodarone should use the same approach as described above
                • Due to amiodarone’s long half-life, patients discontinuing amiodarone should undergo cardiac monitoring prior to starting therapy; patients who develop signs or symptoms of bradycardia, including near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or memory problems should seek medical evaluation immediately
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              Pregnancy & Lactation

              Pregnancy

              If the drug combination is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant; refer to ribavirin prescribing information for more information on ribavirin-associated risks of use during pregnancy

              No adequate human data are available to establish whether or not the drug combination poses a risk to pregnancy outcomes; in animal reproduction studies, no evidence of adverse developmental outcomes was observed with the drug combination ledipasvir or sofosbuvir at exposures greater than those in humans at the recommended human dose (RHD)

              Lactation

              It is not known whether ledipasvir or sofosbuvir, the drug combination, or their metabolites are present in human breast milk, affect human milk production or have effects on the breastfed infant.

              The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for the drug combination and any potential adverse effects on the breastfed child from the drug combination or from the underlying maternal condition

              Pregnancy Categories

              A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

              B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

              C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

              D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

              X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

              NA: Information not available.

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              Pharmacology

              Mechanism of Action

              Ledipasvir: Inhibits HCV NS5A protein, which is required for viral replication; resistance selection in cell culture and cross-resistance studies indicate ledipasvir targets NS5A as its mode of action

              Sofosbuvir: Nucleotide prodrug that undergoes metabolism to the active uridine analog triphosphate, an inhibitor of HCV NS5B RNA-dependent polymerase; its inhibition, in turn, suppresses viral replication

              Absorption

              Peak plasma concentration

              • ledipasvir: 4-4.5 hr
              • sofosbuvir: 0.8-1 hr
              • GS-331007: 3.5-4 hr

              Peak plasma level

              • ledipasvir: 323 ng/mL
              • sofosbuvir: 618 ng/mL
              • GS-331007: 707 ng/mL

              AUC

              • ledipasvir: 7,290 ng•hr/mL
              • sofosbuvir: 1,320 ng•hr/mL
              • GS-331007: 12,000 ng•hr/mL

              Distribution

              Protein bound

              • ledipasvir: >99.8%
              • sofosbuvir: 61-65%
              • GS-331007: minimal

              Metabolism

              ledipasvir: No detectable metabolism

              sofosbuvir: Extensively metabolized in liver to form the pharmacologically active nucleoside analog triphosphate GS-461203; dephosphorylation results in formation of GS331007 (accounts for <90% of total systemic exposure of sofosbuvir)

              Elimination

              Half-life, terminal

              • ledipasvir: 47 hr
              • sofosbuvir: 0.5 hr
              • GS-331007: 27 hr

              Excretion

              • ledipasvir: >98% feces (mostly unchanged); <1% urine
              • GS-331007: 14% feces; 80% urine; 2.5% expired air
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              Administration

              Oral Preparation (Oral Pellets)

              Do not chew pellets

              If pellets are administered with food, sprinkle on ≥1 spoonfuls of nonacidic soft food (eg, pudding, chocolate syrup, mashed potato, ice cream) at or below room temperature

              Take pellets within 30 min of gently mixing with food and swallow entire contents without chewing to avoid a bitter aftertaste

              Oral Administration

              Take with or without food

              Storage

              Tablets and oral pellets: Store <30ºC; dispense in original bottle

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              Images

              BRAND FORM. UNIT PRICE PILL IMAGE
              ledipasvir-sofosbuvir oral
              -
              90-400 mg tablet
              Harvoni oral
              -
              33.75-150 mg pellet
              Harvoni oral
              -
              45-200 mg pellet
              Harvoni oral
              -
              45-200 mg tablet
              Harvoni oral
              -
              90-400 mg tablet
              Harvoni oral
              -
              33.75-150 mg pellet
              Harvoni oral
              -
              45-200 mg pellet

              Copyright © 2010 First DataBank, Inc.

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              Patient Handout

              Patient Education
              ledipasvir-sofosbuvir oral

              LEDIPASVIR/SOFOSBUVIR - ORAL

              (le-DIP-as-vir/soe-FOS-buer-vir)

              COMMON BRAND NAME(S): Harvoni

              WARNING: Although this medication helps many people with hepatitis C, it may cause people who also have another liver problem called hepatitis B to get worse. Before starting this medication, tell your doctor if you have ever had hepatitis B. Tell your doctor right away if you have new or worsening symptoms of liver disease, such as nausea/vomiting that doesn't stop, loss of appetite, stomach/abdominal pain, dark urine or yellowing eyes/skin.

              USES: This medication is a combination of ledipasvir and sofosbuvir and is used to treat chronic (long-lasting) hepatitis C, a viral infection of the liver. It may sometimes be used with another antiviral medication (ribavirin). These drugs work by reducing the amount of hepatitis C virus in your body, which helps your immune system fight the infection and may help your liver recover. Chronic hepatitis C infection can cause serious liver problems such as scarring (cirrhosis), or liver cancer.It is not known if this treatment can prevent you from passing the virus to others. Do not share needles, and practice "safer sex" (including the use of latex condoms) to lower the risk of passing the virus to others.

              HOW TO USE: Read the Patient Information Leaflet and Instructions for Use if available from your pharmacist before you start taking ledipasvir/sofosbuvir and each time you get a refill. If you have any questions, ask your doctor or pharmacist.Take this medication by mouth with or without food as directed by your doctor, usually once daily. The dosage is based on your medical condition and response to treatment. In children, the dosage is also based on weight.If you are using the pellet form of this medication, gently shake the packet before use. To take this medication without food, open the packet and pour the pellets directly into your mouth. Swallow the pellets without chewing. You may drink water after swallowing the pellets if needed. Repeat these steps if your dose is for more than one packet. If you are taking this medication with food, open the packet(s) and pour the pellets into a small bowl with one or more spoonfuls of non-acidic soft food (such as pudding, mashed potato, ice cream). The soft food should be at or below room temperature. After gently mixing, take all of the mixture without chewing within 30 minutes.This medication works best when the amount of drug in your body is kept at a constant level. Take this drug at evenly spaced intervals. To help you remember, take it at the same time each day.Tell your doctor if you vomit within 5 hours after taking this medication. You may need to take another dose.Continue to take ledipasvir/sofosbuvir for the full length of time prescribed, even if symptoms disappear after a short time. Stopping the medication too early may result in a return of the infection.Antacids lower the absorption of ledipasvir. If you are taking an antacid, take it at least 4 hours before or 4 hours after this medication.Other acid-lowering medications for indigestion, heartburn, or ulcers (such as prescription or over-the-counter medications including famotidine, omeprazole) may prevent ledipasvir from working. Ask your doctor or pharmacist how to use these medications safely.

              SIDE EFFECTS: See also Warning section.Tiredness, headache, nausea, diarrhea, or difficulty sleeping may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

              PRECAUTIONS: Before taking ledipasvir/sofosbuvir, tell your doctor or pharmacist if you are allergic to either of the drugs; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before using this medication, tell your doctor or pharmacist your medical history, especially of: other liver problems (such as hepatitis B), diabetes.If you have diabetes, your blood sugar may be lower with hepatitis C treatment. This can increase your risk of low blood sugar, so your doctor may adjust your diabetes treatment plan. Tell your doctor right away if you have symptoms of low blood sugar such as sudden sweating, shaking, fast heartbeat, hunger, blurred vision, dizziness, or tingling hands/feet.Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor. Ledipasvir/sofosbuvir, in combination with ribavirin, must not be used during pregnancy by either the pregnant woman or her male partner. The combination may harm an unborn baby. Two reliable forms of birth control (such as condoms, birth control pills) must be used whenever at least one sexual partner is using these medicines together, and for six months after stopping treatment. If you or your partner becomes pregnant, or if you think you or your partner may be pregnant, tell your doctor right away.It is unknown if this medication passes into breast milk. Consult your doctor before breast-feeding. Breast-feeding is not recommended if this medication is used in combination with ribavirin.

              DRUG INTERACTIONS: See also How to Use section.Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.Some products that may interact with this drug include: amiodarone, a certain other medication used to treat chronic hepatitis C (simeprevir).This medication can slow down the removal of other medications from your body, which may affect how they work. Examples include flibanserin, rosuvastatin, among others.Other medications can affect the removal of ledipasvir/sofosbuvir from your body, which may affect how this medication works. Examples include rifamycins (such as rifampin, rifabutin), St. John's wort, tipranavir/ritonavir, drugs used to treat seizures (such as phenobarbital, carbamazepine, phenytoin, primidone), among others.Do not take this medication with other products that contain sofosbuvir.

              OVERDOSE: If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

              NOTES: Do not share this medication with others.Lab tests (such as liver function, tests for hepatitis B and C) should be done before you start using this medication, while you are using it, and after completing treatment. Keep all medical and lab appointments.If you are using this medication with ribavirin, it is recommended that female patients or female partners of male patients take a pregnancy test before starting this medication. A pregnancy test should also be taken every month while using this medication and for 6 months after treatment ends to make sure no pregnancy occurs.

              MISSED DOSE: If you miss a dose, take it as soon as you remember, unless it is less than 6 hours until the next dose. In that case, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up.

              STORAGE: Store at room temperature away from light and moisture. Store the tablets in the original container. Keep the pellets in the packets and do not open the packets until ready for use. Do not store in the bathroom. Keep all medications away from children and pets.Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

              Information last revised August 2021. Copyright(c) 2021 First Databank, Inc.

              IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

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              Formulary

              FormularyPatient Discounts

              Adding plans allows you to compare formulary status to other drugs in the same class.

              To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

              Adding plans allows you to:

              • View the formulary and any restrictions for each plan.
              • Manage and view all your plans together – even plans in different states.
              • Compare formulary status to other drugs in the same class.
              • Access your plan list on any device – mobile or desktop.

              The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

              Tier Description
              1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
              2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
              3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
              4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              NC NOT COVERED – Drugs that are not covered by the plan.
              Code Definition
              PA Prior Authorization
              Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
              QL Quantity Limits
              Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
              ST Step Therapy
              Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
              OR Other Restrictions
              Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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              Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.