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  • CLASSES

    Other Anti-Hepatitis Drugs

    BOXED WARNING

    Hepatitis B exacerbation

    Use of direct-acting antivirals (DAA), such as ledipasvir and sofosbuvir, to treat hepatitis C virus (HCV) infections in patients currently or previously infected with hepatitis B virus (HBV) has been associated with reactivation and exacerbation of the HBV infection. Hepatitis B reactivation has also occurred in patients receiving certain immunosuppressive or chemotherapeutic medications; the risk of HBV reactivation associated with DAA treatment may be increased in these patients. To decrease the risk of reactivating a HBV infection, screen all potential drug recipients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc). For those patients whose screening reveals serologic evidence of HBV infection, a baseline HBV DNA concentration should be obtained prior to starting ledipasvir; sofosbuvir. Continue to monitor coinfected patients during and after treatment for clinical and laboratory signs of hepatitis B exacerbation (i.e., HBsAg, HBV DNA, hepatic enzymes, bilirubin). In addition, instruct patients to immediately report any signs of liver toxicity (e.g., yellow eyes or skin, fatigue, weakness, loss of appetite, nausea, vomiting, or light-colored stools) to their health care provider. If a ledipasvir; sofosbuvir recipient develops signs of HBV reactivation, initiate appropriate treatment for HBV infection or consult a physician with expertise in the management of hepatitis infections. The FDA has identified and confirmed 24 cases of hepatitis B exacerbation (including fulminant hepatitis, hepatic failure requiring liver transplant n = 1, and death n = 2) in coinfected patients treated with a DAA-based HCV regimen between November 2013 and July 2016. The exact mechanism is unknown; however, a commonly reported sequence of events included initiation of a DAA-based HCV regimen, rapid drop in HCV RNA to undetectable levels within 1 to 2 weeks of liver enzyme normalization, followed by a rise in HBV DNA (with or without increased transaminases) between treatment weeks 4 and 8. Of the 24 reported cases: 8 discontinued the DAA when transaminases began to rise; 12 received HBV treatment with tenofovir or entecavir; 6 did not receive HBV treatment; and 6 did not report whether HBV treatment was used.

    DEA CLASS

    Rx

    DESCRIPTION

    Combination antiviral product
    Used to treat chronic hepatitis C virus (HCV) genotype 1, 4, 5, and 6 infections
    Does not require administration with interferon or ribavirin for efficacy

    COMMON BRAND NAMES

    Harvoni

    HOW SUPPLIED

    Harvoni Oral Tab: 90-400mg

    DOSAGE & INDICATIONS

    For the treatment of chronic hepatitis C infection.
    For the treatment of chronic hepatitis C virus (HCV) genotype 1 infection.
    Oral dosage
    Adults (treatment-naive) without cirrhosis

    1 tablet (90 mg ledipasvir; 400 mg sofosbuvir) PO once daily with or without food. The recommended duration of treatment is 12 weeks; however, an 8-week treatment duration can be considered for those patients with a baseline hepatitis C virus RNA less than 6 million international units/mL. Recommendation includes patients coinfected with HIV.

    Adults (treatment-naive) with compensated (Child-Pugh A) cirrhosis

    1 tablet (90 mg ledipasvir; 400 mg sofosbuvir) PO once daily with or without food. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.

    Adults (treatment-experienced) without cirrhosis

    1 tablet (90 mg ledipasvir; 400 mg sofosbuvir) PO once daily with or without food. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.

    Adults (treatment-experienced) with compensated (Child-Pugh A) cirrhosis

    1 tablet (90 mg ledipasvir; 400 mg sofosbuvir) PO once daily with or without food. The recommended duration of treatment is 24 weeks. Alternatively, treatment duration may be reduced to 12 weeks if ledipasvir; sofosbuvir is administered in combination with ribavirin. Ribavirin must be administered with food in 2 divided doses, and the dose is based on weight as follows: less than 75 kg give 500 mg PO twice daily; 75 kg or more give 600 mg PO twice daily. Recommendation includes patients coinfected with HIV.

    Adults (treatment-naive and experienced) with decompensated (Child-Pugh B or C) cirrhosis

    1 tablet (90 mg ledipasvir; 400 mg sofosbuvir) PO once daily with ribavirin (600 mg PO once daily) for 12 weeks. Ribavirin must be administered with food, and if tolerated, the dose may be increased as follows: if less than 75 kg give 500 mg PO twice daily; if 75 kg or more give 600 mg PO twice daily. Consider decreasing ribavirin dose for abnormal hemoglobin. Recommendation includes patients coinfected with HIV.

    Adults (treatment-naive and experienced) who have undergone liver transplantation and are without cirrhosis or have compensated (Child-Pugh A) cirrhosis

    1 tablet (90 mg ledipasvir; 400 mg sofosbuvir) PO once daily with ribavirin for 12 weeks. Ribavirin must be administered with food in 2 divided doses, and the dose is based on weight as follows: less than 75 kg give 500 mg PO twice daily; 75 kg or more give 600 mg PO twice daily. Recommendation includes patients coinfected with HIV.

    Children and Adolescents 12 to 17 years (treatment-naive) without cirrhosis or with compensated (Child-Pugh A) cirrhosis

    1 tablet (90 mg ledipasvir; 400 mg sofosbuvir) PO once daily with or without food. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.

    Children and Adolescents 12 to 17 years (treatment-experienced) without cirrhosis

    1 tablet (90 mg ledipasvir; 400 mg sofosbuvir) PO once daily with or without food. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.

    Children and Adolescents 12 to 17 years (treatment-experienced) with compensated (Child-Pugh A) cirrhosis

    1 tablet (90 mg ledipasvir; 400 mg sofosbuvir) PO once daily with or without food. The recommended duration of treatment is 24 weeks. Recommendation includes patients coinfected with HIV.

    Children younger than 12 years weighing at least 35 kg (treatment-naive) without cirrhosis or with compensated (Child-Pugh A) cirrhosis

    1 tablet (90 mg ledipasvir; 400 mg sofosbuvir) PO once daily with or without food. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.

    Children younger than 12 years weighing at least 35 kg (treatment-experienced) without cirrhosis

    1 tablet (90 mg ledipasvir; 400 mg sofosbuvir) PO once daily with or without food. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.

    Children younger than 12 years weighing at least 35 kg (treatment-experienced) with compensated (Child-Pugh A) cirrhosis

    1 tablet (90 mg ledipasvir; 400 mg sofosbuvir) PO once daily with or without food. The recommended duration of treatment is 24 weeks. Recommendation includes patients coinfected with HIV.

    For the treatment of chronic hepatitis C virus (HCV) genotypes 5 or 6 infection.
    Oral dosage
    Adults (treatment-naive and experienced) without cirrhosis or who have compensated (Child-Pugh A) cirrhosis

    1 tablet (90 mg ledipasvir; 400 mg sofosbuvir) PO once daily with or without food. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.

    Children and Adolescents 12 to 17 years (treatment-naive and experienced) without cirrhosis or who have compensated (Child-Pugh A) cirrhosis

    1 tablet (90 mg ledipasvir; 400 mg sofosbuvir) PO once daily with or without food. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.

    Children younger than 12 years weighing at least 35 kg (treatment-naive and experienced) without cirrhosis or who have compensated (Child-Pugh A) cirrhosis

    1 tablet (90 mg ledipasvir; 400 mg sofosbuvir) PO once daily with or without food. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.

    For the treatment of chronic hepatitis C virus (HCV) genotype 4 infection.
    Oral dosage
    Adults (treatment-naive and experienced) without cirrhosis or who have compensated (Child-Pugh A) cirrhosis

    1 tablet (90 mg ledipasvir; 400 mg sofosbuvir) PO once daily with or without food. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.

    Adults (treatment-naive and experienced) who have undergone liver transplantation and are without cirrhosis or have compensated (Child-Pugh A) cirrhosis

    1 tablet (90 mg ledipasvir; 400 mg sofosbuvir) PO once daily with ribavirin for 12 weeks. Ribavirin must be administered with food in 2 divided doses, and the dose is based on weight as follows: less than 75 kg give 500 mg PO twice daily; 75 kg or more give 600 mg PO twice daily. Recommendation includes patients coinfected with HIV.

    Children and Adolescents 12 to 17 years (treatment-naive and experienced) without cirrhosis or who have compensated (Child-Pugh A) cirrhosis

    1 tablet (90 mg ledipasvir; 400 mg sofosbuvir) PO once daily with or without food. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.

    Children younger than 12 years weighing at least 35 kg (treatment-naive and experienced) without cirrhosis or who have compensated (Child-Pugh A) cirrhosis

    1 tablet (90 mg ledipasvir; 400 mg sofosbuvir) PO once daily with or without food. The recommended duration of treatment is 12 weeks. Recommendation includes patients coinfected with HIV.

    MAXIMUM DOSAGE

    Adults

    90 mg/day PO for ledipasvir; 400 mg/day PO for sofosbuvir.

    Geriatric

    90 mg/day PO for ledipasvir; 400 mg/day PO for sofosbuvir.

    Adolescents

    90 mg/day PO for ledipasvir; 400 mg/day PO for sofosbuvir.

    Children

    12 years: 90 mg/day PO for ledipasvir; 400 mg/day PO for sofosbuvir.
    younger than 12 years weighing 35 kg or more: 90 mg/day PO for ledipasvir; 400 mg/day PO for sofosbuvir.
    younger than 12 years weighing less than 35 kg: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed for mild or moderate renal impairment. Safety and efficacy have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or end stage renal disease requiring hemodialysis.

    ADMINISTRATION

    Oral Administration

    May be administered with or without food.

    STORAGE

    Harvoni:
    - Store and dispense in original container
    - Store below 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Renal failure, renal impairment

    Safety and efficacy of ledipasvir; sofosbuvir have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or end stage renal failure requiring dialysis. Compared to individuals with normal renal function, patients with mild, moderate, and severe renal impairment display increased exposure to the parent drug sofosbuvir (61%, 107%, and 171% higher, respectively) and the major metabolite, GS-331007, (55%, 88%, and 451% higher, respectively). Exposure to sofosbuvir and GS-331007 in patients with end stage renal failure, as compared to those with normal renal function, is 28% and 1,280% higher, respectively, when dosed 1 hour before hemodialysis and 60% and 2,070% higher, respectively, when dosed 1 hour after hemodialysis. Approximately 18% of the administered sofosbuvir dose is removed during a 4 hour hemodialysis session.

    Pregnancy

    There are no well controlled studies evaluating the use of ledipasvir; sofosbuvir during human pregnancy. In animal studies involving rats and rabbits, no adverse effects on fetal development were observed with either ledipasvir or sofosbuvir. In certain patient populations, ledipasvir; sofosbuvir must be administered with ribavirin, which is contraindicated for use during pregnancy (FDA pregnancy risk category X) and in females who may become pregnant. Ribavirin may cause birth defects and death of the exposed fetus. Studies of ribavirin indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in all the animal species tested. To monitor maternal-fetal outcomes of pregnancies in female patients exposed to ribavirin during treatment and for 6 months following cessation of treatment, health care providers are encouraged to report any cases to the Ribavirin Pregnancy Registry; telephone (800) 593-2214. For patients who are also infected with HIV and taking concomitant antiretroviral agents, an Antiretroviral Pregnancy Registry is available at (800) 258-4263.

    Breast-feeding

    It is unknown whether ledipasvir or sofosbuvir or their metabolites are excreted in human milk, affect milk production, or have an adverse effect on nursing infants. Simeprevir may be considered as an alternative; however, its excretion into human breast milk is also unknown. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.

    Contraception requirements, male-mediated teratogenicity, pregnancy testing, reproductive risk

    In certain patient populations, ledipasvir; sofosbuvir must be administered with ribavirin, which is contraindicated in females who may become pregnant or in men whose female partners are pregnant. Ribavirin may cause birth defects and death of the exposed fetus. Ribavirin therapy also may cause male-mediated teratogenicity. Studies of ribavirin indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in all the animal species tested. Counsel patients about the reproductive risk and contraception requirements during ribavirin treatment. Both men and women of childbearing potential must use 2 forms of effective contraception during treatment and for 6 months after treatment discontinuation. If a female or the female sexual partner of a treated male becomes pregnant while taking ribavirin or within 6 months after discontinuation of treatment, the healthcare provider should be informed right away. Patients who are not willing to practice strict contraception should not receive ledipasvir; sofosbuvir and ribavirin. Females must also undergo pregnancy testing immediately prior to initiation of therapy, monthly during therapy, and for 6 months post-therapy. To monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment, health care providers are encouraged to report any cases to the Ribavirin Pregnancy Registry; telephone (800) 593-2214. For patients who are also infected with HIV and taking concomitant antiretroviral agents, an Antiretroviral Pregnancy Registry is available at (800) 258-4263.

    Hepatitis C and HIV coinfection

    HIV treatment guidelines recommend all adult and adolescent patients presenting with HIV infection undergo testing for hepatitis C, with continued annual screening advised for those persons considered high risk for acquiring hepatitis C. Additionally, perform hepatitis C virus (HCV) screening in any child whose mother is known to have HCV infection. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. For most patients, the benefits of concurrent therapy outweighs the potential risks (i.e., drug-induced hepatic injury, complex drug interactions, overlapping toxicities); therefore, it is recommended to initiate a fully suppressive antiretroviral (ARV) therapy and a hepatitis C regimen in all coinfected patients regardless of CD4 count. However, for antiretroviral naive adult and adolescent patients with CD4 counts greater than 500 cells/mm3, consideration may be given to deferring ARV until the hepatitis C treatment regimen has been completed. Conversely, for patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on fully suppressive ARV regimen. Treatment of HCV infection in children younger than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older with hepatitis C and HIV coinfection who have no contraindications to treatment. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.

    Use with ribavirin

    In certain patient populations, ledipasvir; sofosbuvir is recommended for use with ribavirin. If use with ribavirin is being considered, carefully evaluate the patient to ensure no contraindications to treatment; all contraindications that apply to ribavirin also apply to the combination regimen of ledipasvir; sofosbuvir and ribavirin.

    Hepatitis B exacerbation

    Use of direct-acting antivirals (DAA), such as ledipasvir and sofosbuvir, to treat hepatitis C virus (HCV) infections in patients currently or previously infected with hepatitis B virus (HBV) has been associated with reactivation and exacerbation of the HBV infection. Hepatitis B reactivation has also occurred in patients receiving certain immunosuppressive or chemotherapeutic medications; the risk of HBV reactivation associated with DAA treatment may be increased in these patients. To decrease the risk of reactivating a HBV infection, screen all potential drug recipients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc). For those patients whose screening reveals serologic evidence of HBV infection, a baseline HBV DNA concentration should be obtained prior to starting ledipasvir; sofosbuvir. Continue to monitor coinfected patients during and after treatment for clinical and laboratory signs of hepatitis B exacerbation (i.e., HBsAg, HBV DNA, hepatic enzymes, bilirubin). In addition, instruct patients to immediately report any signs of liver toxicity (e.g., yellow eyes or skin, fatigue, weakness, loss of appetite, nausea, vomiting, or light-colored stools) to their health care provider. If a ledipasvir; sofosbuvir recipient develops signs of HBV reactivation, initiate appropriate treatment for HBV infection or consult a physician with expertise in the management of hepatitis infections. The FDA has identified and confirmed 24 cases of hepatitis B exacerbation (including fulminant hepatitis, hepatic failure requiring liver transplant n = 1, and death n = 2) in coinfected patients treated with a DAA-based HCV regimen between November 2013 and July 2016. The exact mechanism is unknown; however, a commonly reported sequence of events included initiation of a DAA-based HCV regimen, rapid drop in HCV RNA to undetectable levels within 1 to 2 weeks of liver enzyme normalization, followed by a rise in HBV DNA (with or without increased transaminases) between treatment weeks 4 and 8. Of the 24 reported cases: 8 discontinued the DAA when transaminases began to rise; 12 received HBV treatment with tenofovir or entecavir; 6 did not receive HBV treatment; and 6 did not report whether HBV treatment was used.

    Anticoagulant therapy

    Caution is advised when prescribing ledipasvir; sofosbuvir to patients receiving concurrent anticoagulant therapy, specifically warfarin. Fluctuations in International Normalized Ratio (INR) have been observed in warfarin recipients who were also receiving treatment for hepatitis C virus (HCV) infections. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen.

    ADVERSE REACTIONS

    Severe

    suicidal ideation / Delayed / 0-1.0
    angioedema / Rapid / Incidence not known

    Moderate

    dyspnea / Early / 3.0-9.0
    depression / Delayed / 0-5.0
    hyperbilirubinemia / Delayed / 0-3.0

    Mild

    asthenia / Delayed / 18.0-36.0
    headache / Early / 11.0-29.0
    fatigue / Early / 4.0-18.0
    cough / Delayed / 5.0-11.0
    nausea / Early / 6.0-9.0
    myalgia / Early / 4.0-9.0
    irritability / Delayed / 7.0-8.0
    diarrhea / Early / 3.0-7.0
    insomnia / Early / 3.0-6.0
    dizziness / Early / 1.0-5.0
    rash (unspecified) / Early / Incidence not known

    DRUG INTERACTIONS

    Afatinib: (Moderate) If the concomitant use of ledipasvir; sofosbuvir and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of ledipasvir; sofosbuvir. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and ledipasvir is a weak P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Aluminum Hydroxide: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
    Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
    Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
    Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
    Amiodarone: (Major) Coadministration of amiodarone with sofosbuvir is not recommended due to the potential for serious symptomatic bradycardia. Cases of symptomatic bradycardia, including cases requiring pacemaker intervention, have been reported with the concurrent use of amiodarone with sofosbuvir-containing regimens; additionally, a fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir; sofosbuvir). The mechanism of this effect is unknown. If coadministration is required, cardiac monitoring in an inpatient 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. Due to the long half-life of amiodarone, patients discontinuing amiodarone just prior to starting sofosbuvir should also undergo similar cardiac monitoring as outlined above.
    Amlodipine; Atorvastatin: (Moderate) Caution and close monitoring of adverse reactions, such as myopathy and rhabdomyolysis, is advised with concomitant administration of atorvastatin and ledipasvir; sofosbuvir. Concurrent use may result in increased atorvastatin exposure. Atorvastatin is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
    Antacids: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
    Aspirin, ASA; Omeprazole: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
    Atazanavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Cobicistat is an inhibitor of the transporters P-glycoprotein and breast cancer resistance protein (BCRP). Both ledipasvir and sofosbuvir are substrates of P-gp and BCRP. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp or BCRP inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect (Moderate) Caution is warranted when cobicistat is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp or BCRP inhibitors.
    Atorvastatin: (Moderate) Caution and close monitoring of adverse reactions, such as myopathy and rhabdomyolysis, is advised with concomitant administration of atorvastatin and ledipasvir; sofosbuvir. Concurrent use may result in increased atorvastatin exposure. Atorvastatin is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor.
    Atorvastatin; Ezetimibe: (Moderate) Caution and close monitoring of adverse reactions, such as myopathy and rhabdomyolysis, is advised with concomitant administration of atorvastatin and ledipasvir; sofosbuvir. Concurrent use may result in increased atorvastatin exposure. Atorvastatin is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of ledipasvir with phenobarbital. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as phenobarbital. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Azithromycin: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of azithromycin and ledipasvir; sofosbuvir. Both ledipasvir and azithromycin are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of ledipasvir with phenobarbital. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as phenobarbital. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Boceprevir: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of boceprevir and ledipasvir; sofosbuvir. Both ledipasvir and boceprevir are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Budesonide: (Minor) Caution and close monitoring of budesonide-associated adverse reactions is advised with concomitant administration of ledipasvir. Budesonide is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase budesonide plasma concentrations.
    Budesonide; Formoterol: (Minor) Caution and close monitoring of budesonide-associated adverse reactions is advised with concomitant administration of ledipasvir. Budesonide is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase budesonide plasma concentrations.
    Cabozantinib: (Moderate) Monitor for an increase in ledipasvir; sofosbuvir-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of ledipasvir and sofosbuvir may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and both ledipasvir and sofosbuvir are substrates of P-gp; the clinical relevance of this finding is unknown.
    Calcium Carbonate: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
    Calcium Carbonate; Magnesium Hydroxide: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
    Calcium Carbonate; Risedronate: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
    Calcium; Vitamin D: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
    Canagliflozin: (Moderate) Caution and close monitoring of adverse reactions and changes in glycemic control is advised with concomitant administration of canagliflozin and ledipasvir; sofosbuvir. Both ledipasvir and canagliflozin are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Canagliflozin; Metformin: (Moderate) Caution and close monitoring of adverse reactions and changes in glycemic control is advised with concomitant administration of canagliflozin and ledipasvir; sofosbuvir. Both ledipasvir and canagliflozin are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Carbamazepine: (Major) Avoid coadministration of ledipasvir with carbamazepine. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as carbamazepine. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Carvedilol: (Moderate) Concurrent administration of ledipasvir; sofosbuvir and carvedilol may result in elevated plasma concentrations of ledipasvir, sofosbuvir, and carvedilol. All three are substrates for the drug transporter, P-glycoprotein (P-gp), while both ledipasvir and carvedilol are also P-gp inhibitors. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect. For carvediolol, monitor heart rate and blood pressure as per standards of care (Minor) Coadministration of sofosbuvir and carvedilol may result in elevated sofosbuvir plasma concentrations. Sofosbuvir is a substrate for the drug transporter P-glycoprotein (P-gp); carvedilol is a P-gp inhibitor. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect.
    Cimetidine: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with H2-blockers may result in lower ledipasvir plasma concentrations. Ledipasvir; sofosbuvir can be administered with H2-blockers if given simultaneously or separated by 12 hours. The H2-blocker dose should not exceed a dose that is comparable to famotidine 40 mg twice daily.
    Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Cobicistat is an inhibitor of the transporters P-glycoprotein and breast cancer resistance protein (BCRP). Both ledipasvir and sofosbuvir are substrates of P-gp and BCRP. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp or BCRP inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect (Moderate) Caution is warranted when cobicistat is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp or BCRP inhibitors.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Cobicistat is an inhibitor of the transporters P-glycoprotein and breast cancer resistance protein (BCRP). Both ledipasvir and sofosbuvir are substrates of P-gp and BCRP. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp or BCRP inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect (Moderate) Caution is warranted when cobicistat is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp or BCRP inhibitors.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Cobicistat is an inhibitor of the transporters P-glycoprotein and breast cancer resistance protein (BCRP). Both ledipasvir and sofosbuvir are substrates of P-gp and BCRP. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp or BCRP inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect (Moderate) Caution is warranted when cobicistat is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp or BCRP inhibitors. (Moderate) Closely monitor for tenofovir-associated adverse reactions if ledipasvir is administered with tenofovir disoproxil fumarate. In addition, because safety has not been established, avoid use of ledipasvir in combination with HIV regimens that contain tenofovir disoproxil fumarate and HIV protease inhibitors boosted with ritonavir. Consider use of tenofovir alafenamide in place of tenofovir disoproxil fumarate. If coadministration is deemed necessary, closely monitor for tenofovir adverse effects. Plasma concentrations of tenofovir may increase when administered with ledipasvir. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); ledipasvir is an inhibitor of both P-gp and BCRP.
    Cobimetinib: (Minor) If concurrent use of cobimetinib and ledipasvir; sofosbuvir is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and ledipasvir is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
    Colchicine: (Major) Coadministration of colchicine and ledipasvir should be avoided due to the potential for serious and life-threatening toxicity. Colchicine is a substrate of P-glycoprotein (P-gp) and ledipsavir is an inhibitor of P-gp; increased concentrations of colchicine are expected with concurrent use. Colchicine accumulation may be greater in patients with renal or hepatic impairment; therefore the manufacturer of Colcrys contraindicates the use of colchicine and P-gp inhibitors in this population. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine either by reducing the daily dose or reducing the dose frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations for coadministration with P-gp inhibitors are provided by the manufacturer of Colcrys.
    Conivaptan: (Moderate) Caution is warranted when conivaptan is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Conivaptan is P-glycoprotein (P-gp) inhibitor. Both ledipasvir and sofosbuvir are substrates of P-gp. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. (Moderate) Caution is warranted when conivaptan is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Conivaptan is P-glycoprotein (P-gp) inhibitor. Sofosbuvir is a substrate of P-gp. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects.
    Cyclosporine: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of cyclosporine and ledipasvir. Both ledipasvir and cyclosporine are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). In addition, cyclosporine is a breast cancer resistance protein (BCRP) inhibitor; ledipasivr is a BCRP substrate. Taking these drugs together may increase plasma concentrations of both drugs. According to the manufacturer, no significant interactions were observed when these medications were administered concurrently during drug interaction studies.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with ledipasvir; sofosbuvir. Ledipasvir is a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like ledipasvir; sofosbuvir in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with ledipasvir; sofosbuvir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Cobicistat is an inhibitor of the transporters P-glycoprotein and breast cancer resistance protein (BCRP). Both ledipasvir and sofosbuvir are substrates of P-gp and BCRP. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp or BCRP inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect (Moderate) Caution is warranted when cobicistat is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp or BCRP inhibitors.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Caution is warranted when ritonavir is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Ritonavir is an inhibitor of the transporter P-glycoprotein (P-gp). Both ledipasvir and sofosbuvir are substrates of P-gp. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. (Moderate) Caution is warranted when ritonavir is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Ritonvir is an inhibitor of the transporter P-glycoprotein (P-gp). Sofosbuvir is a substrate of P-gp. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. (Moderate) Concurrent administration of ledipasvir; sofosbuvir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of ledipasvir, sofosbuvir, dasabuvir, ombitasvir, paritaprevir and ritonavir. Ledipasvir is an inhibitor of the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. In addition, ritonavir is an inhibitor of the breast cancer resistance protein (BCRP); ledipasvir, dasabuvir and paritaprevir are substrates/inhibitors of BCRP, while sofosbuvir is a BCRP substrate. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of sofosbuvir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of sofosbuvir. Ritonavir is an inhibitor of the breast cancer resistance protein (BCRP); dasabuvir and paritaprevir are substrates/inhibitors of BCRP, while sofosbuvir is a BCRP substrate. Caution and close monitoring are advised if these drugs are administered together (Moderate) Concurrent administration of sofosbuvir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of sofosbuvir. Ritonavir is an inhibitor of the breast cancer resistance protein (BCRP); dasabuvir and paritaprevir are substrates/inhibitors of BCRP, while sofosbuvir is a BCRP substrate. Caution and close monitoring are advised if these drugs are administered together.
    Daunorubicin: (Moderate) Caution and close monitoring of daunorubicin-associated adverse reactions is advised with concomitant administration of ledipasvir. Daunorubicin is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase daunorubicin plasma concentrations.
    Desloratadine: (Minor) Caution and close monitoring of desloratadine-associated adverse reactions is advised with concomitant administration of ledipasvir. Desloratadine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase desloratadine plasma concentrations.
    Desloratadine; Pseudoephedrine: (Minor) Caution and close monitoring of desloratadine-associated adverse reactions is advised with concomitant administration of ledipasvir. Desloratadine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase desloratadine plasma concentrations.
    Dexamethasone: (Moderate) Caution and close monitoring of dexamethasone-associated adverse reactions is advised with concomitant administration of ledipasvir. Dexamethasone is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase dexamethasone plasma concentrations.
    Dexlansoprazole: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
    Dextromethorphan; Quinidine: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of quinidine and ledipasvir; sofosbuvir. Both ledipasvir and quinidine are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Digoxin: (Moderate) Caution and close monitoing of digoxin therapeutic concentrations is advised when administering digoxin with ledipasvir. Digoxin is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase digoxin plasma concentrations.
    Diltiazem: (Moderate) Caution and close monitoring of associated adverse reactions is advised with concomitant administration of diltiazem and ledipasvir; sofosbuvir. Both ledipasvir and diltiazem are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Docetaxel: (Minor) Caution and close monitoring of docetaxel-associated adverse reactions is advised with concomitant administration of ledipasvir. Docetaxel is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase docetaxel plasma concentrations.
    Doxorubicin: (Moderate) Ledipsavir is a P-glycoprotein (P-gp) inhibitor and doxorubicin is a major P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of ledipsavir and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Closely monitor for tenofovir-associated adverse reactions if ledipasvir is administered with tenofovir disoproxil fumarate. In addition, because safety has not been established, avoid use of ledipasvir in combination with HIV regimens that contain tenofovir disoproxil fumarate and HIV protease inhibitors boosted with ritonavir. Consider use of tenofovir alafenamide in place of tenofovir disoproxil fumarate. If coadministration is deemed necessary, closely monitor for tenofovir adverse effects. Plasma concentrations of tenofovir may increase when administered with ledipasvir. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); ledipasvir is an inhibitor of both P-gp and BCRP.
    Elbasvir; Grazoprevir: (Major) Administering ledipasvir with elbasvir may result in elevated ledipasvir plasma concentrations. Ledipasvir is a substrate for the breast cancer resistance protein (BCRP); elbasvir is a BCRP inhibitor. (Major) Administering ledipasvir with grazoprevir may result in elevated ledipasvir plasma concentrations. Ledipasvir is a substrate for the breast cancer resistance protein (BCRP);grazoprevir is a BCRP inhibitor.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Closely monitor for tenofovir-associated adverse reactions if ledipasvir is administered with tenofovir disoproxil fumarate. In addition, because safety has not been established, avoid use of ledipasvir in combination with HIV regimens that contain tenofovir disoproxil fumarate and HIV protease inhibitors boosted with ritonavir. Consider use of tenofovir alafenamide in place of tenofovir disoproxil fumarate. If coadministration is deemed necessary, closely monitor for tenofovir adverse effects. Plasma concentrations of tenofovir may increase when administered with ledipasvir. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); ledipasvir is an inhibitor of both P-gp and BCRP.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Closely monitor for tenofovir-associated adverse reactions if ledipasvir is administered with tenofovir disoproxil fumarate. In addition, because safety has not been established, avoid use of ledipasvir in combination with HIV regimens that contain tenofovir disoproxil fumarate and HIV protease inhibitors boosted with ritonavir. Consider use of tenofovir alafenamide in place of tenofovir disoproxil fumarate. If coadministration is deemed necessary, closely monitor for tenofovir adverse effects. Plasma concentrations of tenofovir may increase when administered with ledipasvir. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); ledipasvir is an inhibitor of both P-gp and BCRP.
    Erythromycin: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of erythromycin and ledipasvir; sofosbuvir. Both ledipasvir and erythromycin are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Erythromycin; Sulfisoxazole: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of erythromycin and ledipasvir; sofosbuvir. Both ledipasvir and erythromycin are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Esomeprazole: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
    Esomeprazole; Naproxen: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
    Etoposide, VP-16: (Minor) Caution and close monitoring of etoposide, VP-16-associated adverse reactions is advised with concomitant administration of ledipasvir. Etoposide is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase etoposide plasma concentrations.
    Ezetimibe; Simvastatin: (Moderate) Caution and close monitoring of adverse reactions, such as myopathy and rhabdomyolysis, is advised with concomitant administration of simvastatin and ledipasvir; sofosbuvir. Both ledipasvir and simvastatin are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Famotidine: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with H2-blockers may result in lower ledipasvir plasma concentrations. Ledipasvir; sofosbuvir can be administered with H2-blockers if given simultaneously or separated by 12 hours. The H2-blocker dose should not exceed a dose that is comparable to famotidine 40 mg twice daily.
    Famotidine; Ibuprofen: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with H2-blockers may result in lower ledipasvir plasma concentrations. Ledipasvir; sofosbuvir can be administered with H2-blockers if given simultaneously or separated by 12 hours. The H2-blocker dose should not exceed a dose that is comparable to famotidine 40 mg twice daily.
    Fentanyl: (Moderate) Caution and close monitoring of fentanyl-associated adverse reactions is advised with concomitant administration of ledipasvir. Fentanyl is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase fentanyl plasma concentrations.
    Fexofenadine: (Minor) Caution and close monitoring of fexofenadine-associated adverse reactions is advised with concomitant administration of ledipasvir. Fexofenadine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase fexofenadine plasma concentrations.
    Fexofenadine; Pseudoephedrine: (Minor) Caution and close monitoring of fexofenadine-associated adverse reactions is advised with concomitant administration of ledipasvir. Fexofenadine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase fexofenadine plasma concentrations.
    Fosamprenavir: (Moderate) Caution is advised when administering sofosbuvir with fosamprenavir, as concurrent use may result in reduced sofosbuvir plasma concentrations. Sofosbuvir is a substrate for the drug transporter P-glycoprotein (P-gp). Amprenavir, the active metabolite of fosamprenavir, is a P-gp inducer.
    Fosphenytoin: (Major) Avoid coadministration of ledipasvir with fosphenytoin. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with fosphenytoin. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and ledipasvir as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Glecaprevir and ledipasvir are both substrates and inhibitors of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). (Moderate) Caution is advised with the coadministration of pibrentasvir and ledipasvir as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Pibrentasvir and ledipasvir are both substrates and inhibitors of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).
    Glyburide: (Moderate) Caution and close monitoring of glyburide-associated adverse reactions is advised with concomitant administration of ledipasvir. Glyburide is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase glyburide plasma concentrations.
    Glyburide; Metformin: (Moderate) Caution and close monitoring of glyburide-associated adverse reactions is advised with concomitant administration of ledipasvir. Glyburide is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase glyburide plasma concentrations.
    H2-blockers: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with H2-blockers may result in lower ledipasvir plasma concentrations. Ledipasvir; sofosbuvir can be administered with H2-blockers if given simultaneously or separated by 12 hours. The H2-blocker dose should not exceed a dose that is comparable to famotidine 40 mg twice daily.
    Imatinib: (Moderate) Caution and close monitoring of imatinib, STI-571-associated adverse reactions is advised with concomitant administration of ledipasvir. Imatinib is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase imatinib plasma concentrations.
    Irinotecan: (Moderate) Caution and close monitoring of irinotecan-associated adverse reactions is advised with concomitant administration of ledipasvir. Irinotecan is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase irinotecan plasma concentrations.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of ledipasvir with potent inducers of intestinal P-glycoprotein (P-gp), such as rifampin. Taking these drugs together may significantly decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir, a P-glycoprotein (P-gp) substrate, with inducers of P-gp, such as rifampin. Taking these drugs together may significantly decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. In a single-dose study, coadministration reduced the sofosbuvir Cmax and AUC to 23% and 28% of normal concentrations, respectively.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of ledipasvir with potent inducers of intestinal P-glycoprotein (P-gp), such as rifampin. Taking these drugs together may significantly decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir, a P-glycoprotein (P-gp) substrate, with inducers of P-gp, such as rifampin. Taking these drugs together may significantly decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. In a single-dose study, coadministration reduced the sofosbuvir Cmax and AUC to 23% and 28% of normal concentrations, respectively.
    Lansoprazole: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
    Lansoprazole; Naproxen: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
    Lapatinib: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of lapatinib and ledipasvir; sofosbuvir. Lapatinib is an inhibitor of the drug transporter P-glycoprotein (P-gp) and a substrate of breast cancer resistance protein (BCRP). Ledipasvir is a P-gp and BCRP inhibitor and substrate; sofosbuvir is a substrate of P-gp and BCRP. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Loperamide: (Moderate) The plasma concentration of loperamide may be increased when administered concurrently with ledipasvir; sofosbuvir. Loperamide is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide may be increased when administered concurrently with ledipasvir; sofosbuvir. Loperamide is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Moderate) Caution is warranted when lopinavir; ritonavir is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Lopinavir; ritonvir is an inhibitor of the transporter P-glycoprotein (P-gp). Both ledipasvir and sofosbuvir are substrates of P-gp. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect. (Moderate) Caution is warranted when lopinavir; ritonavir is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Lopinavir; ritonvir is an inhibitor of the transporter P-glycoprotein (P-gp). Sofosbuvir is a substrate of P-gp. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. (Moderate) Caution is warranted when ritonavir is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Ritonavir is an inhibitor of the transporter P-glycoprotein (P-gp). Both ledipasvir and sofosbuvir are substrates of P-gp. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. (Moderate) Caution is warranted when ritonavir is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Ritonvir is an inhibitor of the transporter P-glycoprotein (P-gp). Sofosbuvir is a substrate of P-gp. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects.
    Loratadine: (Minor) Caution and close monitoring of loratadine-associated adverse reactions is advised with concomitant administration of ledipasvir. Loratadine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase loratadine plasma concentrations.
    Loratadine; Pseudoephedrine: (Minor) Caution and close monitoring of loratadine-associated adverse reactions is advised with concomitant administration of ledipasvir. Loratadine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase loratadine plasma concentrations.
    Lovastatin: (Moderate) Caution and close monitoring of adverse reactions, such as myopathy and rhabdomyolysis, is advised with concomitant administration of lovastatin and ledipasvir; sofosbuvir. Both ledipasvir and lovastatin are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Lovastatin; Niacin: (Moderate) Caution and close monitoring of adverse reactions, such as myopathy and rhabdomyolysis, is advised with concomitant administration of lovastatin and ledipasvir; sofosbuvir. Both ledipasvir and lovastatin are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Lumacaftor; Ivacaftor: (Minor) Although the clinical significance of this interaction is unknown, concurrent use of ledipasvir; sofosbuvir and lumacaftor; ivacaftor may alter ledipasvir; sofosbuvir exposure; avoid concurrent use. Both ledipasvir and sofosbuvir are substrates of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected. FDA-approved labeling for ledipasvir; sofosbuvir recommends to avoid coadministration with P-gp inducers. (Minor) Although the clinical significance of this interaction is unknown, concurrent use of sofosbuvir and lumacaftor; ivacaftor may alter sofosbuvir exposure; caution and close monitoring are advised if these drugs are used together. Sofosbuvir is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events. FDA-approved labeling for sofosbuvir recommends to avoid coadministration with potent P-gp inducers.
    Magnesium Hydroxide: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
    Maraviroc: (Minor) Use caution and closely monitor for increased adverse effects with the coadministration of maraviroc and ledipasvir as increased maraviroc concentrations may occur. Maraviroc is a substrate of P-glycoprotein (P-gp); ledipasvir is a weak inhibitor of P-gp. The effects of P-gp on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
    Mefloquine: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of mefloquine and ledipasvir; sofosbuvir. Both ledipasvir and mefloquine are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Methadone: (Moderate) Caution and close monitoring of methadone-associated adverse reactions is advised with concomitant administration of ledipasvir. Methadone is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase methadone plasma concentrations.
    Mirabegron: (Moderate) Caution and close monitoring of mirabegron-associated adverse reactions is advised with concomitant administration of ledipasvir. Mirabegron is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase mirabegron plasma concentrations.
    Mitomycin: (Moderate) Caution and close monitoring of mitomycin-associated adverse reactions is advised with concomitant administration of ledipasvir. Mitomycin is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase mitomycin plasma concentrations.
    Morphine: (Moderate) Caution and close monitoring of morphine-associated adverse reactions is advised with concomitant administration of ledipasvir. Morphine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase morphine plasma concentrations.
    Morphine; Naltrexone: (Moderate) Caution and close monitoring of morphine-associated adverse reactions is advised with concomitant administration of ledipasvir. Morphine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase morphine plasma concentrations.
    Niacin; Simvastatin: (Moderate) Caution and close monitoring of adverse reactions, such as myopathy and rhabdomyolysis, is advised with concomitant administration of simvastatin and ledipasvir; sofosbuvir. Both ledipasvir and simvastatin are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Nilotinib: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of nilotinib and ledipasvir; sofosbuvir. Both ledipasvir and nilotinib are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Nintedanib: (Moderate) Ledipasvir is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of ledipasvir; sofosbuvir and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Nizatidine: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with H2-blockers may result in lower ledipasvir plasma concentrations. Ledipasvir; sofosbuvir can be administered with H2-blockers if given simultaneously or separated by 12 hours. The H2-blocker dose should not exceed a dose that is comparable to famotidine 40 mg twice daily.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Caution is warranted when ritonavir is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Ritonavir is an inhibitor of the transporter P-glycoprotein (P-gp). Both ledipasvir and sofosbuvir are substrates of P-gp. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. (Moderate) Caution is warranted when ritonavir is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Ritonvir is an inhibitor of the transporter P-glycoprotein (P-gp). Sofosbuvir is a substrate of P-gp. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. (Moderate) Concurrent administration of ledipasvir; sofosbuvir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of ledipasvir, sofosbuvir, dasabuvir, ombitasvir, paritaprevir and ritonavir. Ledipasvir is an inhibitor of the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. In addition, ritonavir is an inhibitor of the breast cancer resistance protein (BCRP); ledipasvir, dasabuvir and paritaprevir are substrates/inhibitors of BCRP, while sofosbuvir is a BCRP substrate. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of sofosbuvir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of sofosbuvir. Ritonavir is an inhibitor of the breast cancer resistance protein (BCRP); dasabuvir and paritaprevir are substrates/inhibitors of BCRP, while sofosbuvir is a BCRP substrate. Caution and close monitoring are advised if these drugs are administered together.
    Omeprazole: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
    Omeprazole; Sodium Bicarbonate: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day. (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
    Ondansetron: (Moderate) Caution and close monitoring of ondansetron-associated adverse reactions is advised with concomitant administration of ledipasvir. Ondansetron is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase ondansetron plasma concentrations.
    Oxcarbazepine: (Major) Avoid coadministration of ledipasvir with oxcarbazepine. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with oxcarbazepine. Taking these drugs together may decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy.
    Paclitaxel: (Minor) Caution and close monitoring of paclitaxel-associated adverse reactions is advised with concomitant administration of ledipasvir. Paclitaxel is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase paclitaxel plasma concentrations.
    Pantoprazole: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
    Pazopanib: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of pazopanib and ledipasvir; sofosbuvir. Both ledipasvir and pazopanib are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp) ; sofosbuvir is a P-gp substrate. In addition pazopanib and sofosbuvir are substrates of and breast cancer resistance protein (BCRP); ledipasvir is an inhibitor and substrate of BCRP. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Phenobarbital: (Major) Avoid coadministration of ledipasvir with phenobarbital. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as phenobarbital. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Phenytoin: (Major) Avoid coadministration of ledipasvir with phenytoin. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as phenytoin. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Posaconazole: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of posaconazole and ledipasvir; sofosbuvir. Both ledipasvir and posaconazole are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Prednisone: (Moderate) Caution and close monitoring of prednisone-associated adverse reactions is advised with concomitant administration of ledipasvir. Prednisone is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase prednisone plasma concentrations.
    Primidone: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein, such as primidone. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Proton pump inhibitors: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
    Quinidine: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of quinidine and ledipasvir; sofosbuvir. Both ledipasvir and quinidine are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Quinine: (Moderate) Caution and close monitoring of quinine-associated adverse reactions is advised with concomitant administration of ledipasvir. Quinine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase quinine plasma concentrations.
    Rabeprazole: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
    Ranitidine: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with H2-blockers may result in lower ledipasvir plasma concentrations. Ledipasvir; sofosbuvir can be administered with H2-blockers if given simultaneously or separated by 12 hours. The H2-blocker dose should not exceed a dose that is comparable to famotidine 40 mg twice daily.
    Ranolazine: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of ranolazine and ledipasvir; sofosbuvir. Both ledipasvir and ranolazine are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Regorafenib: (Moderate) Use caution if coadministration of regorafenib with ledipasvir is necessary, and monitor for an increase in ledipasvir-related adverse reactions. Ledipasvir is a BCRP substrate, and regorafenib is a BCRP inhibitor. Administration of regorafenib for 14 days prior to a single dose of rosuvastatin, another BCRP substrate, increased the mean AUC and Cmax of rosuvastatin by 3.8-fold and a 4.6-fold, respectively. Concomitant use may increase exposure to ledipasvir. (Moderate) Use caution if coadministration of regorafenib with sofosbuvir is necessary, and monitor for an increase in sofosbuvir-related adverse reactions. Sofosbuvir is a BCRP substrate, and regorafenib is a BCRP inhibitor. Administration of regorafenib for 14 days prior to a single dose of rosuvastatin, another BCRP substrate, increased the mean AUC and Cmax of rosuvastatin by 3.8-fold and a 4.6-fold, respectively. Concomitant use may increase exposure to sofosbuvir.
    Rifabutin: (Major) Avoid coadministration of ledipasvir with rifabutin. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with rifabutin. Taking these drugs together may decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy.
    Rifampin: (Major) Avoid coadministration of ledipasvir with potent inducers of intestinal P-glycoprotein (P-gp), such as rifampin. Taking these drugs together may significantly decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir, a P-glycoprotein (P-gp) substrate, with inducers of P-gp, such as rifampin. Taking these drugs together may significantly decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. In a single-dose study, coadministration reduced the sofosbuvir Cmax and AUC to 23% and 28% of normal concentrations, respectively.
    Rifapentine: (Major) Avoid coadministration of ledipasvir with rifapentine. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with rifapentine. Taking these drugs together may decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy.
    Rifaximin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and ledipsavir, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Risperidone: (Moderate) Caution and close monitoring of risperidone-associated adverse reactions is advised with concomitant administration of ledipasvir. Risperidone is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase risperidone plasma concentrations.
    Ritonavir: (Moderate) Caution is warranted when ritonavir is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Ritonavir is an inhibitor of the transporter P-glycoprotein (P-gp). Both ledipasvir and sofosbuvir are substrates of P-gp. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. (Moderate) Caution is warranted when ritonavir is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Ritonvir is an inhibitor of the transporter P-glycoprotein (P-gp). Sofosbuvir is a substrate of P-gp. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects.
    Rivaroxaban: (Moderate) Coadministration of rivaroxaban and ledipasvir may result in increases in rivaroxaban exposure and may increase bleeding risk. Ledipasviris an inhibitor of P-glycoprotein (P-gp) and rivaroxaban is a substrate of P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Rolapitant: (Moderate) Use caution if ledipasvir; sofosbuvir and rolapitant are used concurrently, and monitor for ledipasvir- or sofosbuvir-related adverse effects. Ledipasvir and sofosbuvir are both substrates of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied. (Moderate) Use caution if sofosbuvir and rolapitant are used concurrently, and monitor for sofosbuvir-related adverse effects. Sofosbuvir is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
    Rosuvastatin: (Major) Avoid coadministration of ledipasvir with rosuvastatin. Taking these drugs together may significantly increase rosuvastatin plasma concentrations, potentially resulting in myopathy and rhabdomyolysis. Rosuvastatin is a substrate of the breast cancer resistance protein (BCRP); ledipasvir is a BCRP inhibitor.
    Sapropterin: (Moderate) Caution is advised with concomitant use of sapropterin and ledipasvir as coadministration may result in increased systemic exposure of ledipasvir. Ledipasvir is a substrate for the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); in vitro data show that sapropterin may inhibit these transporters. If these drugs are used together, closely monitor for increased side effects of ledipasvir. (Moderate) Caution is advised with the concomitant use of sapropterin and sofosbuvir as coadministration may result in increased systemic exposure of sofosbuvir. Sofosbuvir is a substrate for the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); in vitro data show that sapropterin may inhibit these transporters. If these drugs are used together, closely monitor for increased side effects of sofosbuvir.
    Silodosin: (Moderate) Caution and close monitoring of silodosin-associated adverse reactions is advised with concomitant administration of ledipasvir. Silodosin is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase silodosin plasma concentrations.
    Simeprevir: (Major) Avoid coadministration of ledipasvir with simeprevir. Taking these drugs together increases ledipasvir exposure by 92% and simeprevir exposure by 116%. Use of these drugs together increases the risk for adverse effects. (Major) Avoid coadministration of sofosbuvir with simeprevir, a P-glycoprotein (P-gp) inhibitor. Taking these drugs together may increase sofosbuvir plasma concentrations, potentially resulting in adverse effects.
    Simvastatin: (Moderate) Caution and close monitoring of adverse reactions, such as myopathy and rhabdomyolysis, is advised with concomitant administration of simvastatin and ledipasvir; sofosbuvir. Both ledipasvir and simvastatin are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Simvastatin; Sitagliptin: (Moderate) Caution and close monitoring of adverse reactions, such as myopathy and rhabdomyolysis, is advised with concomitant administration of simvastatin and ledipasvir; sofosbuvir. Both ledipasvir and simvastatin are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Sirolimus: (Major) Caution and close monitoring of sirolimus-associated adverse reactions is advised with concomitant administration of ledipasvir. Sirolimus is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase sirolimus plasma concentrations. Monitor sirolimus serum concentrations carefully if these drugs need to be coadministered.
    Sodium Bicarbonate: (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
    Sofosbuvir; Velpatasvir: (Severe) Taking these drugs together is a duplication of therapy, and may result in adverse effects.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Severe) Taking these drugs together is a duplication of therapy, and may result in adverse effects. (Major) Avoid concurrent administration of voxilaprevir with ledipasvir. Taking these medications together may increase ledipasvir plasma concentrations, potentially increasing the risk for adverse events. Ledipasvir is a substrate for the drug transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Voxilaprevir is a P-gp and BCRP inhibitor.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of ledipasvir with potent inducers of intestinal P-glycoprotein (P-gp), such as St. John's Wort, Hypericum perforatum. Taking these drugs together may significantly decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir, a P-glycoprotein (P-gp) substrate with inducers of P-gp, such as St. John's Wort, Hypericum perforatum. Taking these drugs together may significantly decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy.
    Tedizolid: (Moderate) If possible, stop use of ledipasvir temporarily during treatment with oral tedizolid. If coadministration cannot be avoided, closely monitor for ledipasvir--associated adverse events. Ledipasvir plasma concentrations may be increased when ledipasvir is administered concurrently with oral tedizolid. Ledipasvir is a substrate of the Breast Cancer Resistance Protein (BCRP); oral tedizolid inhibits BCRP in the intestine. (Moderate) If possible, stop use of sofosbuvir temporarily during treatment with oral tedizolid. If coadministration cannot be avoided, closely monitor for sofosbuvir-associated adverse events. Sofosbuvir plasma concentrations may be increased when administered concurrently with oral tedizolid. Sofosbuvir is a substrate of the Breast Cancer Resistance Protein (BCRP); oral tedizolid inhibits BCRP in the intestine.
    Telotristat Ethyl: (Minor) Use caution if ledipasvir is coadministered with telotristat ethyl, and monitor for an increase in telotristat ethyl-related adverse reactions. Telotristat, the active metabolite of telotristat ethyl, is a substrate of P-glycoprotein (P-gp) and ledipasvir is a weak P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with ledipasvir is necessary, and monitor for an increase in temsirolimus- and ledipasvir-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) substrate / inhibitor in vitro and ledipasvir is also a P-gp substrate and weak inhibitor. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp inhibitors or substrates, but exposure to both ledipasvir and temsirolimus (and active metabolite, sirolimus) is likely to increase. (Minor) Use caution if coadministration of temsirolimus with sofosbuvir is necessary, and monitor for an increase in sofosbuvir-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) inhibitor in vitro, and sofosbuvir is a P-gp substrate. However, the FDA-labeling suggests that inhibitors of P-gp may be coadministered with sofosbuvir. In clinical trials, no clinically significant interaction was noted when sofosbuvir was administered with darunavir/ritonavir (both P-gp inhibitors) or cyclosporine (a P-gp and BCRP inhibitor). Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp substrates.
    Teniposide: (Major) Caution and close monitoring of teniposide-associated adverse reactions is advised with concomitant administration of ledipasvir. Teniposide is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase teniposide plasma concentrations.
    Tenofovir Alafenamide: (Minor) According to the manufacturer, interactions are not expected during coadministration of ledipasvir; sofosbuvir and tenofovir alafenamide; however based on the metabolic pathways of these medications, monitoring for tenofovir-associated adverse reactions should be considered if these drugs are given together. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); ledipasvir is an inhibitor of both P-gp and BCRP. Use of these drugs together may increase tenofovir plasma concentrations. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir, PMPA: (Moderate) Closely monitor for tenofovir-associated adverse reactions if ledipasvir is administered with tenofovir disoproxil fumarate. In addition, because safety has not been established, avoid use of ledipasvir in combination with HIV regimens that contain tenofovir disoproxil fumarate and HIV protease inhibitors boosted with ritonavir. Consider use of tenofovir alafenamide in place of tenofovir disoproxil fumarate. If coadministration is deemed necessary, closely monitor for tenofovir adverse effects. Plasma concentrations of tenofovir may increase when administered with ledipasvir. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); ledipasvir is an inhibitor of both P-gp and BCRP.
    Ticagrelor: (Moderate) Coadministration of ticagrelor and ledipasvir; sofosbuvir may result in increased exposure to all three drugs, which may increase the bleeding risk. Both ledipasvir and ticagrelor are P-glycoprotein (P-gp) substrates and inhibitors; sofosbuvir is a P-gp substrate. No dose adjustment is recommended by the manufacturer. Use combination with caution and monitor for evidence of bleeding.
    Tipranavir: (Major) Avoid coadministration of ledipasvir with tipranavir boosted with ritonavir. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as tipranavir. Taking these drugs together may significantly decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Sofosbuvir is a P-gp substrate. Tipranavir is a P-gp substrate, a weak P-gp inhibitor, and appears to be a potent P-gp inducer. The administration with ritonavir appears to result in a net P-gp induction at steady state, even though, when given alone, ritonavir is a P-gp inhibitor.
    Tolvaptan: (Major) Caution and close monitoring of adverse reactions is advised when administering tolvaptan with ledipasvir; sofosbuvir. Both ledipasvir and tolvaptan are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Topotecan: (Major) Avoid the concomitant use of ledipasvir, a P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) inhibitor, with oral topotecan, a P-gp and BCRP substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of ledipasvir and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea; this also applies to combination products containing ledipasvir, including ledipasvir; sofosbuvir. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant). When oral topotecan was administered concomitantly with escalating doses of a dual inhibitor of Breast Cancer Resistance Protein (BCRP) and P-gp, exposure to both total topotecan and topotecan lactone increased by approximately 2.5-fold compared with control.
    Vandetanib: (Moderate) Use caution if coadministration of vandetanib with ledipasvir is necessary, due to a possible increase in ledipasvir-related adverse reactions. Ledipasvir is a substrate of P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of digoxin, another P-gp substrate, by 29% and 23%, respectively. (Minor) Use caution if coadministration of vandetanib with sofosbuvir is necessary, due to a possible increase in sofosbuvir-related adverse reactions. Sofosbuvir is a substrate of P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of digoxin, another P-gp substrate, by 29% and 23%, respectively. In clinical trials, no clinically significant interaction was noted when sofosbuvir was administered with darunavir/ritonavir (P-gp inhibitors); according to the manufacturer, sofosbuvir may be coadministered with P-gp inhibitors.
    Vemurafenib: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of vemurafenib and ledipasvir; sofosbuvir. Both ledipasvir and vemurafenib are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and ledipasvir; sofosbuvir. Venetoclax is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) and may be a P-gp inhibitor at therapeutic dose levels in the gut; ledipasvir is an inhibitor of P-gp and BCRP and a P-gp substrate. Consider alternative agents. If concomitant use of these drugs is required, reduce the venetoclax dosage by at least 50% (maximum dose of 200 mg/day) and consider administering ledipasvir at least 6 hours before venetoclax. If ledipasvir is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were increased by 106% and 78%, respectively, when a P-gp inhibitor was co-administered in healthy subjects.
    Vinblastine: (Moderate) Caution and close monitoring of vinblastine-associated adverse reactions is advised with concomitant administration of ledipasvir. Vinblastine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase vinblastine plasma concentrations.
    Vincristine Liposomal: (Moderate) Caution and close monitoring of vincristine-associated adverse reactions is advised with concomitant administration of ledipasvir. Vincristine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase vincristine plasma concentrations.
    Vincristine: (Moderate) Caution and close monitoring of vincristine-associated adverse reactions is advised with concomitant administration of ledipasvir. Vincristine is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase vincristine plasma concentrations.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ledipasvir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates. (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and sofosbuvir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no well controlled studies evaluating the use of ledipasvir; sofosbuvir during human pregnancy. In animal studies involving rats and rabbits, no adverse effects on fetal development were observed with either ledipasvir or sofosbuvir. In certain patient populations, ledipasvir; sofosbuvir must be administered with ribavirin, which is contraindicated for use during pregnancy (FDA pregnancy risk category X) and in females who may become pregnant. Ribavirin may cause birth defects and death of the exposed fetus. Studies of ribavirin indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in all the animal species tested. To monitor maternal-fetal outcomes of pregnancies in female patients exposed to ribavirin during treatment and for 6 months following cessation of treatment, health care providers are encouraged to report any cases to the Ribavirin Pregnancy Registry; telephone (800) 593-2214. For patients who are also infected with HIV and taking concomitant antiretroviral agents, an Antiretroviral Pregnancy Registry is available at (800) 258-4263.

    It is unknown whether ledipasvir or sofosbuvir or their metabolites are excreted in human milk, affect milk production, or have an adverse effect on nursing infants. Simeprevir may be considered as an alternative; however, its excretion into human breast milk is also unknown. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Ledipasvir; sofosbuvir is active against chronic infections caused by genotypes 1, 4, 5, and 6 hepatitis C virus (HCV). Ledipasvir is an inhibitor of HCV NS5A protein. Sofosbuvir is a HCV nucleotide analog NS5B polymerase inhibitor.
    •Ledipasvir: Ledipasvir prevents hepatitis C viral replication by inhibiting the HCV NS5A protein. Although the exact mechanism is unknown, data suggest NS5A inhibitors may prevent replication by blocking viral hyperphosphorylation. It has been proposed that tight control of phosphorylation versus hyperphosphorylation is needed for efficient viral function.
    In cell cultures, HCV replicons with NS5A amino acid substitutions Y93H (genotype 1a and 1b) and Q30E (genotype 1a) displayed significant reductions in the susceptibility of the virus to ledipasvir (more than 1,000-fold change in EC50). In clinical trials, 37 patients were deemed virologic failures following treatment with ledipasvir; sofosbuvir. An analysis of these 37 patients found 55% (n = 16/29) of the genotype 1a failures and 88% (n = 7/8) of the genotype 1b failures had viruses with emergent NS5A resistance-associated substitutions. The most common substitutions for genotype 1a failures were Q30R, Y93H/N, and L31M; Y93H was the most common substitution detected in genotype 1b failures. A phenotypic analysis showed these substitutions resulted in a 20- to more than 243-fold reduction in susceptibility to ledipasvir; however, viruses with these substitutions remain susceptible to sofosbuvir. For genotypes 4, 5, and 6, resistance analyses were performed on 6 relapse patients. Of the 6 patients, 5 had pretreatment NS5A sequencing data that showed resistance-associated polymorphisms. For genotype 4, NS5A substitutions Y93C and L28V emerged in 2 patients. Cross resistance is not expected between ledipasvir and sofosbuvir, NS5B non-nucleoside inhibitors, nor NS3 protease inhibitors.
     
    •Sofosbuvir: Sofosbuvir is a nucleotide prodrug that prevents hepatitis C viral replication by inhibiting the activity of HCV NS5B RNA polymerase. It undergoes intracellular metabolism to form GS-461203, a pharmacologically active uridine analog triphosphate. Hepatitis C virus NS5B RNA polymerase incorporates this metabolite into the viral RNA, where it acts as a chain terminator. GS-461203 does not inhibit human DNA or RNA polymerase, nor does it block mitochondrial RNA polymerase.
     
    In cell cultures, recombinant NS5B polymerase expressing a S282T substitution displayed a 2- to 18-fold decrease in susceptibility to sofosbuvir in all genotypes tested. This substitution was detected in one patient with HCV genotype 1 who received ledipasvir; sofosbuvir for 8 weeks, and in 3 patients with genotypes 4, 5, and 6 (one in each genotype) who received treatment for 12 weeks. In addition, the genotype 5 patient also had the emergent nucleotide inhibitor substitution M289I. While sofosbuvir susceptibility is reduced with the S282T substitution, these viruses remain susceptible to ledipasvir. Cross resistance is not expected between sofosbuvir and ribavirin, NS3/4A protease inhibitors, NS5B non-nucleoside inhibitors, or NS5A inhibitors.

    PHARMACOKINETICS

    Ledipasvir; sofosbuvir is administered orally.
    Ledipasvir: Once in systemic circulation, more than 99.8% of the drug is bound to plasma protein. The mechanism by which ledipasvir is metabolized is unknown; however, evidence suggests it undergoes slow oxidative metabolism to form the metabolite M19. Elimination occurs primarily by biliary excretion, with approximately 70% of the administered dose excreted in the feces as the unchanged parent drug and 2.2% excreted as M19. Only 1% of the dose is eliminated via the kidneys. The mean terminal half-life is 47 hours.
    Sofosbuvir: Following administration, approximately 61% to 65% is bound to plasma protein. In the liver, sofosbuvir is converted from the nucleotide prodrug to the pharmacologically active nucleoside analog triphosphate, GS-461203. This conversion occurs via hydrolysis of the carboxy ester moiety by human cathepsin A (CatA) or carboxylesterase 1 (CES1), phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT 1), and phosphorylation by pyrimidine nucleotide biosynthesis pathway. GS-461203 is then further metabolized by dephosphorylation to form GS-331007, a metabolite that lacks anti-HCV activity and cannot be rephosphorylated. GS-331007 is the predominant circulating metabolite and represents more than 90% of drug related material, while the parent drug accounts for approximately 4%. Elimination occurs primarily through the kidneys with approximately 80% of the dose recovered in the urine (78% as GS-331007, 3.5% as sofosbuvir). Other routes of elimination include the feces (14%) and expired air (2.5%). The median terminal elimination half-lives of sofosbuvir and GS-331007 are 0.5 and 27 hours, respectively.
    Affected drug transporters: P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)
    Both ledipasvir and sofosbuvir are substrates of the drug transporters P-gp and BCRP. Ledipasvir is also an inhibitor of P-gp and BCRP. The major inactive metabolite of sofosbuvir, GS-331007, is neither a substrate nor inhibitor of P-gp or BCRP. FDA-labeling suggests that inhibitors of P-gp and BCRP may be coadministered with ledipasvir; sofosbuvir. In clinical trials, no clinically significant interaction was noted when ledipasvir; sofosbuvir was administered with darunavir/ritonavir (P-gp inhibitors) or cyclosporine (a P-gp and BCRP inhibitor).

    Oral Route

    Ledipasvir: Peak plasma concentrations are achieved within 4 to 4.5 hours following oral administration. Compared to healthy subjects, the geometric mean steady state concentrations (AUC) and the maximum plasma concentrations (Cmax) for ledipasvir are 24% and 32% lowered, respectively, in patients infected with hepatitis C. Food does not alter the pharmacokinetic parameters of ledipasvir.
    Sofosbuvir: Following oral administration, the time to reach maximum plasma concentrations (Tmax) is approximately 0.8 to 1 hours for the parent drug sofosbuvir and 3.5 to 4 hours for the major metabolite GS-331007. The geometric mean steady state concentrations (AUC) and the maximum plasma concentrations (Cmax) for sofosbuvir and GS-331007 in patients infected with hepatitis C are similar to those observed in healthy subjects. Administration of a single dose with a moderate fat (600 kcal, 25% to 30% fat) or high fat (1000 kcal, 50% fat) meal resulted in a 2-fold increase in the AUC of sofosbuvir; the Cmax remained unaffected. Food does not alter the pharmacokinetic parameters of GS-331007.