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Olysio

Generic Name: Simeprevir
Class: HCV Protease Inhibitors
Chemical Name: (2R,3aR,10Z,11aS,12aR,14aR) - N - (Cyclopropylsulfonyl) - 2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a - tetradecahydro - 2 - [[7 - methoxy - 8 - methyl - 2 - [4 - (1 - methylethyl) - 2 - thiazolyl] - 4 - quinolinyl]oxy] - 5 - methyl - 4,14 - dioxo - cyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine - 12a(1H) - carboxamide
Molecular Formula: C38H47N5O7S2
CAS Number: 923604-59-5

Introduction

Antiviral;1 HCV NS3/4A protease inhibitor.1 4 5

Uses for Olysio

Chronic HCV Infection

Treatment of chronic HCV genotype 1 or genotype 4 infection in treatment-naive (previously untreated) or previously treated adults, including those with HIV coinfection.1 2 10 11 12 13 14 119

Must be used in conjunction with other antivirals;1 119 do not use alone.1 119

Usually used in multiple-drug regimen that includes simeprevir and sofosbuvir1 12 119 or multiple-drug regimen that includes simeprevir, peginterferon alfa, and ribavirin.1 10 11 13 14

Not recommended in patients in whom prior treatment with a regimen that included simeprevir or any other HCV protease inhibitor failed.1

Not recommended in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).1 (See Hepatic Impairment under Cautions.)

Efficacy of multiple-drug regimen of simeprevir, peginterferon alfa, and ribavirin for treatment of HCV genotype 1a infection is substantially reduced in patients with NS3 Q80K polymorphism at baseline compared with those without NS3 Q80K polymorphism.1 Screening for NS3 Q80K polymorphism at baseline strongly recommended;1 consider alternate therapy in those with NS3 Q80K polymorphism.1 (See General under Dosage and Administration.)

Treatment of chronic HCV infection is complex and rapidly evolving; consult a specialist to obtain the most up-to-date information.119 Information from the American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA), and International Antiviral Society–USA (IAS–USA) regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at .119

Olysio Dosage and Administration

General

  • Must be used in conjunction with other antivirals;1 do not use alone.1

  • Simeprevir in conjunction with sofosbuvir: Use 12- or 24-week regimen of both drugs, depending on presence or absence of cirrhosis.1 (See Table 1.)

  • Simeprevir in conjunction with peginterferon alfa and ribavirin: Use 12-week regimen of all 3 drugs initially, followed by regimen of peginterferon alfa and ribavirin (without simeprevir).1 Monitor plasma HCV RNA levels as clinically indicated to determine need to discontinue treatment in those who have inadequate on-treatment virologic response.1 Use a sensitive assay with lower limit of quantification of at least 25 IU/mL.1 (See Table 2, Table 3, Table 5, and Table 6.)

  • HCV genotype 1a infection: Screening for presence of NS3 Q80K polymorphism strongly recommended prior to initiation of multiple-drug regimen of simeprevir, peginterferon alfa, and ribavirin;1 consider alternative therapy in those infected with HCV genotype 1a containing the Q80K polymorphism.1 Such screening may be considered (but is not strongly recommended) prior to initiation of multiple-drug regimen of simeprevir and sofosbuvir.1

  • Avoid simeprevir dosage reduction or treatment interruption.1 If simeprevir discontinued due to adverse reactions or inadequate on-treatment virologic response, do not reinitiate.1

  • If adverse reactions potentially related to other antivirals in the multiple-drug regimen occur, adjust dosage (dosage modification) or discontinue these drugs according to respective manufacturer’s prescribing information.1 If any antiviral included in the multiple-drug regimen is discontinued for any reason, simeprevir also should be discontinued.1

  • Prior to and during treatment, perform appropriate laboratory tests to evaluate liver function.1 (See Hepatic Effects under Cautions.)

Administration

Oral Administration

Administer orally once daily with food.1 Swallow capsules whole.1

Dosage

Available as simeprevir sodium;1 dosage expressed in terms of simeprevir.1

Adults

Treatment of Chronic HCV Genotype 1 Infection
Simeprevir in Conjunction with Sofosbuvir
Oral

150 mg once daily1 119 with sofosbuvir (400 mg once daily).119 Continue both drugs for 12 or 24 weeks, depending on whether patient has cirrhosis.1 119 (See Table 1.)

Previously treated defined as patients with prior relapse, prior partial response, or prior null response who failed prior interferon-based treatment.1

Table 1. Recommended Treatment Duration of Simeprevir in Conjunction with Sofosbuvir in Adults with HCV Genotype 1 Infection.1119

Patient Type

Duration of Simeprevir in Conjunction with Sofosbuvir

Treatment-naive or previously treated adults (without cirrhosis)

12 weeks

Treatment-naive or previously treated adults (with cirrhosis)

24 weeks

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 2 and Table 3.)

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 log10 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 log10 IU/mL at week 12 during prior interferon-based therapy.1

Table 2. Recommended Treatment Duration of Simeprevir in Conjunction with Peginterferon Alfa and Ribavirin in Adults with HCV Genotype 1 Infection without HIV Coinfection.1

Patient Type

Duration of Simeprevir in Conjunction with Peginterferon Alfa and Ribavirin

Duration of Additional Peginterferon Alfa and Ribavirin Therapy

Total Treatment Duration

Treatment-naive (with or without cirrhosis)

12 weeks

12 weeks

24 weeks

Prior relapse (with or without cirrhosis)

12 weeks

12 weeks

24 weeks

Prior partial response (with or without cirrhosis)

12 weeks

36 weeks

48 weeks

Prior null response (with or without 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 log10 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 log10 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 cirrhosis)

12 weeks

36 weeks

48 weeks

Prior relapse (without cirrhosis)

12 weeks

12 weeks

24 weeks

Prior relapse (with cirrhosis)

12 weeks

36 weeks

48 weeks

Prior partial response (with or without cirrhosis)

12 weeks

36 weeks

48 weeks

Prior null response (with or without 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 log10 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 log10 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 (with or without cirrhosis)

12 weeks

12 weeks

24 weeks

Prior relapse (with or without cirrhosis)

12 weeks

12 weeks

24 weeks

Prior partial response (with or without cirrhosis)

12 weeks

36 weeks

48 weeks

Prior null response (with or without 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 log10 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 log10 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 cirrhosis)

12 weeks

36 weeks

48 weeks

Prior relapse (without cirrhosis)

12 weeks

12 weeks

24 weeks

Prior relapse (with cirrhosis (without cirrhosis)

12 weeks

36 weeks

48 weeks

Prior partial response (with or without cirrhosis)

12 weeks

36 weeks

48 weeks

Prior null response (with or without 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 Olysio

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

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

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

Category C.1

Use during pregnancy only if potential benefits justify potential risks to fetus.1

Advise women of childbearing potential to avoid pregnancy and to use an effective contraceptive method during simeprevir treatment.1

No adequate and well-controlled studies using simeprevir in pregnant women.1 No evidence of teratogenicity in animal studies, but embryofetal developmental toxicity, including decreased fetal weight, increased fetal skeletal variations, in utero fetal losses and early maternal deaths, and decreased body weight and negative effects on physical growth and development in offspring observed.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

Discontinue nursing or the drug.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 (Clcr <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, dizziness, diarrhea, insomnia, pruritus, rash.1

Simeprevir in conjunction with peginterferon alfa and ribavirin: Rash (including photosensitivity), pruritus, hyperbilirubinemia, nausea, myalgia, dyspnea.1

Interactions for Olysio

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 1B31 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 expected1

Antacids

Clinically important interactions not expected1

Antiarrhythmic agents (amiodarone, disopyramide, flecainide, mexiletine, propafenone, quinidine)

Amiodarone, disopyramide, flecainide, mexiletine, propafenone, quinidine: Possible increased concentrations of antiarrhythmic agent1

Amiodarone: Concomitant use with regimen of simeprevir with sofosbuvir may result in serious symptomatic bradycardia1 23 (mechanism unknown);1 effect on amiodarone, simeprevir, and sofosbuvir concentrations unknown1

Disopyramide, flecainide, mexiletine, propafenone, quinidine: Use concomitantly with caution;1 therapeutic drug monitoring of antiarrhythmic agent recommended, if available1

Amiodarone and regimen of simeprevir with sofosbuvir: Concomitant use not recommended;1 if concomitant use required, patient counseling and cardiac monitoring required1 (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 available1

Anticoagulants, oral (warfarin)

No effect on warfarin pharmacokinetics1

Dosage adjustments not needed for either drug1

Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin)

Possible decreased simeprevir concentrations;1 may cause loss of therapeutic effect of the HCV antiviral1

Concomitant use not recommended1

Antifungals, azoles

Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole: Possible increased simeprevir concentrations1

Fluconazole, itraconazole, ketoconazole, posaconazole, fluconazole, voriconazole: Concomitant use not recommended1

Antimycobacterial agents (bedaquiline, rifabutin, rifampin, rifapentine)

Bedaquiline: Clinically important interactions not expected1

Rifabutin, rifampin, rifapentine: Possible decreased simeprevir concentrations;1 may cause loss of therapeutic effect of the HCV antiviral1

Rifabutin, rifampin, rifapentine: Concomitant use not recommended1

Atazanavir

Ritonavir-boosted or unboosted atazanavir: Possible altered (increased or decreased) simeprevir concentrations1

Fixed combination of atazanavir and cobicistat (atazanavir/cobicistat): Possible increased simeprevir concentrations1

Ritonavir-boosted or unboosted atazanavir: Concomitant use not recommended1 200

Atazanavir/cobicistat: Concomitant use not recommended1 200

Benzodiazepines (midazolam, triazolam)

Oral midazolam: Increased midazolam concentrations and AUC1

Oral triazolam: Possible increased triazolam concentrations1

IV midazolam: No clinically important effect on midazolam concentrations or AUC1

Oral midazolam: Use concomitantly with caution1

Oral triazolam: Use concomitantly with caution1

IV midazolam: Dosage adjustments not needed for either drug1

Buprenorphine

Clinically important interactions not expected1

Caffeine

Dosage adjustments not needed1

Calcium-channel blockers (amlodipine, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, verapamil)

Possible increased concentrations of calcium-channel blocker1

Use concomitantly with caution and clinically monitor patient1

Cisapride

Possible increased cisapride concentrations1

Concomitant use not recommended1

Corticosteroids

Dexamethasone (systemic): Possible decreased simeprevir concentrations;1 may lead to loss of therapeutic effect of the HCV antiviral1

Budesonide, fluticasone, methylprednisolone, prednisone: Clinically important interactions not expected1

Dexamethasone (systemic): Concomitant use not recommended1

Daclatasvir

Increased daclatasvir concentrations and AUC;178 increased simeprevir concentrations and AUC178

Darunavir

Ritonavir-boosted darunavir: Increased darunavir, ritonavir, and simeprevir concentrations and AUCs1

Fixed combination of darunavir and cobicistat (darunavir/cobicistat): Possible increased simeprevir concentrations1

Ritonavir-boosted darunavir: Concomitant use not recommended1 200

Darunavir/cobicistat: Concomitant use not recommended1 200

Delavirdine

Possible increased simeprevir concentrations1

Concomitant use not recommended1

Dextromethorphan

No clinically important effect on dextromethorphan pharmacokinetics1

Dosage adjustments not needed for either drug1

Didanosine

Clinically important interactions not expected1

Digoxin

Increased digoxin concentrations and AUC1

Routine monitoring of digoxin concentrations recommended1

Dolutegravir

Clinically important interactions not expected1

Efavirenz

Substantially decreased simeprevir concentrations and AUC;1 no clinically important effect on efavirenz concentrations or AUC1

Concomitant use not recommended1 200

Elvitegravir

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/c/FTC/TDF) or fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (EVG/c/FTC/TAF): Possible increased simeprevir concentrations1 200

EVG/c/FTC/TDF or EVG/c/FTC/TAF: Concomitant use not recommended1 200

Single-entity elvitegravir used in conjunction with a ritonavir-boosted HIV protease inhibitor: Concomitant use not recommended200

Emtricitabine

Clinically important interactions not expected1

Escitalopram

No clinically important effect on escitalopram pharmacokinetics;1 slightly decreased simeprevir concentrations and AUC1

Dosage adjustments not needed for either drug1

Estrogens/progestins

Ethinyl estradiol and norethindrone: No clinically important effect on ethinyl estradiol or norethindrone pharmacokinetics1

Ethinyl estradiol and norethindrone: Dosage adjustments not needed for either drug1

Etravirine

Possible decreased simeprevir concentrations1

Concomitant use not recommended1 200

Fosamprenavir

Ritonavir-boosted or unboosted fosamprenavir: Possible altered (increased or decreased) simeprevir concentrations1

Ritonavir-boosted or unboosted fosamprenavir: Concomitant use not recommended1 200

Histamine H2-receptor antagonists

Clinically important interactions not expected1

HMG-CoA reductase inhibitors (statins)

Atorvastatin, rosuvastatin, simvastatin: Increased statin concentrations and AUCs1

Lovastatin, pitavastatin, pravastatin: Possible increased statin concentrations1

Fluvastatin: Clinically important interactions not expected1

Atorvastatin: Use lowest necessary atorvastatin dosage;1 do not exceed atorvastatin 40 mg once daily1

Rosuvastatin: Initiate rosuvastatin at 5 mg once daily;1 do not exceed rosuvastatin 10 mg once daily1

Lovastatin, pitavastatin, pravastatin, simvastatin: Use lowest necessary dosage;1 titrate carefully and monitor patient for safety1

Immunosuppressants (cyclosporine, sirolimus, tacrolimus)

Cyclosporine: Increased cyclosporine and simeprevir concentrations and AUCs1

Sirolimus: Altered (increased or decreased) sirolimus concentrations1

Tacrolimus: Increased simeprevir concentrations and AUC;1 decreased tacrolimus concentrations and AUC1

Cyclosporine: Concomitant use not recommended1

Sirolimus: Routine monitoring of immunosuppressant concentrations recommended1

Tacrolimus: Dosage adjustments not needed for either drug1

Indinavir

Ritonavir-boosted or unboosted indinavir: Possible altered (increased or decreased) simeprevir concentrations 1

Ritonavir-boosted or unboosted indinavir: Concomitant use not recommended1

Interferons

Interferon: In vitro evidence of synergistic activity against HCV;9 no in vitro evidence of antagonistic anti-HCV effects1 9

Peginterferon alfa and ribavirin: No effect on simeprevir concentrations or AUC1

Lamivudine

Clinically important interactions not expected1

Ledipasvir/sofosbuvir

Ledipasvir: Increased ledipasvir and simeprevir concentrations181

Ledipasvir/sofosbuvir: Concomitant use with simeprevir not recommended181

Lopinavir

Fixed combination of lopinavir and ritonavir (lopinavir/ritonavir): Possible altered (increased or decreased) simeprevir concentrations1

Concomitant use not recommended1 200

Macrolides (azithromycin, clarithromycin, erythromycin, telithromycin)

Azithromycin: Clinically important interactions not expected1

Erythromycin (systemic): Substantially increased simeprevir concentrations and AUC;1 increased erythromycin concentrations and AUC1

Clarithromycin, telithromycin (systemic): Possible increased simeprevir concentrations1

Clarithromycin, erythromycin, telithromycin (systemic): Concomitant use not recommended1

Maraviroc

Clinically important interactions not expected1

Some experts recommend maraviroc 300 mg twice daily in patients receiving simeprevir200

Methadone

No clinically important effect on methadone pharmacokinetics1

Dosage adjustments not needed for either drug1

Methylphenidate

Clinically important interactions not expected1

Milk thistle (Silybum marianum)

Possible increased simeprevir concentrations1

Concomitant use not recommended1

Naloxone

Clinically important interactions not expected1

Nelfinavir

Ritonavir-boosted or unboosted nelfinavir: Possible altered (increased or decreased) simeprevir concentrations1

Ritonavir-boosted or unboosted nelfinavir: Concomitant use not recommended1

Nevirapine

Possible decreased simeprevir concentrations1

Concomitant use not recommended1 200

Proton-pump inhibitors

Clinically important interactions not expected1

Omeprazole: Slightly increased omeprazole concentrations and AUC1

Omeprazole: Dosage adjustments not needed for either drug1

Raltegravir

No clinically important effect on simeprevir pharmacokinetics1

Dosage adjustments not needed for either drug1

Ribavirin

In vitro evidence of synergistic activity against HCV;9 no in vitro evidence of antagonistic anti-HCV effects1 9

Ribavirin and peginterferon alfa: No effect on simeprevir exposure1

Rilpivirine

No clinically important effect on rilpivirine or simeprevir pharmacokinetics1

Dosage adjustments not needed for either drug1 200

Ritonavir

Substantially increased simeprevir concentrations and AUC1

Concomitant use not recommended1

Saquinavir

Ritonavir-boosted or unboosted saquinavir: Possible altered (increased or decreased) simeprevir concentrations1

Ritonavir-boosted or unboosted saquinavir: Concomitant use not recommended1 200

Sildenafil

Potential increased sildenafil concentrations1

Sildenafil for pulmonary arterial hypertension (PAH): Dosage adjustment of sildenafil may be needed;1 consider using lowest initial dosage and titrate as needed with clinical monitoring1

Sildenafil for erectile dysfunction: Dosage adjustments not needed1

Sofosbuvir

Slightly increased sofosbuvir concentrations and AUC;1 no clinically important effect on simeprevir pharmacokinetics1

No in vitro evidence of antagonistic anti-HCV effects between simeprevir and HCV NS5B polymerase inhibitors1

Dosage adjustments not needed for either drug1

St. John's wort (Hypericum perforatum)

Possible decreased simeprevir concentrations;1 may lead to loss of therapeutic effect of the HCV antiviral1

Concomitant use not recommended1

Stavudine

Clinically important interactions not expected1

Tadalafil

Possible increased tadalafil concentrations1

Tadalafil for PAH: Dosage adjustment of tadalafil may be needed;1 consider using lowest initial dosage and titrate as needed with clinical monitoring1

Tadalafil for erectile dysfunction: Dosage adjustments not needed1

Tenofovir

Tenofovir disoproxil fumarate (tenofovir DF): No clinically important effect on tenofovir pharmacokinetics;1 slightly decreased simeprevir concentrations and AUC1

Tenofovir DF: Dosage adjustments not needed for either drug1

Tipranavir

Ritonavir-boosted tipranavir: Possible altered (increased or decreased) simeprevir concentrations1

Ritonavir-boosted tipranavir: Concomitant use not recommended1 200

Vardenafil

Possible increased vardenafil concentrations 1

Vardenafil for erectile dysfunction: Dosage adjustments not needed1

Zidovudine

Clinically important interactions not expected1

Olysio Pharmacokinetics

Absorption

Bioavailability

Mean absolute bioavailability: 62% following single 150-mg oral dose under fed conditions.1

Peak plasma concentrations achieved approximately 4–6 hours after an oral dose.1

Food

Administration after high-fat, high-caloric (928 kcal) or normal-caloric (533 kcal) breakfast in healthy individuals increased AUC by 61 or 69%, respectively;1 absorption delayed 1 or 1.5 hours, respectively.1

Plasma Concentrations

Based on studies using dosage between 75 and 200 mg, peak plasma concentrations and AUC increase in more-than-dose-proportional manner;1 accumulation occurs following repeated dosing.1

Steady state achieved after 7 days of once-daily dosing.1

Special Populations

AUC in HCV-infected adults is twofold to threefold higher compared with adults without HCV infection.1

Moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment without HCV infection: Mean steady-state AUC is 2.4- or 5.2-fold higher, respectively, compared with those with normal hepatic function.1

HCV-infected with mild hepatic impairment (Child-Pugh class A): Liver fibrosis stage has no clinically important effect on pharmacokinetics.1

Severe renal impairment without HCV infection: Mean steady-state AUC is 62% higher compared with those with normal renal function.1

HCV-infected with mild or moderate renal impairment: Clcr does not affect simeprevir pharmacokinetics.1

Mean simeprevir exposures increased 2.1-fold in patients of East Asian ancestry.1 Population pharmacokinetic exposure estimates are comparable between Caucasian and African American HCV-infected individuals.1

Simeprevir exposures slightly lower in individuals with HCV genotype 1 infection and HIV-1 coinfection compared with HCV-infected individuals without HIV coinfection.1

Population pharmacokinetic analysis indicates age (range 18–73 years), gender, body weight, and body mass index do not affect pharmacokinetics.1

Distribution

Extent

In animals, extensively distributed to gut and liver (liver-to-blood ratio of 29:1 in rats).1

Pharmacokinetic modeling and simulations indicate hepatic uptake in humans is mediated by OATP1B1 and 1B3.1

In rats, detected in plasma of suckling pups when administered to lactating mother, likely due to distribution into milk.1 Not known whether distributed into human milk.1

Plasma Protein Binding

Extensively bound to plasma proteins (>99.9%), mainly albumin and, to lesser extent, alfa 1-acid glycoprotein.1

Special Populations

Plasma protein binding not substantially altered in patients with renal or hepatic impairment.1

Elimination

Metabolism

Oxidative metabolism occurs principally by hepatic CYP3A;1 involvement of CYP2C8 and CYP2C19 cannot be excluded.1

Elimination Route

Elimination occurs by biliary excretion.1 Following single 200-mg oral dose, 91% excreted in feces (31% as unchanged drug);1 <1% eliminated in urine.1

Half-life

41 hours in HCV-infected individuals;1 10–13 hours in individuals without HCV infection.1

Special Populations

Clinically important removal by dialysis unlikely due to high plasma protein binding.1

Stability

Storage

Oral

Capsules

Room temperature <30º C.1

Store in original container;1 protect from light.1

Actions and Spectrum

  • Selective inhibitor of HCV NS3/4A protease.1 4 Direct-acting antiviral (DAA) with activity against HCV.1 5

  • Binds noncovalently to active site of HCV NS3/4A protease, thereby blocking enzyme activity essential for viral replication (i.e., cleavage of HCV-encoded polyprotein at NS3/NS4A, NS4A/NS4B, NS4A/NS5A, and NS5A/NS5B junctions).5

  • In vitro studies using cell-based replicon assays indicate simeprevir has activity against HCV genotypes 1a, 1b, 4a, 4d, and 4r.1 5 8 9 Also has some activity against HCV genotypes 2, 5, and 6 (not genotype 3).5 8

  • Certain amino acid substitutions in NS3 protease domain of HCV genotype 1a and 1b (e.g., F43, Q80, S122, R155, A156, D168) have been associated with reduced susceptibility to simeprevir in vitro in replicon studies.1 5 8 Such mutations have been identified at baseline and have emerged during simeprevir treatment.1 Presence of NS3 Q80K was associated with a 10-fold reduction in susceptibility to simeprevir in replicon studies.3

  • In clinical trials in patients with HCV genotype 1a infection, presence of NS3 Q80K polymorphism at baseline was associated with reduced response to simeprevir in conjunction with peginterferon alfa and ribavirin.1 Prevalence of NS3 Q80K polymorphism at baseline in US populations of initial clinical trials was 48 or 0% in those with HCV genotype 1a or genotype 1b infection, respectively.1 Other baseline polymorphisms resulting in reduced response to the drug in clinical trials were uncommon.1 Treatment-emergent NS3 amino acid substitutions at Q80, S122, R155, and/or D168 reported in 91% of patients with HCV genotype 1 infection who did not achieve SVR in clinical trials.1

  • In clinical trials in patients with HCV genotype 4 infection, NS3 Q80K polymorphism not observed at baseline.1 Treatment-emergent NS3 amino acid substitutions at Q80, T122, R155, A156, and/or D168 reported in 88% of patients with HCV genotype 4 infection who did not achieve SVR.1 Most common NS3 amino acid substitutions present at time of treatment failure were at position 168, usually D168V alone or D168E alone or combined with mutations at position 80.14

  • Cross-resistance is expected among HCV NS3/4A protease inhibitors.1 3 Some treatment-emergent NS3 amino acid substitutions observed in patients who did not achieve SVR with simeprevir treatment have been associated with reduced in vitro susceptibility to boceprevir and/or telaprevir (HCV protease inhibitors no longer commercially available in US).1 Treatment-emergent NS3 amino acid substitutions in patients receiving boceprevir or telaprevir (e.g., R155K, A156T, A156V) are expected to affect subsequent treatment with simeprevir.1

Advice to Patients

  • Importance of using simeprevir in conjunction with other antivirals;1 do not use alone.1

  • Advise patients not to reduce or interrupt simeprevir dosage;1 if any antiviral in the multiple-drug regimen discontinued for any reason, simeprevir must also be discontinued.1

  • Advise patients to take simeprevir once daily with food at the regularly scheduled time.1 Importance of taking recommended simeprevir dosage for recommended duration of treatment;1 importance of not missing or skipping doses.1

  • Advise patients that rash or photosensitivity may occur and may be severe.1 If rash or photosensitivity occurs, patients should immediately contact their health-care provider who will decide whether simeprevir should be discontinued.1 Advise patients not to stop taking simeprevir because of a photosensitivity reaction unless instructed to do so by their health-care provider.1

  • Advise patients to use sun protection (e.g., hat, sunglasses, protective clothing, sunscreen), limit exposure to natural sunlight, and avoid exposure to artificial sunlight (e.g., tanning bed, phototherapy).1 (See Photosensitivity Reactions under Cautions.)

  • Advise patients to watch for early warning signs of liver inflammation (e.g., fatigue, weakness, lack of appetite, nausea and vomiting) as well as later signs (e.g., jaundice, discolored feces) and to immediately contact clinician if such manifestations occur.1

  • If regimen containing simeprevir with sofosbuvir is used in a patient receiving amiodarone, advise patient about the risk of serious symptomatic bradycardia and importance of immediately contacting 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) occur.1 (See Cardiovascular Effects under Cautions.)

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise women of importance of avoiding pregnancy and using effective contraception during treatment.1 (See Pregnancy under Cautions.) If simeprevir used in multiple-drug regimen that includes ribavirin, advise men and women of importance of using 2 forms of effective contraception during and for 6 months after ribavirin therapy.349 377 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions.)

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Simeprevir Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

150 mg (of simeprevir)

Olysio

Janssen

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Janssen. Olysio (simeprevir) capsules prescribing information. Titusville, NJ; 2016 Feb.

2. Forns X, Lawitz E, Zeuzem S et al. Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial. Gastroenterology. 2014; :1669-79. [PubMed 24602923]

3. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 205123Orig1s000: Medical review(s). From FDA website.

4. Fried MW, Buti M, Dore GJ et al. Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naïve genotype 1 hepatitis C: the randomized PILLAR study. Hepatology. 2013; 58:1918-29. [PubMed 23907700]

5. Rosenquist A, Samuelsson B, Johansson PO et al. Discovery and Development of Simeprevir (TMC435), a HCV NS3/4A Protease Inhibitor. J Med Chem. 2014; 57:1673-93. [PubMed 24446688]

6. Lenz O, Vijgen L, Berke JM et al. Virologic response and characterisation of HCV genotype 2-6 in patients receiving TMC435 monotherapy (study TMC435-C202). J Hepatol. 2013; 58:445-51. [PubMed 23142061]

7. Moreno C, Berg T, Tanwandee T et al. Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2-6: TMC435-C202, a phase IIa, open-label study. J Hepatol. 2012; 56:1247-53. [PubMed 22326470]

8. Lenz O, Verbinnen T, Lin TI et al. In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435. Antimicrob Agents Chemother. 2010; 54:1878-87. [PubMed 20176898]

9. Lin TI, Lenz O, Fanning G et al. In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor. Antimicrob Agents Chemother. 2009; 53:1377-85. [PubMed 19171797]

10. Jacobson IM, Dore GJ, Foster GR et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2014; :. [PubMed 24907225]

11. Manns M, Marcellin P, Poordad F et al. Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2014; :. [PubMed 24907224]

12. Lawitz E, Sulkowski MS, Ghalib R et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet. 2014; 384:1756-65. [PubMed 25078309]

13. Dieterich D, Rockstroh JK, Orkin C et al. Simeprevir (TMC435) with pegylated interferon/ribavirin in patients coinfected with HCV genotype 1 and HIV-1: a phase 3 study. Clin Infect Dis. 2014; 59:1579-87. [PubMed 25192745]

14. Moreno C, Hezode C, Marcellin P et al. Efficacy and safety of simeprevir with PegIFN/ribavirin in naïve or experienced patients infected with chronic HCV genotype 4. J Hepatol. 2015; 62:1047-55. [PubMed 25596313]

20. Genentech. Pegasys (peginterferon alfa-2a) injection for subcutaneous use prescribing information. South San Francisco, CA; 2013 Jul.

23. US Food and Drug Administration. FDA drug safety communication: FDA warns of serious slowing of the heart rate when antiarrhythmic drug amiodarone is used with hepatitis C treatments containing sofosbuvir (Harvoni) or Sovaldi in combination with another direct acting antiviral. 2015 Mar 24. From FDA website.

119. American Association for the Study of Liver Diseases (AASLD). Recommendations for testing, managing, and treating hepatitis C. From the AASLD website. Accessed 2016 Mar 1.

178. Bristol-Myers Squibb. Daklinza (daclatasvir ) tablets prescribing information. Princeton, NJ; 2016 Feb.

181. Gilead Sciences, Inc. Harvoni (ledipasvir and sofosbuvir) tablets prescribing information. Foster City, CA; 2016 Feb.

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (Jan 28, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website.

349. Merck Sharp & Dohme Corporation. Rebetol (ribavirin) capsules and oral solution prescribing information. Whitehouse Station, NJ; 2013 Nov.

377. Genentech. Copegus (ribavirin) tablets prescribing information. South San Francisco, CA; 2013 Feb.

388. Schering Corporation. PegIntron (peginterferon alfa-2b) injection, powder for solution for subcutaneous use prescribing information. Whitehouse Station, NJ; 2014 Jul.

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