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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 chronic hepatitis C in combination with peginterferon alfa and ribavirin or sofosbuvir 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.

Contraindications

There are no contraindications listed in the manufacturer's labeling. When administered with ribavirin and peginterferon alfa, the contraindications to ribavirin and peginterferon alfa also apply. See Ribavirin and Peginterferon Alfa monographs.

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

Dosing: Adult

Note: If other concomitant 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.

Chronic hepatitis C (CHC): Oral: Note: Treatment-experienced includes prior relapse patients, prior partial responders, and prior null responders who have failed previous interferon-based therapy.

Combination with sofosbuvir: Genotype 1, treatment-naive or treatment-experienced:

Patients without cirrhosis: 150 mg once daily in combination with sofosbuvir for 12 weeks.

Patients with compensated cirrhosis (Child-Pugh class A): 150 mg once daily in combination with sofosbuvir for 24 weeks. Note: This regimen should only be used in genotype 1a patients who are negative for the Q80K polymorphism. Guidelines also recommend that the addition of ribavirin may be considered in genotype 1a and 1b patients with compensated cirrhosis (AASLD/IDSA 2016).

Combination with peginterferon alfa and ribavirin: Note: Combination therapy with peginterferon and ribavirin is not recommended in HCV treatment guidelines, regardless of genotype or treatment status (eg, treatment-naive or treatment-experienced) (AASLD/IDSA 2016).

Genotype 1, treatment-naive or prior relapse patients (patients without cirrhosis or with compensated cirrhosis (Child-Pugh class A) who are mono-infected and 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.

150 mg once daily in combination with peginterferon alfa and ribavirin for 12 weeks, followed by an additional 12 weeks of peginterferon alfa and ribavirin (total treatment duration of 24 weeks).

Genotype 1, treatment-naive or prior relapse patients with compensated cirrhosis (Child-Pugh class A) 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.

150 mg once daily in combination with peginterferon alfa and ribavirin for 12 weeks, followed by an additional 36 weeks of peginterferon alfa and ribavirin (total treatment duration of 48 weeks).

Genotype 1, previously treated mono-infected or HCV/HIV-1 co-infected patients (partial response or null responders) without cirrhosis or with compensated cirrhosis (Child-Pugh class A): 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.

150 mg once daily in combination with peginterferon alfa and ribavirin for 12 weeks, followed by an additional 36 weeks of peginterferon alfa and ribavirin (total treatment duration of 48 weeks).

Discontinuation of therapy: Inadequate on-treatment virologic response (HCV RNA ≥25 units/mL):

Week 4: Discontinue simeprevir, peginterferon alfa, and ribavirin.

Week 12 or 24: Discontinue peginterferon alfa and ribavirin (treatment with simeprevir is complete at week 12).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl >30 mL/minute: No dosage adjustment necessary.

CrCl ≤30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

End-stage renal disease (ESRD), including hemodialysis patients: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). Dialysis is unlikely to result in significant removal of simeprevir.

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 (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Avoid combination

Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). 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

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. Consider therapy modification

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

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Monitor therapy

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

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

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

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

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

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

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: Headache (with sofosbuvir 7% to 49%), fatigue (with sofosbuvir 10% to 47%), insomnia (with sofosbuvir 14%), dizziness (with sofosbuvir 5% to 10%)

Dermatologic: Skin photosensitivity (with sofosbuvir ≤5% to ≤34%; grade 3: ≤1%; with Peg-IFN-alfa and RBV ≤28%; grade 3: <1%), skin rash (with sofosbuvir ≤5% to ≤34%; grade 3: ≤1%; with Peg-IFN-alfa and RBV ≤28%; including erythema, eczema, maculopapular rash, urticaria, toxic skin eruption, dermatitis exfoliative, cutaneous vasculitis; grade 3: ≤1%), pruritus (with Peg-IFN-alfa and RBV 22%; with sofosbuvir 11%)

Endocrine & metabolic: Increased amylase (with sofosbuvir)

Gastrointestinal: Nausea (with sofosbuvir 4% to 40%; with Peg-IFN-alfa and RBV 22%), diarrhea (with sofosbuvir 5% to 18%)

Hepatic: Increased serum bilirubin (<66%), hyperbilirubinemia (with sofosbuvir)

Neuromuscular & skeletal: Myalgia (16%)

Respiratory: Dyspnea (12%)

1% to 10%:

Gastrointestinal: Increased serum lipase (with sofosbuvir)

Hepatic: Increased serum alkaline phosphatase

<1% (Limited to important or life-threatening): Hepatic failure, liver decompensation, reactivation of HBV (FDA Safety Alert Dec. 8, 2016)

ALERT: U.S. Boxed Warning

Hepatitis B virus reactivation:

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with simeprevir. HBV reactivation has been reported in hepatitis C virus (HCV)/HBV co-infected patients who were undergoing or had completed treatment with HCV direct-acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV co-infected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Warnings/Precautions

Concerns related to adverse effects:

• Hepatic decompensation/failure: Hepatic decompensation and failure (including fatal cases) have been reported in patients treated with simeprevir in combination with peginterferon alfa and ribavirin or sofosbuvir. Most cases occurred in patients with advanced and/or decompensated cirrhosis. Modest bilirubin level increases, not impacting hepatic function, have been reported; however, postmarketing cases of hepatic decompensation with markedly elevated bilirubin levels have also been reported. Monitor hepatic function at baseline and as clinically indicated; closely monitor patients who experience an increase in total bilirubin >2.5 times the ULN. Discontinue treatment if elevated bilirubin 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) occur.

• 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), usually to areas exposed to light (face, “v” area of the neck, extensor surfaces of the forearms, dorsa of the hands); 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).

• Hepatitis B virus reactivation: [US Boxed Warning]: Hepatitis B virus (HBV) reactivation has been reported in hepatitis C virus (HCV)/HBV co-infected patients who were receiving or had completed treatment with HCV direct-acting antivirals and were not receiving HBV antiviral therapy; some cases have resulted in fulminant hepatitis, hepatic failure, and death. Test all patients for evidence of current or prior HBV infection prior to initiation of simeprevir; monitor HCV/HBV co-infected patients for hepatitis flare or HBV reactivation during treatment and post-treatment follow-up. Initiate treatment for HBV infection as clinically indicated. HBV reactivation has been reported in HBsAg positive patients and in patients with serologic evidence of resolved HBV infection (ie, HBsAg negative and anti-HBc positive) and is characterized by an abrupt increase in HBV replication manifested as a rapid increase in serum HBV DNA level; reappearance of HBsAg may occur in patients with resolved HBV infection. Risk of HBV reactivation may be increased in patients receiving certain immunosuppressants or chemotherapeutic agents.

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; use only as part of a multiple-drug regimen for treatment of HCV; consult current HCV treatment guidelines for guidance (AASLD/IDSA 2016). Safety and efficacy have not been established in patients who have received liver transplants.

• Resistance: Reduced sustained virologic response (SVR) rates of simeprevir in combination with sofosbuvir were observed in patients infected with hepatitis C genotype 1a with an NS3 Q80K polymorphism compared to patients without the polymorphism; consider alternative therapy in these patients. Patients with compensated cirrhosis and hepatitis C genotype 1a should be evaluated for the presence of the Q80K polymorphism; alternative regimens should be used if Q80K variant is present (AASLD/IDSA 2016).

Monitoring Parameters

Manufacturer's labeling:

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. Screen patients infected with HCV genotype 1a for the presence of virus with the NS3 Q80K polymorphism prior to the initiation of treatment.

Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) prior to initiation; in patients with serologic evidence of hepatitis B virus (HBV) infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during treatment and during post-treatment follow-up.

Alternate recommendations (AASLD/IDSA 2016):

Baseline (within 12 weeks prior to starting antiviral therapy): CBC, INR, hepatic function panel (albumin, total and direct bilirubin, ALT, AST, and alkaline phosphatase), calculated GFR

Baseline (at any time prior to starting antiviral therapy): HCV genotype and subtype, quantitative HCV viral load, resistance assays (if applicable). Screen patients infected with HCV genotype 1a for the presence of virus with the NS3 Q80K polymorphism prior to the initiation of treatment.

During therapy: CBC, serum creatinine, calculated GFR, hepatic function panel (after 4 weeks of therapy and as clinically indicated); quantitative HCV viral load testing (after 4 weeks of therapy and at 12 weeks after completion of therapy). If quantitative HCV viral load is detectable at treatment week 4, repeat testing is recommended after 2 additional weeks of treatment (treatment week 6).

Pregnancy Considerations

Use of this product in combination with ribavirin is contraindicated in pregnant women and men whose female partners are pregnant.

Adverse events have been observed in animal reproduction studies. If used in combination with ribavirin, all warnings related to the use of ribavirin and pregnancy and/or contraception should be followed. Mother-to-child transmission of HCV does not occur if the woman is not viremic; therefore, HCV-infected women of childbearing potential should postpone pregnancy until therapy is complete. Treatment of HCV is not recommended for women who are already pregnant (AASLD/IDSA 2016).

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, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), 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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