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Simeprevir

Pronunciation

(sim E pre vir)

Index Terms

  • Simeprevir Sodium
  • TMC435

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Olysio: 150 mg

Brand Names: U.S.

  • Olysio

Pharmacologic Category

  • Antihepaciviral, Protease Inhibitor (Anti-HCV)
  • NS3/4A Inhibitor

Pharmacology

Simeprevir is an inhibitor of HCV NS3/4A protease, a protease that is essential for viral replication. It is considered a direct-acting antiviral treatment for HCV, also called a specifically targeted antiviral therapy for HCV (STAT-C).

Absorption

Food enhances absorption.

Metabolism

Primarily oxidative metabolism by CYP3A4 (and possibly CYP2C8 and CYP2C19) to unchanged drug and metabolites (minor).

Excretion

Feces (~91%); urine (<1%)

Time to Peak

Serum: 4 to 6 hours

Half-Life Elimination

Plasma: 10 to 13 hours (healthy volunteers); 41 hours (HCV-infected patients)

Protein Binding

>99.9% (albumin and alpha 1-acid glycoprotein)

Special Populations: Hepatic Function Impairment

Mean steady-state AUC of simeprevir was 2.4-fold higher in HCV-uninfected subjects with moderate hepatic impairment (Child-Pugh class B) and 5.2-fold higher in HCV-uninfected subjects with severe hepatic impairment (Child-Pugh class C) compared with HCV-uninfected subjects with normal hepatic function.

Use: Labeled Indications

Chronic hepatitis C: Treatment of genotype 1 or 4 chronic hepatitis C (in combination with other antihepacivirals) in adults without cirrhosis or with compensated cirrhosis

Limitations of use: Not recommended for use in patients who have previously failed a simeprevir-containing regimen or another regimen containing HCV protease inhibitors.

Use: Unlabeled

Chronic hepatitis C: Treatment of genotype 4 chronic hepatitis C (CHC) in treatment-naive patients; treatment of genotype 1 chronic hepatitis C (CHC) (in combination with sofosbuvir and ribavirin) in treatment-naive patients ineligible to receive peginterferon alfa or in genotype 1 relapser patients who were non responders to a previous regimen of ribavirin and peginterferon alfa without an HCV protease inhibitor

Contraindications

There are no contraindications listed in the manufacturer's labeling, however, all contraindications to other antihepaciviral drugs used in combination with simeprevir for the treatment of chronic hepatitis C infection also apply to their use in a simeprevir-containing regimen; refer to each monograph for individual product contraindications

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to simeprevir or any component of the formulation

Dosing: Adult

Note: If other antihepaciviral treatment (sofosbuvir or peginterferon and ribavirin) is discontinued for any reason, simeprevir must also be discontinued. Do not reduce simeprevir dosage or interrupt therapy; if therapy must be interrupted due to adverse reactions or inadequate response, do not reinitiate. In patients with genotype 1a and compensated cirrhosis, screening for HCV with the NS3 Q80K polymorphism may be considered prior to starting therapy. Screening is strongly recommended prior to initiation of combination treatment with peginterferon alfa and ribavirin in patients with genotype 1a; consider alternative therapy in patients infected with HCV genotype 1a containing the Q80K polymorphism.

Treatment of chronic hepatitis C (CHC): Oral:

Manufacturer's labeling: Treatment duration is indication and response-specific.

Missed dose: If a dose is missed within 12 hours of the time it is usually taken, take as soon as possible. If more than 12 hours have passed since the dose is usually taken, do not take the missed dose and the patient should resume the usual schedule.

Treatment-naive or treatment-experienced (includes prior relapse patients, prior partial responders, and prior null responders who failed previous interferon-based therapy) (HCV genotype 1, mono-infected) when used with sofosbuvir: Note: No treatment stopping rules apply to the combination of simeprevir with sofosbuvir:

US labeling:

Patients without cirrhosis: Weeks 1 to 12: Dual therapy: Simeprevir 150 mg once daily in combination with sofosbuvir

Patients with compensated cirrhosis (Child-Pugh class A): Weeks 1 to 24: Dual therapy: Simeprevir 150 mg once daily in combination with sofosbuvir

Canadian labeling:

Patients without cirrhosis: Weeks 1 to 12: Dual therapy: Simeprevir 150 mg once daily in combination with sofosbuvir

Patients with cirrhosis: Weeks 1 to 12: Dual therapy: Simeprevir 150 mg once daily in combination with sofosbuvir. Note: May consider up to 24 weeks treatment duration

Treatment-naive or prior relapse patients (HCV genotype 1 or 4) when used with peginterferon alfa and ribavirin (including those with or without compensated cirrhosis (Child-Pugh class A) who are mono-infected and those patients without cirrhosis who are co-infected with HIV-1): Note: Prior relapsers include patients with an undetectable HCV-RNA upon completion of treatment (prior interferon-based regimen) but with detectable HCV-RNA during the follow up period.

Weeks 1 to 12: Triple therapy: Simeprevir 150 mg once daily in combination with peginterferon alfa and ribavirin

HCV-RNA detectable (level ≥25 units/mL) at week 4: Discontinue simeprevir, peginterferon alfa, and ribavirin (treatment determined to be inadequate).

Weeks 13 to 23 (based on HCV-RNA results at week 12):

HCV-RNA undetectable (level <25 units/mL) at week 12: Discontinue simeprevir (treatment completed). Dual therapy: Peginterferon alfa and ribavirin only (through week 24)

HCV-RNA detectable (level ≥25 units/mL) at week 12: Discontinue simeprevir (treatment completed), peginterferon alfa, and ribavirin (treatment determined to be inadequate).

Week 24 (based on HCV-RNA results at week 24):

HCV-RNA undetectable (level <25 units/mL) at week 24: Dual therapy: Peginterferon alfa and ribavirin only (through week 24)

HCV-RNA detectable (level ≥25 units/mL) at week 24: Discontinue peginterferon alfa and ribavirin (treatment determined to be inadequate).

Treatment-naive or prior relapse patients (HCV genotype 1 or 4) with compensated cirrhosis (Child-Pugh class A) who are co-infected with HIV-1 when used with peginterferon alfa and ribavirin: Note: Prior relapsers include patients with an undetectable HCV-RNA upon completion of treatment (prior interferon-based regimen) but with detectable HCV-RNA during the follow up period.

Weeks 1 to 12: Triple therapy: Simeprevir 150 mg daily in combination with peginterferon alfa and ribavirin

HCV-RNA detectable (level ≥25 units/mL) at week 4: Discontinue simeprevir, peginterferon alfa, and ribavirin (treatment determined to be inadequate).

HCV-RNA undetectable (level <25 units/mL) at week 12: Discontinue simeprevir (treatment completed). Dual therapy: Peginterferon alfa and ribavirin only (through week 48)

Weeks 13 to 48 (based on HCV-RNA results at weeks 12 and 24):

HCV-RNA detectable (level ≥25 units/mL) at week 12: Discontinue simeprevir (treatment completed) and peginterferon alfa and ribavirin (treatment determined to be inadequate).

HCV-RNA undetectable (level <25 units/mL) at week 24: Discontinue simeprevir (treatment was completed after week 12). Dual therapy: Peginterferon alfa and ribavirin only (through week 48)

HCV-RNA detectable (level ≥25 units/mL) at week 24: Discontinue peginterferon alfa, and ribavirin (treatment determined to be inadequate).

Previously treated patients (HCV genotype 1 or 4; partial response or null responders) including those with compensated cirrhosis (Child-Pugh class A) or without cirrhosis and those who are mono-infected or with HIV-1 co-infection when used with peginterferon alfa and ribavirin: Note: Partial response includes patients with a ≥2 log10 HCV-RNA decrease at week 12 but detectable HCV-RNA at the end of prior interferon-based therapy. Prior null responders include patients with a <2 log10 HCV-RNA decrease at week 12 during interferon-based therapy.

Weeks 1 to 12: Triple therapy: Simeprevir 150 mg daily in combination with peginterferon alfa and ribavirin

HCV-RNA detectable (level ≥25 units/mL) at week 4: Discontinue simeprevir, peginterferon alfa, and ribavirin (treatment determined to be inadequate).

HCV-RNA undetectable (level <25 units/mL) at week 12: Discontinue simeprevir (treatment completed). Dual therapy: Peginterferon alfa and ribavirin only (through week 48)

Weeks 13 to 48 (based on HCV-RNA results at weeks 12 and 24):

HCV-RNA detectable (level ≥25 units/mL) at week 12: Discontinue simeprevir (treatment completed) and peginterferon alfa and ribavirin (treatment determined to be inadequate).

HCV-RNA undetectable (level <25 units/mL) at week 24: Discontinued simeprevir (treatment was completed after week 12). Dual therapy: Peginterferon alfa and ribavirin only (through week 48)

HCV-RNA detectable (level ≥25 units/mL) at week 24: Discontinue peginterferon alfa, and ribavirin (treatment determined to be inadequate).

Alternative dosing:

Treatment-naive patients: Patients who cannot receive peginterferon: Genotype 1a (off-label regimen): 150 mg once daily with sofosbuvir and with ribavirin for 12 weeks (without cirrhosis) or 24 weeks (with cirrhosis). Note: A recommended regimen (AASLD/IDSA, 2014)

Relapsed chronic hepatitis C patients (nonresponders to a previous regimen of ribavirin and peginterferon alfa without an HCV protease inhibitor): Genotype 1 patients (off-label regimen): 150 mg once daily with sofosbuvir and with ribavirin for 12 weeks (without cirrhosis) or 24 weeks (with cirrhosis). Note: A recommended regimen (AASLD/IDSA 2014).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary. Not studied in patients with CrCl ≤30 mL/minute or with end-stage renal disease (ESRD), including those requiring hemodialysis.

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate or severe impairment (Child-Pugh class B or C): Use is not recommended.

Administration

Oral: Administer with food. Swallow capsules whole; do not chew, crush, break, cut, or dissolve the capsule.

Storage

Store below 30°C (86°F). Store in the original bottle. Protect from light.

Drug Interactions

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Aminolevulinic Acid: Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid. Monitor therapy

Asunaprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Asunaprevir. Avoid combination

AtorvaSTATin: Simeprevir may increase the serum concentration of AtorvaSTATin. Management: The maximum atorvastatin dose should not exceed 40 mg/day with concurrent use of simeprevir, and use of the lowest necessary atorvastatin dose is recommended. Consider therapy modification

Bosutinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bosutinib. Avoid combination

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Cisapride: Simeprevir may increase the serum concentration of Cisapride. Avoid combination

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CycloSPORINE (Systemic): Simeprevir may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Simeprevir. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Simeprevir. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Simeprevir. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Simeprevir. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Simeprevir. Avoid combination

CYP3A4 Substrates: Simeprevir may increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Delavirdine: May increase the serum concentration of Simeprevir. Avoid combination

Dexamethasone (Systemic): May decrease the serum concentration of Simeprevir. Avoid combination

Digoxin: Simeprevir may increase the serum concentration of Digoxin. Monitor therapy

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

Erythromycin (Systemic): Simeprevir may increase the serum concentration of Erythromycin (Systemic). Erythromycin (Systemic) may increase the serum concentration of Simeprevir. Avoid combination

Escitalopram: May decrease the serum concentration of Simeprevir. Monitor therapy

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

Flecainide: Simeprevir may increase the serum concentration of Flecainide. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Gemfibrozil: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. See separate drug interaction monographs for agents listed as exceptions. Monitor therapy

Grazoprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Grazoprevir. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Ledipasvir: Simeprevir may increase the serum concentration of Ledipasvir. Ledipasvir may increase the serum concentration of Simeprevir. Avoid combination

Lovastatin: Simeprevir may increase the serum concentration of Lovastatin. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Mexiletine: Simeprevir may increase the serum concentration of Mexiletine. Monitor therapy

Midazolam: Simeprevir may increase the serum concentration of Midazolam. Monitor therapy

Milk Thistle: May increase the serum concentration of Simeprevir. Avoid combination

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

Nevirapine: May decrease the serum concentration of Simeprevir. Avoid combination

OXcarbazepine: May decrease the serum concentration of Simeprevir. Avoid combination

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Phosphodiesterase 5 Inhibitors: Simeprevir may increase the serum concentration of Phosphodiesterase 5 Inhibitors. Monitor therapy

Pitavastatin: Simeprevir may increase the serum concentration of Pitavastatin. Monitor therapy

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Pravastatin: Simeprevir may increase the serum concentration of Pravastatin. Monitor therapy

Propafenone: Simeprevir may increase the serum concentration of Propafenone. Monitor therapy

Protease Inhibitors: May increase the serum concentration of Simeprevir. Simeprevir may increase the serum concentration of Protease Inhibitors. Avoid combination

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Rosuvastatin: Simeprevir may increase the serum concentration of Rosuvastatin. Management: Limit initial rosuvastatin dose to 5 mg/day when being started in a patient who is also being treated with simeprevir. The maximum rosuvastatin dose should not exceed 10 mg/day with concurrent use of simeprevir. Consider therapy modification

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simvastatin: Simeprevir may increase the serum concentration of Simvastatin. Monitor therapy

St John's Wort: May decrease the serum concentration of Simeprevir. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tenofovir Disoproxil Fumarate: May decrease the serum concentration of Simeprevir. Simeprevir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Teriflunomide: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Triazolam: Simeprevir may increase the serum concentration of Triazolam. Monitor therapy

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Adverse Reactions

Percentages reported for combination therapy with peginterferon alfa and ribavirin (Peg-IFN-alfa and RBV) unless otherwise noted.

>10%:

Central nervous system: Fatigue (with sofosbuvir 25%), headache (with sofosbuvir 21%), dizziness (with sofosbuvir 16%), insomnia (with sofosbuvir 14%)

Dermatologic: Skin rash (with Peg-IFN-alfa and RBV 28%; including erythema, eczema, rash maculopapular, urticaria, toxic skin eruption, dermatitis exfoliative, cutaneous vasculitis, photosensitivity reaction), pruritus (with Peg-IFN-alfa and RBV 22%; with sofosbuvir 11%)

Gastrointestinal: Nausea (with Peg-IFN-alfa and RBV 22%; with sofosbuvir 21%), diarrhea (with sofosbuvir 16%)

Hepatic: Increased serum bilirubin (<66%)

Neuromuscular & skeletal: Myalgia (16%)

Respiratory: Dyspnea (12%)

1% to 10%:

Dermatologic: Skin photosensitivity (with sofosbuvir 7%; with Peg-IFN-alfa and RBV 5%; grade 3: 1%)

Hepatic: Increased serum alkaline phosphatase (<4%)

<1% (Limited to important or life-threatening): Hepatic failure, liver decompensation

Warnings/Precautions

Concerns related to adverse effects:

• Hepatic decompensation/failure: Hepatic decompensation and failure (including fatal cases) have been reported, most cases in patients with current advanced and/or decompensated cirrhosis; liver transaminases should be monitored at baseline and as clinically indicated. Modest bilirubin level increases, not impacting hepatic function, have been reported; monitoring at baseline and as clinically indicated is recommended, especially if marked increases occur (eg, total bilirubin >2.5 times the ULN); discontinue if elevation is accompanied by liver transaminase increases or clinical signs or symptoms of hepatic decompensation (eg, fatigue, weakness, lack of appetite, nausea and vomiting, jaundice, discolored feces).

• Photosensitivity: Photosensitivity reactions, including serious reactions resulting in hospitalization, have been reported when used in combination with peginterferon alfa and ribavirin. May present as an exaggerated sunburn reaction (burning, erythema, exudation, blistering, and edema); most frequently occurs within the first 4 weeks of treatment. Avoid excessive sunlight, tanning devices, and take precautions to limit exposure (eg, loose fitting clothing, sunscreen). Discontinue use if photosensitivity occurs and monitor until the reaction resolves. If therapy is to be continued in a patient who has experienced photosensitivity, expert consultation is advised.

• Skin reactions: Rash has been typically observed within first 4 weeks of therapy initiation, but can occur at any time during treatment. Severe rashes and rash requiring discontinuation have occurred in combination with peginterferon alfa and ribavirin. If a patient experiences a mild to moderate rash, follow for progression and/or development of mucosal signs (eg, oral lesions, conjunctivitis) or systemic symptoms. If rash becomes severe, discontinue simeprevir and monitor for rash resolution.

• Sulfa allergy: Contains a sulfonamide moiety. In patients with a history of sulfa allergy, no increased incidence of rash or photosensitivity has been reported, although the risk of reaction (or potential severity) cannot be excluded. Discontinue if signs of hypersensitivity are noted.

Disease-related concerns:

• Hepatic impairment: Not recommend in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).

Dosage forms specific issues:

• Lactose: Formulation contains lactose; the Canadian labeling recommends avoiding use in patients with rare hereditary disturbances of galactose intolerance (severe lactase deficiency or glucose-galactose malabsorption).

Concurrent drug therapy issues:

• Amiodarone: Symptomatic bradycardia (some requiring pacemaker intervention) has occurred in patients receiving amiodarone and sofosbuvir in combination with another direct acting antiviral, including simeprevir. Fatal cardiac arrest occurred in a patient receiving a sofosbuvir (eg, ledipasvir/sofosbuvir) combination product. Bradycardia generally occurred within hours to days following coadministration; however, some cases have occurred 2 weeks following the initiation of HCV treatment. The risk of bradycardia may be increased in patients taking beta blockers or patients with underlying cardiac comorbidities and/or advanced liver disease. Bradycardia generally resolves following discontinuation of HCV treatment. Coadministration of amiodarone with simeprevir and sofosbuvir in combination is not recommended. However, if patients have no treatment alternatives, patients should be counseled about the interaction and have in-patient cardiac monitoring for the first 48 hours of coadministration followed by daily outpatient or self-monitoring of heart rate for at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, cardiac monitoring (as described) is also recommended if amiodarone was discontinued just prior to beginning treatment with sofosbuvir and simeprevir. Patients should seek medical attention immediately if they experience fainting or near-fainting, dizziness, lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion, or memory problems.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustments, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Do not use as monotherapy. See other agents for additional warnings and precautions associated with their use. Safety and efficacy have not been established in patients who have received liver transplants, who have HCV genotypes other than genotypes 1 or 4, or who have failed to respond to other HCV direct-acting inhibitors or on repeated courses of simeprevir.

• Resistance: Reduced sustained virologic response (SVR) rates of simeprevir in combination with peginterferon alfa and ribavirin were observed in patients infected with hepatitis C genotype 1a with an NS3 Q80K polymorphism at baseline compared to patients without the polymorphism; consider alternative therapy in these patients. Test hepatitis C genotype 1a patients treated with simeprevir in combination with peginterferon alfa and ribavirin prior to treatment initiation for the Q80K polymorphism; consider testing in hepatitis C genotype 1a patients treated with simeprevir in combination with sofosbuvir (AASLD/IDSA, 2014).

Monitoring Parameters

Bilirubin and liver enzymes (at baseline and during therapy as clinically indicated) at baseline and periodically when clinically indicated.

Liver function tests at baseline and periodically during therapy; serum HCV-RNA at baseline, weeks 4, 12, and 24, at end of treatment, during treatment follow-up, and when clinically indicated. Prior to initiation of treatment in combination with peginterferon alfa and ribavirin, screen patients infected with HCV genotype 1a for the presence of virus with the NS3 Q80K polymorphism; consider screening prior to therapy initiation when used in combination with sofosbuvir.

Pregnancy Considerations

Women of reproductive potential should use effective contraception during therapy. Treatment of HCV is not recommended for women who are already pregnant (AASLD 2014).

Use of simeprevir in combination with ribavirin is contraindicated in women who are pregnant and men whose female partners are pregnant. If simeprevir is used in combination with ribavirin all warnings related to the use of ribavirin and pregnancy and/or contraception should be followed. Current guidelines note that a negative pregnancy test is required before initiation. Female patients (and their male partners) as well as male patients (and their female partners) should use two forms of effective contraception during therapy and for 6 months after therapy is discontinued. Pregnancy testing should be done at appropriate intervals (AASLD 2014).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience itching, nausea, muscle pain, diarrhea, dizziness, headache, loss of strength and energy, or insomnia. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), shortness of breath, severe skin irritation, red, blistered, or swollen skin, mouth sores, or eye irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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