simeprevir (Discontinued)

>10%

Rash; including photosensitivity (28%)

Hyperbilirubinemia, grade 1 (27%)

Pruritus (22%)

Nausea (22%)

Hyperbilirubinemia, grade 2 (18%)

Myalgia (16%)

Dyspnea (12%)

1-10%

Hyperbilirubinemia, grade 3 (4%)

Alkaline phosphatase elevation, grade 1 (3%)

<1%

Hyperbilirubinemia, grade 4

Alkaline phosphatase elevation, grade 2

Postmarketing reports

Serious symptomatic bradycardia (patients taking amiodarone who initiate treatment with sofosbuvir in combination with another HCV direct acting antiviral, including simeprevir

Hepatic decompensation and hepatic failure, including fatal cases reported in patients receiving therapy in combination with peginterferon alfa and ribavirin or in combination with sofosbuvir

Contraindications

Hypersensitivity

Also consider contraindications to peginterferon alfa and ribavirin

Because ribavirin may cause birth defects and fetal death, simeprevir in combination with peginterferon alfa and ribavirin is contraindicated in pregnant women and in men whose female partners are pregnant

Cautions

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV DDAs, and who were not receiving HBV antiviral therapy; HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level (see Black Box Warnings and Dosing Considerations)

Serious symptomatic bradycardia in patients taking amiodarone with sofosbuvir in combination with simeprevir reported, especially in patients receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease; coadministration of amiodarone with simeprever in combination with sofosbuvir not recommended; in patients without alternative treatment options, cardiac monitoring is recommended

Hepatic decompensation and hepatic failure, including fatal cases, reported when coadministered with peginterferon alfa and ribavirin or in combination with sofosbuvir; most cases were reported in patients with advanced and/or decompensated cirrhosis who are at increased risk for hepatic decompensation or hepatic failure; monitor liver chemistry tests before and during simeprevir combination therapy

Photosensitivity reported, including serious reactions which resulted in hospitalization

Rash may occur, most frequently within the first 4 weeks; mild-to-moderate rashes should be followed for possible progression of rash, including the development of mucosal signs (eg, oral lesions, conjunctivitis) or systemic symptoms; discontinue if rash becomes severe

Contains a sulfonamide moiety; in subjects with a history of sulfa allergy (n=16), no increased incidence of rash or photosensitivity reactions was observed; however, insufficient data exist

Must NOT be used as monotherapy

Drug interaction overview

• Avoid coadministering with moderate or strong CYP3A inhibitors; simeprevir AUC increased >7-fold
• Avoid coadministering with moderate or strong CYP3A inducers; simeprevir trough levels decreased >90%

Pregnancy

Simeprevir is coadministered with ribavirin and peginterferon alfa; extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients while taking this combination (see Contraindications)

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; and therefore ribavirin is contraindicated

Women of childbearing potential and their male partners should not receive ribavirin unless they are using effective contraception (2 reliable forms) during treatment with ribavirin and for 6 months after treatment

Ribavirin may cause birth defects and fetal death; avoid pregnancy in female patients and female partners of male patients; patients must have a negative pregnancy test prior to therapy; use 2 or more forms of contraception, 1 of these forms of contraception can be a combined oral contraceptive product containing at least 1 mg of norethindrone (lower doses of norethindrone and other forms of hormonal contraception have not been studied or are contraindicated)

Lactation

Unknown if distributed in human breast milk; because of the potential for adverse reaction, breastfeeding is not recommended

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

In a biochemical assay simeprevir inhibited the proteolytic activity of recombinant genotype 1a and 1b HCV NS3/4A proteases, with median Ki values of 0.5 nM and 1.4 nM, respectively

NS3/4A protease is needed for proteolytic cleavage of the HCV encoded polyprotein into mature forms

Absorption

Food increases systemic exposure by 60-70%

Peak plasma time: 4-6 hr

Predose plasma concentration: 1936 ng/mL

AUC: 57,469 ng•hr/mL

Distribution

Protein bound: >99.9%

Metabolism

Substrate: CYP3A (major); CYP2C8 (minor) and CYP2C19 (minor)

Inhibits OATP1B1/3 and P-gp transporters

Mildly inhibits CYP1A2 and intestinal CYP3A, but does not affect hepatic CYP3A4 activity

Elimination

Half-life: 41 hr (HC- infected); 10-13 hr (HCV-uninfected)

Excretion: Hepatobiliary; 91% feces (31% unchanged); <1% urine

Pharmacogenomics

Efficacy is substantially reduced in patients infected with HCV genotype 1a with an NS3 Q80K polymorphism at baseline; screening patients for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended

Simeprevir exposures are higher in populations with lower amounts of CYP3A and/or OATP1B1/3 including patients of East Asian ancestry

IL28B genetic variant

• A genetic variant near the gene encoding interferon-lambda-3 (IL28B rs12979860, a C to T change) is a strong predictor of response to peginterferon alfa and ribavirin
• Overall, sustained viral response rates were lower in subjects with the CT and TT genotypes compared to those with the CC genotype

Oral Administration

Take with food (bioavailability improved)

Swallow capsule whole