Dosing and uses of Olysio (simeprevir)
Adult dosage forms and strengths
capsule
- 150mg
Chronic Hepatitis C
Indicated for treatment of chronic hepatitis C genotype 1 or 4 infection as a component of a combination antiviral treatment regimen
150 mg PO qDay in combination with peginterferon alfa and ribavirin, or in combination with sofosbuvir
See content below for specific treatment regimens and duration
Combination with peginterferon alfa and ribavirin (Genotype 1 or 4 HCV monoinfection or HIV/HIV-1 coinfection)
- Treatment-naïve and prior relapsed patients (with or without cirrhosis; not coinfected with HIV): 12 weeks of treatment with simeprevir, peginterferon alfa, and ribavirin FOLLOWED by an additional 12 weeks of peginterferon alfa and ribavirin (total treatment duration of 24 wk)
- Treatment-naïve and prior relapsed patients (without cirrhosis; coinfected with HIV): 12 weeks of treatment with simeprevir, peginterferon alfa, and ribavirin FOLLOWED by an additional 12 weeks of peginterferon alfa and ribavirin (total treatment duration of 24 wk)
- Treatment-naïve and prior relapsed patients (with cirrhosis; coinfected with HIV): 12 weeks of treatment with simeprevir, peginterferon alfa, and ribavirin FOLLOWED by an additional 36 weeks of peginterferon alfa and ribavirin (total treatment duration of 48 wk)
- All prior nonresponders (including partial and null-responders; with or without cirrhosis): 12 weeks of treatment with simeprevir, peginterferon alfa, and ribavirin FOLLOWED by an additional 36 weeks of peginterferon alfa and ribavirin (total treatment duration of 48 wk)
Discontinue if inadequate virologic response in combination with Peg-INF-alfa and RBV
- Monitor HCV RNA levels to determine virologic response
- It is unlikely that patients with inadequate on-treatment virologic response will achieve a sustained virologic response (SVR), therefore discontinuation of treatment is recommended in these patients
- -HCV-RNA levels at week 4 ≥25 IU/mL: Discontinue simeprevir, peginterferon alfa, and ribavirin
- -HCV-RNA levels at week 12 ≥25 IU/mL: Discontinue peginterferon alfa and ribavirin (treatment with simeprevir completed at week 12)
- -HCV-RNA levels at week 24 ≥25 IU/mL: Discontinue peginterferon alfa and ribavirin
Combination with sofosbuvir (Genotype 1 HCV monoinfection)
- Treatment-naïve or experienced: 150 mg PO qDay plus sofosbuvir 400 mg qDay x12 weeks (without cirrhosis) or x24 weeks (with cirrhosis)
- No treatment stopping rules apply when combined with sofosbuvir
Dosage modifications
To prevent treatment failure, the dose must not be reduced or interrupted
If treatment is discontinued because of adverse reactions or inadequate on-treatment virologic response, simeprevir must not be reinitiated
If adverse reactions potentially related to peginterferon alfa and/or ribavirin occur which require dosage adjustment or interruption of either medicine, refer to the instructions outlined in the respective prescribing information for these medicines
East Asian ancestry: Higher simeprevir exposure exhibited; insufficient safety data to recommend an appropriate dosage adjustment
Renal impairment (mild, moderate, or severe): No dose adjustment required
Hepatic impairment
- Mild (Child-Pugh A): No dose adjustment required
- Moderate or severe (Child-Pugh B or C): Not recommended
Dosing Considerations
Must not be used as monotherapy; if sofosbuvir, peginterferon alfa, or ribavirin is discontinued for any reason, simeprevir must also be discontinued
Efficacy in combination with peginterferon alfa and ribavirin is substantially reduced in patients infected with HCV genotype 1a with an NS3 Q80K polymorphism at baseline compared to patients without the Q80K polymorphism
Screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended
Alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism
Not recommended in patients who have previously failed therapy with a treatment regimen that included simeprevir or other HCV protease inhibitors (eg, boceprevir, telaprevir)
Not recommended in patients with moderate or severe hepatic impairment (Child–Pugh Class B or C)
Pediatric dosage forms and strengths
Safety and efficacy not established
Olysio (simeprevir) adverse (side) effects
>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
Warnings
Black box warnings
Direct-acting antivirals (DDAs) may reactivate hepatitis B virus (HBV) in patients who have a current or previous HBV infection while being treated for hepatitis C virus
In a few cases, HBV reactivation in patients treated with DAA medicines resulted in serious liver problems or death
Patients should be screened for evidence of current or prior HBV infection before starting treatment with DAAs, and monitored for HBV flare-ups or reactivation during DAA treatment and posttreatment follow-up
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
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)
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
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 and lactation
Pregnancy category: X (ribavirin and peginterferon alfa)
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
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
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.
Pharmacology of Olysio (simeprevir)
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
Administration
Instructions
Take with food (bioavailability improved)
Swallow capsule whole
