encounter [2:<2 log 10 IU/mL at week 12 during prior interferon-based therapy. 1 Table 3. Recommended Treatment Duration of Simeprevir in Conjunction with Peginterferon Alfa and Ribavirin in Adults with HCV Genotype 1 Infection with HIV Coinfection.1 Patient Type Duration of Simeprevir in Conjunction with Peginterferon Alfa and Ribavirin Duration of Additional Peginterferon Alfa and Ribavirin Total Treatment Duration Treatment-naive ( without cirrhosis) 12 weeks 12 weeks 24 weeks Treatment-naive ( with compensated cirrhosis) 12 weeks 36 weeks 48 weeks Prior relapse ( without cirrhosis) 12 weeks 12 weeks 24 weeks Prior relapse ( with compensated cirrhosis) 12 weeks 36 weeks 48 weeks Prior partial response ( without cirrhosis or with compensated cirrhosis) 12 weeks 36 weeks 48 weeks Prior null response ( without cirrhosis or with compensated cirrhosis) 12 weeks 36 weeks 48 weeks Because patients with inadequate on-treatment viral response to simeprevir in conjunction with peginterferon alfa and ribavirin are unlikely to achieve sustained virologic response (SVR), discontinue treatment in such patients based on plasma HCV RNA levels. 1 (See Table 4.) Table 4. Recommendations for Treatment Discontinuance of Simeprevir in Conjunction with Peginterferon Alfa and Ribavirin in Adults with HCV Genotype 1 Infection and Inadequate On-treatment Virologic Response.1 Treatment Week HCV RNA Level Action Week 4 25 IU/mL Discontinue simeprevir, peginterferon alfa, and ribavirin Week 12 25 IU/mL Discontinue peginterferon alfa and ribavirin (treatment with simeprevir already complete at week 12) Week 24 25 IU/mL Discontinue peginterferon alfa and ribavirin (treatment with simeprevir already complete at week 12) Treatment of Chronic HCV Genotype 4 Infection Simeprevir in Conjunction with Peginterferon Alfa and Ribavirin Oral 150 mg once daily for 12 weeks in conjunction with peginterferon alfa and ribavirin. 1 After completion of 12 weeks of the 3-drug regimen, patients require additional treatment with peginterferon alfa and ribavirin for a total treatment duration that depends on the individual's prior treatment experience (i.e., treatment-naive, prior relapse, prior partial response, prior null response), presence of cirrhosis, and presence of HIV coinfection. 1 (See Table 5 and Table 6.) Prior relapse defined as undetectable HCV RNA at end of prior interferon-based therapy, but detectable HCV RNA during follow-up. 1 Prior partial response defined as on-treatment reduction in HCV RNA 2 log 10 IU/mL from baseline at week 12 during prior interferon-based treatment, but detectable HCV RNA at end of treatment. 1 Prior null response defined as on-treatment reduction in HCV RNA> <2 log 10 IU/mL at week 12 during prior interferon-based therapy. 1 Table 5. Recommended Treatment Duration of Simeprevir in Conjunction with Peginterferon Alfa and Ribavirin in Adults with HCV Genotype 4 Infection without HIV Coinfection.1 Patient Type Duration of Simeprevir in Conjunction with Peginterferon Alfa and Ribavirin Duration of Additional Peginterferon Alfa and Ribavirin Total Treatment Duration Treatment-naive ( without cirrhosis or with compensated cirrhosis) 12 weeks 12 weeks 24 weeks Prior relapse ( without cirrhosis or with compensated cirrhosis) 12 weeks 12 weeks 24 weeks Prior partial response ( without cirrhosis or with compensated cirrhosis) 12 weeks 36 weeks 48 weeks Prior null response ( without cirrhosis or with compensated cirrhosis 12 weeks 36 weeks 48 weeks Prior relapse defined as undetectable HCV RNA at end of prior interferon-based therapy, but detectable HCV RNA during follow-up. 1 Prior partial response defined as on-treatment reduction in HCV RNA 2 log 10 IU/mL from baseline at week 12 during prior interferon-based treatment, but detectable HCV RNA at end of treatment. 1 Prior null response defined as on-treatment reduction in HCV RNA> <2 log 10 IU/mL at week 12 during prior interferon-based therapy. 1 Table 6. Recommended Treatment Duration of Simeprevir in Conjunction with Peginterferon Alfa and Ribavirin in Adults with HCV Genotype 4 Infection with HIV Coinfection.1 Patient Type Duration of Simeprevir in Conjunction with Peginterferon Alfa and Ribavirin Duration of Additional Peginterferon Alfa and Ribavirin Total Treatment Duration Treatment-naive ( without cirrhosis) 12 weeks 12 weeks 24 weeks Treatment-naive ( with compensated cirrhosis) 12 weeks 36 weeks 48 weeks Prior relapse ( without cirrhosis) 12 weeks 12 weeks 24 weeks Prior relapse ( with compensated cirrhosis) 12 weeks 36 weeks 48 weeks Prior partial response ( without cirrhosis or with compensated cirrhosis) 12 weeks 36 weeks 48 weeks Prior null response ( without cirrhosis or with compensated cirrhosis) 12 weeks 36 weeks 48 weeks Because patients with inadequate on-treatment viral response to simeprevir in conjunction with peginterferon alfa and ribavirin are unlikely to achieve SVR, discontinue treatment in such patients based on plasma HCV RNA levels. 1 (See Table 7.) Table 7. Recommendations for Treatment Discontinuance of Simeprevir in Conjunction with Peginterferon Alfa and Ribavirin in Adults with HCV Genotype 4 Infection and Inadequate On-treatment Virologic Response.1 Treatment Week HCV RNA Level Action Week 4 25 IU/mL Discontinue simeprevir, peginterferon alfa, and ribavirin Week 12 25 IU/mL Discontinue peginterferon alfa and ribavirin (treatment with simeprevir already complete at week 12) Week 24 25 IU/mL Discontinue peginterferon alfa and ribavirin (treatment with simeprevir already complete at week 12) Prescribing Limits Adults Treatment of Chronic HCV Infection Oral Maximum 150 mg daily. 1 Special Populations Hepatic Impairment Mild hepatic impairment (Child-Pugh class A): Dosage adjustments not needed. 1 Moderate or severe hepatic impairment (Child-Pugh class B or C): Not recommended. 1 Simeprevir exposure increased in such patients; 1 increased simeprevir exposures associated with increased frequency of adverse effects (e.g., increased bilirubin, rash, photosensitivity). In addition, adverse hepatic effects (e.g., hepatic decompensation, hepatic failure) reported in patients with advanced or decompensated cirrhosis. 1 (See Hepatic Impairment under Cautions.) Renal Impairment Mild, moderate, or severe renal impairment: Dosage adjustments not needed. 1 (See Renal Impairment under Cautions.) Dialysis patients: No specific dosage recommendations; 1 unlikely that dialysis would result in clinically important removal of the drug. 1 Geriatric Patients Dosage adjustments not needed. 1 (See Geriatric Use under Cautions.) East Asian Ancestry Although increased simeprevir exposures reported in patients of East Asian ancestry, dosage adjustments not needed based on race. 1 (See East Asian Ancestry under Cautions.) Cautions for Simeprevir Contraindications Because simeprevir must be used in conjunction with other antivirals, consider contraindications for all antivirals included in the multiple-drug regimen. 1 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions.) Simeprevir used in conjunction with peginterferon alfa and ribavirin is contraindicated in women who are or may become pregnant and in male partners of pregnant women. 1 349 377 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions.) Warnings/Precautions Warnings Risk of HBV Reactivation in Patients Coinfected with HCV and HBV Postmarketing reports of reactivation of HBV infection when DAAs were used for treatment of HCV infection in patients with HBV coinfection; 1 25 fulminant hepatitis, hepatic failure, and death reported in some cases. 1 25 HBV reactivation (abrupt increase in HBV replication manifested as rapid increase in serum HBV DNA levels or detection of HBsAg in an individual who was previously HBsAg negative and anti-HBc positive) reported in patients with HCV and HBV coinfection receiving HCV treatment with a regimen that included HCV DAAs without interferon alfa. 1 25 HBV reactivation usually occurred within 4 8 weeks after initiation of HCV treatment. 25 Patients with HBV reactivation heterogeneous in terms of HCV genotype and baseline HBV disease. 25 Some patients were HBsAg positive; others had serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). 1 25 HBV reactivation also reported in patients receiving certain immunosuppressant or chemotherapeutic drugs; 1 risk of reactivation associated with HCV DAAs may be increased in such patients. 1 Mechanism for HBV reactivation in coinfected patients receiving HCV DAAs unknown. 25 Although HCV DAAs not known to cause immunosuppression, HBV reactivation in coinfected patients may result from a complex interplay of host immunologic responses in the setting of infection with 2 hepatitis viruses. 25 Prior to initiating treatment with an HCV DAA, including simeprevir, screen all patients for evidence of current or prior HBV infection by measuring HBsAg, anti-HBs, and anti-HBc. 1 25 119 If there is serologic evidence of HBV infection, measure baseline HBV DNA level. 25 119 In all patients with evidence of current or prior HBV infection, monitor for clinical and laboratory signs (i.e., HBsAg, HBV DNA levels, serum aminotransferase and bilirubin concentrations) of hepatitis flare or HBV reactivation during and after treatment with HCV DAAs. 1 25 119 Initiate appropriate management for HBV infection as clinically indicated. 1 119 Advise coinfected patients to immediately contact a clinician if they develop any signs or symptoms of serious liver injury. 25 (See Advice to Patients.) When making decisions regarding HBV monitoring or HBV treatment in coinfected patients, consult a clinician with expertise in managing HBV infection. 25 119 Sensitivity Reactions Photosensitivity Photosensitivity reported. 1 Serious photosensitivity reactions requiring hospitalization reported in patients receiving multiple-drug regimen of simeprevir in conjunction with peginterferon alfa and ribavirin. 1 Occurs most frequently during first 4 weeks of treatment, but can occur at any time. 1 May present as exaggerated sunburn reaction, usually affecting areas exposed to light (e.g., face, neck, extensor surfaces of forearms, dorsa of the hands). 1 May manifest as burning, erythema, exudation, blistering, or edema. 1 Warn patients to use sun protective measures, limit sun exposure, and avoid use of tanning devices during simeprevir treatment. 1 (See Advice to Patients.) Consider discontinuing simeprevir if photosensitivity reaction occurs; 1 monitor patient until reaction resolves. 1 If decision made to continue simeprevir in a patient with a photosensitivity reaction, expert consultation advised. 1 Sulfonamide Sensitivity Contains sulfonamide moiety. 1 In clinical trials, increased incidence of rash or photosensitivity reactions not reported in patients with history of sulfa allergy. 1 Insufficient data to exclude association between sulfa allergy and frequency or severity of adverse reactions reported with simeprevir. 1 Other Warnings/Precautions Cardiovascular Effects Postmarketing reports of symptomatic bradycardia, including cases requiring pacemaker intervention, in patients receiving amiodarone concomitantly with an HCV treatment regimen containing sofosbuvir in conjunction another HCV direct-acting antiviral (DAA), including simeprevir. 1 23 Fatal cardiac arrest reported in a patient receiving amiodarone concomitantly with fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir). 1 In most reported cases, bradycardia occurred within hours to days after HCV treatment initiated in patients receiving amiodarone (also has been observed up to 2 weeks after initiation of HCV treatment) and resolved after HCV treatment discontinued. 1 Mechanism for this adverse cardiovascular effect unknown. 1 Patients who may be at increased risk for symptomatic bradycardia if amiodarone used concomitantly with regimen of simeprevir with sofosbuvir include those also receiving a β-adrenergic blocking agent, those with underlying cardiac comorbidities, and/or those with advanced liver disease. Concomitant use of amiodarone and regimen of simeprevir with sofosbuvir not recommended. 1 If there are no alternative HCV treatment options and regimen of simeprevir with sofosbuvir must be used in a patient receiving amiodarone, advise patient about the risk of serious symptomatic bradycardia before initiating HCV treatment. 1 Perform cardiac monitoring in an inpatient setting during first 48 hours of concomitant use of amiodarone and regimen of simeprevir with sofosbuvir; 1 heart rate monitoring should then be performed daily (outpatient or self-monitoring) through at least the first 2 weeks of concomitant use. 1 Similar cardiac monitoring recommended in patients who discontinued amiodarone just prior to initiation of simeprevir with sofosbuvir or if there are no other treatment options and amiodarone must be initiated in a patient already receiving simeprevir with sofosbuvir. 1 Advise patients receiving amiodarone concomitantly with regimen of simeprevir with sofosbuvir to immediately contact clinician if signs or symptoms of bradycardia (e.g., near-fainting or fainting, dizziness, lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion, memory problems) develop. 1 Hepatic Effects Postmarketing reports of hepatic decompensation and hepatic failure, including some fatalities, in patients receiving simeprevir with sofosbuvir or simeprevir in conjunction with peginterferon alfa and ribavirin. 1 Most cases occurred in patients with advanced and/or decompensated cirrhosis at increased risk for hepatic decompensation or hepatic failure. 1 Causal relationship with simeprevir not established. 1 Mild to moderate increases in bilirubin concentrations (both direct and indirect bilirubin) reported in simeprevir clinical trials; 1 these increases generally not associated with elevations in liver aminotransaminase concentrations, did not alter hepatic function, rapidly reversed after treatment discontinued, and occurred more frequently in patients with higher simeprevir exposures. 1 Postmarketing reports of hepatic decompensation with markedly increased bilirubin concentrations. 1 Simeprevir inhibits some bilirubin transporters (e.g., organic anion transport polypeptides [OATP] 1B1 and 1B3, multidrug resistance-associated protein [MRP] 2); 1 this inhibition likely contributes to elevated bilirubin concentrations. 1 Evaluate liver function using appropriate chemistry tests prior to initiation of multiple-drug regimen containing simeprevir and as clinically indicated during treatment. 1 Closely monitor patient if total bilirubin concentration increases to> 2.5 times ULN. 1 Discontinue simeprevir regimen if bilirubin concentration increases are accompanied by aminotransaminase concentration increases or if there are clinical signs and symptoms of hepatic decompensation. 1 Advise patients to immediately contact clinician if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice, or discolored feces while receiving simeprevir. 1 Dermatologic Reactions Rash reported. 1 Occurs most frequently during first 4 weeks of treatment, but can occur at any time. 1 Usually mild or moderate in severity, but severe rash and rash requiring discontinuance reported in patients receiving multiple-drug regimen of simeprevir in conjunction with peginterferon alfa and ribavirin. 1 Monitor patients with mild to moderate rash for possible progression (e.g., development of oral lesions, conjunctivitis, systemic symptoms). 1 If rash becomes severe, discontinue simeprevir. 1 Monitor patient until rash resolves. 1 Interactions Concomitant use with certain drugs is not recommended or requires particular caution. 1 (See Specific Drugs under Interactions.) Precautions Related to Multiple-drug Treatment Regimens Simeprevir must be used in conjunction with other antivirals. 1 Consider cautions, precautions, contraindications, and drug interactions associated with each drug in the multiple-drug regimen. 1 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug. 1 When used in conjunction with sofosbuvir, also consider cautions, precautions, and contraindications associated with sofosbuvir. 1 When used in conjunction with peginterferon alfa and ribavirin, 1 consider that ribavirin may cause fetal toxicity and/or death. 349 377 Extreme care must be taken to avoid pregnancy in female patients and female partners of male patients receiving a ribavirin-containing regimen. 349 377 Obtain a negative pregnancy test for female patients of childbearing potential immediately prior to initiating ribavirin; 349 377 perform pregnancy tests monthly during and for 6 months after ribavirin treatment is completed. 349 377 Women of childbearing potential (and their male partners) and male patients (and their female partners) must use at least 2 forms of effective contraception during and for 6 months after ribavirin treatment is completed. 349 377 Specific Populations Pregnancy No adequate and well-controlled studies using simeprevir in pregnant women. 1 Animal studies show embryofetal developmental toxicity, including fetal loss, in mice at simeprevir exposures 1.9 times higher than exposure in humans at the recommended dosage. 1 No adverse embryofetal developmental toxicities were observed in mice and rats at simeprevir exposures similar to those in humans at the recommended dosage. 1 Advise pregnant women of the potential risk to the fetus. 1 When used in conjunction with peginterferon alfa and ribavirin, 1 consider that ribavirin is contraindicated in pregnant women and male partners of pregnant women. 349 377 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions.) Lactation Not known whether distributed into human milk. 1 In rats, detected in plasma of suckling pups when administered to lactating mother, likely due to distribution into milk. 1 Consider benefits of breast-feeding and importance of the drug to the woman; 1 also consider potential adverse effects on the breast-fed child from the drug or underlying maternal condition. 1 When used in conjunction with peginterferon alfa and ribavirin, 1 consider potential for adverse reactions to ribavirin in nursing infants and discontinue nursing or the ribavirin-containing regimen. 349 377 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions.) Pediatric Use Safety and efficacy not established in pediatric patients <18 years of age. 1 Geriatric Use Insufficient experience in patients 65 years of age to determine whether geriatric patients respond differently than younger adults. 1 Hepatic Impairment Safety and efficacy not established in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh class B or C); 1 not recommended in such patients. 1 Safety and efficacy not established in liver transplant patients. 1 Data from individuals without HCV infection indicate simeprevir exposures increased in patients with moderate or severe hepatic impairment. 1 In clinical trials evaluating simeprevir in conjunction with peginterferon alfa and ribavirin, higher simeprevir exposures were associated with increased frequency of adverse reactions (e.g., increased bilirubin concentrations, rash, photosensitivity). 1 Adverse hepatic effects (e.g., hepatic decompensation, hepatic failure) reported in patients with advanced or decompensated cirrhosis receiving multiple-drug regimen containing simeprevir. 1 (See Hepatic Effects under Cautions.) Based on population pharmacokinetics in HCV-infected patients with mild hepatic impairment (Child-Pugh class A), liver fibrosis stage does not have a clinically important effect on simeprevir pharmacokinetics. 1 Simeprevir dosage adjustments not needed in patients with mild hepatic impairment. 1 Renal Impairment Safety and efficacy not studied in HCV-infected patients with severe renal impairment (Cl cr> <30 mL/minute) or end-stage renal disease. 1 Population pharmacokinetic analysis in HCV-infected patients with mild or moderate renal impairment indicate renal impairment not expected to have clinically important effect on simeprevir exposure. 1 Dosage adjustments not needed in patients with mild, moderate, or severe renal impairment. 1 East Asian Ancestry Phase 3 clinical trial conducted in China and South Korea indicates increased simeprevir exposures in patients of East Asian ancestry compared with simeprevir exposures reported in pooled population from global phase 3 clinical trials. 1 However, simeprevir dosage adjustments not needed based on race. 1 Safety profile of simeprevir in patients with chronic HCV genotype 1 infection in phase 3 clinical trial in China and South Korea generally comparable to that reported in pooled population from global phase 3 clinical trials; 1 however, higher incidence of hyperbilirubinemia reported in East Asian patients who received simeprevir in conjunction with peginterferon alfa and ribavirin compared with East Asian patients who received placebo in conjunction with peginterferon alfa and ribavirin. 1 Increased bilirubin concentrations were not associated with elevated liver aminotransaminase concentrations and were reversible after completion of HCV treatment. 1 HCV-infected with HIV Coinfection Simeprevir exposures slightly lower in individuals with HCV genotype 1 infection and HIV-1 coinfection compared with exposures in HIV-infected individuals without HIV coinfection; 1 not considered clinically important. 1 Safety profile of simeprevir in individuals with HCV genotype 1 infection and HIV-1 coinfection generally comparable to that reported in HCV-infected individuals without HIV coinfection. 1 Common Adverse Effects Simeprevir in conjunction with sofosbuvir: Fatigue, headache, nausea, rash (including photosensitivity), increased amylase concentrations, hyperbilirubinemia, dizziness. 1 Simeprevir in conjunction with peginterferon alfa and ribavirin: Rash (including photosensitivity), pruritus, hyperbilirubinemia, nausea, myalgia, dyspnea. 1 Interactions for Simeprevir Metabolized by CYP3A. 1 Mild inhibitor of CYP1A2 and intestinal CYP3A4 (does not affect hepatic CYP3A4 activity). 1 Does not affect CYP2C9, 2C19, or 2D6 in vivo; 1 does not induce CYP1A2 or 3A4 in vitro. 1 Substrate and inhibitor of P-glycoprotein (P-gp) transport in vitro. 1 Substrate and inhibitor of organic anion transport polypeptides (OATP) 1B1 and 1B3 1 and substrate of OATP2B1 in vitro. 1 Substrate of breast cancer resistance protein (BCRP) 1 and substrate and inhibitor of multidrug resistance-associated protein (MRP) 2 in vitro. 1 Inhibits bile salt export pump (BSEP) and sodium/taurocholate cotransporting polypeptide (NTCP) in vitro. 1 No clinically important inhibitory effects on cathepsin A enzyme activity. 1 Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes Potential pharmacokinetic interactions with drugs metabolized principally by CYP3A with possible increased exposure to such drugs. 1 Potential pharmacokinetic interactions with drugs that are inducers or inhibitors of CYP3A with possible alteration in simeprevir metabolism and concentrations. 1 Drugs Affecting or Affected by P-glycoprotein Transport Potential pharmacokinetic interactions with drugs that are substrates for P-gp transport with possible increased exposure to such drugs. 1 Potential pharmacokinetic interactions with drugs that are inducers or inhibitors of P-gp with possible alteration in simeprevir concentrations. 1 Drugs Affecting or Affected by Organic Anion Transport Polypeptides Potential pharmacokinetic interactions with drugs that are substrates for OATP1B1 or 1B3 with possible increased exposure to such drugs. 1 Specific Drugs Drug Interaction Comments Abacavir Clinically important interactions not expected 1 Antacids Clinically important interactions not expected 1 Antiarrhythmic agents (amiodarone, disopyramide, flecainide, mexiletine, propafenone, quinidine) Amiodarone, disopyramide, flecainide, mexiletine, propafenone, quinidine: Possible increased concentrations of antiarrhythmic agent 1 Amiodarone: Concomitant use with regimen of simeprevir with sofosbuvir may result in serious symptomatic bradycardia 1 23 (mechanism unknown); 1 effect on amiodarone, simeprevir, and sofosbuvir concentrations unknown 1 Disopyramide, flecainide, mexiletine, propafenone, quinidine: Use concomitantly with caution; 1 therapeutic drug monitoring of antiarrhythmic agent recommended, if available 1 Amiodarone and regimen of simeprevir with sofosbuvir: Concomitant use not recommended; 1 if concomitant use required, patient counseling and cardiac monitoring required 1 (see Cardiovascular Effects under Cautions) Amiodarone with simeprevir regimen that does not contain sofosbuvir: Use concomitantly with caution; 1 therapeutic drug monitoring of antiarrhythmic agent recommended, if available 1 Anticoagulants, oral (warfarin) No effect on warfarin pharmacokinetics 1 Dosage adjustments not needed for either drug 1 Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin) Possible decreased simeprevir concentrations; 1 may cause loss of therapeutic effect of the HCV antiviral 1 Concomitant use not recommended 1 Antifungals, azoles Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole: Possible increased simeprevir concentrations 1 Fluconazole, itraconazole, ketoconazole, posaconazole, fluconazole, voriconazole: Concomitant use not recommended 1 Antimycobacterial agents (bedaquiline, rifabutin, rifampin, rifapentine) Bedaquiline: Clinically important interactions not expected 1 Rifabutin, rifampin, rifapentine: Possible decreased simeprevir concentrations; 1 may cause loss of therapeutic effect of the HCV antiviral 1 Rifabutin, rifampin, rifapentine: Concomitant use not recommended 1 Atazanavir Ritonavir-boosted or unboosted atazanavir: Possible altered (increased or decreased) simeprevir concentrations 1 Cobicistat-boosted atazanavir, including fixed combination of atazanavir and cobicistat (atazanavir/cobicistat): Possible increased simeprevir concentrations 1 Ritonavir-boosted or unboosted atazanavir: Concomitant use not recommended 1 200 Cobicistat-boosted atazanavir, including atazanavir/cobicistat: Concomitant use not recommended 1 200 Benzodiazepines (midazolam, triazolam) Oral midazolam: Increased midazolam concentrations and AUC 1 Oral triazolam: Possible increased triazolam concentrations 1 IV midazolam: No clinically important effect on midazolam concentrations or AUC 1 Oral midazolam: Use concomitantly with caution 1 Oral triazolam: Use concomitantly with caution 1 IV midazolam: Dosage adjustments not needed for either drug 1 Buprenorphine Clinically important interactions not expected 1 Caffeine Dosage adjustments not needed 1 Calcium-channel blockers (amlodipine, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, verapamil) Possible increased concentrations of calcium-channel blocker 1 Use concomitantly with caution and clinically monitor patient 1 Cisapride Possible increased cisapride concentrations 1 Concomitant use not recommended 1 Corticosteroids Dexamethasone (systemic): Possible decreased simeprevir concentrations; 1 may lead to loss of therapeutic effect of the HCV antiviral 1 Budesonide, fluticasone, methylprednisolone, prednisone: Clinically important interactions not expected 1 Dexamethasone (systemic): Concomitant use not recommended 1 Daclatasvir Increased daclatasvir concentrations and AUC; 1 178 increased simeprevir concentrations and AUC 1 178 Dosage adjustments not needed for either drug 1 Darunavir Ritonavir-boosted darunavir: Increased darunavir, ritonavir, and simeprevir concentrations and AUCs 1 Cobicistat-boosted darunavir, including fixed combination of darunavir and cobicistat (darunavir/cobicistat): Possible increased simeprevir concentrations 1 Ritonavir-boosted darunavir: Concomitant use not recommended 1 200 Cobicistat-boosted darunavir, including darunavir/cobicistat: Concomitant use not recommended 1 200 Delavirdine Possible increased simeprevir concentrations 1 Concomitant use not recommended 1 Dextromethorphan No clinically important effect on dextromethorphan pharmacokinetics 1 Dosage adjustments not needed for either drug 1 Didanosine Clinically important interactions not expected 1 Digoxin Increased digoxin concentrations and AUC 1 Routine monitoring of digoxin concentrations recommended 1 Dolutegravir Clinically important interactions not expected 1 200 Dosage adjustments not needed 200 Efavirenz Substantially decreased simeprevir concentrations and AUC; 1 no clinically important effect on efavirenz concentrations or AUC 1 Concomitant use not recommended 1 200 Elvitegravir Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (EVG/c/FTC/TAF) or fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/c/FTC/TDF): Possible increased simeprevir concentrations 1 200 EVG/c/FTC/TAF or EVG/c/FTC/TDF: Concomitant use not recommended 1 200 Single-entity elvitegravir used in conjunction with a ritonavir-boosted HIV protease inhibitor: Concomitant use not recommended 200 Emtricitabine Clinically important interactions not expected 1 Escitalopram No clinically important effect on escitalopram pharmacokinetics; 1 slightly decreased simeprevir concentrations and AUC 1 Dosage adjustments not needed for either drug 1 Estrogens/progestins Ethinyl estradiol and norethindrone: No clinically important effect on ethinyl estradiol or norethindrone pharmacokinetics 1 Ethinyl estradiol and norethindrone: Dosage adjustments not needed for either drug 1 Etravirine Possible decreased simeprevir concentrations 1 Concomitant use not recommended 1 200 Fosamprenavir Ritonavir-boosted or unboosted fosamprenavir: Possible altered (increased or decreased) simeprevir concentrations 1 Ritonavir-boosted or unboosted fosamprenavir: Concomitant use not recommended 1 200 Histamine H 2 -receptor antagonists Clinically important interactions not expected 1 HMG-CoA reductase inhibitors (statins) Atorvastatin, rosuvastatin, simvastatin: Increased statin concentrations and AUCs; 1 possible increased risk of myopathy and rhabdomyolysis 1 Fluvastatin, lovastatin, pitavastatin, pravastatin: Possible increased statin concentrations; 1 possible increased risk of myopathy and rhabdomyolysis 1 Atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin: Use lowest necessary dosage; 1 titrate carefully and monitor patient for statin-associated adverse effects 1 Immunosuppressants (cyclosporine, sirolimus, tacrolimus) Cyclosporine: Increased cyclosporine and simeprevir concentrations and AUCs 1 Sirolimus: Altered (increased or decreased) sirolimus concentrations 1 Tacrolimus: Increased simeprevir concentrations and AUC; 1 decreased tacrolimus concentrations and AUC 1 Cyclosporine: Concomitant use not recommended 1 Sirolimus: Routine monitoring of immunosuppressant concentrations recommended 1 Tacrolimus: Dosage adjustments not needed for either drug 1 Indinavir Ritonavir-boosted or unboosted indinavir: Possible altered (increased or decreased) simeprevir concentrations 1 Ritonavir-boosted or unboosted indinavir: Concomitant use not recommended 1 Interferons Interferon: In vitro evidence of synergistic activity against HCV; 9 no in vitro evidence of antagonistic anti-HCV effects 1 9 Peginterferon alfa and ribavirin: No effect on simeprevir concentrations or AUC 1 Lamivudine Clinically important interactions not expected 1 Ledipasvir/sofosbuvir Ledipasvir: Increased ledipasvir and simeprevir concentrations 1 181 Ledipasvir/sofosbuvir: Concomitant use with simeprevir not recommended 1 181 Lopinavir Fixed combination of lopinavir and ritonavir (lopinavir/ritonavir): Possible altered (increased or decreased) simeprevir concentrations 1 Concomitant use not recommended 1 200 Macrolides (azithromycin, clarithromycin, erythromycin, telithromycin) Azithromycin: Clinically important interactions not expected 1 Erythromycin (systemic): Substantially increased simeprevir concentrations and AUC; 1 increased erythromycin concentrations and AUC 1 Clarithromycin, telithromycin (systemic): Possible increased simeprevir concentrations 1 Clarithromycin, erythromycin, telithromycin (systemic): Concomitant use not recommended 1 Maraviroc Clinically important interactions not expected 1 Some experts recommend maraviroc 300 mg committed
a pretty big Simeprevir instantly
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