Simeprevir adverse reactions

# Adverse Reactions
OLYSIO should be administered with peginterferon alfa and ribavirin. Refer to the prescribing information of peginterferon alfa and ribavirin for a description of adverse reactions associated with their use.
The following serious and otherwise important adverse drug reactions (ADRs) are discussed in detail in another section of the labeling:
- Embryo-Fetal Toxicity (Use with Ribavirin and Peginterferon alfa) 
- Photosensitivity 
- Rash 

## Clinical Studies Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
The safety profile of OLYSIO in combination with peginterferon alfa and ribavirin in patients with HCV genotype 1 infection who were treatment-naive or who had previously relapsed following interferon therapy with or without ribavirin is based on pooled data from three Phase 3 trials. These trials included a total of 1178 subjects who received OLYSIO or placebo in combination with 24 or 48 weeks of peginterferon alfa and ribavirin. Of the 1178 subjects, 781 subjects were randomized to receive OLYSIO 150 mg once daily for 12 weeks and 397 subjects were randomized to receive placebo once daily for 12 weeks.
In the pooled Phase 3 safety data, the majority of the adverse reactions reported during 12 weeks treatment with OLYSIO in combination with peginterferon alfa and ribavirin were Grade 1 to 2 in severity. Grade 3 or 4 adverse reactions were reported in 23% of subjects receiving OLYSIO in combination with peginterferon alfa and ribavirin versus 25% of subjects receiving placebo in combination with peginterferon alfa and ribavirin. Serious adverse reactions were reported in 2% of subjects receiving OLYSIO in combination with peginterferon alfa and ribavirin and in 3% of subjects receiving placebo in combination with peginterferon alfa and ribavirin. Discontinuation of OLYSIO or placebo due to adverse reactions occurred in 2% and 1% of subjects receiving OLYSIO with peginterferon alfa and ribavirin and subjects receiving placebo with peginterferon alfa and ribavirin, respectively.
The following table lists adverse reactions (all Grades) that occurred with at least 3% higher frequency among subjects receiving OLYSIO 150 mg once daily in combination with peginterferon alfa and ribavirin compared to subjects receiving placebo in combination with peginterferon alfa and ribavirin during the first 12 weeks of treatment in the pooled Phase 3 trials in subjects who were treatment-naive or who had previously relapsed after peginterferon alfa and ribavirin therapy (see Table 3).

## Rash and Photosensitivity
In the Phase 3 clinical trials, rash (including photosensitivity reactions) was observed in 28% of OLYSIO-treated subjects compared to 20% of placebo-treated subjects during the 12 weeks of treatment with OLYSIO/placebo in combination with peginterferon alfa and ribavirin. Fifty-six percent (56%) of rash events in the OLYSIO group occurred in the first 4 weeks, with 42% of cases occurring in the first 2 weeks. Most of the rash events in OLYSIO-treated subjects were of mild or moderate severity (Grade 1 or Grade 2). Severe (Grade 3) rash occurred in 1% of OLYSIO-treated subjects and in none of the placebo-treated subjects. There were no reports of life-threatening (Grade 4) rash. Discontinuation of OLYSIO/placebo due to rash occurred in 1% of OLYSIO-treated subjects, compared to less than 1% of placebo-treated subjects. The frequencies of rash and photosensitivity reactions were higher in subjects with higher simeprevir exposures.
All subjects enrolled in the Phase 3 trials were directed to use sun protection measures. In these trials, adverse reactions under the specific category of photosensitivity were reported in 5% of OLYSIO-treated subjects compared to 1% of placebo-treated subjects during the 12 weeks of treatment with OLYSIO/placebo in combination with peginterferon alfa and ribavirin. Most photosensitivity reactions in OLYSIO-treated subjects were of mild or moderate severity (Grade 1 or 2). Two OLYSIO-treated subjects experienced photosensitivity reactions which resulted in hospitalization. No life-threatening photosensitivity reactions were reported.

## Dyspnea
During the 12 weeks of treatment with OLYSIO, dyspnea was reported in 12% of OLYSIO-treated subjects compared to 8% of placebo-treated subjects (all grades; pooled Phase 3). All dyspnea events reported in OLYSIO-treated subjects were of mild or moderate severity (Grade 1 or 2). There were no Grade 3 or 4 dyspnea events reported and no subjects discontinued treatment with OLYSIO due to dyspnea. Sixty-one percent (61%) of dyspnea events occurred in the first 4 weeks of treatment with OLYSIO.

## Laboratory abnormalities
There were no differences between treatment groups for the following laboratory parameters: hemoglobin, neutrophils, platelets, aspartate aminotransferase, alanine aminotransferase, amylase, or serum creatinine. Treatment-emergent laboratory abnormalities that were observed at a higher incidence in OLYSIO-treated subjects than in placebo-treated subjects are listed in Table 4.
Elevations in bilirubin were predominately mild to moderate (Grade 1 or 2) in severity, and included elevation of both direct and indirect bilirubin. Elevations in bilirubin occurred early after treatment initiation, peaking by study Week 2, and were rapidly reversible upon cessation of OLYSIO. Bilirubin elevations were generally not associated with elevations in liver transaminases.