Ledipasvir

7.3 Serious Symptomatic Bradycardia When Co-administered with Ledipasvir/Sofosbuvir or with Sofosbuvir with Simeprevir Postmarketing cases of symptomatic bradycardia, some requiring pacemaker insertion and at least one fatal, have been reported when ledipasvir/sofosbuvir or sofosbuvir with simeprevir were initiated in patients on amiodarone.

When combined with sofosbuvir, cases of myopathy and rhabdomyolysis reported. Consider risk/benefit of concomitant use.

7.3 Serious Symptomatic Bradycardia When Co-administered with Ledipasvir/Sofosbuvir or with Sofosbuvir with Simeprevir Postmarketing cases of symptomatic bradycardia, some requiring pacemaker insertion and at least one fatal, have been reported when ledipasvir/sofosbuvir or sofosbuvir with simeprevir were initiated in patients on amiodarone.

Intervention: Sofosbuvir/velpatasvir/voxilaprevir Ledipasvir/sofosbuvir Avoid concomitant use with rosuvastatin.

Intervention: Sofosbuvir/velpatasvir/voxilaprevir Ledipasvir/sofosbuvir Avoid concomitant use with rosuvastatin.

Hepatitis C Antiviral Agents ledipasvir/sofosbuvir sofosbuvir/velpatasvir ↑ tenofovir Monitor for adverse reactions associated with TDF. No clinically significant changes in concentration were observed for doravirine when co-administered with the following agents: TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ritonavir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, or methadone [see Clinical Pharmacology (12.3) ] . 7.3 Effect of DELSTRIGO on Other Drugs No clinically significant changes in concentration were observed for the following agents when co-administered with doravirine: lamivudine, TDF, elbasvir and grazoprevir, ledipasvir and sofosbuvir, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, or midazolam.

Ledipasvir/Sofosbuvir ↑ TDF Monitor for adverse reactions associated with TDF.

ledipasvir/sofosbuvir Monitor patients receiving TRUVADA concomitantly with HARVONI ® (ledipasvir/sofosbuvir) without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination for adverse reactions associated with TDF.

Hepatitis C Antiviral Agents: sofosbuvir/velpatasvirc sofosbuvir/velpatasvir/voxilaprevirc ledipasvir/sofosbuvirc ↑ tenofovir Monitor patients receiving emtricitabine and tenofovir disoproxil fumarate concomitantly with EPCLUSA® (sofosbuvir/velpatasvir) or VOSEVI® (sofosbuvir/velpatasvir/voxilaprevir) for adverse reactions associated with TDF. Monitor patients receiving emtricitabine and tenofovir disoproxil fumarate concomitantly with HARVONI® (ledipasvir/sofosbuvir) without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination for adverse reactions associated with TDF.

7.3 Hepatitis C Antiviral Agents Coadministration of TDF, a component of CIMDUO, and EPCLUSA ® (sofosbuvir/velpatasvir) or HARVONI ® (ledipasvir/sofosbuvir) has been shown to increase tenofovir exposure [see Clinical Pharmacology (12.3) ] . In patients receiving CIMDUO concomitantly with ledipasvir/sofosbuvir without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, monitor for adverse reactions associated with tenofovir. In patients receiving CIMDUO concomitantly with ledipasvir/sofosbuvir and an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, consider an alternative HCV or antiretroviral therapy, as the safety of increased tenofovir concentrations in this setting has not been established.

Hepatitis C Antiviral Agents: sofosbuvir/velpatasvir sofosbuvir/velpatasvir/ voxilaprevir ledipasvir/sofosbuvir ↑ tenofovir Monitor patients receiving tenofovir disoproxil fumarate tablets concomitantly with EPCLUSA ® (sofosbuvir/velpatasvir) or VOSEVI ® (sofosbuvir/velpatasvir/voxilaprevir) for adverse reactions associated with tenofovir DF. Monitor patients receiving tenofovir disoproxil fumarate tablets concomitantly with HARVONI ® (ledipasvir/sofosbuvir) without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination for adverse reactions associated with tenofovir DF.

John's wort (Hypericum perforatum) 7.4 Drugs without Clinically Significant Interactions with VEMLIDY Based on drug interaction studies conducted with VEMLIDY, no clinically significant drug interactions have been observed with: ethinyl estradiol, ledipasvir/sofosbuvir, midazolam, norgestimate, sertraline, sofosbuvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir.

Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with atorvastatin. Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with atorvastatin. Examples: Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir .

Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with atorvastatin. • Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with ATORVALIQ. Examples: Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir.

7.6 Drugs without Clinically Significant Interactions with BIKTARVY Based on drug interaction studies conducted with BIKTARVY or the components of BIKTARVY, no clinically significant drug interactions have been observed when BIKTARVY is combined with the following drugs: ethinyl estradiol, ledipasvir/sofosbuvir, midazolam, norgestimate, sertraline, sofosbuvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir.

No clinically significant changes in concentration were observed for doravirine when co-administered with the following agents: dolutegravir, TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ritonavir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, and methadone [see Clinical Pharmacology (12.3) ]. 7.2 Effect of PIFELTRO on Other Drugs No clinically significant changes in concentration were observed for the following agents when co-administered with doravirine: dolutegravir, lamivudine, TDF, elbasvir and grazoprevir, ledipasvir and sofosbuvir, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, and midazolam [see Clinical Pharmacology (12.3) ] .

ledipasvir/sofosbuvir ↑ tenofovir Patients receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate and HARVONI ® (ledipasvir/sofosbuvir) concomitantly should be monitored for adverse reactions associated with TDF.

7.6 Drugs without Clinically Significant Interactions with GENVOYA Based on drug interaction studies conducted with the components of GENVOYA, no clinically significant drug interactions have been observed or are expected when GENVOYA is combined with the following drugs: famciclovir, famotidine, ledipasvir, methadone, omeprazole, prasugrel (active metabolite), sertraline, sofosbuvir, velpatasvir, and voxilaprevir.

Hepatitis C Antiviral Agents: ledipasvir/sofosbuvir sofosbuvir/velpatasvir sofosbuvir/velpatasvir/voxilaprevir ↑ tenofovir The safety of increased tenofovir concentrations in the setting of HARVONI ® (ledipasvir/sofosbuvir) and STRIBILD has not been established.

7.4 Drugs without Clinically Significant Interactions with DESCOVY Based on drug interaction studies conducted with the components of DESCOVY, no clinically significant drug interactions have been either observed or are expected when DESCOVY is combined with the following antiretroviral agents: atazanavir with ritonavir, atazanavir with cobicistat (in those weighing ≥35 kg), darunavir with ritonavir or cobicistat, dolutegravir, efavirenz, ledipasvir, lopinavir/ritonavir, maraviroc, nevirapine, raltegravir, rilpivirine, and sofosbuvir.

Hepatitis C Antiviral Agents: ledipasvir/sofosbuvir sofosbuvir/velpatasvir sofosbuvir/velpatasvir/voxilaprevir ↑ tenofovir Patients receiving COMPLERA concomitantly with HARVONI ® (ledipasvir/sofosbuvir), EPCLUSA ® (sofosbuvir/velpatasvir), or VOSEVI ® (sofosbuvir/velpatasvir/voxilaprevir) should be monitored for adverse reactions associated with TDF. 7.7 Drugs with No Observed Interactions with COMPLERA No clinically significant drug interactions have been observed between FTC and the following medications: famciclovir, ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, or TDF. No clinically significant drug interactions have been observed between RPV and the following medications: acetaminophen, atorvastatin, chlorzoxazone, ethinyl estradiol, ledipasvir/sofosbuvir, norethindrone, sildenafil, simeprevir, sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, or TDF.

7.8 Drugs Without Clinically Significant Interactions with ODEFSEY Based on drug interaction studies conducted with the fixed dose combination or components of ODEFSEY, no clinically significant drug interactions have been observed when ODEFSEY is combined with the following drugs: acetaminophen, atorvastatin, chlorzoxazone, digoxin, ethinyl estradiol, ledipasvir, metformin, midazolam, norethindrone, norgestimate, sildenafil, simeprevir, sofosbuvir, velpatasvir, and voxilaprevir.

Hepatitis C Antiviral Agents: ledipasvir/sofosbuvir sofosbuvir/velpatasvir sofosbuvir/velpatasvir/ voxilaprevir ↑ tenofovir Patients receiving emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets concomitantly with HARVONI ® (ledipasvir/sofosbuvir), EPCLUSA ® (sofosbuvir/velpatasvir), or VOSEVI ® (sofosbuvir/velpatasvir/voxilaprevir) should be monitored for adverse reactions associated with TDF. 7.7 Drugs with No Observed Interactions with Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets No clinically significant drug interactions have been observed between FTC and the following medications: famciclovir, ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, or TDF. No clinically significant drug interactions have been observed between RPV and the following medications: acetaminophen, atorvastatin, chlorzoxazone, ethinyl estradiol, ledipasvir/sofosbuvir, norethindrone, sildenafil, simeprevir, sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, or TDF.

See the prescribing information for other drugs dependent on gastric pH for absorption for administration instructions, including atazanavir, erlotinib, ketoconazole, itraconazole, ledipasvir/sofosbuvir, nilotinib, and rilpivirine.

For administration instructions of other drugs whose absorption is dependent on gastric pH, refer to their prescribing information (e.g., atazanavir, erlotinib, ketoconazole, itraconazole, nilotinib, ledipasvir/sofosbuvir, and rilpivirine).

John's wort): May alter concentrations of ledipasvir and sofosbuvir. ( 7.2 ) 7.1 Potential for Drug Interaction As HARVONI contains ledipasvir and sofosbuvir, any interactions that have been identified with these agents individually may occur with HARVONI. 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.