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    Other Anti-Hepatitis Drugs

    BOXED WARNING

    Hepatitis B exacerbation

    Use of direct-acting antivirals (DAA), such as daclatasvir, 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 daclatasvir. Continue to monitor coinfected patients during and after daclatasvir 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 daclatasvir 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

    Hepatitis C virus (HCV) NS5A inhibitor
    For use with sofosbuvir and with or without ribavirin to treat genotypes 1 and 3 chronic HCV infections
    Consider testing for NS5A resistance-associated polymorphisms prior to treating cirrhotic patients with HCV genotype 1a infections

    COMMON BRAND NAMES

    Daklinza

    HOW SUPPLIED

    Daklinza Oral Tab: 30mg, 60mg, 90mg

    DOSAGE & INDICATIONS

    For the treatment of chronic hepatitis C infection (HCV).
    NOTE: Daclatasvir must be administered in combination with sofosbuvir; certain patients may also require treatment with ribavirin. If sofosbuvir is permanently discontinued, daclatasvir must also be discontinued.
    For the treatment of chronic HCV genotype 1 infection.
    NOTE: Cirrhotic patients infected with HCV genotype 1a should undergo testing for the presence of NS5A resistance-associated polymorphisms prior to initiating therapy; specifically, polymorphisms at amino acid positions M28, Q30, L31, and Y93.
    NOTE: The optimal treatment duration has not been established for genotype 1 infected patients with decompensated (Child-Pugh C) cirrhosis.
    Oral dosage
    Adults without cirrhosis or who have compensated (Child-Pugh A) cirrhosis

    60 mg PO once daily in combination with sofosbuvir 400 mg PO once daily for 12 weeks. Dosing includes patients coinfected with HIV.

    Adults receiving strong CYP3A inhibitors who do not have cirrhosis or who have compensated (Child-Pugh A) cirrhosis

    30 mg PO once daily in combination with sofosbuvir 400 mg PO once daily for 12 weeks. Dosing includes patients coinfected with HIV.

    Adults receiving moderate CYP3A inducers who do not have cirrhosis or who have compensated (Child-Pugh A) cirrhosis

    90 mg PO once daily in combination with sofosbuvir 400 mg PO once daily for 12 weeks. Dosing includes patients coinfected with HIV.

    Adults who have decompensated cirrhosis or who have undergone liver transplantation

    60 mg PO once daily in combination with sofosbuvir (400 mg PO once daily) and ribavirin (600 mg PO once daily) for 12 weeks. Ribavirin must be administered with food, and the dose may be increased to 1000 mg PO daily if tolerated; consider decreasing ribavirin dose for abnormal hemoglobin or creatinine clearance. Dosing includes patients coinfected with HIV.

    Adults receiving strong CYP3A inhibitors who have decompensated cirrhosis or who have undergone liver transplantation

    30 mg PO once daily in combination with sofosbuvir (400 mg PO once daily) and ribavirin (600 mg PO once daily) for 12 weeks. Ribavirin must be administered with food, and the dose may be increased to 1000 mg PO daily if tolerated; consider decreasing ribavirin dose for abnormal hemoglobin or creatinine clearance. Dosing includes patients coinfected with HIV.

    Adults receiving moderate CYP3A inducers who have decompensated cirrhosis or who have undergone liver transplantation

    90 mg PO once daily in combination with sofosbuvir (400 mg PO once daily) and ribavirin (600 mg PO once daily) for 12 weeks. Ribavirin must be administered with food, and the dose may be increased to 1000 mg PO daily if tolerated; consider decreasing ribavirin dose for abnormal hemoglobin or creatinine clearance. Dosing includes patients coinfected with HIV.

    For the treatment of chronic HCV genotype 3 infection.
    NOTE: The optimal treatment duration has not been established for genotype 3 infected patients with cirrhosis.
    Oral dosage
    Adults without cirrhosis

    60 mg PO once daily in combination with sofosbuvir 400 mg PO once daily for 12 weeks. Dosing includes patients coinfected with HIV.

    Adults without cirrhosis receiving strong CYP3A inhibitors

    30 mg PO once daily in combination with sofosbuvir 400 mg PO once daily for 12 weeks. Dosing includes patients coinfected with HIV.

    Adults without cirrhosis receiving moderate CYP3A inducers

    90 mg PO once daily in combination with sofosbuvir 400 mg PO once daily for 12 weeks. Dosing includes patients coinfected with HIV.

    Adults with compensated cirrhosis

    60 mg PO once daily in combination with sofosbuvir (400 mg PO once daily) and ribavirin for 12 weeks. Ribavirin must be administered with food in two 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. Dosing includes patients coinfected with HIV.

    Adults receiving strong CYP3A inhibitors who have compensated cirrhosis

    30 mg PO once daily in combination with sofosbuvir (400 mg PO once daily) and ribavirin for 12 weeks. Ribavirin must be administered with food in two 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. Dosing includes patients coinfected with HIV.

    Adults receiving moderate CYP3A inducers who have compensated cirrhosis

    90 mg PO once daily in combination with sofosbuvir (400 mg PO once daily) and ribavirin for 12 weeks. Ribavirin must be administered with food in two 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. Dosing includes patients coinfected with HIV.

    Adults with decompensated cirrhosis or who have undergone liver transplantation

    60 mg PO once daily in combination with sofosbuvir (400 mg PO once daily) and ribavirin (600 mg PO once daily) for 12 weeks. Ribavirin must be administered with food, and the dose may be increased to 1000 mg PO daily if tolerated; consider decreasing ribavirin dose for abnormal hemoglobin or creatinine clearance. Dosing includes patients coinfected with HIV.

    Adults receiving strong CYP3A inhibitors who have decompensated cirrhosis or who have undergone liver transplantation

    30 mg PO once daily in combination with sofosbuvir (400 mg PO once daily) and ribavirin (600 mg PO once daily) for 12 weeks. Ribavirin must be administered with food, and the dose may be increased to 1000 mg PO daily if tolerated; consider decreasing ribavirin dose for abnormal hemoglobin or creatinine clearance. Dosing includes patients coinfected with HIV.

    Adults receiving moderate CYP3A inducers who have decompensated cirrhosis or who have undergone liver transplantation

    90 mg PO once daily in combination with sofosbuvir (400 mg PO once daily) and ribavirin (600 mg PO once daily) for 12 weeks. Ribavirin must be administered with food, and the dose may be increased to 1000 mg PO daily if tolerated; consider decreasing ribavirin dose for abnormal hemoglobin or creatinine clearance. Dosing includes patients coinfected with HIV.

    MAXIMUM DOSAGE

    Adults

    90 mg daily PO.

    Geriatric

    90 mg daily PO.

    Adolescents

    Safety and efficacy not established.

    Children

    Safety and efficacy not established.

    Infants

    Safety and efficacy not established.

    Neonates

    Safety and efficacy not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustments are needed.

    Renal Impairment

    No dosage adjustments are needed.

    ADMINISTRATION

     
    NOTE: Daclatasvir MUST be administered in combination with sofosbuvir; certain patients may also require treatment with ribavirin. If sofosbuvir is permanently discontinued, daclatasvir must also be discontinued.

    Oral Administration

    May be administered with or without food.

    STORAGE

    Daklinza:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Use with ribavirin

    In certain patient populations, daclatasvir is recommended for use with ribavirin; therefore, any contraindication to ribavirin will also apply to the combination regimen. See the ribavirin monograph for additional information.

    Hepatitis C and HIV coinfection

    Daclatasvir is approved for use in patients coinfected with hepatitis C and HIV. HIV treatment guidelines recommend all 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. 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 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. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.

    Pregnancy

    No human data are available regarding use of daclatasvir during pregnancy, and it is unknown if the drug poses a risk to the fetus or is associated with adverse reactions on the human reproductive system. The manufacturer advises caution and careful consideration when deciding if the drugs should be administered to a pregnant woman. In animal studies involving rat and rabbits, no evidence of fetal harm was observed following drug exposures during organogenesis that were 6- and 22-times, respectively, the recommended human dose of 60 mg. In certain patient populations, daclatasvir must be administered with ribavirin. Use of daclatasvir in combination with ribavirin is contraindicated in pregnant women. Ribavirin may cause birth defects and death of the exposed fetus; thus, the drug is contraindicated for use during pregnancy (FDA pregnancy risk category X) and in females who may become pregnant. Studies of ribavirin indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in all of 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 patient who are also infected with HIV and taking concomitant antiretroviral agents, an Antiretroviral Pregnancy Registry is available at (800) 258-4263.

    Breast-feeding

    According to the manufacturer, it is not known if daclatasvir is excreted in human milk. 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.

    Antimicrobial resistance

    Daclatasvir is contraindicated for use with strong CYP3A4 inducers, as coadministration may result in lower daclatasvir exposures, loss of antiviral efficacy, and development of antimicrobial resistance. The drug may be administered with moderate CYP3A4 inducers and strong CYP3A4 inhibitors; however, daclatasvir dosage adjustments are recommended during concurrent use. Evaluate patients' medication profile for potential interacting drugs prior to and during treatment with daclatasvir; monitor for the development of adverse drug reactions.

    Male-mediated teratogenicity, pregnancy testing

    In certain patient populations, daclatasvir must be administered with ribavirin. Use of daclatasvir in combination with ribavirin is contraindicated in male partners of women who are pregnant. Ribavirin may cause birth defects and death of the exposed fetus. Ribavirin therapy also may cause male-mediated teratogenicity and is contraindicated for use in men whose female partners are pregnant. Studies of ribavirin indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in all of the animal species tested. Patients and their partners are required use 2 reliable forms of effective contraception during treatment and for 6 months after use of the combination therapy. Patients who are not willing to practice strict contraception should not receive daclatasvir with 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 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 patient who are also infected with HIV and taking concomitant antiretroviral agents, an Antiretroviral Pregnancy Registry is available at (800) 258-4263.

    Hepatitis B exacerbation

    Use of direct-acting antivirals (DAA), such as daclatasvir, 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 daclatasvir. Continue to monitor coinfected patients during and after daclatasvir 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 daclatasvir 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 daclatasvir 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

    Moderate

    anemia / Delayed / 19.0-20.0
    hyperbilirubinemia / Delayed / 5.0-8.0
    elevated hepatic enzymes / Delayed / 2.0-3.0

    Mild

    headache / Early / 8.0-30.0
    fatigue / Early / 14.0-17.0
    nausea / Early / 6.0-15.0
    rash (unspecified) / Early / 2.0-8.0
    diarrhea / Early / 3.0-7.0
    dizziness / Early / 6.0-6.0
    insomnia / Early / 3.0-6.0

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Systemic exposure of dolutegravir, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of dolutegravir; monitor patients for potential adverse effects.
    Afatinib: (Moderate) If the concomitant use of daclatasvir 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 daclatasvir. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and daclatasvir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. The ratio of digoxin Cmax, AUC, and Cmin when administered with daclatasvir (60 mg daily) or alone was 1.65, 1.27, and 1.18, respectively. 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.
    Aliskiren: (Moderate) Systemic exposure of aliskiren, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of aliskiren; monitor patients for potential adverse effects.
    Aliskiren; Amlodipine: (Moderate) Systemic exposure of aliskiren, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of aliskiren; monitor patients for potential adverse effects.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Systemic exposure of aliskiren, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of aliskiren; monitor patients for potential adverse effects.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Systemic exposure of aliskiren, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of aliskiren; monitor patients for potential adverse effects.
    Aliskiren; Valsartan: (Moderate) Systemic exposure of aliskiren, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of aliskiren; monitor patients for potential adverse effects. (Moderate) Systemic exposure of valsartan, a substrate of the drug transporter organic anion transporting polypeptides (OATP), may be increased when administered concurrently with daclatasvir, an OATP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of valsartan; monitor patients for potential adverse effects.
    Amiodarone: (Major) Coadministration of amiodarone with daclatasvir plus sofosbuvir is not recommended due to the potential for serious symptomatic bradycardia. Cases of symptomatic bradycardia, some requiring pacemaker intervention, have been reported when amiodarone was administered with sofosbuvir and another direct-acting antiviral, including daclatasvir. One patient developed a fatal cardiac arrest after receiving amiodarone with ledipasvir; sofosbuvir. Bradycardia generally occurs within hours to days; however, cases have been observed up to 2 weeks after initiating the hepatitis C virus (HCV) treatment regimen. 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 the HCV regimen should also undergo similar cardiac monitoring as outlined above.
    Amlodipine; Atorvastatin: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Systemic exposure of valsartan, a substrate of the drug transporter organic anion transporting polypeptides (OATP), may be increased when administered concurrently with daclatasvir, an OATP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of valsartan; monitor patients for potential adverse effects.
    Amlodipine; Valsartan: (Moderate) Systemic exposure of valsartan, a substrate of the drug transporter organic anion transporting polypeptides (OATP), may be increased when administered concurrently with daclatasvir, an OATP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of valsartan; monitor patients for potential adverse effects.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as clarithromycin. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. (Minor) Systemic exposure of lansoprazole, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of lansoprazole; monitor patients for potential adverse effects.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as clarithromycin. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. (Minor) Systemic exposure of omeprazole, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of omeprazole; monitor patients for potential adverse effects.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if daclatasvir and aprepitant, fosaprepitant are used concurrently and monitor for an increase in daclatasvir-related adverse effects for several days after administration of a multi-day aprepitant regimen. Daclatasvir is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of daclatasvir. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Armodafinil: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as armodafinil. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance. Conversely, the therapeutic effects of armodafinil, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor.
    Aspirin, ASA; Omeprazole: (Minor) Systemic exposure of omeprazole, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of omeprazole; monitor patients for potential adverse effects.
    Aspirin, ASA; Pravastatin: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
    Atazanavir: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with atazanavir, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions. If atazanavir is boosted with cobicistat, the dose of daclatasvir must be reduced to 30 mg PO once daily.
    Atazanavir; Cobicistat: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as cobicistat. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with atazanavir, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions. If atazanavir is boosted with cobicistat, the dose of daclatasvir must be reduced to 30 mg PO once daily.
    Atorvastatin: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
    Atorvastatin; Ezetimibe: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Severe) Concomitant use of daclatasvir with phenobarbital is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to daclatasvir. Phenobarbital is a potent inducer of the hepatic isoenzyme CYP3A4; daclatasvir is a substrate of this isoenzyme.
    Azithromycin: (Moderate) Systemic exposure of azithromycin, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of azithromycin; monitor patients for potential adverse effects.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Severe) Concomitant use of daclatasvir with phenobarbital is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to daclatasvir. Phenobarbital is a potent inducer of the hepatic isoenzyme CYP3A4; daclatasvir is a substrate of this isoenzyme.
    Bexarotene: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as bexarotene. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Boceprevir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as boceprevir. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. In addition, the therapeutic effects of boceprevir, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor.
    Bosentan: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as bosentan. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance. Conversely, the therapeutic effects of bosentan, a substrate of the organic anion transporting polypeptides (OATP), may be increased by daclatasvir, an OATP inhibitor
    Brigatinib: (Major) Consider increasing the dose of daclatasvir to 90 mg once daily if coadministration with brigatinib is necessary; monitor for changes in the efficacy and adverse reaction profile of daclatasvir. Daclatasvir is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of daclatasvir may decrease. The Cmax and AUC of daclatasvir were decreased by 56% and 79%, respectively, when coadministered with a strong CYP3A4 inducer.
    Budesonide: (Moderate) Systemic exposure of budesonide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of budesonide; monitor patients for potential adverse effects.
    Budesonide; Formoterol: (Moderate) Systemic exposure of budesonide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of budesonide; monitor patients for potential adverse effects.
    Buprenorphine: (Moderate) Systemic exposure of buprenorphine may be increased when administered concurrently with daclatasvir. Taking these drugs together could increase or prolong the therapeutic effects of buprenorphine. No dosage adjustments are recommended; however, close monitoring of patients for potential adverse effects is advised.
    Buprenorphine; Naloxone: (Moderate) Systemic exposure of buprenorphine may be increased when administered concurrently with daclatasvir. Taking these drugs together could increase or prolong the therapeutic effects of buprenorphine. No dosage adjustments are recommended; however, close monitoring of patients for potential adverse effects is advised.
    Canagliflozin: (Moderate) Systemic exposure of canagliflozin, a P-glycoprotein (P-gp) substrate, may be increased when canagliflozin is administered concurrently with daclatasvir, a P-gp inhibitor. Drug interactions with canagliflozin and P-gp inhibitors have not been studied. Taking these drugs together could theoretically increase or prolong the therapeutic effects of canagliflozin. Monitor patients for potential canagliflozin adverse effects, such as hypoglycemia, increased urination, and hypotension, genital fungal infections, and urinary tract infection.
    Canagliflozin; Metformin: (Moderate) Systemic exposure of canagliflozin, a P-glycoprotein (P-gp) substrate, may be increased when canagliflozin is administered concurrently with daclatasvir, a P-gp inhibitor. Drug interactions with canagliflozin and P-gp inhibitors have not been studied. Taking these drugs together could theoretically increase or prolong the therapeutic effects of canagliflozin. Monitor patients for potential canagliflozin adverse effects, such as hypoglycemia, increased urination, and hypotension, genital fungal infections, and urinary tract infection.
    Carbamazepine: (Severe) Concomitant use of daclatasvir with carbamazepine is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to daclatasvir. Carbamazepine is a potent inducer of the hepatic isoenzyme CYP3A4; daclatasvir is a substrate of this isoenzyme.
    Carvedilol: (Moderate) Systemic exposure of carvedilol, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of carvedilol; monitor patients for potential adverse effects.
    Ceritinib: (Moderate) Monitor for an increase in daclatasvir-related adverse reactions if coadministration with ceritinib is necessary. Ceritinib is a CYP3A4 inhibitor and daclatasvir is primarily metabolized by CYP3A4. Coadministration with a strong CYP3A4 inhibitor increased the Cmax and AUC of daclatasvir by 1.57-fold and 3-fold, respectively.
    Chloramphenicol: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as chloramphenicol. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
    Ciprofloxacin: (Moderate) According to the manufacturer, concurrent administration of daclatasvir, a CYP3A4 substrate, with ciprofloxacin, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Clarithromycin: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as clarithromycin. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
    Clobazam: (Moderate) Systemic exposure of clobazam, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of clobazam; monitor patients for potential adverse effects.
    Cobicistat: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as cobicistat. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as cobicistat. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as cobicistat. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
    Cobimetinib: (Minor) If concurrent use of cobimetinib and daclatasvir is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and daclatasvir 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: (Moderate) Systemic exposure of colchicine, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of colchicine; monitor patients for potential adverse effects.
    Conivaptan: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as conivaptan. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with daclatasvir, 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 daclatasvir 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 daclatasvir, 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.
    Dabrafenib: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as dabrafenib. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Dalfopristin; Quinupristin: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as dalfopristin; quinupristin . Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
    Danazol: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with danazol, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Dapagliflozin; Saxagliptin: (Moderate) Monitor blood glucose to avoid hypoglycemia if daclatasvir is coadministered with saxagliptin due to the potential for increased saxagliptin exposure. Saxagliptin is a P-glycoprotein (P-gp) substrate; daclatasvir is a P-gp inhibitor.
    Darunavir: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with darunavir, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions. When darunavir is boosted with cobicistat, the dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily.
    Darunavir; Cobicistat: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as cobicistat. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with darunavir, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions. When darunavir is boosted with cobicistat, the dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Taking daclatasvir with dasabuvir may increase serum concentrations of dasabuvir, and potentially increase the risk for adverse effects. Dasabuvir is a P-glycoprotein (P-gp) substrates; daclatasvir is a P-gp inhibitor. (Major) Taking daclatasvir with ombitasvir may increase serum concentrations of ombitasvir, and potentially increase the risk for adverse effects. Ombitasvir is a P-glycoprotein (P-gp) substrates; daclatasvir is a P-gp inhibitor. (Major) Taking daclatasvir with paritaprevir may increase serum concentrations of paritaprevir, and potentially increase the risk for adverse effects. Paritaprevir is a P-glycoprotein (P-gp) substrates; daclatasvir is a P-gp inhibitor. (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as ritonavir. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. In addition, the therapeutic effects of ritonavir, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor.
    Daunorubicin: (Moderate) Systemic exposure of daunorubicin, a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), may be increased when administered concurrently with daclatasvir, a P-gp and BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of daunorubicin; monitor patients for potential adverse effects.
    Deferasirox: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as deferasirox. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Delavirdine: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as delavirdine. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
    Desloratadine: (Minor) Systemic exposure of desloratadine, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of desloratadine; monitor patients for potential adverse effects.
    Desloratadine; Pseudoephedrine: (Minor) Systemic exposure of desloratadine, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of desloratadine; monitor patients for potential adverse effects.
    Dexamethasone: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as dexamethasone. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance. Conversely, the therapeutic effects of dexamethasone, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor.
    Dextromethorphan; Quinidine: (Major) Systemic exposure of quinidine, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of quinidine; monitor patients for potential adverse effects.
    Digoxin: (Major) Coadministration of daclatasvir with digoxin may increase digoxin exposure leading to increased or prolonged therapeutic effects and adverse events. If digoxin is initiated in a patients already receiving daclatasvir, start digoxin at the lowest appropriate dose followed by gradual and caution dose adjustments. If daclatasvir is started in a patients already receiving digoxin, obtain digoxin serum concentrations before giving daclatasvir and decrease the digoxin dose by 30% to 50%. Alternatively, the digoxin dose may be reduced by prolonging the dosing interval. Digoxin is a substrate for P-glycoprotein (P-gp); daclatasvir is a P-gp inhibitor.
    Diltiazem: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with diltiazem; enalapril, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. In addition, the therapeutic effects of diltiazem, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as hypotension, headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Docetaxel: (Moderate) Systemic exposure of docetaxel, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of docetaxel; monitor patients for potential adverse effects.
    Dolutegravir: (Moderate) Systemic exposure of dolutegravir, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of dolutegravir; monitor patients for potential adverse effects.
    Doxorubicin: (Moderate) Systemic exposure of doxorubicin, a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), may be increased when administered concurrently with daclatasvir, a P-gp and BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of doxorubicin; monitor patients for potential adverse effects.
    Dronedarone: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with dronedarone, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Efavirenz: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as efavirenz. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Efavirenz; Emtricitabine; Tenofovir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as efavirenz. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Elbasvir; Grazoprevir: (Severe) Concurrent administration of grazoprevir with daclatasvir is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Daclatasvir is an inhibitor of the organic anion transporting polypeptide (OATP1B1/3). Grazoprevir is a substrate of OATP1B1/3.
    Eletriptan: (Moderate) Systemic exposure of eletriptan, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of eletriptan; monitor patients for potential adverse effects.
    Eluxadoline: (Moderate) Systemic exposure of eluxadoline, a substrate of the drug transporter organic anion transporting polypeptides (OATP), may be increased when administered concurrently with daclatasvir, an OATP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of eluxadoline; monitor patients for potential adverse effects.
    Enzalutamide: (Severe) Concomitant use of daclatasvir with enzalutamide is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to daclatasvir. Enzalutamide is a potent inducer of the hepatic isoenzyme CYP3A4; daclatasvir is a substrate of this isoenzyme.
    Erythromycin: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with erythromycin, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. In addition, the therapeutic effects of erythromycin, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Erythromycin; Sulfisoxazole: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with erythromycin, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. In addition, the therapeutic effects of erythromycin, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Eslicarbazepine: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as eslicarbazepine. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Ethanol: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as ethanol. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Etoposide, VP-16: (Major) Systemic exposure of etoposide, VP-16, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of etoposide; monitor patients for potential adverse effects.
    Etravirine: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as etravirine. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Ezetimibe; Simvastatin: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
    Fentanyl: (Moderate) Systemic exposure of fentanyl, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of fentanyl; monitor patients for potential adverse effects.
    Fexofenadine: (Minor) Systemic exposure of fexofenadine, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of fexofenadine; monitor patients for potential adverse effects.
    Fexofenadine; Pseudoephedrine: (Minor) Systemic exposure of fexofenadine, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of fexofenadine; monitor patients for potential adverse effects.
    Fluconazole: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with fluconazole, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Flutamide: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as flutamide. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Systemic exposure of umeclidinium; vilanterol, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of umeclidinium; vilanterol; monitor patients for potential adverse effects.
    Fluvastatin: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
    Fosamprenavir: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with fosamprenavir, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. In addition, the therapeutic effects of fosamprenavir, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Fosphenytoin: (Severe) Concomitant use of daclatasvir with phenytoin or fosphenytoin is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to daclatasvir. Phenytoin is a potent inducer of the hepatic isoenzyme CYP3A4; daclatasvir is a substrate of this isoenzyme.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and daclatasvir as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of organic anion transporting polypeptide (OATP) 1B1/3, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP); daclatasvir is an inhibitor of all these drug transporters. (Moderate) Caution is advised with the coadministration of pibrentasvir and daclatasvir as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); daclatasvir is an inhibitor of P-gp and BCRP.
    Glyburide: (Moderate) Systemic exposure of glyburide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of glyburide; monitor patients for potential adverse effects.
    Glyburide; Metformin: (Moderate) Systemic exposure of glyburide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of glyburide; monitor patients for potential adverse effects.
    Grapefruit juice: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as grapefruit juice. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
    Griseofulvin: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as griseofulvin. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    HMG-CoA reductase inhibitors: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Systemic exposure of valsartan, a substrate of the drug transporter organic anion transporting polypeptides (OATP), may be increased when administered concurrently with daclatasvir, an OATP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of valsartan; monitor patients for potential adverse effects.
    Idelalisib: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as idelalisib. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
    Imatinib: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with imatinib, STI-571, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. In addition, the therapeutic effects of imatinib, a substrate for P-glycoprotein (P-gp) and the breast cancer resistant protein (BCRP), may be increased by daclatasvir, a P-gp and BCRP inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Indinavir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as indinavir. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. In addition, the therapeutic effects of indinavir, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor.
    Irinotecan: (Moderate) Systemic exposure of irinotecan, a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), may be increased when administered concurrently with daclatasvir, a P-gp and BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of irinotecan; monitor patients for potential adverse effects.
    Isavuconazonium: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with isavuconazonium, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Isoniazid, INH: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with isoniazid, INH, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Severe) Concomitant use of daclatasvir with rifampin is contraindicated due to the potential for hepatitis C treatment failure. Coadministration reduces systemic exposes to daclatasvir by 79%. Rifampin is a potent inducer of the hepatic isoenzyme CYP3A4; daclatasvir is a substrate of this isoenzyme. (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with isoniazid, INH, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Isoniazid, INH; Rifampin: (Severe) Concomitant use of daclatasvir with rifampin is contraindicated due to the potential for hepatitis C treatment failure. Coadministration reduces systemic exposes to daclatasvir by 79%. Rifampin is a potent inducer of the hepatic isoenzyme CYP3A4; daclatasvir is a substrate of this isoenzyme. (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with isoniazid, INH, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Itraconazole: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as itraconazole. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. In addition, the therapeutic effects of itraconazole, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor.
    Ketoconazole: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as ketoconazole. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
    Lansoprazole: (Minor) Systemic exposure of lansoprazole, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of lansoprazole; monitor patients for potential adverse effects.
    Lansoprazole; Naproxen: (Minor) Systemic exposure of lansoprazole, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of lansoprazole; monitor patients for potential adverse effects.
    Lapatinib: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with lapatinib, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. In addition, the therapeutic effects of lapatinib, a substrate for the breast cancer resistant protein (BCRP), may be increased by daclatasvir, a BCRP inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of daclatasvir; monitor for potential reduction in efficacy. Daclatasvir is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of daclatasvir; monitor for potential reduction in efficacy. Daclatasvir is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Loperamide: (Moderate) The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a potent inhibitor of P-gp. 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, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a potent inhibitor of P-gp. 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: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as lopinavir; ritonavir. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. In addition, the therapeutic effects of ritonavir, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor. (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as ritonavir. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. In addition, the therapeutic effects of ritonavir, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor.
    Loratadine: (Minor) Systemic exposure of loratadine, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of loratadine; monitor patients for potential adverse effects.
    Loratadine; Pseudoephedrine: (Minor) Systemic exposure of loratadine, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of loratadine; monitor patients for potential adverse effects.
    Lovastatin: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
    Lovastatin; Niacin: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
    Maraviroc: (Moderate) Use caution and closely monitor for increased adverse effects with the coadministration of maraviroc and daclatasvir as increased maraviroc concentrations may occur. Maraviroc is a substrate of P-glycoprotein (P-gp); daclatasvir is an 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) Systemic exposure of mefloquine, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of mefloquine; monitor patients for potential adverse effects.
    Metformin; Repaglinide: (Moderate) Systemic exposure of repaglinide, a substrate of the drug transporter organic anion transporting polypeptides (OATP), may be increased when administered concurrently with daclatasvir, an OATP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of repaglinide; monitor patients for potential adverse effects.
    Metformin; Saxagliptin: (Moderate) Monitor blood glucose to avoid hypoglycemia if daclatasvir is coadministered with saxagliptin due to the potential for increased saxagliptin exposure. Saxagliptin is a P-glycoprotein (P-gp) substrate; daclatasvir is a P-gp inhibitor.
    Methotrexate: (Minor) Systemic exposure of methotrexate, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with daclatasvir, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of methotrexate; monitor patients for potential adverse effects.
    Methylprednisolone: (Moderate) Systemic exposure of methylprednisolone, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of methylprednisolone; monitor patients for potential adverse effects.
    Metyrapone: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as metyrapone. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Mifepristone, RU-486: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with mifepristone, RU-486, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Mirabegron: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with mirabegron, a moderate CYP3A4 inhibitor, increases daclatasvir serum concentrations. In addition, the therapeutic effects of mirabegron, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Mitomycin: (Moderate) Systemic exposure of mitomycin, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of mitomycin; monitor patients for potential adverse effects.
    Mitotane: (Severe) Concomitant use of daclatasvir with mitotane is contraindicated due to the potential for hepatitis C treatment failure. Mitotane is a strong CYP3A4 inducer and daclatasvir is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of daclatasvir.
    Mitoxantrone: (Moderate) Systemic exposure of mitoxantrone, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with daclatasvir, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of mitoxantrone; monitor patients for potential adverse effects.
    Modafinil: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as modafinil. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Morphine: (Moderate) Systemic exposure of morphine, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of morphine; monitor patients for potential adverse effects.
    Morphine; Naltrexone: (Moderate) Systemic exposure of morphine, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of morphine; monitor patients for potential adverse effects.
    Nafcillin: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as nafcillin. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with daclatasvir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; daclatasvir is a moderate P-gp inhibitor.
    Nebivolol; Valsartan: (Moderate) Systemic exposure of valsartan, a substrate of the drug transporter organic anion transporting polypeptides (OATP), may be increased when administered concurrently with daclatasvir, an OATP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of valsartan; monitor patients for potential adverse effects.
    Nefazodone: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as nefazodone. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
    Nelfinavir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as nelfinavir. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. In addition, the therapeutic effects of nelfinavir, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor.
    Netupitant; Palonosetron: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with netupitant; palonosetron, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Nevirapine: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as nevirapine. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Niacin; Simvastatin: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
    Nicardipine: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with nicardipine, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Nilotinib: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with nilotinib, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. In addition, the therapeutic effects of nilotinib, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Nintedanib: (Moderate) Systemic exposure of nintedanib, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of nintedanib; monitor patients for potential adverse effects.
    Octreotide: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with octreotide, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Taking daclatasvir with ombitasvir may increase serum concentrations of ombitasvir, and potentially increase the risk for adverse effects. Ombitasvir is a P-glycoprotein (P-gp) substrates; daclatasvir is a P-gp inhibitor. (Major) Taking daclatasvir with paritaprevir may increase serum concentrations of paritaprevir, and potentially increase the risk for adverse effects. Paritaprevir is a P-glycoprotein (P-gp) substrates; daclatasvir is a P-gp inhibitor. (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as ritonavir. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. In addition, the therapeutic effects of ritonavir, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor.
    Omeprazole: (Minor) Systemic exposure of omeprazole, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of omeprazole; monitor patients for potential adverse effects.
    Omeprazole; Sodium Bicarbonate: (Minor) Systemic exposure of omeprazole, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of omeprazole; monitor patients for potential adverse effects.
    Ondansetron: (Moderate) Systemic exposure of ondansetron, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of ondansetron; monitor patients for potential adverse effects.
    Oxcarbazepine: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as oxcarbazepine. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Paclitaxel: (Moderate) Systemic exposure of paclitaxel, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of paclitaxel; monitor patients for potential adverse effects.
    Paliperidone: (Moderate) Systemic exposure of paliperidone, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of paliperidone; monitor patients for potential adverse effects.
    Panobinostat: (Major) Systemic exposure of panobinostat, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of panobinostat; monitor patients for potential adverse effects.
    Pantoprazole: (Minor) The therapeutic effects of pantoprazole, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor. If these drugs are administered together, monitor patients for pantoprazole-related adverse effects.
    Pazopanib: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with pazopanib, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. In addition, the therapeutic effects of pazopanib, a substrate for P-glycoprotein (P-gp) and the breast cancer resistant protein (BCRP), may be increased by daclatasvir, a P-gp and BCRP inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Phenobarbital: (Severe) Concomitant use of daclatasvir with phenobarbital is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to daclatasvir. Phenobarbital is a potent inducer of the hepatic isoenzyme CYP3A4; daclatasvir is a substrate of this isoenzyme.
    Phenytoin: (Severe) Concomitant use of daclatasvir with phenytoin or fosphenytoin is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to daclatasvir. Phenytoin is a potent inducer of the hepatic isoenzyme CYP3A4; daclatasvir is a substrate of this isoenzyme.
    Posaconazole: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as posaconazole. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. In addition, the therapeutic effects of posaconazole, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor.
    Pravastatin: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
    Prednisone: (Moderate) Systemic exposure of prednisone, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of prednisone; monitor patients for potential adverse effects.
    Primidone: (Severe) Concomitant use of daclatasvir with primidone is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to daclatasvir. Primidone is a potent inducer of the hepatic isoenzyme CYP3A4; daclatasvir is a substrate of this isoenzyme.
    Quinidine: (Major) Systemic exposure of quinidine, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of quinidine; monitor patients for potential adverse effects.
    Ranolazine: (Moderate) Systemic exposure of ranolazine, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of ranolazine; monitor patients for potential adverse effects.
    Repaglinide: (Moderate) Systemic exposure of repaglinide, a substrate of the drug transporter organic anion transporting polypeptides (OATP), may be increased when administered concurrently with daclatasvir, an OATP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of repaglinide; monitor patients for potential adverse effects.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with daclatasvir is necessary, as the systemic exposure of daclatasvir may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and daclatasvir is a CYP3A4 substrate. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with daclatasvir is necessary, as the systemic exposure of daclatasvir may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and daclatasvir is a CYP3A4 substrate. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Rifabutin: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as rifabutin. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Rifampin: (Severe) Concomitant use of daclatasvir with rifampin is contraindicated due to the potential for hepatitis C treatment failure. Coadministration reduces systemic exposes to daclatasvir by 79%. Rifampin is a potent inducer of the hepatic isoenzyme CYP3A4; daclatasvir is a substrate of this isoenzyme.
    Rifapentine: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as rifapentine. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Rifaximin: (Major) The dose of daclatasvir, a CYP3A4 substrate, may need to be increased to 90 mg PO once daily when administered in combination with rifaximin. Rifaximin is categorized as a moderate CYP3A4 inducer; however in patients with normal hepatic function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance. Conversely, the therapeutic effects of rifaximin, a substrate of P-glycoprotein (P-gp) and organic anion transporting polypeptides (OATP), may be increased by daclatasvir, a P-gp and OATP inhibitor.
    Riociguat: (Minor) Systemic exposure of riociguat, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of riociguat; monitor patients for potential adverse effects.
    Risperidone: (Moderate) Systemic exposure of risperidone, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of risperidone; monitor patients for potential adverse effects.
    Ritonavir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as ritonavir. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. In addition, the therapeutic effects of ritonavir, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor.
    Rivaroxaban: (Minor) Systemic exposure of rivaroxaban, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of rivaroxaban; monitor patients for potential adverse effects.
    Romidepsin: (Moderate) Systemic exposure of romidepsin, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of romidepsin; monitor patients for potential adverse effects.
    Rosuvastatin: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
    Sacubitril; Valsartan: (Moderate) Systemic exposure of valsartan, a substrate of the drug transporter organic anion transporting polypeptides (OATP), may be increased when administered concurrently with daclatasvir, an OATP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of valsartan; monitor patients for potential adverse effects.
    Saquinavir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as saquinavir. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. In addition, the therapeutic effects of saquinavir, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor.
    Saxagliptin: (Moderate) Monitor blood glucose to avoid hypoglycemia if daclatasvir is coadministered with saxagliptin due to the potential for increased saxagliptin exposure. Saxagliptin is a P-glycoprotein (P-gp) substrate; daclatasvir is a P-gp inhibitor.
    Silodosin: (Moderate) Systemic exposure of silodosin, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of silodosin; monitor patients for potential adverse effects.
    Simeprevir: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with simeprevir, a moderate CYP3A4 inhibitor, increases daclatasvir serum concentrations by 94%. In addition, the pharmacokinetic properties (i.e., Cmax, Cmin, and AUC) of simeprevir, a substrate of the drug transporters P-glycoprotein (P-gp) and organic anion transporting polypeptides (OATP), are increased by daclatasvir, a P-gp and OATP inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Simvastatin: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
    Simvastatin; Sitagliptin: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
    Sirolimus: (Moderate) Systemic exposure of sirolimus, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of sirolimus; monitor patients for potential adverse effects.
    Sofosbuvir; Velpatasvir: (Severe) Do not coadminister velpatasvir with daclatasvir. Taking these drugs together is a duplication of therapy, and may result in adverse effects.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Severe) Do not coadminister velpatasvir with daclatasvir. Taking these drugs together is a duplication of therapy, and may result in adverse effects. (Major) Avoid concurrent administration of voxilaprevir and daclatasvir. Taking these medications together may increase voxilaprevir plasma concentrations, potentially increasing the risk for adverse events. Voxilaprevir is a substrate for the drug transporter Organic Anion Transporting Polypeptides 1B1/1B3 (OATP1B1/1B3). Daclatasvir is an OATP1B1/1B3 inhibitor.
    St. John's Wort, Hypericum perforatum: (Severe) Concomitant use of daclatasvir with St. John's Wort, Hypericum perforatum is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to daclatasvir. St. John's Wort is a potent inducer of the hepatic isoenzyme CYP3A4; daclatasvir is a substrate of this isoenzyme.
    Streptogramins: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as dalfopristin; quinupristin . Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
    Sulfasalazine: (Moderate) Systemic exposure of sulfasalazine, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with daclatasvir, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of sulfasalazine; monitor patients for potential adverse effects.
    Telithromycin: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as telithromycin. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
    Telotristat Ethyl: (Major) Increase the dose of daclatasvir to 90 mg once daily if coadministration of telotristat ethyl is necessary, as the systemic exposure of daclatasvir may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. Daclatasvir is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and daclatasvir is a P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with daclatasvir is necessary, and monitor for an increase in temsirolimus-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) substrate / inhibitor in vitro, and daclatasvir is a moderate P-gp inhibitor. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp inhibitors, but temsirolimus (and active metabolite, sirolimus) exposure is likely to increase.
    Teniposide: (Moderate) Systemic exposure of teniposide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of teniposide; monitor patients for potential adverse effects.
    Tenofovir Alafenamide: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with daclatasvir. Coadministration may result in increased tenofovir alafenamide plasma concentrations. Tenofovir alafenamide is a substrate of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the organic anion transport protein (OATP1B1 and 1B3); daclatasvir is an inhibitor all three transporters. If these drugs are administered together, closely monitor for tenofovir-associated adverse reactions. 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.
    Testosterone: (Minor) Systemic exposure of testosterone, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of testosterone; monitor patients for potential adverse effects.
    Ticagrelor: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with ticagrelor, a moderate CYP3A4 inhibitor, increases daclatasvir serum concentrations. In addition, the therapeutic effects of ticagrelor, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Tipranavir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as tipranavir boosted with ritonavir. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. In addition, the therapeutic effects of tipranavir, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor.
    Tolvaptan: (Moderate) Systemic exposure of tolvaptan, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of tolvaptan; monitor patients for potential adverse effects.
    Topotecan: (Major) Systemic exposure of topotecan, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with daclatasvir, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of topotecan; monitor patients for potential adverse effects.
    Trandolapril; Verapamil: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with verapamil, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. In addition, the therapeutic effects of verapamil, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as hypotension, headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Umeclidinium: (Moderate) Systemic exposure of umeclidinium; vilanterol, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of umeclidinium; vilanterol; monitor patients for potential adverse effects.
    Umeclidinium; Vilanterol: (Moderate) Systemic exposure of umeclidinium; vilanterol, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of umeclidinium; vilanterol; monitor patients for potential adverse effects.
    Valsartan: (Moderate) Systemic exposure of valsartan, a substrate of the drug transporter organic anion transporting polypeptides (OATP), may be increased when administered concurrently with daclatasvir, an OATP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of valsartan; monitor patients for potential adverse effects.
    Vemurafenib: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as vemurafenib. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance. Conversely, the therapeutic effects of vemurafenib, a substrate of P-glycoprotein (P-gp), may be increased by daclatasvir, a P-gp inhibitor.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and daclatasvir. Venetoclax is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); daclatasvir is an inhibitor of P-gp and BCRP. 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). If daclatasvir 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.
    Verapamil: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with verapamil, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. In addition, the therapeutic effects of verapamil, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as hypotension, headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Vinca alkaloids: (Moderate) Systemic exposure of the vinca alkaloids, which are P-glycoprotein (P-gp) substrates, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of the vinca alkaloids; monitor patients for potential adverse effects.
    Voriconazole: (Moderate) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as voriconazole. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.

    PREGNANCY AND LACTATION

    Pregnancy

    No human data are available regarding use of daclatasvir during pregnancy, and it is unknown if the drug poses a risk to the fetus or is associated with adverse reactions on the human reproductive system. The manufacturer advises caution and careful consideration when deciding if the drugs should be administered to a pregnant woman. In animal studies involving rat and rabbits, no evidence of fetal harm was observed following drug exposures during organogenesis that were 6- and 22-times, respectively, the recommended human dose of 60 mg. In certain patient populations, daclatasvir must be administered with ribavirin. Use of daclatasvir in combination with ribavirin is contraindicated in pregnant women. Ribavirin may cause birth defects and death of the exposed fetus; thus, the drug is contraindicated for use during pregnancy (FDA pregnancy risk category X) and in females who may become pregnant. Studies of ribavirin indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in all of 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 patient who are also infected with HIV and taking concomitant antiretroviral agents, an Antiretroviral Pregnancy Registry is available at (800) 258-4263.

    In certain patient populations, daclatasvir must be administered with ribavirin. Use of daclatasvir in combination with ribavirin is contraindicated in male partners of women who are pregnant. Ribavirin may cause birth defects and death of the exposed fetus. Ribavirin therapy also may cause male-mediated teratogenicity and is contraindicated for use in men whose female partners are pregnant. Studies of ribavirin indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in all of the animal species tested. Patients and their partners are required use 2 reliable forms of effective contraception during treatment and for 6 months after use of the combination therapy. Patients who are not willing to practice strict contraception should not receive daclatasvir with 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 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 patient who are also infected with HIV and taking concomitant antiretroviral agents, an Antiretroviral Pregnancy Registry is available at (800) 258-4263.

    MECHANISM OF ACTION

    Daclatasvir is active against chronic infections caused by hepatitis C virus (HCV) genotypes 1 and 3. The drug prevents viral RNA replication and virion assembly by binding to the N-terminus of NS5A. This binding causes structural distortion, which results in impaired NS5A protein function.
     
    HCV genotype 1a, 1b, and 3a replicons with reduced susceptibility to daclatasvir were selected in cell culture, and the genotype and phenotype of daclatasvir-resistant NS5A amino acid variants were identified. For genotype 1a, phenotypic analysis found single NS5A substitutions at M28T, Q30E, Q30H, Q30R, L31V, Y93C, Y93H, and Y93N resulted in 500-, 18,500-, 1,083-, 900-, 2,500-, 1,367-, 8,500-, and 34,833-fold reduced susceptibility to daclatasvir, respectively. For genotype 1b, single substitutions at L31V and Y93H, and combination substitutions at L31M/Y93H and L31V/y93H resulted in 33-, 30-, 16,000-, and 33,667-fold reductions in susceptibility to daclatasvir, respectively. Further, a P32-deletion (P32X) in genotype 1b reduced daclatasvir susceptibility by more than 1,000,000-fold. For genotype 3a, reductions in susceptibility to daclatasvir of 117-, 320-, 240-, and 3,733-fold were observed with single substitutions at A30K, L31F, L31I, and Y93H, respectively.
     
    In clinical trials, 31 drug recipients were deem virologic failures (11 with genotype 1a, 1 with genotype 1b, 19 with genotype 3a). An analysis of these 31 patients found all harbored at least 1 NS5A resistance-associated substitution at the time of virologic failure. The most common substitution in genotype 3a-infected patients was Y93H, found in 17 of the 19 virologic failure subjects. For genotype 1a, the most common substitution occurred at position Q30 (Q30H/K/R; found in 8 of 11 patients). In addition to the NS5A substitutions, 6 patients were also found to have a virus with NS5B resistance-associated substitution deemed possibly associated with sofosbuvir resistance or exposure: A112T, L159F, E237G, Q355H (for genotype 1a) or S282T+Q355H (for genotype 3a).
     
    Cross-resistance with other NS5A inhibitors is expected; however, resistance with other classes of direct-acting antiviral is not expected. The drug is NOT antagonistic with interferon alfa, NS3/4A protease inhibitors, NS5B nucleoside analogs inhibitors, or NS5B non-nucleoside inhibitors.

    PHARMACOKINETICS

    Daclatasvir is administered orally. Systemically absorbed daclatasvir has a steady state volume of distribution of approximately 47 L, and is extensively protein bound at 99%. Metabolism occurs via the hepatic isoenzymes CYP3A4. The feces are the main route of elimination, accounting for 88% of a radiolabeled dose, with urine accounting for only 6.6% of the dose. Daclatasvir has a terminal elimination half-life ranging from 12 to 15 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-glycoprotein (P-gp), organic anion transporting polypeptides (OATP1B1 and OATP1B3), breast cancer resistance protein (BCRP)
    Daclatasvir is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter P-gp. The drug is also a P-gp inhibitor, and an inhibitor of the transporters OATP1B1, OATP1B3, and BCRP.

    Oral Route

    Based on in vitro data, the estimated absolute oral bioavailability of daclatasvir is 67%. Following oral administration, peak plasma concentrations are achieved within 2 hours, with steady state concentrations (AUC) reached after 4 days of once daily dosing. Pharmacokinetic parameters (i.e., AUC, Cmax, Cmin), increase in a dose proportional manner up to the recommended 60 mg dose. The drug may be administered with or without food. Low-fat, low-caloric meals do not alter the pharmacokinetic parameters; however, high-fat, high-caloric meals have been found to decrease the drugs AUC and Cmax by 23% and 28%, respectively, compared to fasting state.