LEDIPASVIR Drug Interactions: What You Need to Know

INTERACTIONS Coadministration with amiodarone may result in serious symptomatic bradycardia. Use of ledipasvir and sofosbuvir with amiodarone is not recommended. ( 5.2 , 6.2 , 7.2 ) P-gp inducers (e.g., rifampin, St. John's wort): May alter concentrations of ledipasvir and sofosbuvir. Use of ledipasvir and sofosbuvir with P-gp inducers is not recommended. ( 5.3 , 7 , 12.3 ) Consult the full prescribing information prior to use for potential drug interactions. ( 5.2 , 5.3 , 7 , 12.3 ) Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact safe and effective use of concomitant medications. Frequent monitoring of relevant laboratory parameters (INR or blood glucose) and dose adjustments of certain concomitant medications may be necessary. ( 7.2 )

7.1 Potential for Drug Interaction Any interactions that have been identified with ledipasvir or sofosbuvir individually may occur with ledipasvir and sofosbuvir. After oral administration of ledipasvir and sofosbuvir, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic extraction. In clinical pharmacology studies, both sofosbuvir and the inactive metabolite GS-331007 were monitored for purposes of pharmacokinetic analyses. Ledipasvir is an inhibitor of the drug transporters P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters. Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. P-gp inducers (e.g., rifampin, St. John&apos;s wort) may decrease ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect of ledipasvir and sofosbuvir, and the use with P-gp inducers is not recommended with ledipasvir and sofosbuvir <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> .

7.2 Established and Potentially Significant Drug Interactions Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies. Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment. Frequent monitoring of relevant laboratory parameters (e.g., 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 (e.g., certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary.

Table

6 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either ledipasvir and sofosbuvir tablets (90 mg/400 mg) or ledipasvir and sofosbuvir as individual agents, or are predicted drug interactions that may occur with ledipasvir and sofosbuvir [see Warnings and Precautions (5.2 , 5.3) and Clinical Pharmacology (12.3) ] .

Table

6 Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction This table is not all inclusive.

Concomitant Drug

Class: Drug Name Effect on Concentration ↓ = decrease, ↑ = increase Clinical Comment tenofovir DF = tenofovir disoproxil fumarate Acid Reducing Agents: ↓ ledipasvir Ledipasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease concentration of ledipasvir. Antacids (e.g., aluminum and magnesium hydroxide) It is recommended to separate antacid and ledipasvir and sofosbuvir administration by 4 hours. H 2 -receptor antagonists These interactions have been studied in healthy adults. (e.g., famotidine) H 2 -receptor antagonists may be administered simultaneously with or 12 hours apart from ledipasvir and sofosbuvir at a dose that does not exceed doses comparable to famotidine 40 mg twice daily. Proton-pump inhibitors (e.g., omeprazole) Proton-pump inhibitor doses comparable to omeprazole 20 mg or lower can be administered simultaneously with ledipasvir and sofosbuvir under fasted conditions. Antiarrhythmics: amiodarone Effect on amiodarone, ledipasvir, and sofosbuvir concentrations unknown Coadministration of amiodarone with ledipasvir and sofosbuvir may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Coadministration of amiodarone with ledipasvir and sofosbuvir is not recommended; if coadministration is required, cardiac monitoring is recommended [see Warnings and Precautions (5.2) , Adverse Reactions (6.2) ]. digoxin ↑ digoxin Coadministration of ledipasvir and sofosbuvir with digoxin may increase the concentration of digoxin. Therapeutic concentration monitoring of digoxin is recommended when coadministered with ledipasvir and sofosbuvir. Anticonvulsants: carbamazepine phenytoin phenobarbital ↓ ledipasvir ↓ sofosbuvir Coadministration of ledipasvir and sofosbuvir with carbamazepine, phenytoin, or phenobarbital is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of ledipasvir and sofosbuvir. Coadministration is not recommended. Antimycobacterials: rifabutin rifampin rifapentine ↓ ledipasvir ↓ sofosbuvir Coadministration of ledipasvir and sofosbuvir with rifampin, rifabutin, or rifapentine is not recommended [see Warnings and Precautions (5.3) ].

Hiv

Antiretrovirals: Regimens containing tenofovir DF without an HIV protease inhibitor/ritonavir or cobicistat ↑ tenofovir Monitor for tenofovir-associated adverse reactions in patients receiving ledipasvir and sofosbuvir concomitantly with a regimen containing tenofovir DF without an HIV protease inhibitor/ritonavir or cobicistat. Refer to Viread ® or Truvada ® prescribing information for recommendations on renal monitoring. Regimens containing tenofovir DF and an HIV protease inhibitor/ritonavir or cobicistat atazanavir/ritonavir or cobicistat + emtricitabine/tenofovir DF darunavir/ritonavir or cobicistat + emtricitabine/tenofovir DF lopinavir/ritonavir + emtricitabine/tenofovir DF ↑ tenofovir The safety of increased tenofovir concentrations in the setting of ledipasvir and sofosbuvir and an HIV protease inhibitor/ritonavir or cobicistat has not been established. Consider alternative HCV or antiretroviral therapy to avoid increases in tenofovir exposures. If coadministration is necessary, monitor for tenofovir-associated adverse reactions. Refer to Viread or Truvada prescribing information for recommendations on renal monitoring. elvitegravir, cobicistat, emtricitabine, tenofovir DF ↑ tenofovir The safety of increased tenofovir concentrations in the setting of ledipasvir and sofosbuvir and the combination of elvitegravir, cobicistat, emtricitabine, and tenofovir DF has not been established. Coadministration is not recommended. tipranavir/ritonavir ↓ ledipasvir ↓ sofosbuvir Coadministration of ledipasvir and sofosbuvir with tipranavir/ritonavir is expected to decrease the concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of ledipasvir and sofosbuvir. Coadministration is not recommended.

Hcv

Products: simeprevir ↑ ledipasvir ↑ simeprevir Concentrations of ledipasvir and simeprevir are increased when simeprevir is coadministered with ledipasvir. Coadministration of ledipasvir and sofosbuvir with simeprevir is not recommended.

Herbal

Supplements: St. John's wort (Hypericum perforatum) ↓ ledipasvir ↓ sofosbuvir Coadministration of ledipasvir and sofosbuvir with St. John's wort, a P-gp inducer, is not recommended [see Warnings and Precautions (5.3) ]. HMG-CoA Reductase Inhibitors: rosuvastatin ↑ rosuvastatin Coadministration of ledipasvir and sofosbuvir with rosuvastatin may significantly increase the concentration of rosuvastatin, which is associated with increased risk of myopathy, including rhabdomyolysis. Coadministration of ledipasvir and sofosbuvir with rosuvastatin is not recommended. atorvastatin ↑ atorvastatin Coadministration of ledipasvir and sofosbuvir with atorvastatin may be associated with increased risk of myopathy, including rhabdomyolysis. Monitor closely for HMG-CoA reductase inhibitor-associated adverse reactions, such as myopathy and rhabdomyolysis.

7.3 Drugs without Clinically Significant Interactions with Ledipasvir and Sofosbuvir Based on drug interaction studies conducted with ledipasvir, sofosbuvir, or ledipasvir and sofosbuvir tablets (90 mg/400 mg) no clinically significant drug interactions have been either observed or are expected when ledipasvir and sofosbuvir is used with the following drugs <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>: abacavir, atazanavir/ritonavir, cyclosporine, darunavir/ritonavir, dolutegravir, efavirenz, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, emtricitabine, lamivudine, methadone, midazolam, oral contraceptives, pravastatin, raltegravir, rilpivirine, tacrolimus, or verapamil.

See Table

6 for use of ledipasvir and sofosbuvir with certain HIV antiretroviral regimens [see Drug Interactions (7.2) ] .

If ledipasvir and sofosbuvir is administered with ribavirin, the contraindications to ribavirin also apply to this combination regimen. Refer to the ribavirin prescribing information for a list of contraindications for ribavirin [see Dosage and Administration (2.2) ] . If used in combination with ribavirin, all contraindications to ribavirin also apply to ledipasvir and sofosbuvir combination therapy. ( 4 )

AND PRECAUTIONS Risk of Hepatitis B Virus Reactivation: Test all patients for evidence of current or prior HBV infection before initiation of HCV treatment. Monitor HCV/HBV coinfected patients for HBV reactivation and hepatitis flare during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. ( 5.1 ) Bradycardia with amiodarone coadministration: Serious symptomatic bradycardia may occur in patients taking amiodarone, particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. Coadministration of amiodarone with ledipasvir and sofosbuvir is not recommended. In patients without alternative, viable treatment options, cardiac monitoring is recommended. ( 5.2 , 6.2 , 7.2 )

5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were 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 (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressants or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients. HBV reactivation is characterized as an 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, i.e., 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 treatment with ledipasvir and sofosbuvir. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with ledipasvir and sofosbuvir and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

5.2 Serious Symptomatic Bradycardia When Coadministered with Amiodarone Postmarketing cases of symptomatic bradycardia, as well as fatal cardiac arrest and cases requiring pacemaker intervention, have been reported when amiodarone is coadministered with ledipasvir and sofosbuvir. Bradycardia has generally occurred within hours to days, but cases have been observed 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 with ledipasvir and sofosbuvir is not recommended. For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered ledipasvir and sofosbuvir: Counsel patients about the risk of serious symptomatic bradycardia Cardiac monitoring in an in-patient setting for the first 48 hours 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. Patients who are taking ledipasvir and sofosbuvir who need to start amiodarone therapy due to no other alternative, viable treatment options should undergo similar cardiac monitoring as outlined above. Due to amiodarone&apos;s long half-life, patients discontinuing amiodarone just prior to starting ledipasvir and sofosbuvir should also undergo similar cardiac monitoring as outlined above. Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion, or memory problems <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) , Drug Interactions (7.2) ]</span> .

5.3 Risk of Reduced Therapeutic Effect Due to Use with P-gp Inducers The concomitant use of ledipasvir and sofosbuvir and P-gp inducers may significantly decrease ledipasvir and sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect of ledipasvir and sofosbuvir. Therefore, the use of ledipasvir and sofosbuvir with P-gp inducers (e.g., rifampin, St. John&apos;s wort) is not recommended <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span> .

5.4 Risks Associated with Ribavirin Combination Treatment If ledipasvir and sofosbuvir is administered with ribavirin, the warnings and precautions for ribavirin, in particular the pregnancy avoidance warning, apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of the warnings and precautions for ribavirin <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span>.