- Treatment of hepatitis C virus (HCV) genotype 1 infection in combination with sofosbuvir in patients with or without compensated cirrhosis.
- Treatment of HCV genotype 1 or 4 infection in combination with peginterferon alfa and ribavirin in patients with or without compensated cirrhosis.
Inhibits viral replication; a direct-acting antiviral (DAA).
Clearing of infection with decreased severity and sequelae of HCV.
Absorption: Well absorbed following oral administration, food ↑ and delays absorption (blood levels are ↑ in HCV-infected patients as compared to non-HCV-infected patients).
Protein Binding: >99.9%.
Metabolism and Excretion: Highly metabolized (primarily by CYP3A), eliminated primarily via biliary excretion, 31% excreted unchanged in feces, <1% in urine.
Half-life: HCV-infected patients–41 hr; HCV-uninfected patients –10–13 hr.
TIME/ACTION PROFILE (blood levels)
|PO||unknown||6–8 hr||24 hr|
- Patients with NS3 Q80K polymorphism (↓ efficacy of simeprevir + peginterferon alfa + ribavirin);
- Moderate-to-severe hepatic impairment;
- Previous failure to simeprevir or another HCV protease inhibitor;
- Any condition in which peginterferon alpha or ribavirin is contraindicated;
- Concurrent use of moderate or strong inhibitors or inducers of the CYP3A system (may significantly change blood levels, effectiveness and risk of toxicity/adverse reactions);
- OB: Pregnant women and men whose female partners are pregnant (ribavirin contraindication).
Use Cautiously in:
- History of sulfonamide hypersensitivity (cross sensitivity may occur);
- East Asian ancestry (high blood levels, ↑ risk of adverse reactions including rash and photosensitivity);
- Receiving immunosuppressant or chemotherapy medications (↑ risk of hepatitis B virus reactivation);
- Severe renal impairment/dialysis.
Adverse Reactions/Side Effects
Reflects combination use with peginterferon alfa and ribavirin
GI: HEPATOTOXICITY, hyperbilirubinemia, nausea
Derm: photosensitivity, pruritus, rash
Misc: hepatitis B virus reactivation
* CAPITALS indicate life-threatening.
Underline indicate most frequent.
- Blood levels and the risk of toxicity may be ↑ moderate or strong inhibitors CYP3A including clarithromycin, cobicistat-containing products, darunavir/ritonavir, erythromycin, fluconazole, itraconazole, posiconazole, ritonavir, and voriconazole; concurrent use not recommended.
- May ↑ levels and risk of toxicity of digoxin due to inhibition of P-gp; monitor digoxin levels.
- Blood levels and therapeutic effects may be ↓ by inducers of CYP3A and CYP3A4 including carbamazepine, dexamethasone, efavirenz, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine; concurrent use not recommended.
- Blood levels may be altered (↑ or ↓) by atazanavir, delavirdine, etravirine, fosamprenavir, lopinavir, indinavir, nelfinavir, nevirapine, saquinavir, or tipranavir; concurrent use not recommended.
- May ↑ levels of ledipasvir; concurrent use not recommended.
- May ↑ blood levels and risk of toxicity with amlodipine, atorvastatin (use lowest effective dose), diltiazem, disopyramide, felodipine, flecainide, fluvastatin (use lowest effective dose), lovastatin (use lowest effective dose), mexiletine, nicardipine, nifdipine, nisoldipine, pitavastatin (use lowest effective dose), pravastatin (use lowest effective dose), propafenone, quinidine, rosuvastatin (use lowest effective dose), simvastatin (use lowest effective dose), and verapamil(clinical and/or blood level monitoring recommended).
- May ↑ or ↓ blood levels of sirolimus; monitor sirolimus levels.
- May ↑ blood levels and risk of adverse reactions/toxicity of sildenafil, tadalafil and vardenafil; no adjustments needed when used for erectile dysfunction, when sildenafil or tadalafil are used for pulmonary arterial hypertension, use lowest effective dose and monitor clinically.
- May ↑ blood levels and the risk of sedation with midazolam or triazolam; use cautiously.
- Concomitant use with cyclosporine may ↑ cyclosporine and simeprevir levels; concomitant use not recommended
- Amiodarone may ↑ risk of symptomatic bradycardia when used with simeprevir and sofosbuvir; concurrent use not recommended; if amiodarone necessary, monitor patients in inpatient setting for first 48 hr of concomitant use and then monitor heart rate on outpatient basis for at least the first 2 wk of treatment (follow same monitoring procedure if discontinuing amiodarone immediately before initiation of sofosbuvir and simeprevir therapy)
- Blood levels and risk of toxicity may be ↑ by milk thistle (concurrent use is not recommended).
- Blood levels and effectiveness may be ↓ by St. John's wort, concurrent use is not recommended.
PO (Adults) With peginterferon alfa and ribavirin (genotype 1 or 4)–150 mg once daily for 12 wk. Treatment with peginterferon alfa and ribavirin may continue for an additional 12 wk (for treatment-naïve patients and prior relapsers with or without compensated cirrhosis who are not co-infected with HIV and in those without cirrhosis who are co-infected with HIV) or an additional 36 wk (for treatment-naïve patients and prior relapsers with compensated cirrhosis who are co-infected with HIV and for all prior non-responders); With sofosbuvir (genotype 1)–150 mg once daily for 12 wk (patients without cirrhosis) or 24 wk (patients with compensated cirrhosis).
Capsules: 150 mg
- Monitor for signs and symptoms of chronic hepatitis C.
- Assess for rash, especially during first 4 wk of therapy. Monitor mild to moderate rashes for progression, including mucosal signs (oral lesions, conjunctivitis). If rash becomes severe, discontinue simeprevir and monitor until rash resolved.
Lab Test Considerations:
Determine current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before starting HCV therapy. In patients with HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation (rapid ↑ in serum HBV DNA level) during HCV therapy and during post-therapy follow-up.
- A negative pregnancy test must be obtained immediately before beginning therapy and monthly thereafter.
- Use a sensitive assay with a lower limit of quantification of at least 25 IU/mL for monitoring HCV RNA levels during treatment. In treatment wk 4, if HCV RNA ≥25 IU/mL, discontinue simeprevir, peginterferon alfa, and ribavirin. In treatment wk 12, if HCV RNA ≥25 IU/mL, discontinue peginterferon alfa and ribavirin; simeprevir is completed at wk 12. In treatment wk 24, if HCV RNA ≥25 IU/mL, discontinue peginterferon alfa and ribavirin.
- Prior to starting therapy with simprevir + peginterferon alfa + ribavirin, screen patient with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism. Consider alternative therapy for patients infected with HCV genotype 1a containing the Q80K polymorphism. May be considered before starting therapy with simeprevir + sobosuvir.
- Monitor liver function tests prior to and periodically during therapy, as clinically indicated. May cause ↑ alkaline phosphatase and bilirubin. Monitor closely if serum bilirubin ↑ 2.5 x upper limit of normal. If accompanied by liver transaminase ↑ or clinical signs and symptoms of hepatic decompensation, discontinue therapy.
- Risk for infection (Indications)
- Must be administered in conjunction with ribavirin and peginterferon alfa. If ribavirin and peginterferon alfa are discontinued, simeprevir must be discontinued. If simeprevir is discontinued due to adverse reactions or inadequate response, do not restart simprevir.
- PO Administer once daily with food.
- Instruct patient to take simeprevir with ribavirin and pegainterferon alfa as directed. Take missed doses within 12 hr with food or skip dose and take next scheduled dose; do not double doses. Advise patient to read Patient Information before starting and with each refill in case of changes.
- Caution patient to wear sunscreen and protective clothing and avoid tanning devices to prevent photosensitivity reaction.
- Advise patient to notify health care professional if rash, signs and symptoms of hepatotoxicity (fatigue, weakness, lack of appetite, nausea and vomiting, jaundice, discolored feces) or photosensitivity reaction (burning, redness, swelling or blisters on skin; mouth sores or ulcers; red or inflamed eyes like pink eye or conjunctivitis) occurs.
- Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. Johns wort.
- Rep: Advise female patients and male patients with female partners who are pregnant or may become pregnant to use effective contraception due to risks for birth defects and fetal death and avoid breast feeding. Women and male partners must use 2 forms of non-hormonal contraception during and for at least 6 mo after discontinuation of therapy. Advise women who become pregnant to enroll in the Ribavirin Pregnancy Registry by calling 1-800-593-2214.
Evaluation/Desired OutcomesDecreased severity and sequelae of HCV following treatment with simeprevir, ribavirin, and peginterferon alfa for 12 wk.
- Patients who are treatment-naïve and prior relapser, including those with cirrhosis, should receive an additional 12 wk of peginterferon alfa and ribavirin for a total of 24 wk.
- Prior non-responders should receive an additional 36 wk of peginterferon alfa and ribavirin for a total of 48 wk.
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