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  • CLASSES

    Protease Inhibitors for Hepatitis

    BOXED WARNING

    Hepatitis B exacerbation

    Use of direct-acting antivirals (DAA), such as simeprevir, 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 simeprevir. Continue to monitor coinfected patients during and after treatment for clinical and laboratory signs of hepatitis B exacerbation (i.e., HBsAg, HBV DNA, hepatic enzymes, bilirubin). In addition, instruct patients to immediately report any signs of liver toxicity (e.g., yellow eyes or skin, fatigue, weakness, loss of appetite, nausea, vomiting, or light-colored stools) to their health care provider. If a simeprevir 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 NS3/4A protease inhibitor
    For treatment of chronic hepatitis C virus infection (genotype 1 and 4) in adults
    Must be used with either sofosbuvir or peginterferon plus ribavirin; avoid monotherapy

    COMMON BRAND NAMES

    Olysio

    HOW SUPPLIED

    Olysio Oral Cap: 150mg

    DOSAGE & INDICATIONS

    For the treatment of chronic hepatitis C infection.
    For the treatment of chronic hepatitis C infection, genotype 1, in patients with compensated liver disease.
    Oral dosage (with sofosbuvir)
    Treatment-naive and experienced adults WITHOUT cirrhosis

    150 mg PO once daily with sofosbuvir for 12 weeks; never administer as monotherapy. If sofosbuvir is discontinued for any reason, then simeprevir must also be discontinued. Once simeprevir is discontinued, it must not be reinitiated. Prior to initiating therapy, screen patients for the presence of NS3 Q80K polymorphism. Efficacy of simeprevir may be substantially reduced in the presence of this polymorphism and an alternative therapy should be considered. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors.  The American Association for the study of liver diseases (AASLD) guidance recommends simeprevir plus sofosbuvir, with or without ribavirin, for 12 weeks as preferred option. These recommendations include HIV coinfected patients without significant drug interactions.

    Treatment-naive and experienced adults WITH cirrhosis (Child-Pugh A)

    150 mg PO once daily with sofosbuvir for 24 weeks; never administer as monotherapy. If sofosbuvir is discontinued for any reason, then simeprevir must also be discontinued. Once simeprevir is discontinued, it must not be reinitiated. Prior to initiating therapy, screen patients for the presence of NS3 Q80K polymorphism. Efficacy of simeprevir may be substantially reduced in the presence of this polymorphism and an alternative therapy should be considered. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors. The American Association for the study of liver diseases (AASLD) guidance recommends simeprevir plus sofosbuvir, with or without ribavirin, for 12 weeks as preferred option. These recommendations include HIV coinfected patients without significant drug interactions.

    Oral dosage (with peginterferon alfa and ribavirin)
    Treatment-naive and prior relapse adults with or without cirrhosis (Child-Pugh A) who are HIV-negative

    150 mg PO once daily with peginterferon alfa and ribavirin, for an initial 12 weeks of treatment; never administer simeprevir as monotherapy. After the initial 3-drug regimen, give an additional 12 weeks of only peginterferon alfa and ribavirin (24 weeks for total course). Monitor HCV RNA at treatment weeks 4 and 12; if concentrations are greater than or equal to 25 International Units/mL, discontinue all 3 drugs. Once simeprevir is discontinued, it must not be reinitiated. If a coadministered antiviral medication is discontinued for any reason, then simeprevir must also be discontinued. Prior to initiating therapy, screen patients for the presence of NS3 Q80K polymorphism. Efficacy of simeprevir, peginterferon alfa, and ribavirin is substantially reduced in the presence of this polymorphism, and an alternative therapy should be considered. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors. The American Association for the study of liver diseases (AASLD) guidance recommends simeprevir plus peginterferon alfa and ribavirin as an alternative option for patients able to receive interferon products. These recommendations include HIV coinfected patients without significant drug interactions.

    Treatment-naive and prior relapse adults with HIV coinfection but without cirrhosis

    150 mg PO once daily with peginterferon alfa and ribavirin, for an initial 12 weeks of treatment; never administer simeprevir as monotherapy. After the initial 3-drug regimen, give an additional 12 weeks of only peginterferon alfa and ribavirin (24 weeks for total course). Monitor HCV RNA at treatment weeks 4 and 12; if concentrations are greater than or equal to 25 International Units/mL, discontinue all 3 drugs. Once simeprevir is discontinued, it must not be reinitiated. If a coadministered antiviral medication is discontinued for any reason, then simeprevir must also be discontinued. Prior to initiating therapy, screen patients for the presence of NS3 Q80K polymorphism. Efficacy of simeprevir, peginterferon alfa, and ribavirin is substantially reduced in the presence of this polymorphism, and an alternative therapy should be considered. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors. The American Association for the study of liver diseases (AASLD) guidance recommends simeprevir plus peginterferon alfa and ribavirin as an alternative option for patients able to receive interferon products. These recommendations include HIV coinfected patients without significant drug interactions.

    Treatment-naive and prior relapse adults with HIV coinfection and cirrhosis (Child-Pugh A)

    150 mg PO once daily with peginterferon alfa and ribavirin, for an initial 12 weeks of treatment; never administer simeprevir as monotherapy. After the initial 3-drug regimen, give an additional 36 weeks of only peginterferon alfa and ribavirin (48 weeks for total course). Monitor HCV RNA at treatment weeks 4, 12, and 24; if concentrations are greater than or equal to 25 International Units/mL, discontinue treatment. Once simeprevir is discontinued, it must not be reinitiated. If a coadministered antiviral medication is discontinued for any reason, then simeprevir must also be discontinued. Prior to initiating therapy, screen patients for the presence of NS3 Q80K polymorphism. Efficacy of simeprevir, peginterferon alfa, and ribavirin is substantially reduced in the presence of this polymorphism and an alternative therapy should be considered. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors. The American Association for the study of liver diseases (AASLD) guidance recommends simeprevir plus peginterferon alfa and ribavirin as an alternative option for patients able to receive interferon products. These recommendations include HIV coinfected patients without significant drug interactions.

    Adult prior nonresponders (including partial and null responders) with or without cirrhosis (Child-Pugh A) and with or without HIV coinfection

    150 mg PO once daily with peginterferon alfa and ribavirin, for an initial 12 weeks of treatment; never administer simeprevir as monotherapy. After the initial 3-drug regimen, give an additional 36 weeks of only peginterferon alfa and ribavirin (48 weeks for total course). Monitor HCV RNA at treatment weeks 4, 12, and 24; if concentrations are greater than or equal to 25 International Units/mL, discontinue treatment. Once simeprevir is discontinued, it must not be reinitiated. If a coadministered antiviral medication is discontinued for any reason, then simeprevir must also be discontinued. Prior to initiating therapy, screen patients for the presence of NS3 Q80K polymorphism. Efficacy of simeprevir, peginterferon alfa, and ribavirin is substantially reduced in the presence of this polymorphism and an alternative therapy should be considered. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors. The American Association for the study of liver diseases (AASLD) guidance recommends simeprevir plus peginterferon alfa and ribavirin as an alternative option for patients able to receive interferon products. These recommendations include HIV coinfected patients without significant drug interactions.

    For the treatment of chronic hepatitis C infection, genotype 4, in patients with compensated liver disease.
    Oral dosage
    Treatment-naive and prior relapse adults with or without cirrhosis (Child-Pugh A) who are HIV-negative

    150 mg PO once daily in combination with peginterferon alfa and ribavirin for an initial 12 weeks of treatment; never administer simeprevir as monotherapy. After the initial 3-drug regimen, give an additional 12 weeks of only peginterferon alfa and ribavirin (24 weeks for total course). Monitor HCV RNA at treatment weeks 4 and 12; if concentrations are greater than or equal to 25 International Units/mL, discontinue all 3 drugs. If peginterferon alfa or ribavirin is discontinued for any reason, then simeprevir must also be discontinued. Once simeprevir is discontinued, it must not be reinitiated. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors.

    Treatment-naive and prior relapse adults with HIV coinfection but without cirrhosis

    150 mg PO once daily in combination with peginterferon alfa and ribavirin for an initial 12 weeks of treatment; never administer simeprevir as monotherapy. After the initial 3-drug regimen, give an additional 12 weeks of only peginterferon alfa and ribavirin (24 weeks for total course). Monitor HCV RNA at treatment weeks 4 and 12; if concentrations are greater than or equal to 25 International Units/mL, discontinue all 3 drugs. If peginterferon alfa or ribavirin is discontinued for any reason, then simeprevir must also be discontinued. Once simeprevir is discontinued, it must not be reinitiated. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors.

    Treatment-naive and prior relapse adults with HIV coinfection and cirrhosis (Child-Pugh A)

    150 mg PO once daily in combination with peginterferon alfa and ribavirin for an initial 12 weeks of treatment; never administer simeprevir as monotherapy. After the initial 3-drug regimen, give an additional 36 weeks of only peginterferon alfa and ribavirin (48 weeks for total course). Monitor HCV RNA at treatment weeks 4, 12, and 24; if concentrations are greater than or equal to 25 International Units/mL, discontinue treatment. If peginterferon alfa or ribavirin is discontinued for any reason, then simeprevir must also be discontinued. Once simeprevir is discontinued, it must not be reinitiated. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors.

    Adult prior nonresponders (including partial and null responders) with or without cirrhosis (Child-Pugh A) and with or without HIV coinfection

    150 mg PO once daily in combination with peginterferon alfa and ribavirin for an initial 12 weeks of treatment; never administer simeprevir as monotherapy. After the initial 3-drug regimen, give an additional 36 weeks of only peginterferon alfa and ribavirin (48 weeks for total course). Monitor HCV RNA at treatment weeks 4, 12, and 24; if concentrations are greater than or equal to 25 International Units/mL, discontinue treatment. If peginterferon alfa or ribavirin is discontinued for any reason, then simeprevir must also be discontinued. Once simeprevir is discontinued, it must not be reinitiated. Simeprevir is also not recommended in patients who have previously failed therapy with other HCV protease inhibitors.

    For the treatment of recurrent hepatitis C infection in patients after liver transplantation†, including those with compensated cirrhosis.
    Oral dosage
    Adults

    150 mg PO daily combined with sofosbuvir with or without ribavirin for 12 to 24 weeks is the preferred regimen.

    MAXIMUM DOSAGE

    Adults

    150 mg/day PO.

    Geriatric

    150 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustments are needed for mild hepatic impairment (Child-Pugh Class A). Avoid use in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C), as drug exposure and risk of adverse reactions are increased in these patients. In addition, the combined use with peginterferon alfa and ribavirin is contraindicated in decompensated cirrhosis (moderate or severe hepatic impairment).

    Renal Impairment

    No dosage adjustments are needed in patients with mild, moderate, or severe renal impairment; however, simeprevir has not been studied in patients with end-stage renal disease (ESRD) and those requiring hemodialysis.

    ADMINISTRATION

     
    NOTE: MUST be administered in combination with either sofosbuvir or peginterferon alfa plus ribavirin; never administer as monotherapy.

    Oral Administration
    Oral Solid Formulations

    Administer with food.
    Swallow capsule whole.

    STORAGE

    Olysio:
    - Protect from light
    - Store below 86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Simeprevir must be used in combination with either sofosbuvir or peginterferon alfa plus ribavirin; therefore, any contraindication to these antiviral medications also applies to simeprevir. See sofosbuvir, ribavirin, or peginterferon alfa monographs for additional information regarding contraindications and warnings associated with these products.

    Male-mediated teratogenicity, pregnancy

    There are no well controlled studies evaluating the use of simeprevir in pregnant women; however, when the drug is administered in combination with peginterferon alfa and ribavirin, use of simeprevir is contraindicated in pregnant women and in the male partners of women who are pregnant. Use of ribavirin may cause birth defects or death of the exposed fetus. Ribavirin therapy also may cause male-mediated teratogenicity and is contraindicated for use during pregnancy, in females who may become pregnant, or 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. Use of peginterferon alfa has produced abortifacient effects in animals, and thus, the potential for abortifacient effects in humans must be considered. Health care providers must also consider the potential for decreased efficacy of systemic hormonal contraception as interferon therapy may decrease serum estradiol and progesterone concentrations. Patients and their partners are required use 2 reliable forms of effective contraception (e.g., intrauterine devices, barrier methods) during treatment and for 6 months post-therapy. Patients who are not willing to practice strict contraception should not receive treatment with simeprevir, peginterferon alfa, and ribavirin. Females must also undergo a pregnancy test prior to initiation of therapy, monthly during therapy, and for 6 months post-therapy. To monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment, health care providers are encouraged to report any cases to the Ribavirin Pregnancy Registry; telephone (800) 593-2214.

    Breast-feeding

    According to the manufacturer, it is not known if simeprevir is excreted in human milk and a decision must be made whether to discontinue nursing or discontinue treatment with the drug. Boceprevir may be considered as an alternative; however, its excretion into human breast milk is also unknown. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.

    Sulfonamide hypersensitivity

    Simeprevir contains a sulfonamide moiety, and may increase the risk for allergic reactions if administered to patients with a sulfonamide hypersensitivity. During clinical trials, subjects with a history of sulfa allergy (n = 16) did not exhibit an increased incidence of rash or photosensitivity. However, according to the manufacturer, data are insufficient to determine if there is an association between sulfonamide hypersensitivity and the frequency or severity of adverse drug reactions (i.e., rash or photosensitivity).

    Sunlight (UV) exposure

    Protective measures to limit sunlight (UV) exposure are recommended during treatment with simeprevir, as photosensitivity reactions have been observed. These reactions may present as an exaggerated sunburn (i.e., skin burning, erythema, exudation, blistering, edema) on areas of the skin exposed to light (e.g., face, neck, extensor surfaces of the forearms, dorsa of the hand). In some cases, reactions have been serious enough to require hospitalization. Although photosensitivity reactions may develop any time during treatment, most cases occurred within the first 4 weeks. Advise patients to limit sun exposure and avoid use of tanning devices while receiving simeprevir. If a photosensitivity reaction develops, discontinue use of the drug and monitor the patient until the reaction has resolved. If continued treatment with simeprevir is required, expert consultation is advised.

    Serious rash

    Rashes have been observed in patients receiving simeprevir. In most cases, these rashes were reported as mild to moderate in severity (Grade 1 or 2); however, 1% of drug recipients developed a serious rash (Grade 3) that required treatment discontinuation. Simeprevir-induced rashes most frequently develop within the first 4 weeks of treatment; however, they may occur at any time. Health care providers are advised to monitor drug recipients for the development of a rash. If a mild to moderate rash is observed, use of the drug may continue. If the rash progresses to include mucosal signs (oral lesions, conjunctivitis) or systemic symptoms, use of the drug should be stopped. In either case, monitor the patient until the rash has resolved.

    Liver transplant

    Safety and efficacy of simeprevir have not been established in patients who have received a liver transplant.

    Hepatic disease

    Avoid use of simeprevir in patients with moderate to severe hepatic disease (Child-Pugh B or C). Use of the drug in these patients can result in elevated steady-state drug exposure, which may increase the risk for adverse events (e.g., elevated bilirubin concentrations, rash, and photosensitivity). It is recommended to monitor liver chemistry tests before and during treatment with simeprevir, as clinically indicated. Close monitoring is advised for those patients with total bilirubin concentrations greater than 2.5-times the upper limit of normal. If elevated bilirubin concentrations are accompanied by elevated transaminase or sign of hepatic decompensation, discontinue use of simeprevir. Cases of hepatic decompensation, hepatic failure, and deaths have been reported during post-marketing use of the drug in patients with advanced or decompensated cirrhosis. Instruct patients to report any symptoms of liver toxicity, such as fatigue, weakness, lack of appetite, nausea, vomiting, jaundice, or discolored urine.

    Children, infants, neonates

    Safe and effective use of simeprevir has not been established in neonates, infants, children, and adolescents younger than 18 years of age.

    Asian patients

    During clinical trials, East Asian patients achieved a mean simeprevir plasma exposure that was 2.1-fold higher than the pooled Phase 3 population from global trials. Despite these higher drug concentrations, the safety profile of simeprevir was found to be comparable between the 2 groups; thus, no dosage adjustments are required for patients of East Asian ancestry.

    Hepatitis C and HIV coinfection

    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.

    Hepatitis B exacerbation

    Use of direct-acting antivirals (DAA), such as simeprevir, 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 simeprevir. Continue to monitor coinfected patients during and after treatment for clinical and laboratory signs of hepatitis B exacerbation (i.e., HBsAg, HBV DNA, hepatic enzymes, bilirubin). In addition, instruct patients to immediately report any signs of liver toxicity (e.g., yellow eyes or skin, fatigue, weakness, loss of appetite, nausea, vomiting, or light-colored stools) to their health care provider. If a simeprevir 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 simeprevir to patients receiving concurrent anticoagulant therapy, specifically warfarin. Fluctuations in International Normalized Ratio (INR) have been observed in warfarin recipients who were also receiving treatment for hepatitis C virus (HCV) infections. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen.

    ADVERSE REACTIONS

    Severe

    hepatic failure / Delayed / Incidence not known

    Moderate

    hyperbilirubinemia / Delayed / 0-27.0
    hyperamylasemia / Delayed / 5.0-26.0
    dyspnea / Early / 12.0-12.0

    Mild

    fatigue / Early / 16.0-32.0
    photosensitivity / Delayed / 12.0-28.0
    rash (unspecified) / Early / 12.0-28.0
    headache / Early / 17.0-23.0
    pruritus / Rapid / 22.0-22.0
    nausea / Early / 13.0-22.0
    diarrhea / Early / 6.0-16.0
    dizziness / Early / 3.0-16.0
    myalgia / Early / 16.0-16.0

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Major) Avoid concurrent use of simeprevir and barbiturates, such as phenobarbital. Induction of CYP3A4 by barbiturates may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Acetaminophen; Butalbital; Caffeine: (Major) Avoid concurrent use of simeprevir and barbiturates, such as phenobarbital. Induction of CYP3A4 by barbiturates may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Avoid concurrent use of simeprevir and barbiturates, such as phenobarbital. Induction of CYP3A4 by barbiturates may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Acetaminophen; Dextromethorphan: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Acetaminophen; Dextromethorphan; Doxylamine: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Acetaminophen; Hydrocodone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of hydrocodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of hydrocodone, such as CNS or respiratory depression.
    Acetaminophen; Oxycodone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of oxycodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of oxycodone, such as CNS and respiratory depression.
    Acetaminophen; Tramadol: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of tramadol, which is partially metabolized by CYP3A4. Monitor patients for adverse effects of tramadol, such as seizures and serotonin syndrome.
    Afatinib: (Moderate) If the concomitant use of simeprevir 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 simeprevir. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and simeprevir is a weak P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Coadministration with simeprevir (150 mg daily for 7 days) increased the Cmax and AUC of another P-gp substrate, digoxin (single dose, 0.5 mg), by 1.31 and 1.39, 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.
    Aldesleukin, IL-2: (Major) Avoid concurrent use of simeprevir and aldesleukin, IL-2. Inhibition of CYP3A4 by aldesleukine, IL-2 may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Alfentanil: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of alfentanil, which is a CYP3A4 substrate. Monitor patients for adverse effects of alfentanil, such as hypotension, nausea, itching, and respiratory depression.
    Alfuzosin: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of alfuzosin, which is a CYP3A4 substrate. Monitor patients for adverse effects of alfuzosin, such as dizziness, hypotension, and syncope.
    Aliskiren; Amlodipine: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    Aliskiren; Valsartan: (Minor) Concomitant use of simeprevir and valsartan may result in increased valsartan plasma concentrations and side effects. Valsartan is metabolized by OATP1B1 in vitro and simeprevir is a OATP1B1 inhibitor. Monitor patients for adverse events such as hypotension, headache, and dizziness.
    Almotriptan: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of almotriptan, which is a CYP3A4 substrate. Monitor patients for adverse effects of almotriptan, such as serotonin syndrome.
    Alogliptin; Pioglitazone: (Moderate) Use caution with concurrent use of simeprevir and pioglitazone. Pioglitazone is a weak CYP3A4 inducer in vitro, and the FDA labeling states that moderate or strong inducers may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. Additionally, simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of pioglitazone, which is a CYP3A4 substrate. Monitor patients for adverse effects of pioglitazone, such as hypoglycemia.
    Alprazolam: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of alprazolam, which is a CYP3A4 substrate. Monitor patients for adverse effects of alprazolam, such as sedation.
    Amiodarone: (Major) Use of orally administered amiodarone with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in amiodarone plasma concentrations; monitoring of amiodarone plasma concentrations (if available) is recommended. However, use of amiodarone should be avoided in patients receiving hepatitis C regimens containing both simeprevir and sofosbuvir due to the potential for serious symptomatic bradycardia. Cases of symptomatic bradycardia, including cases requiring pacemaker intervention, have been reported when amiodarone is administered concurrenlty with simeprevir and sofosbuvir; additionally, a fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir; sofosbuvir). The mechanism of this effect is unknown. If coadministration of all three medications is required, cardiac monitoring in an inpatient setting for the first 48 hours 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 simeprevir in combination with sofosbuvir should also undergo similar cardiac monitoring as outlined above.
    Amitriptyline: (Moderate) Simeprevir, a mild CY1A2 inhibitor and mild intestinal CYP3A4 inhibitor, may increase the side effects of amitriptyline, which is a CYP3A4 and CYP1A2 substrate. Monitor patients for adverse effects of amitriptyline, such as anticholinergic activity, orthostatic hypotension, and sedation.
    Amitriptyline; Chlordiazepoxide: (Moderate) Simeprevir, a mild CY1A2 inhibitor and mild intestinal CYP3A4 inhibitor, may increase the side effects of amitriptyline, which is a CYP3A4 and CYP1A2 substrate. Monitor patients for adverse effects of amitriptyline, such as anticholinergic activity, orthostatic hypotension, and sedation.
    Amlodipine: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    Amlodipine; Atorvastatin: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together. (Moderate) Coadministration of atorvastatin with simeprevir, an inhibitor of OATP1B1 and intestinal CYP3A4, results in increased atorvastatin plasma concentrations. If these drugs are given together, use the lowest effective atorvastatin dose; do not exceed 40 mg daily. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    Amlodipine; Benazepril: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together. (Minor) Concomitant use of simeprevir and valsartan may result in increased valsartan plasma concentrations and side effects. Valsartan is metabolized by OATP1B1 in vitro and simeprevir is a OATP1B1 inhibitor. Monitor patients for adverse events such as hypotension, headache, and dizziness.
    Amlodipine; Olmesartan: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    Amlodipine; Telmisartan: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    Amlodipine; Valsartan: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together. (Minor) Concomitant use of simeprevir and valsartan may result in increased valsartan plasma concentrations and side effects. Valsartan is metabolized by OATP1B1 in vitro and simeprevir is a OATP1B1 inhibitor. Monitor patients for adverse events such as hypotension, headache, and dizziness.
    Amobarbital: (Major) Avoid concurrent use of simeprevir and barbiturates, such as phenobarbital. Induction of CYP3A4 by barbiturates may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid concurrent use of simeprevir and clarithromycin; consider use of azithromycin in place of clarithromycin. Inhibition of CYP3A4 by clarithromycin may increase the plasma concentrations of simeprevir, resulting in adverse effects. (Minor) Simeprevir, a P-glycoprotein (P-gp) and a mild intestinal CYP3A4 inhibitor, may increase the side effects of lansoprazole, which is a P-gp and CYP3A4 substrate. Additionally, increase side effects of simeprevir may occur as lansoprazole is a P-gp inhibitor and simeprevir is a P-gp substrate in vitro. Monitor patients for adverse effects of lansoprazole, such as electrolyte changes, and simeprevir, such as rash and phototoxicity.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concurrent use of simeprevir and clarithromycin; consider use of azithromycin in place of clarithromycin. Inhibition of CYP3A4 by clarithromycin may increase the plasma concentrations of simeprevir, resulting in adverse effects. (Minor) Simeprevir, a P-glycoprotein (P-gp) and a mild intestinal CYP3A4 inhibitor, may increase the side effects of omeprazole, which is a P-gp and CYP3A4 substrate. Additionally, increased side effects of simeprevir may occur as omeprazole is a P-gp inhibitor and simeprevir is a P-gp substrate in vitro. Monitor patients for adverse effects of omeprazole, such as GI events, and simeprevir, such as rash and phototoxicity.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if simeprevir and aprepitant, fosaprepitant are used concurrently and monitor for an increase in simeprevir-related adverse effects for several days after administration of a multi-day aprepitant regimen. Simeprevir is a CYP3A4 substrate in vitro. 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 simeprevir. 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. Simeprevir is also a weak CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Information is not available regarding the use of aprepitant with weak CYP3A4 inhibitors.
    Aripiprazole: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase plasma concentrations of aripiprazole, which is a partial CYP3A4 substrate. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 inhibitor.
    Armodafinil: (Major) Avoid concurrent use of simeprevir and armodafinil. Potential induction of CYP3A4 by armodafinil (an in vitro inducer) may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Artemether; Lumefantrine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of artemether; lumefantrine, which is a CYP3A4 substrate. Monitor patients for adverse effects of artemether; lumefantrine, such as QT prolongation.
    Asenapine: (Moderate) Simeprevir, a mild CYP1A2 and a mild intestinal CYP3A4 inhibitor, may increase the side effects of asenapine, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of asenapine, such as extrapyramidal symptoms; however, because asenapine is metabolized by multiple CYP pathways, a clinically significant interaction is less likely to occur.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid concurrent use of simeprevir and barbiturates, such as phenobarbital. Induction of CYP3A4 by barbiturates may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid concurrent use of simeprevir and barbiturates, such as phenobarbital. Induction of CYP3A4 by barbiturates may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Aspirin, ASA; Omeprazole: (Minor) Simeprevir, a P-glycoprotein (P-gp) and a mild intestinal CYP3A4 inhibitor, may increase the side effects of omeprazole, which is a P-gp and CYP3A4 substrate. Additionally, increased side effects of simeprevir may occur as omeprazole is a P-gp inhibitor and simeprevir is a P-gp substrate in vitro. Monitor patients for adverse effects of omeprazole, such as GI events, and simeprevir, such as rash and phototoxicity.
    Aspirin, ASA; Oxycodone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of oxycodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of oxycodone, such as CNS and respiratory depression.
    Aspirin, ASA; Pravastatin: (Moderate) Although coadministration of pravastatin with simeprevir has not been studied, use of these drugs together is expected to increase pravastatin exposure. If these drugs are given together, titrate the pravastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    Atazanavir: (Major) Avoid concurrent use of simeprevir and atazanavir. Inhibition of CYP3A4 and organic anion transporting polypeptide (OATP1B1) by atazanavir may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Atazanavir; Cobicistat: (Major) Avoid concurrent use of simeprevir and atazanavir. Inhibition of CYP3A4 and organic anion transporting polypeptide (OATP1B1) by atazanavir may increase the plasma concentrations of simeprevir, resulting in adverse effects. (Major) Avoid concurrent use of simeprevir and cobicistat. Inhibition of CYP3A4 by cobicistat may significantly increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Atorvastatin: (Moderate) Coadministration of atorvastatin with simeprevir, an inhibitor of OATP1B1 and intestinal CYP3A4, results in increased atorvastatin plasma concentrations. If these drugs are given together, use the lowest effective atorvastatin dose; do not exceed 40 mg daily. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    Atorvastatin; Ezetimibe: (Moderate) Coadministration of atorvastatin with simeprevir, an inhibitor of OATP1B1 and intestinal CYP3A4, results in increased atorvastatin plasma concentrations. If these drugs are given together, use the lowest effective atorvastatin dose; do not exceed 40 mg daily. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid concurrent use of simeprevir and barbiturates, such as phenobarbital. Induction of CYP3A4 by barbiturates may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Axitinib: (Moderate) Use caution if coadministration of axitinib with simeprevir is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Simeprevir is a weak CYP1A2 and intestinal CYP3A4 inhibitor. Simeprevir increased the AUC and Cmax of oral midazolam, another CYP3A4 substrate, by 1.45-fold and 1.31-fold, respectively; the AUC of IV midazolam was increased by 1.1-fold. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
    Barbiturates: (Major) Avoid concurrent use of simeprevir and barbiturates, such as phenobarbital. Induction of CYP3A4 by barbiturates may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Basiliximab: (Major) Avoid concurrent use of simeprevir and basiliximab. Binding of basiliximab to the IL-2 receptors on activated T cells may allow circulating IL-2 to bind to IL-2 receptors on hepatic and intestinal cells, which may cause a down-regulation of CYP3A4 enzyme activity. Reduced CYP3A4 activity may increase concentrations of CYP3A4 substrates such as simeprevir, resulting in adverse effects.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid concurrent use of simeprevir and barbiturates, such as phenobarbital. Induction of CYP3A4 by barbiturates may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. (Major) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of ergotamine, which is a CYP3A4 substrate. Monitor patients for adverse effects of ergotamine, such as ergot toxicity.
    Bendamustine: (Major) Bendamustine is metabolized to minimally active metabolites by CYP1A2. Concurrent administration of a CYP1A2 inhibitor such as simeprevir (a mild inhibitior) may increase bendamustine concentrations in plasma. Caution should be exercised, or alternative treatments considered, when coadministering bendamustine with a CYP1A2 inhibitor.
    Bexarotene: (Major) Avoid concurrent use of simeprevir and bexarotene. Induction of CYP3A4 by bexarotene may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. Additionally, simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of systemic bexarotene, which is a CYP3A4 substrate. Monitor patients for adverse effects of bexarotene, such as photosensitivity and hyperlipidemia.
    Boceprevir: (Major) Avoid concurrent use of simeprevir and boceprevir. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by boceprivir may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionaly, simeprivir, a P-gp inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of boceprevir, a Pg-p and CYP3A4 substrate.
    Bortezomib: (Moderate) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of bortezomib, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of bortezomib, such as peripheral neuropathy, hematologic toxicities, and GI events.
    Bosentan: (Major) Avoid concurrent use of simeprevir and bosentan. Induction of CYP3A4 by bosentan may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. Additionally, simeprevir, a mild intestinal CYP3A4 inhibitor and an inhibitor of OATP1B1/3, may increase the side effects of bosentan, which is a CYP3A4 and OATP substrate. Monitor patients for adverse effects of bosentan, such as headache, nausea, vomiting, hyptension, and increased heart rate.
    Bosutinib: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of bosutinib, which is a CYP3A4 substrate. Additionally, bosutinib, a P-glycoprotein (P-gp) inhibitor in vitro, may increase plasma concentratins of simeprivier, a P-gp substrate in vitro. FDA-labeling recommends avoiding concomitant moderate and strong CYP3A4 inhibitors with bosutinib. Monitor patients for adverse effects, such as rash, diarrhea, nausea, vomiting, myelosuppresion, and hepatic adverse events.
    Brigatinib: (Major) Coadministration of brigatinib with simeprevir is not recommended due to decreased plasma exposure to simeprevir which may result in decreased efficacy and viral resistance. Simeprevir is a CYP3A4 substrate and brigatinib is a CYP3A4 inducer in vitro.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of hydrocodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of hydrocodone, such as CNS or respiratory depression.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of hydrocodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of hydrocodone, such as CNS or respiratory depression.
    Budesonide: (Minor) Simeprevir, a P-glycoprotein (P-gp) inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of budesonide, which is a CYP3A4 and P-gp substrate. Monitor patients for adverse effects of budesonide, such as excessive HPA-axis suppresion.
    Budesonide; Formoterol: (Minor) Simeprevir, a P-glycoprotein (P-gp) inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of budesonide, which is a CYP3A4 and P-gp substrate. Monitor patients for adverse effects of budesonide, such as excessive HPA-axis suppresion.
    Bupivacaine Liposomal: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of bupivacaine, which is a CYP3A4 substrate. Monitor patients for adverse effects of bupivacaine, such as CNS or respiratory depression.
    Bupivacaine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of bupivacaine, which is a CYP3A4 substrate. Monitor patients for adverse effects of bupivacaine, such as CNS or respiratory depression.
    Bupivacaine; Lidocaine: (Moderate) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of lidocaine, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of lidocaine, such as CNS and cardiovascular effects. (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of bupivacaine, which is a CYP3A4 substrate. Monitor patients for adverse effects of bupivacaine, such as CNS or respiratory depression.
    Buprenorphine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of buprenorphine, which is a CYP3A4 substrate. Monitor patients for adverse effects of buprenorphine, such as CNS or respiratory depression.
    Buprenorphine; Naloxone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of buprenorphine, which is a CYP3A4 substrate. Monitor patients for adverse effects of buprenorphine, such as CNS or respiratory depression.
    Buspirone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of buspirone, which is a CYP3A4 substrate. Monitor patients for adverse effects of buspirone.
    Butabarbital: (Major) Avoid concurrent use of simeprevir and barbiturates, such as phenobarbital. Induction of CYP3A4 by barbiturates may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Cabozantinib: (Moderate) Monitor for an increase in simeprevir-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of simeprevir may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and simeprevir is a substrate of P-gp in vitro; the clinical relevance of this finding is unknown. Cabozantinib is also a CYP3A4 substrate while simeprevir is a weak CYP3A4 inhibitor in vitro; however, this is not expected to have a clinically relevant effect.
    Caffeine; Ergotamine: (Major) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of ergotamine, which is a CYP3A4 substrate. Monitor patients for adverse effects of ergotamine, such as ergot toxicity.
    Canagliflozin: (Moderate) Use caution with concurrent use of simeprevir and canagliflozin as increased plasma concentrations of both drugs may occur. Canagliglozin is a substrate and weak inhibitor of P-glycloprotein (P-gp), while simeprevir is an inhibitor of P-gp and a substrate of P-gp in vitro. Montior for adverse effects, such as rash, hypoglycemia, and hyperkalemia.
    Canagliflozin; Metformin: (Moderate) Use caution with concurrent use of simeprevir and canagliflozin as increased plasma concentrations of both drugs may occur. Canagliglozin is a substrate and weak inhibitor of P-glycloprotein (P-gp), while simeprevir is an inhibitor of P-gp and a substrate of P-gp in vitro. Montior for adverse effects, such as rash, hypoglycemia, and hyperkalemia.
    Carbamazepine: (Major) Avoid concurrent use of simeprevir and carbamazepine. Induction of CYP3A4 by carbamazepine may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of hydrocodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of hydrocodone, such as CNS or respiratory depression.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of hydrocodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of hydrocodone, such as CNS or respiratory depression.
    Carvedilol: (Moderate) Concomitant use of simeprevir and carvedilol may result in increased carvedilol plasma concentrations and side effects. Carvedilol is partially metabolized by P-glycoprotein (P-gp) and simeprevir inhibits P-gp. Monitor patients for adverse events such as cardivascular events.
    Ceritinib: (Major) Avoid coadministration of ceritinib with simeprevir due to increased simeprevir exposure; concomitant use is not recommended. Ceritinib is a CYP3A4 inhibitor and simeprevir is primarily metabolized by CYP3A4. Coadministration with a moderate CYP3A4 inhibitor increased simeprevir exposure by approximately 7.5-fold.
    Cerivastatin: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of cerivastatin, which is a CYP3A4 substrate. Monitor patients for adverse effects of cerivastatin, such as myopathy and rhabdomyolysis.
    Cevimeline: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of cevimeline, which is a CYP3A4 substrate. Monitor patients for adverse effects of cevimeline, such as GI events and hyperhydrosis.
    Chloramphenicol: (Major) Avoid concurrent use of simeprevir and chloramphenicol. Inhibition of CYP3A4 by chloramphenicol may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Chlorpheniramine; Dextromethorphan: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of hydrocodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of hydrocodone, such as CNS or respiratory depression.
    Chlorpheniramine; Hydrocodone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of hydrocodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of hydrocodone, such as CNS or respiratory depression.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of hydrocodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of hydrocodone, such as CNS or respiratory depression.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of hydrocodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of hydrocodone, such as CNS or respiratory depression.
    Cilostazol: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of cilostazol, which is a CYP3A4 substrate. Monitor patients for adverse effects of cilostazol, such as increased bleeding.
    Cimetidine: (Moderate) Use caution with concurrent use of simeprevir and cimetidine. Cimetidine weakly inhibits CYP3A4 which may increase the plasma concentrations of simeprevir, resulting in adverse effects. The FDA-labeling recommends avoiding moderate and strong CYP3A4 inhibitors.
    Cinacalcet: (Moderate) Simeprevir, a mild CYP1A2 and a mild intestinal CYP3A4 inhibitor, may increase the side effects of cinacalcet, which is a CYP1A2 and CYP3A4 substrate. Monitor PTH and calcium concentrations.
    Cisapride: (Major) Avoid concurrent use of simeprevir and cisapride. Inhibition of intestinal CYP3A4 by simeprevir may increase the plasma concentrations of cisapride, potentially resulting in adverse events such as cardiac arrhythmias.
    Citalopram: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of citalopram, which is a CYP3A4 substrate. Monitor patients for adverse effects of citalopram, such as QT prolongation, serotonin syndrome, and neuroleptic malignant syndrome.
    Clarithromycin: (Major) Avoid concurrent use of simeprevir and clarithromycin; consider use of azithromycin in place of clarithromycin. Inhibition of CYP3A4 by clarithromycin may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Clobazam: (Moderate) Use caution with concurrent use of simeprevir and clobazam. Clobazam is a weak CYP3A4 inducer, and the FDA labeling states that moderate or strong inducers may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. Additionally, simeprevir, a mild intestinal CYP3A4 inhibitor and a P-glycoprotein (P-gp) inhibitor, may increase the side effects of clobazam, which is a CYP3A4 and P-gp substrate. Monitor patients for adverse effects of clobazam, such as CNS effects.
    Clomipramine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of clomipramine, which is a CYP3A4 substrate. Monitor patients for adverse effects of clomipramine, such as QT prolongation.
    Clonazepam: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of clonazepam, which is a CYP3A4 substrate. Monitor patients for adverse effects of clonazepam, such as CNS depression.
    Clopidogrel: (Minor) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may decrease the effects of clopidogrel, which is a partially metabolized by CYP3A4 and CYP1A2 to its active metabolite. Monitor patients for therapeutic effectiveness.
    Clozapine: (Moderate) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of clozapine, which is a CYP1A2 and CYP3A4 substrate. Elevated plasma concentrations of clozapine may increase the risk for QT prolongation, torsade de pointes (TdP), sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 or CYP1A2 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cobicistat: (Major) Avoid concurrent use of simeprevir and cobicistat. Inhibition of CYP3A4 by cobicistat may significantly increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concurrent use of simeprevir and cobicistat. Inhibition of CYP3A4 by cobicistat may significantly increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent use of simeprevir and cobicistat. Inhibition of CYP3A4 by cobicistat may significantly increase the plasma concentrations of simeprevir, resulting in adverse effects. (Moderate) Closely monitor for tenofovir-associated adverse reactions if simeprevir is administered with tenofovir, PMPA. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); simeprevir is an inhibitor of both P-gp and BCRP.
    Cobimetinib: (Moderate) If concurrent use of cobimetinib and simeprevir is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro as well as a P-glycoprotein (P-gp) substrate; simeprevir is a weak inhibitor of both CYP3A and P-gp. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
    Colchicine: (Major) As colchicine is a CYP3A4 and P-glycoprotein (P-gp) substrate and simepriver is mild intestinal CYP3A4 inhibitor and P-gp inhibitor, increased concentrations of colchicine may occur with concurrent use. Dosage adjustments of colchicine may be required. The increase in colchicine concentrations may be greater in patients with renal or hepatic impairment. Use simeprivir with extreme care, if at all, concomitantly with colchicine.
    Conivaptan: (Major) Avoid concomitant use of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and CYP3A4 substrate, and simeprevir, a CYP3A4/P-gp substrate and mild CYP3A4 inhibitor. Coadministration may result in elevated concentrations of both conivaptan and simeprevir. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Crizotinib: (Major) Concurrent use of crizotinib with simeprevir is not recommended due to increased plasma concentrations of simeprevir. Simeprevir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Crizotinib is a moderate CYP3A4 inhibitor as well as an inhibitor of P-gp at clinically relevant concentrations. Coadministration with another moderate CYP3A4 inhibitor increased simeprevir exposure by 7.47-fold.
    Cyclobenzaprine: (Moderate) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of cyclobenzaprine, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of cyclobenzaprine, such as CNS depression.
    Cyclophosphamide: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of cyclophosphamide, which is a CYP3A4 substrate. Monitor patients for adverse effects of cyclophosphamide, such as neurotoxicity.
    Cyclosporine: (Major) Avoid concurrent use of simeprevir and cyclosporine. Inhibition of the hepatic isoenzyme CYP3A4 and the drug transporters OATP1B1 and P-glycoprotein (P-gp) by cyclosporine causes significant increases in the plasma concentrations of simeprevir. Similarly, the plasma concentrations of cyclosporine are increased when administered with simeprevir. Use of these drugs together may increase the potential for adverse events.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with simeprevir, a mild 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 simeprevir in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation andsevere renal impairment (CrCl less than 30 mL/minute), avoid coadministration with simeprevir, 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.
    Daclatasvir: (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.
    Dalfopristin; Quinupristin: (Major) Avoid concurrent use of simeprevir and dalfopristin; quinupristin. Inhibition of CYP3A4 by quinupristin may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Danazol: (Major) Avoid concurrent use of simeprevir and danazol. Inhibition of CYP3A4 by danazol may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Dapsone: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dapsone, which is a CYP3A4 substrate. Monitor patients for adverse effects of dapsone, such as peripheral neuropathy or hematologic changes.
    Darifenacin: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of darifenacin, which is a CYP3A4 substrate. Monitor patients for adverse effects of darifenacin, such as anticholinergic effects.
    Darunavir: (Major) Avoid concurrent use of simeprevir and darunavir boosted with ritonavir. Inhibition of CYP3A4 by darunavir/ritonavir causes increased plasma concentrations of simeprevir, potentially resulting in adverse effects.
    Darunavir; Cobicistat: (Major) Avoid concurrent use of simeprevir and cobicistat. Inhibition of CYP3A4 by cobicistat may significantly increase the plasma concentrations of simeprevir, resulting in adverse effects. (Major) Avoid concurrent use of simeprevir and darunavir boosted with ritonavir. Inhibition of CYP3A4 by darunavir/ritonavir causes increased plasma concentrations of simeprevir, potentially resulting in adverse effects.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concurrent use of simeprevir and ritonavir. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by ritonavir causes significantly increased plasma concentrations of simeprevir, potentially resulting in adverse effects. (Major) Avoid the coadministration of simeprevir and dasabuvir; ombitasvir; paritaprevir; ritonavir. The FDA-approved labeling for simeprevir, a CYP3A4 substrate, states that coadministration with strong CYP3A4 inhibitors, including ritonavir, is not recommended as significant increases in simeprevir could result. Additional metabolic interactions are expected which would lead to elevated plasma concentrations of simeprevir, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Simeprevir is a P-glycoprotein (P-gp) substrate/inhibitor, ritonavir is a P-gp substrate/inhibitor, and dasabuvir, ombitasvir, and paritaprevir are P-gp substrates. Simeprevir and paritaprevir are both OATP1B1/3 substrate/inhibitors. Finally, simeprevir is a mild CYP3A4 inhibitor and dasabuvir, paritaprevir, and ritonavir are CYP3A4 substrates. (Major) Avoid the coadministration of simeprevir and dasabuvir; ombitasvir; paritaprevir; ritonavir. The FDA-approved labeling for simeprevir, a CYP3A4 substrate, states that coadministration with strong CYP3A4 inhibitors, including ritonavir, is not recommended as significant increases in simeprevir could result. Additional metabolic interactions are expected which would lead to elevated plasma concentrations of simeprevir, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Simeprevir is a P-glycoprotein (P-gp) substrate/inhibitor, ritonavir is a P-gp substrate/inhibitor, dasabuvir, ombitasvir, and paritaprevir are P-gp substrates, and paritaprevir is a P-gp inhibitor. Simeprevir and paritaprevir are both OATP1B1/3 substrate/inhibitors. Finally, simeprevir is a mild CYP3A4 inhibitor and dasabuvir, paritaprevir, and ritonavir are CYP3A4 substrates.
    Dasatinib: (Major) Avoid concurrent use of simeprevir and dasatinib. Inhibition of CYP3A4 by dasatinib may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionaly, simeprivir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dasatanib, a CYP3A4 substrate.
    Daunorubicin: (Major) Concomitant use of simeprevir and daunorubicin may result in increased daunorubicin plasma concentrations and side effects. Daunorubicin is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), while simeprevir inhibits P-gp and BCRP. Monitor patients for adverse events such as myelosupression and cardiotoxicity.
    Delavirdine: (Major) Avoid concurrent use of simeprevir and delavirdine. Inhibition of CYP3A4 by delavirdine may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Desloratadine: (Minor) Concomitant use of simeprevir and desloratadine may result in increased desloratadine plasma concentrations and side effects. Desloratadine is metabolized by P-glycoprotein (P-gp) and simeprevir inhibits P-gp. Monitor patients for adverse events such as drowsiness.
    Desloratadine; Pseudoephedrine: (Minor) Concomitant use of simeprevir and desloratadine may result in increased desloratadine plasma concentrations and side effects. Desloratadine is metabolized by P-glycoprotein (P-gp) and simeprevir inhibits P-gp. Monitor patients for adverse events such as drowsiness.
    Dexamethasone: (Major) Avoid concurrent use of simeprevir and systemic dexamethasone. Induction of CYP3A4 by dexamethasone may reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Dexlansoprazole: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dexlansoprazole, which is a CYP3A4 substrate. Monitor patients for adverse effects of dexlansoprazole, such as electroyle changes.
    Dextromethorphan: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Dextromethorphan; Guaifenesin: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Dextromethorphan; Promethazine: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Dextromethorphan; Quinidine: (Moderate) Use of orally administered quinidine with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in quinidine plasma concentrations. If these drugs are administered together, monitoring of quinidine plasma concentrations (if available) is recommended. (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dextromethorphan, which is a CYP3A4 substrate. Monitor patients for adverse effects of dextromethorphan, such as dizziness and drowsiness.
    Diazepam: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of diazepam, which is a CYP3A4 substrate. Monitor patients for adverse effects of diazepam, such as CNS effects and respiratory depression.
    Diclofenac: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of diclofenac, which is a CYP3A4 substrate. Monitor patients for adverse effects of diclofenac, such as bleeding or nephrotoxicity.
    Diclofenac; Misoprostol: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of diclofenac, which is a CYP3A4 substrate. Monitor patients for adverse effects of diclofenac, such as bleeding or nephrotoxicity.
    Digoxin: (Moderate) Coadministration of digoxin with simeprevir, a P-glycoprotein (P-gp) inhibitor, results in increased digoxin plasma concentrations. If these drugs are administered together, routine monitoring of digoxin plasma concentrations is recommended.
    Dihydroergotamine: (Major) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dihydroergotamine, which is a CYP3A4 substrate. Monitor patients for adverse effects of dihydroergotamine, such as ergot toxicity.
    Diltiazem: (Moderate) Coadministration of orally administered diltiazem with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased diltiazem plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of hydrocodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of hydrocodone, such as CNS or respiratory depression.
    Disopyramide: (Moderate) Coadministration of disopyramide with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in disopyramide plasma concentrations. If these drugs are administered together, monitoring of disopyramide plasma concentrations (if available) is recommended.
    Disulfiram: (Minor) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of disulfiram, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of disulfiram.
    Docetaxel: (Moderate) Simeprevir, a P-glycoprotein (P-gp) inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of docetaxel, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of docetaxel, such as myelosuppression and cutaneous reactions.
    Dolasetron: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dolasetron, which is a CYP3A4 substrate. Monitor patients for adverse effects of dolasetron, such as QT prolongation.
    Donepezil: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of donepezil, which is a CYP3A4 substrate. Monitor patients for adverse effects of donepezil, such as cholinomimetic effects.
    Donepezil; Memantine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of donepezil, which is a CYP3A4 substrate. Monitor patients for adverse effects of donepezil, such as cholinomimetic effects.
    Doxorubicin: (Major) Simeprevir, a breast cancer resistance protein (BCRP) inhibitor, P-glycoprotein inhibitor (P-gp), and a mild intestinal CYP3A4 inhibitor, may increase the side effects of doxorubicin, which is a BCRP, P-gp and CYP3A4 substrate. Avoid coadministration of simeprevir and doxorubicin if possible. If avoidance is not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Dronedarone: (Major) Avoid concurrent use of simeprevir and dronedarone. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by dronedarone may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionaly, simeprivir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of dronedarone, a CYP3A4 substrate.
    Dutasteride; Tamsulosin: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of tamsulosin, which is a CYP3A4 substrate. Monitor patients for adverse effects of tamsulosin, such as hypotension, dizziness, syncope, and vertigo.
    Edoxaban: (Moderate) Coadministration of edoxaban and simeprevir may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and simeprevir is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of simeprevir; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Efavirenz: (Major) Avoid concurrent use of simeprevir and efavirenz. Induction of CYP3A4 by efavirenz significantly reduces the plasma concentrations of simeprevir, potentially resulting in treatment failure. Concurrent treatment for 14 days has resulted in decreased Cmax, AUC, and Cmin of simeprevir by 51% (90% CI: 46% to 56%), 71% (90% CI: 67% to 74%), and 91% (90% CI: 88% to 92%), respectively.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid concurrent use of simeprevir and efavirenz. Induction of CYP3A4 by efavirenz significantly reduces the plasma concentrations of simeprevir, potentially resulting in treatment failure. Concurrent treatment for 14 days has resulted in decreased Cmax, AUC, and Cmin of simeprevir by 51% (90% CI: 46% to 56%), 71% (90% CI: 67% to 74%), and 91% (90% CI: 88% to 92%), respectively. (Moderate) Closely monitor for tenofovir-associated adverse reactions if simeprevir is administered with tenofovir, PMPA. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); simeprevir is an inhibitor of both P-gp and BCRP.
    Elbasvir; Grazoprevir: (Major) Concurrent administration of elbasvir with simeprevir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations). Simeprevir is a substrate and inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with simeprevir should be avoided if possible. 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). Simeprevir is a substrate and inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, simeprevir is a weak inhibitor of the organic anion transporting polypeptide (OATP); grazoprevir is a substrate of OATP1B1/3.
    Eletriptan: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of eletriptan, which is a CYP3A4 substrate. Monitor patients for adverse effects of eletriptan, such as cardiovascular events.
    Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of simeprevir and eliglustat is not recommended. Simeprevir is a weak CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias) in these patients.
    Eluxadoline: (Major) When administered concurrently with simeprevir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); simeprevir is an OATP inhibitor and in vitro substrate. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Closely monitor for tenofovir-associated adverse reactions if simeprevir is administered with tenofovir, PMPA. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); simeprevir is an inhibitor of both P-gp and BCRP.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Closely monitor for tenofovir-associated adverse reactions if simeprevir is administered with tenofovir, PMPA. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); simeprevir is an inhibitor of both P-gp and BCRP.
    Enalapril; Felodipine: (Moderate) Coadministration of felodipine with simeprevir, an inhibitor of intestinal CYP3A4, may result in increased felodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    Enzalutamide: (Moderate) Coadministration of simeprevir with enzalutamide is not recommended as there is a potential for decreased simeprevir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Simeprevir is metabolized by CYP3A4 and enzalutamide is a strong CYP3A4 inducer.
    Eplerenone: (Major) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of eplerenone, which is a CYP3A4 substrate. Monitor patients for adverse effects of eplerenone, such as hyperkalemia and hypotension.
    Ergotamine: (Major) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of ergotamine, which is a CYP3A4 substrate. Monitor patients for adverse effects of ergotamine, such as ergot toxicity.
    Erlotinib: (Major) Avoid the coadministration of erlotinib with simeprevir due to the risk of increased erlotinib-related adverse reactions; if concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Simeprevir is a weak CYP3A4 and 1A2 inhibitor. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%; coadministration with simeprevir may also increase erlotinib exposure.
    Erythromycin: (Major) Avoid concurrent use of simeprevir and erythromycin; consider use of azithromycin in place of erythromycin. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by both drugs results in increased plasma concentrations of simeprevir by 647% and erythromycin by 90%. Administering these drugs together may result in adverse effects.
    Erythromycin; Sulfisoxazole: (Major) Avoid concurrent use of simeprevir and erythromycin; consider use of azithromycin in place of erythromycin. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by both drugs results in increased plasma concentrations of simeprevir by 647% and erythromycin by 90%. Administering these drugs together may result in adverse effects.
    Escitalopram: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of escitalopram, which is a CYP3A4 substrate. Monitor patients for adverse effects of escitalopram, such as GI effects or serotonin syndrome.
    Eslicarbazepine: (Major) Avoid concurrent use of simeprevir and eslicarbazepine. Induction of CYP3A4 by eslicarbazepine may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Esomeprazole: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of esomeprazole, which is a CYP3A4 substrate. Monitor patients for adverse effects of esomeprazole, such as GI events.
    Esomeprazole; Naproxen: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of esomeprazole, which is a CYP3A4 substrate. Monitor patients for adverse effects of esomeprazole, such as GI events.
    Estazolam: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of estazolam, which is a CYP3A4 substrate in vitro. Monitor patients for adverse effects of estazolam, such as CNS or respiratory depression.
    Eszopiclone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of eszopiclone, which is a CYP3A4 substrate. Monitor patients for adverse effects of eszopiclone, such as prolonged sedative effects.
    Ethanol: (Major) Avoid concurrent use of simeprevir and ethanol (alcohol). Induction of CYP3A4 by ethanol may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Ethosuximide: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of ethosuximide, which is a CYP3A4 substrate. Monitor patients for adverse effects of ethosuximide, such as CNS or GI effects.
    Etoposide, VP-16: (Minor) Simeprevir, a P-glycoprotein (P-gp) inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of etoposide, VP-16, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of etoposide, such as myelosuppression.
    Etravirine: (Major) Avoid concurrent use of simeprevir and etravirine. Induction of CYP3A4 by etravirine may reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Ezetimibe; Simvastatin: (Moderate) Coadministration of simvastatin with simeprevir, an inhibitor of OATP1B1 and intestinal CYP3A4, results in increased simvastatin plasma concentrations. If these drugs are given together, titrate the simvastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    Felbamate: (Major) Avoid concurrent use of simeprevir and felbamate. Induction of CYP3A4 by felbamate may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Felodipine: (Moderate) Coadministration of felodipine with simeprevir, an inhibitor of intestinal CYP3A4, may result in increased felodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    Fentanyl: (Moderate) Simeprevir, a P-glycoprotein (P-gp) inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of fentanyl, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of fentanyl, such as oversedation, respiratory depression, and hypotension.
    Flecainide: (Moderate) Coadministration of flecainide with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in flecainide plasma concentrations. If these drugs are administered together, monitoring of flecainide plasma concentrations (if available) is recommended.
    Flibanserin: (Major) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including simeprevir, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the risks of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
    Fluconazole: (Major) Avoid concurrent use of simeprevir and fluconazole. Inhibition of CYP3A4 by fluconazole may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Fluoxetine: (Moderate) Use caution with concurrent use of simeprevir and fluoxetine. Fluoxetine weakly inhibits CYP3A4 which may increase the plasma concentrations of simeprevir, resulting in adverse effects. The FDA-labeling recommends avoiding moderate and strong CYP3A4 inhibitors.
    Fluoxetine; Olanzapine: (Moderate) Use caution with concurrent use of simeprevir and fluoxetine. Fluoxetine weakly inhibits CYP3A4 which may increase the plasma concentrations of simeprevir, resulting in adverse effects. The FDA-labeling recommends avoiding moderate and strong CYP3A4 inhibitors. (Minor) Simeprevir is an inhibitor of CYP1A2, which may result in decreased clearance of olanzapine. Decreased metabolism of olanzapine may lead to clinically important adverse reactions such as extrapyramidal symptoms, sedation, or orthostatic hypotension. In addition, olanzapine is associated with a possible risk for QT prolongation and TdP and should be used cautiously with CYP1A2 inhibitors.
    Flurazepam: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of flurazepam, which is a CYP3A4 substrate. Monitor patients for adverse effects of flurazepam, such as CNS effects or respiratory depression.
    Flutamide: (Major) Avoid concurrent use of simeprevir and flutamide. Induction of CYP3A4 by flutamide (an in vitro inducer) may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. Additionally, simeprevir, a mild intestinal CYP3A4 inhibitor and a mild CYP1A2 inhibitor, may increase the side effects of systemic flutamide, which is primarily metabolized by CYP1A2 with CYP3A4 as a minor metabolic pathway. Monitor patients for adverse effects of flutamide, such as libido decrease, impotence, and hot flashes.
    Fluvastatin: (Moderate) Although coadministration of fluvastatin with simeprevir has not been studied, use of these drugs together is expected to increase fluvastatin exposure. If these drugs are given together, titrate the fluvastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    Fluvoxamine: (Major) Avoid concurrent use of simeprevir and fluvoxamine. Inhibition of CYP3A4 by fluvoxamine may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionally, simeprivir, a mild CYP1A2 inhibitor, may increase the side effects of fluvoxaine, a CYP1A2 substrate.
    Fosamprenavir: (Major) Avoid concurrent use of simeprevir and fosamprenavir (with or without ritonavir). Administration of unboosted fosamprenavir with simeprevir may increase or decrease the plasma concentration of simeprevir. However, when fosamprenavir is boosted with ritonavir, the plasma concentration of simeprevir is expected to increase, and could result in adverse effects.
    Fosphenytoin: (Major) Avoid concurrent use of simeprevir and fosphenytoin. Induction of CYP3A4 by phenytoin may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Gefitinib: (Minor) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and simeprevir are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and simeprevir is a weak CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with weak CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Gemfibrozil: (Minor) Use caution with concurrent use of simeprevir and gemfibrozil. Gemfibrozil is an inhibitor of OAT1B1, which may increase the plasma concentrations of simeprevir, a substrate of OATP1B1/3 in vitro, resulting in adverse effects, such as rash.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and simeprevir as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Glecaprevir and simeprevir are both substrates and inhibitors of organic anion transporting polypeptide (OATP) 1B1/3 and P-glycoprotein (P-gp). Additionally, glecaprevir is a substrate of breast cancer resistance protein (BCRP) while simeprevir is an inhibitor of BCRP. (Moderate) Caution is advised with the coadministration of pibrentasvir and simeprevir as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Simeprevir is a substrate of of P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) 1B1/3; pibrentasvir is an inhibitor of these drug transporters. Additionally, pibrentasvir is a substrate of P-gp and BCRP while simeprevir is an inhibitor of P-gp and BCRP.
    Glimepiride; Pioglitazone: (Moderate) Use caution with concurrent use of simeprevir and pioglitazone. Pioglitazone is a weak CYP3A4 inducer in vitro, and the FDA labeling states that moderate or strong inducers may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. Additionally, simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of pioglitazone, which is a CYP3A4 substrate. Monitor patients for adverse effects of pioglitazone, such as hypoglycemia.
    Glyburide: (Moderate) Concomitant use of simeprevir and glyburide may result in increased glyburide plasma concentrations and side effects. Glyburide is metabolized by P-glycoprotein (P-gp) and simeprevir inhibits P-gp. Monitor patients for adverse events such as hypoglycemia.
    Glyburide; Metformin: (Moderate) Concomitant use of simeprevir and glyburide may result in increased glyburide plasma concentrations and side effects. Glyburide is metabolized by P-glycoprotein (P-gp) and simeprevir inhibits P-gp. Monitor patients for adverse events such as hypoglycemia.
    Grapefruit juice: (Major) Avoid concurrent use of simeprevir and grapefruit juice. Inhibition of CYP3A4 by grapefruit juice may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Griseofulvin: (Major) Avoid concurrent use of simeprevir and griseofulvin. Potential induction of CYP3A4 by griseofulvin (an in vitro inducer) may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Guaifenesin; Hydrocodone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of hydrocodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of hydrocodone, such as CNS or respiratory depression.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of hydrocodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of hydrocodone, such as CNS or respiratory depression.
    Haloperidol: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of haloperidol, which is a CYP3A4 substrate. Monitor patients for adverse effects of haloperidol, such as QT prolongation and CNS effects.
    Homatropine; Hydrocodone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of hydrocodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of hydrocodone, such as CNS or respiratory depression.
    Hydrochlorothiazide, HCTZ; Triamterene: (Minor) Concomitant use of simeprevir and triamterene may result in increased triamterene plasma concentrations and side effects. Triamterene is metabolized by CYP1A2 and simeprevir is a mild CYP1A2 inhibitor. Monitor patients for adverse events such as hyperkalemia.
    Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Concomitant use of simeprevir and valsartan may result in increased valsartan plasma concentrations and side effects. Valsartan is metabolized by OATP1B1 in vitro and simeprevir is a OATP1B1 inhibitor. Monitor patients for adverse events such as hypotension, headache, and dizziness.
    Hydrocodone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of hydrocodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of hydrocodone, such as CNS or respiratory depression.
    Hydrocodone; Ibuprofen: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of hydrocodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of hydrocodone, such as CNS or respiratory depression.
    Hydrocodone; Phenylephrine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of hydrocodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of hydrocodone, such as CNS or respiratory depression.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of hydrocodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of hydrocodone, such as CNS or respiratory depression.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of hydrocodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of hydrocodone, such as CNS or respiratory depression.
    Hydrocodone; Pseudoephedrine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of hydrocodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of hydrocodone, such as CNS or respiratory depression.
    Ibuprofen; Oxycodone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of oxycodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of oxycodone, such as CNS and respiratory depression.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with simeprevir, a CYP3A substrate, as simeprevir toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Moderate) Use caution with concurrent use of simeprevir and iloperidone as increased plasma concentrations of both drugs may occur. Iloperidone is a substrate of CYP3A4 and weak inhibitor of P-glycloprotein (P-gp), while simeprevir is a mild intestinal CYP3A4 inhibitor and a substrate of P-gp in vitro. Montior for adverse effects, such as rash, estrapyramidal symptoms, and QT prolongation.
    Imatinib: (Major) Avoid concurrent use of simeprevir and imatinib, STI-571. Inhibition of CYP3A4 by imatinib may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionally, simeprivir, a breast cancer resistance protein (BCRP) inhibitor, P-gp inhibitor, and a mild intestinal CYP3A4 inhibitor, may increase the side effects of imatinib, a BCRP, Pg-p, and CYP3A4 substrate.
    Imipramine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of imipramine, which is a CYP3A4 substrate. Monitor patients for adverse effects of imipramine, such as CNS or cardiovascular effects.
    Indacaterol: (Moderate) Simeprevir is a P-glycoprotein (P-gp) inhibitor and a CYP3A4 inhibitor, and might increase the concentrations and AUC of indacaterol, which is a P-gp and CYP3A4 substrate. When indacaterol has been administered with dual CYP3A4/P-gp inhibitors, the AUC has increased by 1.4- to 1.9-fold, depending on the agent used. An increase in maximal concentrations may also occur. Monitor patients for adverse effects of indacaterol, such as nervousness, tremor, and increased heart rate.
    Indacaterol; Glycopyrrolate: (Moderate) Simeprevir is a P-glycoprotein (P-gp) inhibitor and a CYP3A4 inhibitor, and might increase the concentrations and AUC of indacaterol, which is a P-gp and CYP3A4 substrate. When indacaterol has been administered with dual CYP3A4/P-gp inhibitors, the AUC has increased by 1.4- to 1.9-fold, depending on the agent used. An increase in maximal concentrations may also occur. Monitor patients for adverse effects of indacaterol, such as nervousness, tremor, and increased heart rate.
    Indinavir: (Major) Avoid concurrent use of simeprevir and indinavir. Inhibition of CYP3A4 by indinavir may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Irinotecan Liposomal: (Moderate) Use caution if irinotecan liposomal is coadministered with simeprevir, a weak CYP3A4 inhibitor, due to a possible increased risk of irinotecan-related toxicity. The metabolism of liposomal irinotecan has not been evaluated; however, coadministration of ketoconazole, a strong CYP3A4 and UGT1A1 inhibitor, with non-liposomal irinotecan HCl resulted in increased exposure to both irinotecan and its active metabolite, SN-38.
    Irinotecan: (Moderate) Simeprevir, a breast cancer resistance protein (BCRP) inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of irinotecan, which is a BCRP and CYP3A4 substrate. Monitor patients for adverse effects of irinotecan, such as hematologic and GI events.
    Isavuconazonium: (Major) Avoid concurrent use of simeprevir and isavuconazonium. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by isavuconazole, the active moiety of isavuconazonium, may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionally, simeprivir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of isavuconazole, a sensitive CYP3A4 substrate.
    Isoniazid, INH: (Major) Avoid concurrent use of simeprevir and isoniazid, INH. Inhibition of CYP3A4 by isoniazid may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concurrent use of simeprevir and isoniazid, INH. Inhibition of CYP3A4 by isoniazid may increase the plasma concentrations of simeprevir, resulting in adverse effects. (Major) Avoid concurrent use of simeprevir and rifampin, rifabutin, and rifapentine. Induction of CYP3A4 by the rifamycins may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. When administered with rifampin, the Cmin and AUC of simeprevir decrease by 92% and 48%, respectively.
    Isoniazid, INH; Rifampin: (Major) Avoid concurrent use of simeprevir and isoniazid, INH. Inhibition of CYP3A4 by isoniazid may increase the plasma concentrations of simeprevir, resulting in adverse effects. (Major) Avoid concurrent use of simeprevir and rifampin, rifabutin, and rifapentine. Induction of CYP3A4 by the rifamycins may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. When administered with rifampin, the Cmin and AUC of simeprevir decrease by 92% and 48%, respectively.
    Isradipine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of isradipine, which is a CYP3A4 substrate. Monitor patients for adverse effects of isradipine, such as cardivascular effects, including hypotension.
    Itraconazole: (Major) Simeprevir administration is not recommended during or for 2 weeks after itraconazole therapy. Inhibition of CYP3A4 by itraconazole may significantly increase the plasma concentrations of simeprevir, resulting in adverse effects. Itraconazole is a strong CYP3A4 inhibitor; simeprevir is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the AUC of simeprevir by 7-fold.
    Ivabradine: (Moderate) Use caution during coadministration of ivabradine and simeprevir as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; simeprevir is a mild inhibitor of CYP3A. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ixabepilone: (Moderate) Simeprevir is a mild intestinal CYP3A4 inhibitor. Ixabepilone is a CYP3A4 substrate, and concomitant use of ixabepilone with mild or moderate CYP3A4 inhibitors has not been studied. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. Caution is recommended if ixabepilone is coadministered with a mild or moderate CYP3A4 inhibitor; closely monitor patients for ixabepilone-related toxicities, such as periopheral neuropathy, GI effects, and musculoskeletal effects.
    Ketoconazole: (Major) Avoid concurrent use of simeprevir and ketoconazole. Inhibition of CYP3A4 by ketoconazole may significantly increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Lansoprazole: (Minor) Simeprevir, a P-glycoprotein (P-gp) and a mild intestinal CYP3A4 inhibitor, may increase the side effects of lansoprazole, which is a P-gp and CYP3A4 substrate. Additionally, increase side effects of simeprevir may occur as lansoprazole is a P-gp inhibitor and simeprevir is a P-gp substrate in vitro. Monitor patients for adverse effects of lansoprazole, such as electrolyte changes, and simeprevir, such as rash and phototoxicity.
    Lansoprazole; Naproxen: (Minor) Simeprevir, a P-glycoprotein (P-gp) and a mild intestinal CYP3A4 inhibitor, may increase the side effects of lansoprazole, which is a P-gp and CYP3A4 substrate. Additionally, increase side effects of simeprevir may occur as lansoprazole is a P-gp inhibitor and simeprevir is a P-gp substrate in vitro. Monitor patients for adverse effects of lansoprazole, such as electrolyte changes, and simeprevir, such as rash and phototoxicity.
    Lapatinib: (Major) Avoid concurrent use of simeprevir and lapatinib. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by lapatinib may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionally, simeprivir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of lapatinib, a CYP3A4 substrate.
    Ledipasvir; Sofosbuvir: (Major) Avoid coadministration of ledipasvir with simeprevir. Taking these drugs together increases ledipasvir exposure by 92% and simeprevir exposure by 116%. Use of these drugs together increases the risk for adverse effects. (Major) Avoid coadministration of sofosbuvir with simeprevir, a P-glycoprotein (P-gp) inhibitor. Taking these drugs together may increase sofosbuvir plasma concentrations, potentially resulting in adverse effects.
    Lidocaine: (Moderate) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of lidocaine, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of lidocaine, such as CNS and cardiovascular effects.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP3A4 and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with simeprevir, a mild CYP3A4 and P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP3A4 and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with simeprevir, a mild CYP3A4 and P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Major) Avoid concurrent use of simeprevir and lopinavir; ritonavir. Inhibition of CYP3A4, organic anion transporting polypeptide (OATP1B1), and P-glycoprotein (P-gp) by lopinavir; ritonavir may increase the plasma concentrations of simeprevir, resulting in adverse effects. (Major) Avoid concurrent use of simeprevir and ritonavir. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by ritonavir causes significantly increased plasma concentrations of simeprevir, potentially resulting in adverse effects.
    Loratadine: (Minor) Theoretically, simeprevir could lead to elevated loratadine concentrations due to P-glycoprotein and mild intestinal CYP3A4 inhibition. Elevated loratadine serum concentrations do not result in clinically significant QT prolongation, ECG changes, or any significant differences in adverse reactions compared to control patients. However, caution should be exercised with using this drug combination in a patient with concurrent risk factors for arrhythmogenic events. Although significant drug interactions have not been confirmed between loratadine and agents that inhibit CYP, caution should be used when loratadine is administered with highly potent CYP3A4 inhibitors due to the serious nature of interactions between these drugs and certain other H1-antagonists.
    Loratadine; Pseudoephedrine: (Minor) Theoretically, simeprevir could lead to elevated loratadine concentrations due to P-glycoprotein and mild intestinal CYP3A4 inhibition. Elevated loratadine serum concentrations do not result in clinically significant QT prolongation, ECG changes, or any significant differences in adverse reactions compared to control patients. However, caution should be exercised with using this drug combination in a patient with concurrent risk factors for arrhythmogenic events. Although significant drug interactions have not been confirmed between loratadine and agents that inhibit CYP, caution should be used when loratadine is administered with highly potent CYP3A4 inhibitors due to the serious nature of interactions between these drugs and certain other H1-antagonists.
    Lovastatin: (Moderate) Although coadministration of lovastatin with simeprevir has not been studied, use of these drugs together is expected to increase lovastatin exposure. If these drugs are given together, titrate the lovastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    Lovastatin; Niacin: (Moderate) Although coadministration of lovastatin with simeprevir has not been studied, use of these drugs together is expected to increase lovastatin exposure. If these drugs are given together, titrate the lovastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor is expected to alter the systemic exposure of simeprevir; concurrent use is not recommended as it may result in treatment failure. In vitro studies indicate simeprevir is a primary substrate and mild inhibitor of CYP3A and a substrate of the P-glycoprotein (P-gp) efflux transporter. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp. Although induction of simeprevir metabolism through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear.
    Lurasidone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of lurasidone, which is a CYP3A4 substrate. Monitor patients for adverse effects of lurasidone, such as dizziness, drowsiness, othorstatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures.
    Maraviroc: (Minor) Use caution if coadministration of maraviroc with simepravir is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A and P-glycoprotein (P-gp) substrate and simepravir is a weak CYP3A4/P-gp inhibitor. Monitor for an increase in adverse effects with concomitant use.
    Mefloquine: (Moderate) Use caution with concurrent use of simeprevir and mefloquine as increased plasma concentrations of both drugs may occur. Mefloquine is a substrate of CYP3A4 and P-glycloprotein (P-gp) as well as an inhibitor of P-gp, while simeprevir is a mild intestinal CYP3A4 inhibitor and a substrate of P-gp in vitro. Montior for adverse effects, such as rash, estrapyramidal symptoms, and QT prolongation.
    Mephobarbital: (Major) Avoid concurrent use of simeprevir and barbiturates, such as phenobarbital. Induction of CYP3A4 by barbiturates may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Metformin; Pioglitazone: (Moderate) Use caution with concurrent use of simeprevir and pioglitazone. Pioglitazone is a weak CYP3A4 inducer in vitro, and the FDA labeling states that moderate or strong inducers may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. Additionally, simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of pioglitazone, which is a CYP3A4 substrate. Monitor patients for adverse effects of pioglitazone, such as hypoglycemia.
    Metformin; Repaglinide: (Moderate) Simeprevir, an inhibitor of OATP1B1/3 and a mild intestinal CYP3A4 inhibitor, may increase the side effects of repaglinide, which is a OATP1B1 and CYP3A4 substrate. Monitor patients for adverse effects of repaglinide, such as hypoglycemia.
    Methadone: (Moderate) Simeprevir, a P-glycoprotein (P-gp) inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of methadone, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of methadone, such as CNS and respiratory depression.
    Methohexital: (Major) Avoid concurrent use of simeprevir and barbiturates, such as phenobarbital. Induction of CYP3A4 by barbiturates may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Methotrexate: (Minor) Systemic exposure of methotrexate, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with simeprevir, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of methotrexate; monitor patients for potential adverse effects.
    Methylprednisolone: (Minor) Simeprevir, a P-glycoprotein (P-gp) inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of methylprednisolone, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of methylprednisolone, such as enhanced adrenal suppression.
    Metyrapone: (Major) Avoid concurrent use of simeprevir and metyrapone. Induction of CYP3A4 by metyrapone may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Mexiletine: (Moderate) Coadministration of mexiletine with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in mexiletine plasma concentrations. If these drugs are administered together, monitoring of mexiletine plasma concentrations (if available) is recommended.
    Midazolam: (Moderate) Coadministration of orally administered midazolam with simeprevir, an intestinal CYP3A4 inhibitor, results in increased midazolam plasma concentrations. Caution is advised if these drugs are administered concurrently.
    Mifepristone, RU-486: (Major) Avoid concurrent use of simeprevir and mifepristone, RU-486. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by mifepristone may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionally, simeprivir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of mifepristone, a CYP3A4 substrate.
    Milk Thistle, Silybum marianum: (Major) Avoid concurrent use of simeprevir and milk thistle, Silybum marianum. Inhibition of CYP3A4 by milk thistle may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Mirabegron: (Moderate) Use caution with concurrent use of simeprevir and mirabegron. Mirabegron is a weak CYP3A4 inhibitor and may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionaly, simeprivir, a P-gp inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of mirabegron, a Pg-p and CYP3A4 substrate.
    Mitotane: (Major) Concomitant use of mitotane with simeprevir is not recommended as it could result in decreased plasma concentrations of simeprevir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mitotane is a strong CYP3A4 inducer and simeprevir is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of simeprevir. When coadministered with another strong CYP3A4 inducer (rifampin 600 mg daily; n = 18), the ratio of simeprevir pharmacokinetic parameters was significantly affected as follows (where 1 = no change): Cmax, 1.31 (90% CI, 1.03 to 1.66), AUC, 0.52 (90% CI, 0.41 to 0.67), and Cmin, 0.08 (90% CI, 0.06 to 0.11).
    Mitoxantrone: (Moderate) Use mitoxantrone and simeprevir together with caution; increased systemic exposure of mitoxantrone may occur resulting in increased mitoxantrone adverse effects. If these drugs are taken together, monitor patients for signs of mitoxantrone adverse effects. Mitoxantrone is a substrate of the breast cancer resistance protein (BCRP) drug transporter and simeprevir may inhibit BCRP.
    Modafinil: (Major) Avoid concurrent use of simeprevir and modafinil. Induction of CYP3A4 by modafinil may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. Additionally, simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of modafinil, which is a CYP3A4 substrate. Monitor patients for adverse effects of modafinil, such as CNS effects.
    Montelukast: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of montelukast, which is a CYP3A4 substrate. Monitor patients for adverse effects of montelukast.
    Morphine: (Moderate) Concomitant use of simeprevir and morphine may result in increased morphine plasma concentrations and side effects. Morphine is metabolized by P-glycoprotein (P-gp) and simeprevir inhibits P-gp. Monitor patients for adverse events such as CNS and respiratory depression.
    Morphine; Naltrexone: (Moderate) Concomitant use of simeprevir and morphine may result in increased morphine plasma concentrations and side effects. Morphine is metabolized by P-glycoprotein (P-gp) and simeprevir inhibits P-gp. Monitor patients for adverse events such as CNS and respiratory depression.
    Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with simeprevir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; simeprevir is a moderate P-gp inhibitor.
    Nateglinide: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of nateglinide, which is a CYP3A4 substrate. Monitor patients for adverse effects of nateglinide, such as hypoglycemic effects.
    Nebivolol; Valsartan: (Minor) Concomitant use of simeprevir and valsartan may result in increased valsartan plasma concentrations and side effects. Valsartan is metabolized by OATP1B1 in vitro and simeprevir is a OATP1B1 inhibitor. Monitor patients for adverse events such as hypotension, headache, and dizziness.
    Nefazodone: (Major) Avoid concurrent use of simeprevir and nefazodone. Inhibition of CYP3A4 by nefazodone may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionally, simeprivir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of nefazodone, a CYP3A4 substrate.
    Nelfinavir: (Major) Avoid concurrent use of simeprevir and nelfinavir. Inhibition of CYP3A4 by nelfinavir may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Neratinib: (Moderate) Monitor for an increase in simeprevir-related adverse reactions if coadministration with neratinib is necessary. Simeprevir is a P-glycoprotein (P-gp) substrate. Neratinib may inhibit the transport of P-gp substrates.
    Nevirapine: (Major) Avoid concurrent use of simeprevir and nevirapine. Induction of CYP3A4 by nevirapine may reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Niacin; Simvastatin: (Moderate) Coadministration of simvastatin with simeprevir, an inhibitor of OATP1B1 and intestinal CYP3A4, results in increased simvastatin plasma concentrations. If these drugs are given together, titrate the simvastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    Nicardipine: (Moderate) Coadministration of orally administered nicardipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased nicardipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    Nifedipine: (Moderate) Coadministration of nifedipine with simeprevir, an inhibitor of intestinal CYP3A4, may result in increased nifedipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    Nimodipine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of nimodipine, which is a CYP3A4 substrate. Monitor patients for adverse effects of nimodipine, such as hypotension.
    Nintedanib: (Moderate) Simeprevir is a mild inhibitor of both CYP3A4 and P-glycoprotein (P-gp); nintedanib is a P-gp substrate and a minor substrate of CYP3A4. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of simeprevir and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Nisoldipine: (Moderate) Coadministration of nisoldipine with simeprevir, an inhibitor of intestinal CYP3A4, may result in increased nisoldipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    Obeticholic Acid: (Minor) Obeticholic acid may increase the exposure to simeprevir. Simeprevir is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if these drugs are used together.
    Octreotide: (Major) Avoid concurrent use of simeprevir and octreotide. Octreotide suppresses growth hormone secretion, which may cause a decrease in the metabolic clearance of drugs metabolized by CYP3A4 which may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Olanzapine: (Minor) Simeprevir is an inhibitor of CYP1A2, which may result in decreased clearance of olanzapine. Decreased metabolism of olanzapine may lead to clinically important adverse reactions such as extrapyramidal symptoms, sedation, or orthostatic hypotension. In addition, olanzapine is associated with a possible risk for QT prolongation and TdP and should be used cautiously with CYP1A2 inhibitors.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concurrent use of simeprevir and ritonavir. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by ritonavir causes significantly increased plasma concentrations of simeprevir, potentially resulting in adverse effects. (Major) Avoid the coadministration of simeprevir and dasabuvir; ombitasvir; paritaprevir; ritonavir. The FDA-approved labeling for simeprevir, a CYP3A4 substrate, states that coadministration with strong CYP3A4 inhibitors, including ritonavir, is not recommended as significant increases in simeprevir could result. Additional metabolic interactions are expected which would lead to elevated plasma concentrations of simeprevir, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Simeprevir is a P-glycoprotein (P-gp) substrate/inhibitor, ritonavir is a P-gp substrate/inhibitor, and dasabuvir, ombitasvir, and paritaprevir are P-gp substrates. Simeprevir and paritaprevir are both OATP1B1/3 substrate/inhibitors. Finally, simeprevir is a mild CYP3A4 inhibitor and dasabuvir, paritaprevir, and ritonavir are CYP3A4 substrates. (Major) Avoid the coadministration of simeprevir and dasabuvir; ombitasvir; paritaprevir; ritonavir. The FDA-approved labeling for simeprevir, a CYP3A4 substrate, states that coadministration with strong CYP3A4 inhibitors, including ritonavir, is not recommended as significant increases in simeprevir could result. Additional metabolic interactions are expected which would lead to elevated plasma concentrations of simeprevir, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Simeprevir is a P-glycoprotein (P-gp) substrate/inhibitor, ritonavir is a P-gp substrate/inhibitor, dasabuvir, ombitasvir, and paritaprevir are P-gp substrates, and paritaprevir is a P-gp inhibitor. Simeprevir and paritaprevir are both OATP1B1/3 substrate/inhibitors. Finally, simeprevir is a mild CYP3A4 inhibitor and dasabuvir, paritaprevir, and ritonavir are CYP3A4 substrates.
    Omeprazole: (Minor) Simeprevir, a P-glycoprotein (P-gp) and a mild intestinal CYP3A4 inhibitor, may increase the side effects of omeprazole, which is a P-gp and CYP3A4 substrate. Additionally, increased side effects of simeprevir may occur as omeprazole is a P-gp inhibitor and simeprevir is a P-gp substrate in vitro. Monitor patients for adverse effects of omeprazole, such as GI events, and simeprevir, such as rash and phototoxicity.
    Omeprazole; Sodium Bicarbonate: (Minor) Simeprevir, a P-glycoprotein (P-gp) and a mild intestinal CYP3A4 inhibitor, may increase the side effects of omeprazole, which is a P-gp and CYP3A4 substrate. Additionally, increased side effects of simeprevir may occur as omeprazole is a P-gp inhibitor and simeprevir is a P-gp substrate in vitro. Monitor patients for adverse effects of omeprazole, such as GI events, and simeprevir, such as rash and phototoxicity.
    Oritavancin: (Major) Simeprevir is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of simeprevir may be reduced if these drugs are administered concurrently. Caution is warranted with the concomitant oritavancin and simeprevir. The effects of oritavancin on simeprevir have not been determined; however, the manufacturer warns that coadministration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir and lead to loss of efficacy, which may result in treatment failure.
    Oxcarbazepine: (Major) Avoid concurrent use of simeprevir and oxcarbazepine. Induction of CYP3A4 by oxcarbazepine may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Oxybutynin: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of oxybutynin, which is a CYP3A4 substrate. Monitor patients for adverse effects of oxybutynin, such as CNS and anticholinergic effects.
    Oxycodone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of oxycodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of oxycodone, such as CNS and respiratory depression.
    Paclitaxel: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of paclitaxel, which is a CYP3A4 substrate. Monitor patients for adverse effects of paclitaxel, such as myelosuppression, myalgia/arthralgia, and peripheral neuropathy.
    Palbociclib: (Moderate) Monitor for an increase in simeprevir-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A while simeprevir is a CYP3A4 substrate. Coadministration of simeprevir with a moderate CYP3A4 inhibitor increased the simeprevir AUC by more than 7-fold. Although the simeprevir manufacturer does not provide recommendations for use with weak CYP3A4 inhibitors, coadministration may also increase simeprevir exposure.
    Pantoprazole: (Moderate) Close clinical monitoring is advised when administering pantoprazole with simeprevir due to an increased potential for pantoprazole or simeprevir-related adverse events. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of pantoprazole and simeprevir. Both pantoprazole and simeprevir are substrates and inhibitors of the drug efflux transporter, P-glycoprotein (PGP). When used in combination, the plasma concentrations of both medications may be elevated.
    Paricalcitol: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of paricalcitol, which is a CYP3A4 substrate. Monitor patients for adverse effects of paricalcitol, such as nausea and vomiting. Plasma PTH and serum calcium and phosphorous concentrations should be closely monitored.
    Pazopanib: (Moderate) Concurrent administration of simeprevir, a CYP3A4 substrate, with pazopanib, a moderate CYP3A4 inhibitor, may increase simeprevir serum concentrations. In addition, the therapeutic effects of pazopanib, a substrate for CYP3A4, P-glycoprotein (P-gp), and the breast cancer resistant protein (BCRP), may be increased by simeprevir, a P-gp, BCRP, and a mild intestinal CYP3A4 inhibitor. If these drugs are administered together, monitor patients for adverse effects,.
    Pentobarbital: (Major) Avoid concurrent use of simeprevir and barbiturates, such as phenobarbital. Induction of CYP3A4 by barbiturates may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Perampanel: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of perampanel, which is a CYP3A4 substrate. Monitor patients for adverse effects of perampanel, such as CNS and psychiatric events.
    Perindopril; Amlodipine: (Moderate) Coadministration of amlodipine with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased amlodipine plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    Perphenazine; Amitriptyline: (Moderate) Simeprevir, a mild CY1A2 inhibitor and mild intestinal CYP3A4 inhibitor, may increase the side effects of amitriptyline, which is a CYP3A4 and CYP1A2 substrate. Monitor patients for adverse effects of amitriptyline, such as anticholinergic activity, orthostatic hypotension, and sedation.
    Phenobarbital: (Major) Avoid concurrent use of simeprevir and barbiturates, such as phenobarbital. Induction of CYP3A4 by barbiturates may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Phentermine; Topiramate: (Major) Avoid concurrent use of simeprevir and topiramate. Induction of CYP3A4 by topiramate may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Phenytoin: (Major) Avoid concurrent use of simeprevir and phenytoin. Induction of CYP3A4 by phenytoin may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Pimozide: (Major) Simeprevir, a mild CYP1A2 and a mild intestinal CYP3A4 inhibitor, may increase the side effects of pimozide, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of pimozide, such as QT prolongation and CNS effects.
    Pioglitazone: (Moderate) Use caution with concurrent use of simeprevir and pioglitazone. Pioglitazone is a weak CYP3A4 inducer in vitro, and the FDA labeling states that moderate or strong inducers may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. Additionally, simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of pioglitazone, which is a CYP3A4 substrate. Monitor patients for adverse effects of pioglitazone, such as hypoglycemia.
    Pitavastatin: (Moderate) Although coadministration of pitavastatin with simeprevir has not been studied, use of these drugs together is expected to increase pitavastatin exposure. If these drugs are given together, titrate the pitavastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    Posaconazole: (Major) Avoid concurrent use of simeprevir and posaconazole. Inhibition of CYP3A4 by posaconazole may significantly increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Pravastatin: (Moderate) Although coadministration of pravastatin with simeprevir has not been studied, use of these drugs together is expected to increase pravastatin exposure. If these drugs are given together, titrate the pravastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    Prednisolone: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of prednisolone, which is a CYP3A4 substrate. Monitor patients for adverse effects of prednisolone, such as enhanced adrenal suppression.
    Prednisone: (Minor) Simeprevir, a P-glycoprotein (P-gp) inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of prednisone, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of prednisone, such as enhanced adrenal suppression.
    Primidone: (Major) Avoid concurrent use of simeprevir and barbiturates, such as phenobarbital. Induction of CYP3A4 by barbiturates may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Propafenone: (Moderate) Coadministration of propafenone with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in propafenone plasma concentrations. If these drugs are administered together, monitoring of propafenone plasma concentrations (if available) is recommended.
    Quazepam: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of quazepam, which is a CYP3A4 substrate. Monitor patients for adverse effects of quazepam, such as CNS and respiratory depression.
    Quetiapine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of quetiapine, which is a CYP3A4 substrate. Monitor patients for adverse effects of quetiapine, such as QT prolongation and GI effects.
    Quinidine: (Moderate) Use of orally administered quinidine with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in quinidine plasma concentrations. If these drugs are administered together, monitoring of quinidine plasma concentrations (if available) is recommended.
    Quinine: (Major) Interactions between simeprevir and quinine are complicated and coadministration should be avoided. Simeprevir concentrations may be altered as it is a substrate of CYP3A4, while quinine is an inhibitor and an inducer of CYP3A4. Additionally, quinine concentrations may be increased due to inhibition of CYP1A2 and P-glycoprotein (P-gp) as well as mild intestinal CYP3A4 inhibition by simeprevir.
    Rabeprazole: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of rabeprazole, which is a CYP3A4 substrate. Monitor patients for adverse effects of rabeprazole, such as GI effects.
    Ramelteon: (Moderate) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of ramelteon, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of ramelteon, such as CNS effects.
    Ranolazine: (Major) Avoid concurrent use of simeprevir and ranolazine. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by ranolazine may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionally, simeprivir, a P-gp inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of ranolazine, a P-gp and CYP3A4 substrate.
    Rasagiline: (Major) Simeprevir is a mild CYP1A2 inhibitor. Rasagiline plasma concentrations may increase up to 2-fold in patients using concomitant CYP1A2 inhibitors, resulting in the potential for increased adverse events. Adult patients taking concomitant CYP1A2 inhibitors should not exceed a dose of rasagiline 0.5 mg PO once daily. Rasagiline is a selective inhibitor of MAO-B that does not have an alternate metabolic pathway other than CYP1A2 and thus these drug interactions may be of clinical significance. Closely monitor for increased adverse effects including dyskinesia, postural hypotension, headache, nausea or vomiting, loss of appetite, joint pain, dry mouth, abnormal dreams, and falls. Additionally, if therapy with a CYP1A2 inhibitor is halted, the dosage may require adjustment to attain appropriate clinical outcomes.
    Regorafenib: (Major) Avoid concurrent use of simeprevir and regorafenib. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by regorafenib may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionally, simeprivir, a P-gp inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of regorafenib, a P-gp and CYP3A4 substrate.
    Repaglinide: (Moderate) Simeprevir, an inhibitor of OATP1B1/3 and a mild intestinal CYP3A4 inhibitor, may increase the side effects of repaglinide, which is a OATP1B1 and CYP3A4 substrate. Monitor patients for adverse effects of repaglinide, such as hypoglycemia.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with simeprevir is necessary, as the systemic exposure of simeprevir may be increased resulting in increase in treatment-related adverse reactions; adjust the dose of simeprevir if necessary. Exposure to ribociclib may also increase, increasing in ribociclib-related adverse reactions (e.g., neutropenia, QT prolongation). Both simeprevir and ribociclib are CYP3A4 substrates. Simeprevir is also a mild intestinal CYP3A4 inhibitor and ribociclib is a moderate CYP3A4 inhibitor.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with simeprevir is necessary, as the systemic exposure of simeprevir may be increased resulting in increase in treatment-related adverse reactions; adjust the dose of simeprevir if necessary. Exposure to ribociclib may also increase, increasing in ribociclib-related adverse reactions (e.g., neutropenia, QT prolongation). Both simeprevir and ribociclib are CYP3A4 substrates. Simeprevir is also a mild intestinal CYP3A4 inhibitor and ribociclib is a moderate CYP3A4 inhibitor.
    Rifabutin: (Major) Avoid concurrent use of simeprevir and rifampin, rifabutin, and rifapentine. Induction of CYP3A4 by the rifamycins may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. When administered with rifampin, the Cmin and AUC of simeprevir decrease by 92% and 48%, respectively.
    Rifampin: (Major) Avoid concurrent use of simeprevir and rifampin, rifabutin, and rifapentine. Induction of CYP3A4 by the rifamycins may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. When administered with rifampin, the Cmin and AUC of simeprevir decrease by 92% and 48%, respectively.
    Rifamycins: (Major) Avoid concurrent use of simeprevir and rifampin, rifabutin, and rifapentine. Induction of CYP3A4 by the rifamycins may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. When administered with rifampin, the Cmin and AUC of simeprevir decrease by 92% and 48%, respectively.
    Rifapentine: (Major) Avoid concurrent use of simeprevir and rifampin, rifabutin, and rifapentine. Induction of CYP3A4 by the rifamycins may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. When administered with rifampin, the Cmin and AUC of simeprevir decrease by 92% and 48%, respectively.
    Rifaximin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) and organic anion-transporting polypeptide (OATP1A1/1B1/1B3) substrate, with simeprevir, a P-gp and OATP inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp and OATP inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Ritonavir: (Major) Avoid concurrent use of simeprevir and ritonavir. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by ritonavir causes significantly increased plasma concentrations of simeprevir, potentially resulting in adverse effects.
    Rivaroxaban: (Minor) Coadministration of rivaroxaban and simeprevir may result in increases in rivaroxaban exposure and may increase bleeding risk. Simeprevir is a mild inhibitor of P-glycoprotein (P-gp), and rivaroxaban is a substrate of P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Ropinirole: (Moderate) Simeprevir mildly inhibits CYP1A2, which can potentially lead to increased plasma concentrations of ropinirole. If these drugs are coadministered, adjustment of ropinirole dose may be required.
    Ropivacaine: (Moderate) Simeprevir, a mild CYP1A2 inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of ropivacaine, which is a CYP1A2 and CYP3A4 substrate. Monitor patients for adverse effects of ropivacaine, such as hypotension, CNS toxicity, and respiratory depression.
    Rosuvastatin: (Moderate) Coadministration of rosuvastatin with simeprevir, an inhibitor of the breast cancer resistance protein (BCRP) and OATP1B1 transporters, results in increased rosuvastatin plasma concentrations. If these drugs are given together, initiate rosuvastatin therapy at 5 mg once daily; do not exceed 10 mg once daily. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    Sacubitril; Valsartan: (Minor) Concomitant use of simeprevir and valsartan may result in increased valsartan plasma concentrations and side effects. Valsartan is metabolized by OATP1B1 in vitro and simeprevir is a OATP1B1 inhibitor. Monitor patients for adverse events such as hypotension, headache, and dizziness.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and simeprevir as coadministration may result in increased systemic exposure of simeprevir. Simeprevir is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of simeprevir.
    Saquinavir: (Major) Avoid concurrent use of simeprevir and saquinavir. Inhibition of CYP3A4 by saquinavir may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Secobarbital: (Major) Avoid concurrent use of simeprevir and barbiturates, such as phenobarbital. Induction of CYP3A4 by barbiturates may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Sertraline: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of sertraline, which is a CYP3A4 substrate. Monitor patients for adverse effects of sertraline, such as QT prolongation and CNS and GI effects.
    Sibutramine: (Minor) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of sibutramine, which is a CYP3A4 substrate. Although the maginitude of interaction may be small, monitor patients for adverse effects.
    Sildenafil: (Moderate) Coadministration of sildenafil with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in sildenafil plasma concentrations. No dose adjustments are required when treating erectile dysfunction. If treating pulmonary arterial hypertension, start at the lowest sildenafil dose and increase as needed while monitoring clinically.
    Silodosin: (Moderate) Simeprevir, a P-glycoprotein (P-gp) inhibitor and a mild intestinal CYP3A4 inhibitor, may increase the side effects of silodosin, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of silodosin, such as dizziness and hypotension.
    Simvastatin: (Moderate) Coadministration of simvastatin with simeprevir, an inhibitor of OATP1B1 and intestinal CYP3A4, results in increased simvastatin plasma concentrations. If these drugs are given together, titrate the simvastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    Simvastatin; Sitagliptin: (Moderate) Coadministration of simvastatin with simeprevir, an inhibitor of OATP1B1 and intestinal CYP3A4, results in increased simvastatin plasma concentrations. If these drugs are given together, titrate the simvastatin dose carefully and use the lowest effective dose. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
    Sirolimus: (Moderate) Caution is advised when administering simeprevir with sirolimus, as concurrent use may result in altered sirolimus plasma concentrations. Although no dose adjustments are recommended, routine monitoring of sirolimus plasma concentrations is advised.
    Sofosbuvir: (Major) Avoid coadministration of sofosbuvir with simeprevir, a P-glycoprotein (P-gp) inhibitor. Taking these drugs together may increase sofosbuvir plasma concentrations, potentially resulting in adverse effects.
    Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of sofosbuvir with simeprevir, a P-glycoprotein (P-gp) inhibitor. Taking these drugs together may increase sofosbuvir plasma concentrations, potentially resulting in adverse effects. (Moderate) Use caution when administering velpatasvir with simeprevir. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). Simeprevir also inhibits the Breast Cancer Resistance Protein (BCRP); while velpatasvir is a BCRP substrate.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of sofosbuvir with simeprevir, a P-glycoprotein (P-gp) inhibitor. Taking these drugs together may increase sofosbuvir plasma concentrations, potentially resulting in adverse effects. (Moderate) Use caution when administering velpatasvir with simeprevir. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). Simeprevir also inhibits the Breast Cancer Resistance Protein (BCRP); while velpatasvir is a BCRP substrate.
    Solifenacin: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of solifenacin, which is a CYP3A4 substrate. Monitor patients for adverse effects of solifenacin, such as antimuscarinic effects.
    Sorafenib: (Minor) Use caution with concurrent use of simeprevir and sorafenib. Sorafenib is an inhibitor of P-glycloprotein (P-gp) in vitro, which may increase the plasma concentrations of simeprevir, a substrate of P-gp in vitro, resulting in adverse effects, such as rash.
    St. John's Wort, Hypericum perforatum: (Major) Avoid concurrent use of simeprevir and St. John's Wort, Hypericum perforatum. Induction of CYP3A4 by St. John's Wort may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Streptogramins: (Major) Avoid concurrent use of simeprevir and dalfopristin; quinupristin. Inhibition of CYP3A4 by quinupristin may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Sufentanil: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of sufentanil, which is a CYP3A4 substrate. Monitor patients for adverse effects of sufentanil, such as CNS and respiratory depression.
    Sulfasalazine: (Moderate) Systemic exposure of sulfasalazine, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with simeprevir, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of sulfasalazine; monitor patients for potential adverse effects.
    Sunitinib: (Major) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of sunitinib, which is a CYP3A4 substrate. Monitor patients for adverse effects of sunitinib, such as QT prolongation, skin reactions, and bleeding.
    Tadalafil: (Moderate) Coadministration of tadalafil with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in tadalafil plasma concentrations. No dose adjustments are required when treating erectile dysfunction. If treating pulmonary arterial hypertension, start at the lowest tadalafil dose and increase as needed while monitoring clinically.
    Tamoxifen: (Major) Concomitant use of simeprevir and tamoxifen may result in increased simeprevir exposure and decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for increased side effects of simeprevir and changes in the therapeutic efficacy of tamoxifen. Simeprevir is a weak CYP3A4 inhibitor; tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Simeprevir may inhibit the metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Additionally, simeprevir is a substrate of P-glycoprotein (P-gp); tamoxifen inhibits P-gp.
    Tamsulosin: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of tamsulosin, which is a CYP3A4 substrate. Monitor patients for adverse effects of tamsulosin, such as hypotension, dizziness, syncope, and vertigo.
    Telithromycin: (Major) Avoid concurrent use of simeprevir and telithromycin. Inhibition of CYP3A4 by telithromycin may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and simeprevir is necessary, as the systemic exposure of simeprevir may be decreased resulting in reduced efficacy and viral resistance; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of simeprevir as well as an increase in adverse reactions related to telotristat ethyl. Simeprevir 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 simeprevir is a weak P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with simeprevir is necessary, and monitor for an increase in temsirolimus- and simeprevir-related adverse reactions. Temsirolimus is a CYP3A4 substrate, as well as a P-glycoprotein (P-gp) substrate / inhibitor in vitro. Simeprevir is a weak inhibitor of intestinal CYP3A4, but does not affect hepatic CYP3A4 activity; it is also a P-gp substrate (in vitro) and weak inhibitor. Pharmacokinetic data are not available for concomitant use of temsirolimus with weak CYP3A4 inhibitors, or P-gp inhibitors / substrates, but exposure to both simeprevir and temsirolimus (and active metabolite, sirolimus) is likely to increase. When coadministered with oral midazolam, simeprevir increased the mean AUC by a ratio 1.31 (90% CI, 1.19 to 1.45) and AUC by a ratio of 1.45 (90% CI, 1.35 to 1.57); the mean Cmax of IV midazolam decreased by a ratio of 0.78 (90% CI, 0.51 to 1.17), but the AUC increased by a ratio of 1.1 (90% CI, 0.95 to 1.26).
    Teniposide: (Moderate) Simeprevir, a P-glycoprotein (P-gp) and a mild intestinal CYP3A4 inhibitor, may increase the side effects of teniposide, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of teniposide, such as bone marrow suppression and GI effects.
    Tenofovir Alafenamide: (Moderate) Closely monitor for tenofovir-associated adverse reactions if simeprevir is administered with tenofovir alafenamide. Tenofovir alafenamide is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); simeprevir is an inhibitor of both P-gp and BCRP. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir, PMPA: (Moderate) Closely monitor for tenofovir-associated adverse reactions if simeprevir is administered with tenofovir, PMPA. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); simeprevir is an inhibitor of both P-gp and BCRP.
    Teriflunomide: (Minor) Use caution with concurrent use of simeprevir and teriflunomide. Teriflunomide is an inhibitor of OAT1B1, which may increase the plasma concentrations of simeprevir, a substrate of OATP1B1/3 in vitro, resulting in adverse effects, such as rash.
    Theophylline, Aminophylline: (Moderate) Theophylline, aminophylline is primarily metabolized by CYP1A2 isoenzymes. Since the therapeutic range is narrow for theophylline, it is prudent to monitor theophylline serum concentrations upon initiation, dosage adjustment, or discontinuation of medications that may alter the function of CYP1A2, such as simeprevir, which is a mild CYP1A2 inhibitor.
    Thiabendazole: (Moderate) Concomitant use of simeprevir and thiabendazole may result in increased thiabendazole plasma concentrations and side effects. Thiabendazole is primarily metabolized by CYP1A2 and simeprevir is a mild CYP1A2 inhibitor. Monitor patients for adverse events such as anorexia, nausea, vomiting, drowsiness, and dizziness.
    Thiopental: (Major) Avoid concurrent use of simeprevir and barbiturates, such as phenobarbital. Induction of CYP3A4 by barbiturates may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Tiagabine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of tiagabine, which is a CYP3A4 substrate. Monitor patients for adverse effects of tiagabine, such as CNS effects.
    Ticagrelor: (Minor) Coadministration of ticagrelor and simeprevir may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and simeprevir is a mild P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Tinidazole: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of tinidazole, which is a CYP3A4 substrate. Monitor patients for adverse effects of tinidazole, such as GI effects.
    Tipranavir: (Major) Avoid concurrent use of simeprevir and tipranavir. Inhibition of CYP3A4 by tipranavir may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Tizanidine: (Moderate) Tizanidine is primarily metabolized by CYP1A2. Tizanidine clearance may be reduced by coadministration of mild inhibitors of CYP1A2, such as simeprevir. Increased tizanidine concentrations may lead to oversedation, significant hypotension, potential liver problems, and other events.
    Tolterodine: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of tolterodine, which is a CYP3A4 substrate.Tolterodine is metabolized primarily by CYP2D6 and, alternatively, CYP3A4 in those patients who are poor CYP2D6 metabolizers; however, it is difficult to assess which patients will be poor CYP2D6 metabolizers. Monitor patients for adverse effects of tolterodine, such as QT prolongation which is dose-dependent, especially in poor CYP2D6 metabolizers.
    Tolvaptan: (Major) Use caution with concurrent use of simeprevir and tolvaptan as increased plasma concentrations of both drugs may occur. Tolvaptan is a substrate of CYP3A4 and P-glycloprotein (P-gp) as well as an inhibitor of P-gp, while simeprevir is a mild intestinal CYP3A4 inhibitor and a substrate of P-gp in vitro. In general, the use of tolvaptan with CYP3A4 inhibitors should be avoided.
    Topiramate: (Major) Avoid concurrent use of simeprevir and topiramate. Induction of CYP3A4 by topiramate may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Topotecan: (Major) Avoid the concomitant use of simeprevir, a weak P-glycoprotein (P-gp) inhibitor and a breast cancer resistance protein (BCRP) inhibitor, with oral topotecan, a P-gp and BCRP substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of simeprevir and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. Although there is not data with a P-gp inhibitor alone, in a pharmacokinetic cohort study, coadministration of oral topotecan with elacradir, a potent P-gp and BCRP inhibitor, (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant). In a separate study, when oral topotecan was administered concomitantly with escalating doses of a dual BCRP and P-gp inhibitor, exposure to both total topotecan and topotecan lactone increased by approximately 2.5-fold compared with control.
    Trabectedin: (Moderate) Use caution if coadministration of trabectedin and simeprevir is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and simeprevir is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Tramadol: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of tramadol, which is partially metabolized by CYP3A4. Monitor patients for adverse effects of tramadol, such as seizures and serotonin syndrome.
    Trandolapril; Verapamil: (Moderate) Coadministration of orally administered verapamil with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased verapamil plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    Trazodone: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of trazodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of trazodone, such as QT prolongation and drowsiness/sedation.
    Triamterene: (Minor) Concomitant use of simeprevir and triamterene may result in increased triamterene plasma concentrations and side effects. Triamterene is metabolized by CYP1A2 and simeprevir is a mild CYP1A2 inhibitor. Monitor patients for adverse events such as hyperkalemia.
    Triazolam: (Moderate) Coadministration of orally administered triazolam with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in triazolam plasma concentrations. Caution is advised if these drugs are administered concurrently.
    Ulipristal: (Minor) Use caution with concurrent use of simeprevir and ulipristal. Ulipristal is an inhibitor of P-glycloprotein (P-gp) in vitro, which may increase the plasma concentrations of simeprevir, a substrate of P-gp in vitro, resulting in adverse effects, such as rash.
    Valsartan: (Minor) Concomitant use of simeprevir and valsartan may result in increased valsartan plasma concentrations and side effects. Valsartan is metabolized by OATP1B1 in vitro and simeprevir is a OATP1B1 inhibitor. Monitor patients for adverse events such as hypotension, headache, and dizziness.
    Vandetanib: (Moderate) Use caution if coadministration of vandetanib with simeprevir is necessary, due to a possible increase in simeprevir-related adverse reactions. Simeprevir is primarily metabolized by CYP3A, but is also a substrate of P-glycoprotein (P-gp) in vitro. Coadministration with vandetanib increased the Cmax and AUC of digoxin, another P-gp substrate, by 29% and 23%, respectively. Simeprevir is also a weak CYP3A4 inhibitor. While strong CYP3A4 inducers affect serum concentrations of both vandetanib and its active metabolite, N-desmethyl-vandetanib, simeprevir is not expected to affect vandetanib exposure based on a crossover study (n = 14) in which no clinically significant interaction was noted between vandetanib and the strong CYP3A4 inhibitor itraconazole.
    Vardenafil: (Moderate) Coadministration of vardenafil with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in vardenafil plasma concentrations. No dose adjustments are required when treating erectile dysfunction.
    Vemurafenib: (Major) Avoid concurrent use of simeprevir and vemurafenib as the interaction is complex. Induction of CYP3A4 by vemurafenib may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure. However, vemurafenib is also a P-glycoprotein (P-gp) inhbitor, while simeprevir is P-gp substrate in vitro. Additionally, simeprevir, a mild intestinal CYP3A4 inhibitor and P-gp inhibitor, may increase the side effects of vemurafenib, which is a CYP3A4 and P-gp substrate. Monitor patients for adverse effects of vemurafenib, such as QT prolongation.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and simeprevir; venetoclax is a substrate of CYP3A4 and P-glycoprotein (P-gp) and simeprevir is a mild intestinal CYP3A4 inhibitor and P-gp inhibitor. 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 simeprevir 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) Coadministration of orally administered verapamil with simeprevir, an inhibitor of P-glycoprotein (P-gp) and intestinal CYP3A4, may result in increased verapamil plasma concentrations. Caution and clinical monitoring are recommended if these drugs are administered together.
    Vinblastine: (Minor) Simeprevir, a P-glycoprotein (P-gp) and a mild intestinal CYP3A4 inhibitor, may increase the side effects of vinblastine, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of vinblastine, such as myelosupression.
    Vincristine Liposomal: (Minor) Simeprevir, a P-glycoprotein (P-gp) and a mild intestinal CYP3A4 inhibitor, may increase the side effects of vincristine, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of vincristine, such as myelosuppression and neurotoxicity.
    Vincristine: (Minor) Simeprevir, a P-glycoprotein (P-gp) and a mild intestinal CYP3A4 inhibitor, may increase the side effects of vincristine, which is a P-gp and CYP3A4 substrate. Monitor patients for adverse effects of vincristine, such as myelosuppression and neurotoxicity.
    Vinorelbine: (Moderate) Use caution with concurrent use of simeprevir, a weak CYP3A4 inhibitor, and vinorelbine, a CYP3A4 substrate, as the metabolism of vinorelbine may be decreased. Monitor patients for an earlier onset and/or an increased severity of adverse effects including neurotoxicity and myelosuppression.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and simeprevir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with simeprevir, a mild CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Voriconazole: (Major) Avoid concurrent use of simeprevir and voriconazole. Inhibition of CYP3A4 by voriconazole may increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Zafirlukast: (Moderate) Use caution with concurrent use of simeprevir and zafirlukast. Zafirlukast is a minor inhibitor of CYP3A4 which may increase the plasma concentrations of simeprevir, resulting in adverse effects. The FDA-labeling recommends avoiding moderate and strong CYP3A4 inhibitors.
    Ziprasidone: (Major) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of ziprasidone, which is a CYP3A4 substrate. Monitor patients for adverse effects of ziprasidone, such as QT prolongation, CNS effects, and extrapyramidal symptoms.
    Zolpidem: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of zolpidem, which is a CYP3A4 substrate. Monitor patients for adverse effects of zolpidem.
    Zonisamide: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of zonisamide, which is a CYP3A4 substrate. Monitor patients for adverse effects of zonisamide.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no well controlled studies evaluating the use of simeprevir in pregnant women; however, when the drug is administered in combination with peginterferon alfa and ribavirin, use of simeprevir is contraindicated in pregnant women and in the male partners of women who are pregnant. Use of ribavirin may cause birth defects or death of the exposed fetus. Ribavirin therapy also may cause male-mediated teratogenicity and is contraindicated for use during pregnancy, in females who may become pregnant, or 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. Use of peginterferon alfa has produced abortifacient effects in animals, and thus, the potential for abortifacient effects in humans must be considered. Health care providers must also consider the potential for decreased efficacy of systemic hormonal contraception as interferon therapy may decrease serum estradiol and progesterone concentrations. Patients and their partners are required use 2 reliable forms of effective contraception (e.g., intrauterine devices, barrier methods) during treatment and for 6 months post-therapy. Patients who are not willing to practice strict contraception should not receive treatment with simeprevir, peginterferon alfa, and ribavirin. Females must also undergo a pregnancy test prior to initiation of therapy, monthly during therapy, and for 6 months post-therapy. To monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment, health care providers are encouraged to report any cases to the Ribavirin Pregnancy Registry; telephone (800) 593-2214.

    MECHANISM OF ACTION

    Simeprevir prevents hepatitis C viral (HCV) replication by blocking the proteolytic activity of HCV NS3/4A protease. Hepatitis C virus NS3/4A protease is an enzyme responsible for the conversion of HCV encoded polyproteins to mature and functioning viral proteins. These mature proteins, NS4A, NS4B, NS5A, and NS5B, are essential for viral replication.
    Hepatitis C viral resistance to simeprevir has been demonstrated in both cell cultures and during clinical studies. An evaluation of cell cultures found viruses containing amino acid substitutions in the NS3 domain display reduced susceptibility to simeprevir. In HCV genotype 1 infected patients treated with simeprevir, peginterferon, ribavirin who did not achieve sustained viral response during clinical trials, 91% (n = 180 of 197) were found to have emerging amino acid substitutions at NS3 positions (Q80, S122, R155K, D168V). Similarly, NS3 substitutions at Q80, T122, R155, A156, D168 were identified in 88% (n = 30 of 34) of patients with HCV genotype 4 who did not achieve SVR. For those receiving simeprevir in combination with sofosbuvir for treatment of HCV genotype 1, the majority of patients that did not achieve sustained viral response had emerging NS3 amino acid substitutions at position 168 or R155k. Cross-resistance is expected among NS3/4A protease inhibitors (i.e., boceprevir, grazoprevir). No cross-resistance is expected between direct-acting antiviral agents with different mechanisms of action (i.e., NS5A inhibitors, NS5B nucleoside, and non-nucleoside polymerase inhibitors).

    PHARMACOKINETICS

    Simeprevir is administered orally. Following administration, more than 99.9% of the systemically absorbed drug is bound to plasma protein, primarily albumin and, to a smaller degree, alpha 1-acid glycoprotein. It distributes into the gut and liver, with hepatic uptake occurring via the OATP1B1/3 transporter. Once in the liver, simeprevir undergoes oxidative metabolism by CYP3A; involvement of CYP2C8 and CYP2C19 has not been fully excluded. Biliary excretion is the primary elimination route, with 91% of the total dose recovered in the feces; 31% as unchanged drug. Renal clearance is negligible with less than 1% of the dose recovered in the urine. The terminal elimination half-life is 10 to 13 hours in HCV-uninfected patients and 41 hours in HCV-infected patients.
    Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP3A4, P-glycoprotein (P-gp)/MDR1, OATP1B1/3, OATP2B1, BCRP, MRP2, NTCP, BSEP
    Simeprevir is a primarily metabolized by the CYP3A isoenzyme and is a mild inhibitor of intestinal CYP3A4 and CYP1A2; it does not affect hepatic CYP3A4 activity. According to the FDA labeling, coadministration with moderate and strong CYP3A4 inducers or inhibitors is not recommended as this may lead to significantly lower or higher simeprevir exposure, respectively. Additionally, concurrent administration with drugs that are primarily metabolized by CYP3A4 may cause the plasma concentrations of the coadministered drugs to be increased. In vitro studies show simeprevir to be a substrate for the drug transporters P-gp, MRP2, BCRP, OATP1B1/3, and OATP2B1. In addition, simeprevir inhibits the drug uptake transporters OATP1B1/3 and NTCP, and the drug efflux transporters P-gp/MDR1, MRP2, BRCP, and BSEP. Simeprevir does not induce CYP1A2 or CYP3A4, nor does it affect CYP2C9, CYP2C19, CYP2D6, or cathepsin A enzyme activity. Simeprevir does not inhibit OCT2.

    Oral Route

    The mean absolute oral bioavailability of a single simeprevir dose under fed conditions is 62%. Following oral administration, the time to reach maximum plasma concentrations is 4 to 6 hour (Tmax) with steady state simeprevir concentrations achieved after 7 daily doses. Accumulation occurs after repeated dosing, and exposure (AUC) in HCV-infected patients are 2- to 3-fold higher than uninfected subjects. Administration with a high-fat, high-caloric meal (928 kcal) and a normal-caloric meal (533 kcal) increases the relative bioavailability by 61% and 69%, respectively, and delays absorption by 1 hour and 1.5 hours, respectively.