FDA Update - OLYSIO (simeprevir) label revised to include pharmacokinetic, safety and efficacy data in treatment-naïve adult patients of East Asian ancestry with chronic hepatitis C virus genotype 1 infection.

OLYSIO 

The OLYSIO (simeprevir) label was updated to include pharmacokinetic, safety and efficacy data in treatment-naïve adult patients of East Asian ancestry with chronic hepatitis C virus genotype 1 infection.

Patients of East Asian ancestry exhibit higher simeprevir plasma exposures but no dosage adjustment is required based on race.

In a Phase 3 trial conducted in China and South Korea, the mean plasma exposure of simeprevir in East Asian HCV infected subjects was 2.1 fold higher compared to non Asian HCV infected subjects in a pooled Phase 3 population from global trials

Adverse Reactions in East Asian Subjects

OLYSIO in combination with Peg IFN alfa and RBV was studied in a Phase 3 trial conducted in China and South Korea in treatment naïve subjects with chronic HCV genotype 1 infection (TIGER). The safety profile of OLYSIO in East Asian subjects was similar to that of the pooled Phase 3 population from global trials; however, a higher incidence of the laboratory abnormality hyperbilirubinemia was observed in patients receiving 150 mg OLYSIO plus Peg IFN alfa and RBV compared to patients receiving placebo plus Peg IFN alfa and RBV. Elevation of total bilirubin (all grades) was observed in 66% (99/151) of subjects treated with 150 mg OLYSIO plus Peg IFN alfa and RBV and in 26% (40/152) of subjects treated with placebo plus Peg IFN alfa and RBV. Bilirubin elevations were mainly Grade 1 or Grade 2. Grade 3 elevations in bilirubin were observed in 9% (13/151) of subjects treated with 150 mg OLYSIO plus Peg IFN alfa and RBV and in 1% (2/152) of subjects treated with placebo plus Peg IFN alfa and RBV. There were no Grade 4 elevations in bilirubin. The bilirubin elevations were not associated with increases in liver transaminases and were reversible after the end of treatment.

Treatment Naïve East Asian Subjects with HCV Genotype 1 Infection

TIGER was a Phase 3, randomized, double blind, placebo controlled trial in HCV genotype 1 infected treatment naïve adult subjects from China and South Korea.

In this trial, 152 subjects received 12 weeks of once daily treatment with 150 mg OLYSIO plus Peg IFN alfa 2a and RBV, followed by 12 or 36 weeks of therapy with Peg IFN alfa 2a and RBV in accordance with protocol defined RGT criteria; and 152 subjects received 12 weeks of placebo plus Peg IFN alfa 2a and RBV, followed by 36 weeks therapy with Peg IFN alfa 2a and RBV. These 304 subjects had a median age of 45 years (range: 18 to 68 years; with 2% above 65 years); 49% were male; all were East Asians (81% were enrolled in China, and 19% in South Korea); 3% had a body mass index (BMI) greater or equal to 30 kg/m2; 84% had baseline HCV RNA levels greater than 800000 IU/mL; 82% had METAVIR fibrosis score F0, F1 or F2, 12% METAVIR fibrosis score F3, and 6% METAVIR fibrosis score F4 (cirrhosis); 1% had HCV genotype 1a, and 99% HCV genotype 1b; less than 1% of the overall population had Q80K polymorphism at baseline; 79% had IL28B CC genotype, 20% IL28B CT genotype, and 1% IL28B TT genotype. Demographics and baseline characteristics were balanced across the OLYSIO 150 mg and placebo treatment groups.

SVR12 rates were 91% (138/152) in the OLYSIO 150 mg treatment group and 76% (115/152) in the placebo treatment group

You can view the complete label at drugs@fda or dailymed.

Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration

Kimberly Struble
Division of Antiviral Products
Food and Drug Administration

Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration

For more information about the Hepatitis Liaison Program visit the FDA Patient Network

FDA approved revisions to the Olysio (simeprevir) label to include dosing recommendations for the treatment of HCV/HIV-1 coinfection and to expand the indications and usage to include genotype 4 infection.

On October 5, 2015 FDA approved revisions to the Olysio (simeprevir) label to include dosing recommendations for the treatment of HCV/HIV-1 coinfection and to expand the indications and usage to include genotype 4 infection.

The recommended dosage regimens and treatment duration for genotype 1 and HCV/HIV-1 co-infected patients was added to the following table:

Table 1: Recommended Dosage Regimens and Treatment Duration for OLYSIO, Peg IFN alfa, and RBV Combination Therapy for Treatment of CHC Infection in HCV Genotype 1 or 4 Mono infected and HCV/HIV 1  Co infected Patients
Patient Population	Treatment Regimen and Duration
Treatment naïve patients and prior relapsers*
with or without cirrhosis, who are not co infected with HIV	12 weeks of OLYSIO in combination with Peg IFN alfa and RBV followed by an additional 12 weeks of Peg IFN alfa and RBV (total treatment duration of 24 weeks)†
without cirrhosis, who are co infected with HIV
with cirrhosis, who are co infected with HIV	12 weeks of OLYSIO in combination with Peg-IFN-alfa and RBV followed by an additional 36 weeks of Peg IFN alfa and RBV (total treatment duration of 48 weeks)†
Prior non responders (including partial‡ and null responders#), with or without cirrhosis, with or without HIV co infection	12 weeks of OLYSIO in combination with Peg-IFN-alfa and RBV followed by an additional 36 weeks of Peg IFN alfa and RBV (total treatment duration of 48 weeks)†

†HIV = human immunodeficiency virus.
* Prior relapser: HCV RNA not detected at the end of prior IFN based therapy and HCV RNA detected during follow up [see Clinical Studies (14)].
‡† Recommended duration of treatment if patient does not meet stopping rules (see Table 3).
#‡ Prior partial responder: prior on-treatment ≥ 2 log10 IU/mL reduction in HCV RNA from baseline at Week 12 and HCV RNA detected at end of prior IFN based therapy [see Clinical Studies (14)].
§# Prior null responder: prior on treatment < 2 log10 reduction in HCV RNA from baseline at Week 12 during prior IFN based therapy [see Clinical Studies (14)].

Section 6 Adverse Reactions was updated with the following information.

OLYSIO in combination with Peg IFN alfa and RBV was studied in 106 subjects with HCV genotype 1/HIV 1 co infection. The safety profile in HCV/HIV co-infected subjects was generally comparable to HCV mono infected subjects.

OLYSIO in combination with Peg IFN alfa and RBV was studied in 107 subjects with HCV genotype 4 infection. The safety profile of OLYSIO in subjects with HCV genotype 4 infection was comparable to subjects with HCV genotype 1 infection.

Azithromycin, bedaquiline and dolutegravir were added to the list of drugs without clinically significant interactions with OLYSIO (see section 7.4 of the label).

Section 12.3 Pharmacokinetics was updated to include the following statements.

Patients co infected with HIV 1

Simeprevir exposures were slightly lower in subjects with HCV genotype 1 infection with HIV 1 co infection compared to subjects with HCV genotype 1 mono infection. This difference is not considered to be clinically meaningful.

Section 12.4 Microbiology was updated to include data on genotype 4 as follows:

Chimeric replicons carrying NS3 sequences derived from HCV protease inhibitor treatment naïve genotype 4a-, 4d-, or 4r infected patients displayed median FC in EC50 values of 0.5 (IQR: 0.4 to 0.6; N=38), 0.4 (IQR: 0.2 to 0.5; N=24), and 1.6 (IQR: 0.7 to 4.5; N=8), compared to reference genotype 1b replicon, respectively. A pooled analysis of chimeric replicons carrying the NS3 sequences from HCV protease inhibitor naïve patients infected with other HCV genotype 4 subtypes, including 4c (N=1), 4e (N=2), 4f (N=3), 4h (N=3), 4k (N=1), 4o (N=2), 4q (N=2), or unidentified subtype (N=7) displayed a median FC in EC50 value of 0.7 (IQR: 0.5 to 1.1; N=21) compared to reference genotype 1b replicon.

In the RESTORE trial in genotype 4 infected subjects, 30 out of 34 (88%) subjects who did not achieve SVR had emerging amino acid substitutions at NS3 positions Q80, T122, R155, A156 and/or D168 (mainly substitutions at position D168; 26 out of 34 [76%] subjects), similar to the emerging amino acid substitutions observed in genotype 1 infected subjects.

Table 11: SVR12 Rates by IL28B rs12979860 Genotype in Adult Patients Receiving OLYSIO 150 mg Once Daily in Combination with Peg IFN alfa and RBV (Trials C212 and RESTORE)
Trial (Population)	IL28B  rs12979860  Genotype	Treatment- Naïve  Subjects % (n/N)	Prior  Relapsers % (n/N)	Prior Partial Responders % (n/N)	Prior Null Responders % (n/N)
C212 (HIV 1 co infection)	C/C	100 (15/15)	100 (7/7)	100 (1/1)	80 (4/5)
	C/T	70 (19/27)	100 (6/6)	71 (5/7)	53 (10/19)
	T/T	80 (8/10)	0 (0/2)	50 (1/2)	50 (2/4)
RESTORE (HCV genotype 4)	C/C	100 (7/7)	100 (1/1)	-	-
	C/T	82 (14/17)	82 (14/17)	60 (3/5)	41 (9/22)
	T/T	0 (8/10)	00 (4/4)	60 (3/5)	39 (77/18)

SVR12: sustained virologic response 12 weeks after planned EOT.

Section 14 Clinical Studies was updated to include the trial results from the HCV/HIV- coinfected trial and the genotype 4 trial.

Subjects with HCV/HIV 1 Co Infection
C212 was an open label, single arm Phase 3 trial in HIV 1 subjects co infected with HCV genotype 1 who were treatment naïve or failed prior HCV therapy with Peg IFN alfa and RBV (including prior relapsers, partial responders or null responders). Non cirrhotic treatment naïve subjects or prior relapsers received 12 weeks of once daily treatment with 150 mg OLYSIO plus Peg IFN alfa 2a and RBV, followed by 12 or 36 weeks of therapy with Peg IFN alfa 2a and RBV in accordance with the protocol defined RGT criteria. Prior non responder subjects (partial and null response) and all cirrhotic subjects (METAVIR fibrosis score F4) received 36 weeks of Peg IFN alfa 2a and RBV after the initial 12 weeks of OLYSIO in combination with Peg IFN alfa 2a and RBV.

The 106 enrolled subjects in the C212 trial had a median age of 48 years (range: 27 to 67 years; with 2% above 65 years); 85% were male; 82% were White, 14% Black or African American, 1% Asian, and 6% Hispanic; 12% had a BMI greater than or equal to 30 kg/m2; 86% had HCV RNA levels greater than 800,000 IU/mL; 68% had METAVIR fibrosis score F0, F1 or F2, 19% METAVIR fibrosis score F3, and 13% METAVIR fibrosis score F4; 82% had HCV genotype 1a, and 17% HCV genotype 1b; 28% of the overall population and 34% of the subjects with genotype 1a had Q80K polymorphism at baseline; 27% had IL28B CC genotype, 56% IL28B CT genotype, and 17% IL28B TT genotype; 50% (n=53) were HCV treatment naïve subjects, 14% (n=15) prior relapsers, 9% (n=10) prior partial responders, and 26% (n=28) prior null responders. Eighty eight percent (n=93) of the subjects were on highly active antiretroviral therapy (HAART), with nucleoside reverse transcriptase inhibitors and the integrase inhibitor raltegravir being the most commonly used HIV antiretroviral. HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors (except rilpivirine) were prohibited from use in this study.

The median baseline HIV 1 RNA levels and CD4+ cell count in subjects not on HAART were 4.18 log10 copies/mL (range: 1.3 4.9 log10 copies/mL) and 677 × 106 cells/L (range: 489 1076 × 106 cells/L), respectively. The median baseline CD4+ cell count in subjects on HAART was 561 × 106 cells/mL (range: 275 1407 × 106 cells/mL).

Table 17 shows the response rates in treatment naïve, prior relapsers, prior partial responders and null responders.

Table 17: Response Rates in Adult Subjects with HCV Genotype 1 Infection and HIV 1 Co Infection (C212 Trial)
Response Rates	Treatment Naïve Subjects N=53 % (n/N)	Prior Relapsers N=15 % (n/N)	Prior Partial Responders N=10 % (n/N)	Prior Null Responders N=28 % (n/N)
Overall SVR12 (genotype 1a and 1b) Genotype 1a Genotype 1b	79 (42/53) 77 (33/43) 90 (9/10)	87 (13/15) 83 (10/12) 100 (3/3)	70 (7/10) 67 (6/9) 100 (1/1)	57 (16/28) 54 (13/24) 75 (3/4)
Outcome for all subjects without SVR12
On treatment failure*	9 (5/53)	0 (0/15)	20 (2/10)	39 (11/28)
Viral relapse†	10 (5/48)	13 (2/15)	0 (0/7)	12 (2/17)

150 mg OLYSIO for 12 weeks with Peg IFN alfa 2a and RBV for 24 or 48 weeks.
* On treatment failure was defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including but not limited to subjects who met the protocol specified treatment stopping rules and/or experienced viral breakthrough).
† Viral relapse rates are calculated with a denominator of subjects with undetectable HCV RNA at actual EOT and with at least one follow up HCV RNA assessment. Includes one prior null responder who experienced relapse after SVR12.

Eighty nine percent (n=54/61) of the OLYSIO treated treatment naïve subjects and prior relapsers without cirrhosis were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 87%.

Seventy-one percent (n=37/52), 93% (n=14/15), 80% (n=8/10) and 36% (n=10/28) of OLYSIO treated treatment naïve subjects, prior relapsers, prior partial responders and prior null responders had undetectable HCV RNA at week 4 (RVR). In these subjects the SVR12 rates were 89%, 93%, 75% and 90%, respectively.

Table 18 shows the SVR rates by METAVIR fibrosis scores.

Table 18: SVR12 Rates by METAVIR Fibrosis Score in Adult Subjects with HCV Genotype 1 Infection and HIV 1 co Infection (C212 Trial)
Subgroup	Treatment Naïve  Subjects % (n/N)	Prior  Relapsers % (n/N)	Prior Partial Responders % (n/N)	Prior Null Responders % (n/N)
F0 2	89 (24/27)	78 (7/9)	50 (1/2)	57 (4/7)
F3 4	57 (4/7)	100 (2/2)	67 (2/3)	60 (6/10)

Two subjects had HIV virologic failure defined as confirmed HIV 1 RNA ≥ 200 copies/mL after previous < 50 copies/mL; these failures occurred 36 and 48 weeks after end of OLYSIO treatment.

Adult Subjects with HCV Genotype 4 Infection
RESTORE was an open label, single arm Phase 3 trial in subjects with HCV genotype 4 infection who were treatment naïve or failed prior therapy with Peg IFN alfa and RBV (including prior relapsers, partial responders or null responders). Treatment naïve subjects or prior relapsers received once daily treatment with 150 mg OLYSIO plus Peg IFN alfa 2a and RBV for 12 weeks, followed by 12 or 36 weeks of therapy with Peg IFN alfa 2a and RBV in accordance with the protocol defined RGT criteria. Prior non responder subjects (partial and null response) received once daily treatment with 150 mg OLYSIO plus Peg IFN alfa 2a and RBV for 12 weeks, followed by 36 weeks of Peg IFN alfa 2a and RBV.

The 107 enrolled subjects in the RESTORE trial with HCV genotype 4 had a median age of 49 years (range: 27 to 69 years; with 5% above 65 years); 79% were male; 72% were White, 28% Black or African American, and 7% Hispanic; 14% had a BMI greater than or equal to 30 kg/m2; 60% had HCV RNA levels greater than 800,000 IU/mL; 57% had METAVIR fibrosis score F0, F1 or F2, 14% METAVIR fibrosis score F3, and 29% METAVIR fibrosis score F4; 42% had HCV genotype 4a, and 24% had HCV genotype 4d; 8% had IL28B CC genotype, 58% IL28B CT genotype, and 35% IL28B TT genotype; 33% (n=35) were treatment naïve HCV subjects, 21% (n=22) prior relapsers, 9% (n=10) prior partial responders, and 37% (n=40) prior null responders.

Table 19 shows the response rates in treatment naïve, prior relapsers, prior partial responders and null responders. Table 20 shows the SVR rates by METAVIR fibrosis scores.

Table 19: Response Rates in Adult Subjects with HCV Genotype 4 Infection (RESTORE Trial)
Response Rates	Treatment Naïve Subjects N=35 % (n/N)	Prior Relapsers N=22 % (n/N)	Prior Partial Responders N=10 % (n/N)	Prior Null Responders N=40 % (n/N)
Overall SVR12	83 (29/35)	86 (19/22)	60 (6/10)	40 (16/40)
Outcome for all subjects without SVR12
On treatment failure*	9 (3/35)	9 (2/22)	20 (2/10)	45 (18/40)
Viral relapse†	9 (3/35)	5 (1/22)	20 (2/10)	15 (6/40)

150 mg OLYSIO for 12 weeks with Peg IFN alfa 2a and RBV for 24 or 48 weeks.
* On treatment failure was defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including but not limited to subjects who met the protocol specified treatment stopping rules and/or experienced viral breakthrough).
† Viral relapse rates are calculated with a denominator of subjects with undetectable (or unconfirmed detectable) HCV RNA at actual EOT.

Table 20: SVR12 Rates by METAVIR Fibrosis Score in Adult Subjects with HCV Genotype 4 Infection (RESTORE Trial)
Subgroup	Treatment Naïve Subjects % (n/N)	Prior Relapsers % (n/N)	Prior Partial Responders % (n/N)	Prior Null Responders % (n/N)
F0-2	85 (22/26)	91 (10/11)	100 (5/5)	47 (8/17)
F3-4	78 (7/9)	82 (9/11)	20 (1/5)	35 (7/20)

You will be able to view the complete label at drugs@fda or dailymed.

Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration

Kimberly Struble
Division of Antiviral Products
Food and Drug Administration

Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration

For more information about the Hepatitis Liaison Program visit the FDA Patient Network

FDA approved changes to the Olysio (simeprevir) package insert to include two new Warnings and Precautions;

Related
March 21 - FDA Update - Important safety information: Harvoni and Sovaldi‏

FDA approved changes to the Olysio (simeprevir) package insert to include two new Warnings and Precautions;

1. serious symptomatic bradycardia when co-administered with sofosbuvir and amiodarone
2. hepatic decompensation and hepatic failure.

Additional changes to the Indication and Usage, Dosage and Administration, Adverse Reactions, Drug Interactions, Use in Specific Populations and Pharmacokinetic sections of the label were made based on these Warnings and Precautions and are summarized below.

Summary of new WARNINGS AND PRECAUTIONS

5              WARNINGS AND PRECAUTIONS

5.1          Serious Symptomatic Bradycardia When Co-administered with Sofosbuvir and Amiodarone

Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is co administered with sofosbuvir in combination with another HCV direct acting antiviral, including OLYSIO. A fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir/sofosbuvir). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with co administration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this bradycardia effect is unknown.

Co administration of amiodarone with OLYSIO in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no other alternative treatment options, and who will be co administered OLYSIO and sofosbuvir:

• Counsel patients about the risk of serious symptomatic bradycardia
• Cardiac monitoring in an in-patient setting for the first 48 hours of co administration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.

Patients who are taking sofosbuvir in combination with OLYSIO who need to start amiodarone therapy due to no other alternative treatment options should undergo similar cardiac monitoring as outlined above.

Due to amiodarone’s long elimination half-life, patients discontinuing amiodarone just prior to starting sofosbuvir in combination with OLYSIO should also undergo similar cardiac monitoring as outlined above.

Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems [see Adverse Reactions (6.2) and Drug Interactions (7.3)].

5.2          Hepatic Decompensation and Hepatic Failure

Hepatic decompensation and hepatic failure, including fatal cases, have been reported postmarketing in patients treated with OLYSIO in combination 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. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between treatment with OLYSIO and these events has not been established [see Adverse Reactions (6.2)].

OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) [see Dosage and Administration (2.5) and Use in Specific Populations (8.8)].

In clinical trials of OLYSIO, modest increases in bilirubin levels were observed without impacting hepatic function [see Adverse Reactions (6.1)]. Postmarketing cases of hepatic decompensation with markedly elevated bilirubin levels have been reported. Monitor liver chemistry tests before and as clinically indicated during OLYSIO combination therapy. Patients who experience an increase in total bilirubin to greater than 2.5 times the upper limit of normal should be closely monitored:

• Patients should be instructed to contact their healthcare provider if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces.
• Discontinue OLYSIO if elevation in bilirubin is accompanied by liver transaminase increases or clinical signs and symptoms of hepatic decompensation.

Additional Changes

The Indications and Usage section was updated to state:

Limitations of Use:

• OLYSIO is not recommended in patients with moderate or severe hepatic impairment (Child Pugh Class B or C) [see Dosage and Administration (2.5), Warnings and Precautions (5.2), Adverse Reactions (6.1, 6.2), Use in Specific Populations (8.8) and Clinical Pharmacology (12.3)].

The Dosage and Administration section was updated as follows:

2              DOSAGE AND ADMINISTRATION

2.1          OLYSIO Combination Treatment

Administer OLYSIO in combination with other antiviral drugs for the treatment of CHC infection. Monitor liver chemistry tests before and during OLYSIO combination therapy [see Warnings and Precautions (5.2)]. OLYSIO monotherapy is not recommended. For specific dosing recommendations for the antiviral drugs used in combination with OLYSIO, refer to their respective prescribing information.

2.5          Hepatic Impairment

OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child Pugh Class B or C) [see Use in Specific Populations (8.8)]. There have been postmarketing reports of hepatic decompensation, hepatic failure, and death in patients with advanced or decompensated cirrhosis receiving OLYSIO combination therapy [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)]. Simeprevir exposures are increased in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) [see Clinical Pharmacology (12.3)].

In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including increased bilirubin, rash and photosensitivity [see Adverse Reactions (6.1)].

OLYSIO in combination with Peg IFN alfa and RBV is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment) [see Peg IFN alfa prescribing information].

The Adverse Reactions section was updated as follows:

6              ADVERSE REACTIONS

Laboratory abnormalities

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. The frequency of elevated bilirubin was higher in subjects with higher simeprevir exposures.

6.2          Postmarketing Experience

The following adverse reactions have been reported during post approval use of OLYSIO. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship between drug exposure and these adverse reactions.

Cardiac Disorders: Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with sofosbuvir in combination with another HCV direct acting antiviral, including OLYSIO [see Warnings and Precautions (5.1) and Drug Interactions (7.3)].

Hepatobiliary Ddisorders: hepatic decompensation, hepatic failure [see Warnings and Precautions (5.2)].

Section 7 Drug Interactions was updated to include revisions to the antiarrhythmic section.

Table 6:                Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class Drug Name	Effect on Concentration of Simeprevir orConcomitant Drug	Clinical Comment
Antiarrhythmics
Amiodarone	Effect on amiodarone, simeprevir, and sofosbuvir concentrations unknown	Co‑administration of amiodarone with OLYSIO in combination with sofosbuvir is not recommended because it may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. If co‑administration is required, cardiac monitoring is recommended [see Warnings and Precautions (5.1), Adverse Reactions (6.2)].
	amiodarone	Caution is warranted and therapeutic drug monitoring of amiodarone, if available, is recommended for concomitant use of amiodarone with an OLYSIO-containing regimen that does not contain sofosbuvir. Concomitant use of OLYSIO with amiodarone when given orally may result in mild increases in amiodarone concentrations due to intestinal CYP3A4 inhibition by simeprevir.

Section 8 Use in Specific Populations was updated as follows:

8              USE IN SPECIFIC POPULATIONS

8.8          Hepatic Impairment

No dose adjustment of OLYSIO is required in patients with mild hepatic impairment (Child Pugh Class A) [see Clinical Pharmacology (12.3)].

The safety and efficacy of OLYSIO have not been established in HCV infected patients with moderate or severe hepatic impairment (Child Pugh Class B or C).

OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child Pugh Class B or C) [see Dosage and Administration (2.5)]. There have been postmarketing reports of hepatic decompensation, hepatic failure, and death in patients with advanced or decompensated cirrhosis receiving OLYSIO combination therapy [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)]. Simeprevir exposures are increased in patients with moderate or severe hepatic impairment (Child Pugh Class B or C) [see Clinical Pharmacology (12.3)]. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including increased bilirubin, rash and photosensitivity [see Adverse Reactions (6.1)].

Refer to the prescribing information for the antiviral drug(s) used in combination with OLYSIO regarding their use in patients with hepatic impairment. The combination of OLYSIO with Peg IFN alfa and RBV is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment).

Section 12.3 Pharmacokinetics included the following updates:

12.3        Pharmacokinetics

Specific Populations

Hepatic Impairment

Simeprevir is primarily metabolized by the liver. Compared to HCV uninfected subjects with normal hepatic function, the 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).

No dose adjustment of OLYSIO is necessary in patients with mild hepatic impairment (Child Pugh Class A).

The safety and efficacy of OLYSIO have not been established in HCV infected patients with moderate or severe hepatic impairment (Child Pugh Class B or C).

OLYSIO is not recommended for use in patients with moderate or severe hepatic impairment (Child Pugh Class B or C) [see Dosage and Administration (2.5), Warnings and Precautions (5.2) and Use in Specific Populations (8.8)].

In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including increased bilirubin, rash and photosensitivity [see Adverse Reactions (6.1)].

Based on a population pharmacokinetic analysis of HCV infected subjects with mild hepatic impairment (Child-Pugh Class A) treated with OLYSIO, liver fibrosis stage did not have a clinically relevant effect on the pharmacokinetics of simeprevir.

Refer to the prescribing information for the antiviral drugs used in combination with OLYSIO regarding their use in patients with hepatic impairment.

Drug Interactions

[See also Warnings and Precautions (5.67) and Drug Interactions (7)]

In vitro studies indicated that simeprevir is a substrate and mild inhibitor of CYP3A. Simeprevir does not affect CYP2C9, CYP2C19 or CYP2D6 in vivo. Simeprevir does not induce CYP1A2 or CYP3A4 in vitro. In vivo, simeprevir mildly inhibits the CYP1A2 activity and intestinal CYP3A4 activity, while it does not affect hepatic CYP3A4 activity. Simeprevir is not a clinically relevant inhibitor of cathepsin A enzyme activity.

In vitro, simeprevir is a substrate for P gp, MRP2, BCRP, OATP1B1/3 and OATP2B1; simeprevir inhibits the uptake transporters OATP1B1/3 and NTCP and the efflux transporters P gp/MDR1, MRP2 and BSEP. The inhibitory effects of simeprevir on the bilirubin transporters OATP1B1/3 and MRP2 likely contribute to clinical observations of elevated bilirubin [see Adverse Reactions (6.1)].

The updated product label will be available soon at DailyMed or at Drugs@FDA.

Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration