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Olysio

Generic Name: simeprevir
Dosage Form: capsule

Indications and Usage for Olysio

Olysio® is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 or 4 infection as a component of a combination antiviral treatment regimen.

Limitations of Use:

  • Efficacy of Olysio in combination with peginterferon alfa (Peg-IFN-alfa) and ribavirin (RBV) is substantially reduced in patients infected with HCV genotype 1a with an NS3 Q80K polymorphism at baseline compared to patients infected with hepatitis C virus (HCV) genotype 1a without the Q80K polymorphism [see Dosage and Administration (2.1) and Microbiology (12.4)].
  • Olysio is not recommended in patients who have previously failed therapy with a treatment regimen that included Olysio or other HCV protease inhibitors [see Microbiology (12.4)].

Olysio Dosage and Administration

Testing Prior to Initiation of Therapy

Q80K Testing in HCV Genotype 1a-Infected Patients

Prior to initiation of treatment with Olysio in combination with sofosbuvir, screening patients infected with HCV genotype 1a for the presence of virus with the NS3 Q80K polymorphism may be considered [see Microbiology (12.4)].

Prior to initiation of treatment with Olysio in combination with Peg-IFN-alfa and RBV, screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism is strongly recommended and alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism [see Indications and Usage (1) and Microbiology (12.4)].

Hepatic Laboratory Testing

Monitor liver chemistry tests before and during Olysio combination therapy [see Warnings and Precautions (5.2)].

Olysio Combination Treatment

Administer Olysio in combination with other antiviral drugs for the treatment of chronic HCV infection. Olysio monotherapy is not recommended. The recommended dosage of Olysio is one 150 mg capsule taken orally once daily with food [see Clinical Pharmacology (12.3)]. The capsule should be swallowed as a whole. For specific dosing recommendations for the antiviral drugs used in combination with Olysio, refer to their respective prescribing information.

Olysio can be taken in combination with sofosbuvir or in combination with Peg-IFN-alfa and RBV.

Olysio + Sofosbuvir:

Table 1 displays the recommended treatment regimen and duration of Olysio in combination with sofosbuvir in mono-infected patients with HCV genotype 1 infection.

Table 1: Recommended Treatment Regimen and Duration for Olysio and Sofosbuvir Combination Therapy in Patients with Chronic HCV Genotype 1 Infection
Patient Population (Genotype 1) Treatment Regimen and Duration
*
Treatment-experienced patients include prior relapsers, prior partial responders and prior null responders who failed prior IFN-based therapy.
Treatment-naïve and treatment-experienced patients:*
  without cirrhosis 12 weeks of Olysio + sofosbuvir
  with cirrhosis 24 weeks of Olysio + sofosbuvir

Olysio + Peg-IFN-alfa + RBV:

Table 2 displays the recommended treatment regimen and duration of Olysio in combination with Peg-IFN-alfa and RBV in mono-infected and HCV/HIV-1 co-infected patients with HCV genotype 1 or 4 infection. Refer to Table 3 for treatment stopping rules for Olysio combination therapy with Peg-IFN-alfa and RBV.

Table 2: Recommended Treatment Regimen and Duration for Olysio, Peg-IFN-alfa, and RBV Combination Therapy in Patients with Chronic HCV Genotype 1 or 4 Infection
Patient Population (Genotype 1 or 4) Treatment Regimen and Duration
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 IU/mL reduction in HCV RNA from baseline at Week 12 during prior IFN-based therapy [see Clinical Studies (14)].
Treatment-naïve patients and prior relapsers:*
  with or without cirrhosis, who are not co-infected with HIV 12 weeks of Olysio + Peg-IFN-alfa + RBV followed by an additional 12 weeks of Peg-IFN-alfa + 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 + Peg-IFN-alfa + RBV followed by an additional 36 weeks of Peg-IFN-alfa + 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 + Peg-IFN-alfa + RBV followed by an additional 36 weeks of Peg-IFN-alfa + RBV (total treatment duration of 48 weeks)

Discontinuation of Dosing

Use with Sofosbuvir

No treatment stopping rules apply to the combination of Olysio with sofosbuvir [see Clinical Studies (14)].

Use with Peg-IFN-Alfa and RBV

During treatment, HCV RNA levels should be monitored as clinically indicated using a sensitive assay with a lower limit of quantification of at least 25 IU/mL.

Because patients with an inadequate on-treatment virologic response (i.e., HCV RNA greater or equal to 25 IU/mL) are not likely to achieve a sustained virologic response (SVR), discontinuation of treatment is recommended in these patients. Table 3 presents treatment stopping rules for patients who experience an inadequate on-treatment virologic response at Weeks 4, 12, and 24.

Table 3: Treatment Stopping Rules in Patients Receiving Olysio in Combination with Peg-IFN-alfa and RBV with Inadequate On-Treatment Virologic Response
Treatment Week HCV RNA Action
Week 4 ≥ 25 IU/mL Discontinue Olysio, Peg-IFN-alfa, and RBV
Week 12 Discontinue Peg-IFN-alfa, and RBV (treatment with Olysio is complete at Week 12)  
Week 24 Discontinue Peg-IFN-alfa, and RBV (treatment with Olysio is complete at Week 12)  

Dosage Adjustment or Interruption

To prevent treatment failure, avoid reducing the dosage of Olysio or interrupting treatment. If treatment with Olysio is discontinued because of adverse reactions or inadequate on-treatment virologic response, Olysio treatment must not be reinitiated [see Warnings and Precautions (5.2)].

If adverse reactions potentially related to the antiviral drug(s) used in combination with Olysio occur, refer to the instructions outlined in their respective prescribing information for recommendations on dosage adjustment or interruption.

If any of the other antiviral drugs used in combination with Olysio for the treatment of chronic HCV infection are permanently discontinued for any reason, Olysio should also be discontinued.

Not Recommended in Patients with Moderate or Severe Hepatic Impairment

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

Dosage Forms and Strengths

Olysio is available as a white gelatin capsule marked with "TMC435 150" in black ink. Each capsule contains 150 mg simeprevir.

Contraindications

Because Olysio is used only in combination with other antiviral drugs (including Peg-IFN-alfa and RBV) for the treatment of chronic HCV infection, the contraindications to other drugs also apply to the combination regimen. Refer to the respective prescribing information for a list of contraindications.

Warnings and Precautions

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)].

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 Peg-IFN-alfa and RBV 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.

Risk of Serious Adverse Reactions Associated with Combination Treatment

Because Olysio is used in combination with other antiviral drugs for the treatment of chronic HCV infection, consult the prescribing information for these drugs before starting therapy with Olysio. Warnings and Precautions related to these drugs also apply to their use in Olysio combination treatment.

Photosensitivity

Photosensitivity reactions have been observed with Olysio combination therapy. Serious photosensitivity reactions resulting in hospitalization have been observed with Olysio in combination with Peg-IFN-alfa and RBV [see Adverse Reactions (6.1)]. Photosensitivity reactions occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Photosensitivity may present as an exaggerated sunburn reaction, usually affecting areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, and dorsa of the hands). Manifestations may include burning, erythema, exudation, blistering, and edema.

Use sun protective measures and limit sun exposure during treatment with Olysio. Avoid use of tanning devices during treatment with Olysio. Discontinuation of Olysio should be considered if a photosensitivity reaction occurs and patients should be monitored until the reaction has resolved. If a decision is made to continue Olysio in the setting of a photosensitivity reaction, expert consultation is advised.

Rash

Rash has been observed with Olysio combination therapy [see Adverse Reactions (6.1)]. Rash occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Severe rash and rash requiring discontinuation of Olysio have been reported in subjects receiving Olysio in combination with Peg-IFN-alfa and RBV. Most of the rash events in Olysio-treated patients were of mild or moderate severity [see Adverse Reactions (6.1)]. Patients with mild to moderate rashes should be followed for possible progression of rash, including the development of mucosal signs (e.g., oral lesions, conjunctivitis) or systemic symptoms. If the rash becomes severe, Olysio should be discontinued. Patients should be monitored until the rash has resolved.

Sulfa Allergy

Olysio contains a sulfonamide moiety. In subjects with a history of sulfa allergy (n=16), no increased incidence of rash or photosensitivity reactions has been observed. However, there are insufficient data to exclude an association between sulfa allergy and the frequency or severity of adverse reactions observed with the use of Olysio.

Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions

Co-administration of Olysio with substances that are moderate or strong inducers or inhibitors of cytochrome P450 3A (CYP3A) is not recommended as this may lead to significantly lower or higher exposure of simeprevir, respectively, which may result in reduced therapeutic effect or adverse reactions [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

Adverse Reactions

Because Olysio is administered in combination with other antiviral drugs, refer to the prescribing information of the antiviral drugs used in combination with Olysio for a description of adverse reactions associated with their use.

The following serious and otherwise important adverse reactions are described below and in other sections of the labeling:

Clinical Trials 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.

Adverse Reactions when Used with Sofosbuvir

In the COSMOS trial, the most common (greater than 10%) adverse reactions reported during 12 weeks treatment with Olysio in combination with sofosbuvir (without RBV) were fatigue (25%), headache (21%), nausea (21%), insomnia (14%) and pruritus (11%). Rash and photosensitivity were reported in 11% and 7% of subjects, respectively. During 24 weeks treatment with Olysio in combination with sofosbuvir, dizziness (16%), and diarrhea (16%) were also commonly reported.

Adverse Reactions when Used in Combination with Peg-IFN-Alfa and RBV

The safety profile of Olysio in combination with Peg-IFN-alfa and RBV in patients with HCV genotype 1 infection who were treatment-naïve or who had previously relapsed following interferon therapy with or without RBV is based on pooled data from three Phase 3 trials (QUEST-1, QUEST-2 and PROMISE) [see Clinical Studies (14)]. These trials included a total of 1178 subjects who received Olysio or placebo in combination with 24 or 48 weeks of Peg-IFN-alfa and RBV. 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 Peg-IFN-alfa and RBV were Grade 1 to 2 in severity. Grade 3 or 4 adverse reactions were reported in 23% of subjects receiving Olysio in combination with Peg-IFN-alfa and RBV versus 25% of subjects receiving placebo in combination with Peg-IFN-alfa and RBV. Serious adverse reactions were reported in 2% of subjects receiving Olysio in combination with Peg-IFN-alfa and RBV and in 3% of subjects receiving placebo in combination with Peg-IFN-alfa and RBV. Discontinuation of Olysio or placebo due to adverse reactions occurred in 2% and 1% of subjects receiving Olysio with Peg-IFN-alfa and RBV and subjects receiving placebo with Peg-IFN-alfa and RBV, respectively.

The following table lists adverse reactions (all Grades) that occurred with at least 3% higher frequency among subjects with HCV genotype 1 infection receiving Olysio 150 mg once daily in combination with Peg-IFN-alfa and RBV, compared to subjects receiving placebo in combination with Peg-IFN-alfa and RBV, during the first 12 weeks of treatment in the pooled Phase 3 trials in subjects who were treatment-naïve or who had previously relapsed after Peg-IFN-alfa and RBV therapy (see Table 4).

Table 4: Adverse Reactions (all Grades) that Occurred with at Least 3% Higher Frequency Among Subjects with HCV Genotype 1 Infection Receiving Olysio 150 mg Once Daily in Combination with Peg-IFN-alfa and RBV Compared to Subjects Receiving Placebo in Combination with Peg-IFN-alfa and RBV During the First 12 Weeks of Treatment in Subjects with Chronic HCV Infection* (Pooled Phase 3 Trials)
Adverse Reaction Olysio 150 mg + Peg-IFN-alfa+ RBV
First 12 Weeks
N=781
% (n)
Placebo + Peg-IFN-alfa+ RBV
First 12 Weeks
N=397
% (n)
*
Subjects were treatment-naïve or had previously relapsed after Peg-IFN-alfa and RBV therapy.
Pooled Phase 3 trials: QUEST 1, QUEST 2, PROMISE.
Adverse reactions that occurred at ≥ 3% higher frequency in the Olysio treatment group than in the placebo treatment group.
Rash (including photosensitivity) 28 (218) 20 (79)
Pruritus 22 (168) 15 (58)
Nausea 22 (173) 18 (70)
Myalgia 16 (126) 13 (53)
Dyspnea 12 (92) 8 (30)

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 or placebo in combination with Peg-IFN-alfa and RBV. 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 or 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 or placebo in combination with Peg-IFN-alfa and RBV. 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 trials). 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. Laboratory abnormalities that were observed at a higher incidence in Olysio-treated subjects than in placebo-treated subjects are listed in Table 5.

Table 5: Laboratory Abnormalities (WHO Worst Toxicity Grades 1 to 4) Observed at a Higher Incidence in Olysio-Treated Subjects (Pooled Phase 3 Trials*; First 12 Weeks of Treatment)
Laboratory Parameter WHO Toxicity Range Olysio 150 mg + Peg-IFN-alfa + RBV
N=781
%
Placebo + Peg-IFN-alfa + RBV
N=397
%
*
Pooled Phase 3 trials: QUEST 1, QUEST 2, PROMISE.
No Grade 3 or 4 changes in alkaline phosphatase were observed.
ULN = Upper Limit of Normal
Chemistry
Alkaline phosphatase
  Grade 1 > 1.25 to ≤ 2.50 × ULN 3 1
  Grade 2 > 2.50 to ≤ 5.00 × ULN < 1 0
Hyperbilirubinemia
  Grade 1 > 1.1 to ≤ 1.5 × ULN 27 15
  Grade 2 > 1.5 to ≤ 2.5 × ULN 18 9
  Grade 3 > 2.5 to ≤ 5.0 × ULN 4 2
  Grade 4 > 5.0 × ULN < 1 0

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.

Adverse Reactions in HCV/HIV-1 Co-infection

Olysio in combination with Peg-IFN-alfa and RBV was studied in 106 subjects with HCV genotype 1/HIV-1 co-infection (C212). The safety profile in HCV/HIV co-infected subjects was generally comparable to HCV mono-infected subjects.

Adverse Reactions in HCV Genotype 4 Infection

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

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 [see Use in Specific Populations (8.6) and Clinical Studies (14.2)].

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

Drug Interactions

Potential for Olysio to Affect Other Drugs

Simeprevir mildly inhibits CYP1A2 activity and intestinal CYP3A4 activity, but does not affect hepatic CYP3A4 activity. Co-administration of Olysio with drugs that are primarily metabolized by CYP3A4 may result in increased plasma concentrations of such drugs (see Table 6).

Simeprevir inhibits OATP1B1/3 and P-glycoprotein (P-gp) transporters. Co-administration of Olysio with drugs that are substrates for OATP1B1/3 and P-gp transport may result in increased plasma concentrations of such drugs (see Table 6).

Potential for Other Drugs to Affect Olysio

The primary enzyme involved in the biotransformation of simeprevir is CYP3A [see Clinical Pharmacology (12.3)]. Clinically relevant effects of other drugs on simeprevir pharmacokinetics via CYP3A may occur. Co-administration of Olysio with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir. Co-administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir and lead to loss of efficacy (see Table 6). Therefore, co-administration of Olysio with substances that are moderate or strong inducers or inhibitors of CYP3A is not recommended [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)].

Established and Other Potentially Significant Drug Interactions

Table 6 shows the established and other potentially significant drug interactions based on which alterations in dose or regimen of Olysio and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with Olysio are also included in Table 6. For information regarding the magnitude of interaction, see Tables 7 and 8 [see Clinical Pharmacology (12.3)].

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 or Concomitant Drug Clinical Comment
The direction of the arrow (↑ = increase, ↓ = decrease, ↔ = no change) indicates the direction of the change in PK.
*
These interactions have been studied in healthy adults with the recommended dose of 150 mg simeprevir once daily unless otherwise noted [see Clinical Pharmacology (12.3), Tables 7 and 8].
The dose of Olysio in this interaction study was 200 mg once daily both when given alone and when co-administered with rifampin 600 mg once daily.
The dose of Olysio in this interaction study was 50 mg when co-administered in combination with darunavir/ritonavir, compared to 150 mg in the Olysio alone treatment group.
§
The dose of Olysio in this interaction study was 200 mg once daily both when given alone and when co-administered in combination with ritonavir 100 mg given twice daily.
Studied in combination with an investigational drug and RBV in a Phase 2 trial in HCV-infected post-liver transplant patients.
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. 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.  
Digoxin* ↑ digoxin Routine therapeutic drug monitoring of digoxin concentrations is recommended.
Oral administration
Disopyramide, Flecainide, Mexiletine, Propafenone, Quinidine
↑ antiarrhythmics Therapeutic drug monitoring for these antiarrhythmics, if available, is recommended when co-administered with Olysio.
Anticonvulsants
Carbamazepine, Oxcarbazepine, Phenobarbital, Phenytoin ↓ simeprevir Co-administration is not recommended.
Anti-infectives
Antibiotics (systemic administration):
Erythromycin*
↑ simeprevir
↑ erythromycin
Co-administration is not recommended.
Antibiotics (systemic administration):
Clarithromycin, Telithromycin
↑ simeprevir Co-administration is not recommended.
Antifungals (systemic administration):
Itraconazole, Ketoconazole, Posaconazole
↑ simeprevir Co-administration is not recommended.
Antifungals (systemic administration):
Fluconazole, Voriconazole
↑ simeprevir Co-administration is not recommended.
Antimycobacterials:
Rifampin*, Rifabutin, Rifapentine
↓ simeprevir
↔ rifampin, rifabutin, rifapentine
Co-administration is not recommended.
Calcium Channel Blockers (oral administration)
Amlodipine, Diltiazem, Felodipine, Nicardipine, Nifedipine, Nisoldipine, Verapamil ↑ calcium channel blockers Clinical monitoring of patients is recommended when Olysio is co-administered with calcium channel blockers.
Corticosteroids
Systemic
Dexamethasone
↓ simeprevir Co-administration is not recommended.
Gastrointestinal Products
Propulsive:
Cisapride
↑ cisapride Co-administration is not recommended.
Herbal Products
Milk thistle
(Silybum marianum)
↑ simeprevir Co-administration is not recommended.
St. John's wort (Hypericum perforatum) ↓ simeprevir Co-administration of Olysio with products containing St. John's wort is not recommended.
HIV Products
Cobicistat-containing products ↑ simeprevir Co-administration is not recommended.
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs):
Efavirenz*
↓ simeprevir
↔ efavirenz
Co-administration is not recommended.
Other NNRTIs
Delavirdine
Etravirine, Nevirapine

↑ simeprevir
↓ simeprevir
Co-administration is not recommended.
Protease Inhibitors (PIs):
Darunavir/ritonavir*
↑ simeprevir
↑ darunavir
Co-administration is not recommended.
Protease Inhibitors (PIs):
Ritonavir*§
↑ simeprevir Co-administration is not recommended.
Other ritonavir-boosted or unboosted HIV PIs (Atazanavir, Fosamprenavir, Lopinavir, Indinavir, Nelfinavir, Saquinavir, Tipranavir) ↑ or ↓ simeprevir Co-administration of Olysio with any HIV PI, with or without ritonavir is not recommended.
HMG CO-A Reductase Inhibitors
Rosuvastatin* ↑ rosuvastatin Initiate rosuvastatin therapy with 5 mg once daily. The rosuvastatin dose should not exceed 10 mg daily when co-administered with Olysio.
Atorvastatin* ↑ atorvastatin Use the lowest necessary dose of atorvastatin, but do not exceed a daily dose of 40 mg when co-administering with Olysio.
Simvastatin* ↑ simvastatin Use the lowest necessary dose of simvastatin, titrate the simvastatin dose carefully, and monitor for safety when simvastatin is co-administered with Olysio.
Pitavastatin, Pravastatin, Lovastatin ↑ pitavastatin, pravastatin, lovastatin Use the lowest necessary dose of pitavastatin, pravastatin or lovastatin, titrate the dose carefully, and monitor for safety when co-administered with Olysio.
Immunosuppressants
Cyclosporine* ↑ cyclosporine
↑ simeprevir
Co-administration is not recommended.
Sirolimus ↑ or ↓ sirolimus Routine monitoring of blood concentrations of sirolimus is recommended.
Phosphodiesterase Type 5 (PDE-5) Inhibitors
Sildenafil, Tadalafil, Vardenafil ↑ PDE-5 inhibitors Dose adjustment of the PDE-5 inhibitor may be required when Olysio is co-administered with sildenafil or tadalafil administered chronically at doses used for the treatment of pulmonary arterial hypertension. Consider starting with the lowest dose of the PDE-5 inhibitor and increase as needed, with clinical monitoring as appropriate.
No dose adjustment is required when Olysio is co-administered with doses of sildenafil, tadalafil or vardenafil indicated for the treatment of erectile dysfunction.
Sedatives/Anxiolytics
Midazolam* (oral administration) ↑ midazolam Caution is warranted when midazolam, which has a narrow therapeutic index, is co-administered with Olysio.
Triazolam (oral administration) ↑ triazolam Caution is warranted when triazolam, which has a narrow therapeutic index, is co-administered with Olysio.

Drugs without Clinically Significant Interactions with Olysio

In addition to the drugs included in Table 6, the interaction between Olysio and the following drugs were evaluated in clinical studies and no dose adjustments are needed for either drug [see Clinical Pharmacology (12.3)]: caffeine, dextromethorphan, escitalopram, ethinyl estradiol/norethindrone, methadone, midazolam (intravenous administration), omeprazole, raltegravir, rilpivirine, sofosbuvir, tacrolimus, tenofovir disoproxil fumarate, and warfarin.

No clinically relevant drug-drug interaction is expected when Olysio is co-administered with antacids, azithromycin, bedaquiline, corticosteroids (budesonide, fluticasone, methylprednisolone, and prednisone), dolutegravir, fluvastatin, H2-receptor antagonists, the narcotic analgesics buprenorphine and naloxone, NRTIs (such as abacavir, didanosine, emtricitabine, lamivudine, stavudine, zidovudine), maraviroc, methylphenidate, and proton pump inhibitors.

USE IN SPECIFIC POPULATIONS

Pregnancy

Because Olysio is administered in combination with other antiviral drugs, refer to prescribing information of the drugs used in combination with Olysio for information regarding use in pregnancy.

Pregnancy Category C

Risk Summary

Adequate and well-controlled trials with Olysio have not been conducted in pregnant women. In animal reproduction studies with simeprevir, embryofetal developmental toxicity was observed at drug exposures higher than human exposure at the recommended clinical dose. Olysio should be used during pregnancy only if the potential benefit justifies the potential risk. Female patients of childbearing potential should use an effective contraceptive method.

If Olysio is administered with Peg-IFN-alfa and RBV, refer to the prescribing information for Peg-IFN-alfa and RBV for information on use in pregnancy.

Animal Data

Simeprevir showed no teratogenicity in rats and mice at exposures 0.5 times (in rats) and 6 times (in mice) the mean area under the plasma concentration time curve (AUC) in humans at the recommended dose of 150 mg once daily.

In a mouse embryofetal study at doses up to 1000 mg/kg, simeprevir resulted in early and late in utero fetal losses and early maternal deaths at an exposure approximately 6 times higher than the mean AUC in humans at the recommended 150 mg daily dose. Significantly decreased fetal weights and an increase in fetal skeletal variations were seen at exposures approximately 4 times higher than the mean AUC in humans at the recommended daily dose.

In a rat pre- and postnatal study, maternal animals were exposed to simeprevir during gestation and lactation at doses up to 1000 mg/kg/day. In pregnant rats, simeprevir resulted in early deaths at 1000 mg/kg/day corresponding to exposures similar to the mean AUC in humans at the recommended 150 mg once-daily dose. Significant reduction in body weight gain was seen at an exposure 0.7 times the mean AUC in humans at the recommended 150 mg once-daily dose. The developing rat offspring exhibited significantly decreased body weight and negative effects on physical growth (delay and small size) and development (decreased motor activity) following simeprevir exposure in utero (via maternal dosing) and during lactation (via maternal milk to nursing pups) at a maternal exposure similar to the mean AUC in humans at the recommended 150 mg once-daily dose. Subsequent survival, behavior and reproductive capacity were not affected.

Nursing Mothers

It is not known whether Olysio or its metabolites are present in human breast milk. When administered to lactating rats, simeprevir was detected in plasma of suckling rats likely due to excretion of simeprevir via milk. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue treatment with Olysio, taking into account the importance of the therapy to the mother.

If Olysio is administered in a regimen containing RBV, the information for RBV with regard to nursing mothers also applies to this combination regimen. Refer to RBV prescribing information for additional information on use in nursing mothers.

Pediatric Use

The safety and efficacy of Olysio in pediatric patients have not been established.

Geriatric Use

Clinical studies of Olysio did not include sufficient numbers of patients older than 65 years to determine whether they respond differently from younger patients. No dosage adjustment of Olysio is required in geriatric patients [see Clinical Pharmacology (12.3)].

Race

Patients of East Asian ancestry exhibit higher simeprevir plasma exposures, but no dosage adjustment is required based on race [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.2)].

Renal Impairment

No dosage adjustment of Olysio is required in patients with mild, moderate or severe renal impairment [see Clinical Pharmacology (12.3)]. The safety and efficacy of Olysio have not been studied in HCV-infected patients with severe renal impairment (creatinine clearance below 30 mL/min) or end-stage renal disease, including patients requiring dialysis. Simeprevir is highly protein-bound; therefore, dialysis is unlikely to result in significant removal of simeprevir [see Clinical Pharmacology (12.3)].

Refer to the prescribing information for the other antiviral drug(s) used in combination with Olysio regarding their use in patients with renal impairment.

Hepatic Impairment

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

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

The safety and efficacy of Olysio have not been established in liver transplant patients.

See the Peg-IFN-alfa prescribing information regarding its contraindication in patients with hepatic decompensation.

Overdosage

Human experience of overdose with Olysio is limited. There is no specific antidote for overdose with Olysio. In the event of an overdose, the patient's clinical status should be observed and the usual supportive measures employed.

Simeprevir is highly protein-bound; therefore, dialysis is unlikely to result in significant removal of simeprevir [see Clinical Pharmacology (12.3)].

Olysio Description

Olysio (simeprevir) is an inhibitor of the HCV NS3/4A protease.

The chemical name for simeprevir is (2R,3aR,10Z,11aS,12aR,14aR)-N - (cyclopropylsulfonyl) - 2 - [[2 - (4 - isopropyl - 1,3 - thiazol - 2 - yl) - 7 - methoxy - 8 - methyl - 4 - quinolinyl]oxy] - 5 - methyl - 4,14 - dioxo - 2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a - tetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamide. Its molecular formula is C38H47N5O7S2 and its molecular weight is 749.94. Simeprevir has the following structural formula:

Simeprevir drug substance is a white to almost white powder. Simeprevir is practically insoluble in water over a wide pH range. It is practically insoluble in propylene glycol, very slightly soluble in ethanol, and slightly soluble in acetone. It is soluble in dichloromethane and freely soluble in some organic solvents (e.g., tetrahydrofuran and N,N-dimethylformamide).

Olysio (simeprevir) for oral administration is available as 150 mg strength hard gelatin capsules. Each capsule contains 154.4 mg of simeprevir sodium salt, which is equivalent to 150 mg of simeprevir. Olysio (simeprevir) capsules contain the following inactive ingredients: colloidal anhydrous silica, croscarmellose sodium, lactose monohydrate, magnesium stearate and sodium lauryl sulphate. The white capsule contains gelatin and titanium dioxide (E171) and is printed with ink containing iron oxide black (E172) and shellac (E904).

Olysio - Clinical Pharmacology

Mechanism of Action

Simeprevir is a direct-acting antiviral (DAA) agent against the hepatitis C virus [see Microbiology (12.4)].

Pharmacodynamics

Cardiac Electrophysiology

In a thorough QT/QTc study in 60 healthy subjects, simeprevir 150 mg (recommended dose) and 350 mg (2.3 times the recommended dose) did not affect the QT/QTc interval.

Pharmacokinetics

The pharmacokinetic properties of simeprevir have been evaluated in healthy adult subjects and in adult HCV-infected subjects. Plasma Cmax and AUC increased more than dose-proportionally after multiple doses between 75 mg and 200 mg once daily, with accumulation occurring following repeated dosing. Steady-state was reached after 7 days of once-daily dosing. Plasma exposure (AUC) of simeprevir in HCV-infected subjects was about 2- to 3-fold higher compared to that observed in HCV-uninfected subjects. Plasma Cmax and AUC of simeprevir were similar during co-administration of simeprevir with Peg-IFN-alfa and RBV compared with administration of simeprevir alone. In HCV-infected subjects, the mean steady-state pre-dose plasma concentration was 1936 ng/mL (standard deviation: 2640) and the mean steady-state AUC24 was 57469 ng.h/mL (standard deviation: 63571).

Absorption

The mean absolute bioavailability of simeprevir following a single oral 150 mg dose of Olysio in fed conditions is 62%. Maximum plasma concentrations (Cmax) are typically achieved between 4 to 6 hours post-dose.

In vitro studies with human Caco-2 cells indicated that simeprevir is a substrate of P-gp.

Effects of Food on Oral Absorption

Compared to intake without food, administration of simeprevir with food to healthy subjects increased the AUC by 61% after a high-fat, high-caloric breakfast (928 kcal) and by 69% after a normal-caloric breakfast (533 kcal), and delayed the absorption by 1 hour and 1.5 hours, respectively.

Distribution

Simeprevir is extensively bound to plasma proteins (greater than 99.9%), primarily to albumin and, to a lesser extent, alfa 1-acid glycoprotein. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.

In animals, simeprevir is extensively distributed to gut and liver (liver:blood ratio of 29:1 in rat) tissues. In vitro data and physiologically-based pharmacokinetic modeling and simulations indicate that hepatic uptake in humans is mediated by OATP1B1/3.

Metabolism

Simeprevir is metabolized in the liver. In vitro experiments with human liver microsomes indicated that simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A system. Involvement of CYP2C8 and CYP2C19 cannot be excluded. Co-administration of Olysio with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir, and co-administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir [see Drug Interactions (7)].

Following a single oral administration of 200 mg (1.3 times the recommended dosage) 14C-simeprevir to healthy subjects, the majority of the radioactivity in plasma (mean: 83%) was accounted for by unchanged drug and a small part of the radioactivity in plasma was related to metabolites (none being major metabolites). Metabolites identified in feces were formed via oxidation at the macrocyclic moiety or aromatic moiety or both and by O-demethylation followed by oxidation.

Elimination

Elimination of simeprevir occurs via biliary excretion. Renal clearance plays an insignificant role in its elimination. Following a single oral administration of 200 mg 14C-simeprevir to healthy subjects, on average 91% of the total radioactivity was recovered in feces. Less than 1% of the administered dose was recovered in urine. Unchanged simeprevir in feces accounted for on average 31% of the administered dose.

The terminal elimination half-life of simeprevir was 10 to 13 hours in HCV-uninfected subjects and 41 hours in HCV-infected subjects receiving 200 mg (1.3 times the recommended dosage) of simeprevir.

Specific Populations

Geriatric Use

There is limited data on the use of Olysio in patients aged 65 years and older. Age (18–73 years) had no clinically meaningful effect on the pharmacokinetics of simeprevir based on a population pharmacokinetic analysis of HCV-infected subjects treated with Olysio [see Use in Specific Populations (8.5)].

Renal Impairment

Compared to HCV-uninfected subjects with normal renal function (classified using the Modification of Diet in Renal Disease [MDRD] eGFR formula; eGFR greater than or equal to 80 mL/min) the mean steady-state AUC of simeprevir was 62% higher in HCV-uninfected subjects with severe renal impairment (eGFR below 30 mL/min).

In a population pharmacokinetic analysis of mild or moderate renally impaired HCV-infected subjects treated with Olysio 150 mg once daily, creatinine clearance was not found to influence the pharmacokinetic parameters of simeprevir. It is therefore not expected that renal impairment will have a clinically relevant effect on the exposure to simeprevir [see Use in Specific Populations (8.7)].

As simeprevir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

Hepatic Impairment

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) [see Use in Specific Populations (8.8)].

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.

Gender, Body Weight, Body Mass Index

Gender, body weight or body mass index have no clinically meaningful relevant effect on the pharmacokinetics of simeprevir based on a population pharmacokinetic analysis of HCV-infected subjects treated with Olysio.

Race

Population pharmacokinetic estimates of exposure of simeprevir were comparable between Caucasian and Black/African American HCV-infected subjects.

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 [see Use in Specific Populations (8.6)].

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.

Drug Interactions

[See also Warnings and Precautions (5.7) 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)].

Simeprevir is transported into the liver by OATP1B1/3 where it undergoes metabolism by CYP3A. Based on results from in vivo studies, co-administration of Olysio with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir and co-administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir, which may lead to loss of efficacy.

Drug interaction studies were performed in healthy adults with simeprevir (at the recommended dose of 150 mg once daily unless otherwise noted) and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the Cmax, AUC, and Cmin values of simeprevir are summarized in Table 7 (effect of other drugs on Olysio). The effect of co-administration of Olysio on the Cmax, AUC, and Cmin values of other drugs are summarized in Table 8 (effect of Olysio on other drugs). For information regarding clinical recommendations, see Drug Interactions (7).

Table 7: Drug Interactions: Pharmacokinetic Parameters for Simeprevir in the Presence of Co-administered Drugs
Co-administered Drug Dose (mg) and Schedule N Effect on PK* LS Mean Ratio (90% CI) of Simeprevir PK Parameters with/without Drug
Drug Simeprevir Cmax AUC Cmin
CI = Confidence Interval; N = number of subjects with data; NA = not available; PK = pharmacokinetics; LS = least square; q.d. = once daily; b.i.d. = twice daily; t.i.d. = three times a day
*
The direction of the arrow (↑ = increase, ↓ = decrease, ↔ = no change) indicates the direction of the change in PK (i.e., AUC).
Comparison based on historic controls. Interim data from a Phase 2 trial in combination with an investigational drug and RBV in HCV-infected post-liver transplant patients.
Individualized dose at the discretion of the physician, according to local clinical practice.
§
Comparison based on historic controls. The interaction between simeprevir and sofosbuvir was evaluated in a pharmacokinetic substudy within a Phase 2 trial.
The dose of Olysio in this interaction study was 50 mg when co-administered in combination with darunavir/ritonavir compared to 150 mg once daily in the Olysio alone treatment group.
Cyclosporine individualized dose 150 mg q.d. for 14 days 9 4.74
(3.12–7.18)
5.81
(3.56–9.48)
NA
Erythromycin 500 mg t.i.d. for 7 days 150 mg q.d. for 7 days 24 4.53
(3.91–5.25)
7.47
(6.41–8.70)
12.74
(10.19–15.93)
Escitalopram 10 mg q.d. for 7 days 150 mg q.d. for 7 days 18 0.80
(0.71–0.89)
0.75
(0.68–0.83)
0.68
(0.59–0.79)
Rifampin 600 mg q.d. for 7 days 200 mg q.d. for 7 days 18 1.31
(1.03–1.66)
0.52
(0.41–0.67)
0.08
(0.06–0.11)
Tacrolimus individualized dose 150 mg q.d. for 14 days 11 1.79
(1.22–2.62)
1.85
(1.18–2.91)
NA
Anti-HCV Drug
Sofosbuvir§ 400 mg q.d. 150 mg q.d. 21 0.96
(0.71–1.30)
0.94
(0.67–1.33)
NA
Anti-HIV Drugs
Darunavir/Ritonavir 800/100 mg q.d. for 7 days 50 mg and 150 mg q.d. for 7 days 25 1.79
(1.55–2.06)
2.59
(2.15–3.11)
4.58
(3.54–5.92)
Efavirenz 600 mg q.d. for 14 days 150 mg q.d. for 14 days 23 0.49
(0.44–0.54)
0.29
(0.26–0.33)
0.09
(0.08–0.12)
Raltegravir 400 mg b.i.d. for 7 days 150 mg q.d. for 7 days 24 0.93
(0.85–1.02)
0.89
(0.81–0.98)
0.86
(0.75–0.98)
Rilpivirine 25 mg q.d. for 11 days 150 mg q.d. for 11 days 21 1.10
(0.97–1.26)
1.06
(0.94–1.19)
0.96
(0.83–1.11)
Ritonavir 100 mg b.i.d. for 15 days 200 mg q.d. for 7 days 12 4.70
(3.84–5.76)
7.18
(5.63–9.15)
14.35
(10.29–20.01)
Tenofovir disoproxil fumarate 300 mg q.d. for 7 days 150 mg q.d. for 7 days 24 0.85
(0.73–0.99)
0.86
(0.76–0.98)
0.93
(0.78–1.11)
Table 8: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Olysio
Co-administered Drug Dose (mg) and Schedule N Effect on PK* LS Mean Ratio (90% CI) of Co-Administered Drug PK Parameters with/without Olysio
Drug Simeprevir Cmax AUC Cmin
CI = Confidence Interval; i.v.= intravenous; N = number of subjects with data; NA = not available; PK = pharmacokinetics; LS = least square; q.d. = once daily; b.i.d. = twice daily; t.i.d. = three times a day
*
The direction of the arrow (↑ = increase, ↓ = decrease, ↔ = no change) indicates the direction of the change in PK (i.e., AUC).
The interaction between Olysio and the drug was evaluated in a pharmacokinetic study in opioid-dependent adults on stable methadone maintenance therapy.
Comparison based on historic controls. The interaction between simeprevir and sofosbuvir was evaluated in a pharmacokinetic substudy within a Phase 2 trial.
§
Primary circulating metabolite of sofosbuvir.
The dose of Olysio in this interaction study was 50 mg when co-administered in combination with darunavir/ritonavir which is lower than the recommended 150 mg dose.
Atorvastatin 40 mg single dose 150 mg q.d. for 10 days 18 1.70
(1.42–2.04)
2.12
(1.72–2.62)
NA
2-hydroxy-atorvastatin 1.98
(1.70–2.31)
2.29
(2.08–2.52)
NA
Caffeine 150 mg 150 mg q.d. for 11 days 16 1.12
(1.06–1.19)
1.26
(1.21–1.32)
NA
Cyclosporine 100 mg single dose 150 mg q.d. for 7 days 14 1.16
(1.07–1.26)
1.19
(1.13–1.26)
NA
Dextromethorphan 30 mg 150 mg q.d. for 11 days 16 1.21
(0.93–1.57)
1.08
(0.87–1.35)
NA
Dextrorphan 1.03
(0.93–1.15)
1.09
(1.03–1.15)
NA
Digoxin 0.25 mg single dose 150 mg q.d. for 7 days 16 1.31
(1.14–1.51)
1.39
(1.16–1.67)
NA
Erythromycin 500 mg t.i.d. for 7 days 150 mg q.d. for 7 days 24 1.59
(1.23–2.05)
1.90
(1.53–2.36)
3.08
(2.54–3.73)
Escitalopram 10 mg q.d. for 7 days 150 mg q.d. for 7 days 17 1.03
(0.99–1.07)
1.00
(0.97–1.03)
1.00
(0.95–1.05)
Ethinyl estradiol (EE), co-administered with norethindrone (NE) 0.035 mg q.d. EE + 1 mg q.d. NE for 21 days 150 mg q.d. for 10 days 18 1.18
(1.09–1.27)
1.12
(1.05–1.20)
1.00
(0.89–1.13)
Midazolam (oral) 0.075 mg/kg 150 mg q.d. for 10 days 16 1.31
(1.19–1.45)
1.45
(1.35–1.57)
NA
Midazolam (i.v.) 0.025 mg/kg 150 mg q.d. for 11 days 16 0.78
(0.52–1.17)
1.10
(0.95–1.26)
NA
R(-) methadone 30–150 mg q.d., individualized dose 150 mg q.d. for 7 days 12 1.03
(0.97–1.09)
0.99
(0.91–1.09)
1.02
(0.93–1.12)
Norethindrone (NE), co-administered with EE 0.035 mg q.d. EE + 1 mg q.d. NE for 21 days 150 mg q.d. for 10 days 18 1.06
(0.99–1.14)
1.15
(1.08–1.22)
1.24
(1.13–1.35)
Omeprazole 40 mg single dose 150 mg q.d. for 11 days 16 1.14
(0.93–1.39)
1.21
(1.00–1.46)
NA
Rifampin 600 mg q.d. for 7 days 200 mg q.d. for 7 days 18 0.92
(0.80–1.07)
1.00
(0.93–1.08)
NA
25-desacetyl-rifampin 17 1.08
(0.98–1.19)
1.24
(1.13–1.36)
NA
Rosuvastatin 10 mg single dose 150 mg q.d. for 7 days 16 3.17
(2.57–3.91)
2.81
(2.34–3.37)
NA
Simvastatin 40 mg single dose 150 mg q.d. for 10 days 18 1.46
(1.17–1.82)
1.51
(1.32–1.73)
NA
Simvastatin acid 3.03
(2.49–3.69)
1.88
(1.63–2.17)
NA
Tacrolimus 2 mg single dose 150 mg q.d. for 7 days 14 0.76
(0.65–0.90)
0.83
(0.59–1.16)
NA
S-Warfarin 10 mg single dose 150 mg q.d. for 11 days 16 1.00
(0.94–1.06)
1.04
(1.00–1.07)
NA
Anti-HCV Drug
Sofosbuvir 400 mg q.d. 150 mg q.d. 22 1.91
(1.26–2.90)
3.16
(2.25–4.44)
NANA
GS-331007§ 0.69
(0.52–0.93)
1.09
(0.87–1.37)
NA
Anti-HIV Drugs
Darunavir 800 mg q.d. for 7 days 50 mg q.d. for 7 days 25 1.04
(0.99–1.10)
1.18
(1.11–1.25)
1.31
(1.13–1.52)
Ritonavir 100 mg q.d. for 7 days 1.23
(1.14–1.32)
1.32
(1.25–1.40)
1.44
(1.30–1.61)
Efavirenz 600 mg q.d. for 14 days 150 mg q.d. for 14 days 23 0.97
(0.89–1.06)
0.90
(0.85–0.95)
0.87
(0.81–0.93)
Raltegravir 400 mg b.i.d. for 7 days 150 mg q.d. for 7 days 24 1.03
(0.78–1.36)
1.08
(0.85–1.38)
1.14
(0.97–1.36)
Rilpivirine 25 mg q.d. for 11 days 150 mg q.d. for 11 days 23 1.04
(0.95–1.13)
1.12
(1.05–1.19)
1.25
(1.16–1.35)
Tenofovir disoproxil fumarate 300 mg q.d. for 7 days 150 mg q.d. for 7 days 24 1.19
(1.10–1.30)
1.18
(1.13–1.24)
1.24
(1.15–1.33)

Microbiology

Mechanism of Action

Simeprevir is an inhibitor of the HCV NS3/4A protease which is essential for viral replication. 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.

Antiviral Activity

The median simeprevir EC50 and EC90 values against a HCV genotype 1b replicon were 9.4 nM (7.05 ng/mL) and 19 nM (14.25 ng/mL), respectively. Chimeric replicons carrying NS3 sequences derived from HCV protease inhibitor treatment-naïve genotype 1a- or genotype 1b-infected patients displayed median fold change (FC) in EC50 values of 1.4 (interquartile range, IQR: 0.8 to 11; N=78) and 0.4 (IQR: 0.3 to 0.7; N=59) compared to reference genotype 1b replicon, respectively. Genotype 1a (N=33) and 1b (N=2) isolates with a baseline Q80K polymorphism resulted in median FC in simeprevir EC50 value of 11 (IQR: 7.4 to 13) and 8.4, respectively. 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. The presence of 50% human serum reduced simeprevir replicon activity by 2.4-fold. Combination of simeprevir with IFN, RBV, NS5A inhibitors, nucleoside analog NS5B polymerase inhibitors or non-nucleoside analog NS5B polymerase inhibitors, including NS5B thumb 1-, thumb 2-, and palm-domain targeting drugs, was not antagonistic.

Resistance in Cell Culture

Resistance to simeprevir was characterized in HCV genotype 1a and 1b replicon-containing cells. Ninety-six percent (96%) of simeprevir-selected genotype 1 replicons carried one or multiple amino acid substitutions at NS3 protease positions F43, Q80, R155, A156, and/or D168, with substitutions at NS3 position D168 being most frequently observed (78%). Additionally, resistance to simeprevir was evaluated in HCV genotype 1a and 1b replicon assays using site-directed mutants and chimeric replicons carrying NS3 sequences derived from clinical isolates. Amino acid substitutions at NS3 positions F43, Q80, S122, R155, A156, and D168 reduced susceptibility to simeprevir. Replicons with D168V or A, and R155K substitutions displayed large reductions in susceptibility to simeprevir (FC in EC50 value greater than 50), whereas other substitutions such as Q80K or R, S122R, and D168E displayed lower reductions in susceptibility (FC in EC50 value between 2 and 50). Other substitutions such as Q80G or L, S122G, N or T did not reduce susceptibility to simeprevir in the replicon assay (FC in EC50 value lower than 2). Amino acid substitutions at NS3 positions Q80, S122, R155, and/or D168 that were associated with lower reductions in susceptibility to simeprevir when occurring alone, reduced susceptibility to simeprevir by more than 50-fold when present in combination.

Resistance in Clinical Studies

In a pooled analysis of subjects treated with 150 mg Olysio in combination with Peg-IFN-alfa and RBV who did not achieve SVR in the controlled Phase 2 and Phase 3 clinical trials (PILLAR, ASPIRE, QUEST 1 and QUEST 2, PROMISE), emerging virus with amino acid substitutions at NS3 positions Q80, S122, R155 and/or D168 were observed in 180 out of 197 (91%) subjects. Substitutions D168V and R155K alone or in combination with other substitutions at these positions emerged most frequently (Table 9). Most of these emerging substitutions have been shown to reduce susceptibility to simeprevir in cell culture replicon assays.

HCV genotype 1 subtype-specific patterns of simeprevir treatment-emergent amino acid substitutions were observed. HCV genotype 1a predominately had emerging R155K alone or in combination with amino acid substitutions at NS3 positions Q80, S122 and/or D168, while HCV genotype 1b had most often an emerging D168V substitution (Table 9). In HCV genotype 1a with a baseline Q80K amino acid polymorphism, an emerging R155K substitution was observed most frequently at failure.

Table 9: Emergent Amino Acid Substitutions in Controlled Phase 2 and Phase 3 Trials: Subjects who did not Achieve SVR with 150 mg Olysio in Combination with Peg-IFN-alfa and RBV
Emerging Amino Acid Substitutions in NS3 Genotype 1a*
N=116
% (n)
Genotype 1b
N=81
% (n)
Note: substitutions at NS3 position F43 and A156 were selected in cell culture and associated with reduced simeprevir activity in the replicon assay but were not observed at time of failure.
*
May include few subjects infected with HCV genotype 1 viruses of non-1a/1b subtypes.
Alone or in combination with other substitutions (includes mixtures).
Substitutions only observed in combinations with other emerging substitutions at one or more of the NS3 positions Q80, S122, R155 and/or D168.
§
Subjects with virus carrying these combinations are also included in other rows describing the individual substitutions. × represents multiple amino acids. Other double or triple substitutions were observed with lower frequencies.
Emerged alone (n=2) or in combination with R155K (n=3).
Any substitution at NS3 position F43, Q80, S122, R155, A156, or D168 95 (110) 86 (70)
D168E 15 (17) 17 (14)
D168V 10 (12) 60 (49)
Q80R 4 (5) 12 (10)
R155K 77 (89) 0 (0)
Q80X+D168X§ 4 (5) 14 (11)
R155X+D168X§ 13 (15) 4 (3)
Q80K, S122A/G/I/T, S122R, R155Q, D168A, D168F, D168H, D168T, I170T Less than 10% Less than 10%

In the COSMOS trial in HCV genotype 1-infected subjects treated with Olysio in combination with sofosbuvir (without or with RBV), virus from 5 out of 6 (83%) subjects with relapse had emerging NS3 amino acid substitutions R155K or D168E. No emerging NS5B amino acid substitutions associated with sofosbuvir resistance were observed.

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.

Persistence of Resistance–Associated Substitutions

The persistence of simeprevir-resistant virus was assessed following treatment failure in the pooled analysis of subjects receiving 150 mg Olysio in combination with Peg-IFN-alfa and RBV in the controlled Phase 2 and Phase 3 trials. The proportion of subjects with detectable levels of treatment-emergent, resistance-associated variants was followed post-treatment for a median time of 28 weeks (range 0 to 70 weeks). Resistant variants remained at detectable levels in 32 out of 66 subjects (48%) with single emerging R155K and in 16 out of 48 subjects (33%) with single emerging D168V.

The lack of detection of virus containing a resistance-associated substitution does not necessarily indicate that the resistant virus is no longer present at clinically significant levels. The long-term clinical impact of the emergence or persistence of virus containing Olysio-resistance-associated substitutions is unknown.

Effect of Baseline HCV Polymorphisms on Treatment Response

Analyses were conducted to explore the association between naturally-occurring baseline NS3/4A amino acid substitutions (polymorphisms) and treatment outcome. In the pooled analysis of the Phase 3 trials QUEST 1 and QUEST 2, and in the PROMISE trial, the efficacy of Olysio in combination with Peg-IFN-alfa and RBV was substantially reduced in subjects infected with HCV genotype 1a virus with the NS3 Q80K polymorphism at baseline [see Clinical Studies (14.2)].

The observed prevalence of NS3 Q80K polymorphic variants at baseline in the overall population of the Phase 2 and Phase 3 trials (PILLAR, ASPIRE, PROMISE, QUEST 1 and QUEST 2) was 14%; while the observed prevalence of the Q80K polymorphism was 30% in subjects infected with HCV genotype 1a and 0.5% in subjects infected with HCV genotype 1b. The observed prevalence of Q80K polymorphic variants at baseline in the U.S. population of these Phase 2 and Phase 3 trials was 35% overall, 48% in subjects infected with HCV genotype 1a and 0% in subjects infected with HCV genotype 1b. With the exception of the NS3 Q80K polymorphism, baseline HCV variants with polymorphisms at NS3 positions F43, Q80, S122, R155, A156, and/or D168 that were associated with reduced simeprevir activity in replicon assays were generally uncommon (1.3%) in subjects with HCV genotype 1 infection in these Phase 2 and Phase 3 trials (n=2007).

The Q80K polymorphic variant was not observed in subjects infected with HCV genotype 4 (RESTORE).

Cross-Resistance

Cross-resistance is expected among NS3/4A protease inhibitors. Some of the treatment-emergent virus detected in Olysio-treated subjects who did not achieve SVR in clinical trials, including virus expressing R155K, which emerged frequently, and I170T, which emerged infrequently, have been shown to be less susceptible to the NS3/4A protease inhibitors, boceprevir and/or telaprevir.

The most frequently occurring boceprevir or telaprevir treatment-emergent viruses that are expected to impact subsequent treatment with Olysio include variants expressing NS3 R155K, A156T, or A156V. Virus expressing the NS3 amino substitutions V36A or G and I170A or T, which displayed slight shifts in susceptibility to simeprevir in replicon cultures, may emerge in patients who do not achieve SVR with boceprevir or telaprevir, and may therefore also impact subsequent treatment with Olysio. Failure to achieve SVR with simeprevir does not select virus that is cross-resistant to the nucleotide analog NS5B polymerase inhibitor sofosbuvir or vice versa.

Pharmacogenomics

A genetic variant near the gene encoding interferon-lambda-3 (IL28B rs12979860, a C [cytosine] to T [thymine] substitution) is a strong predictor of response to Peg-IFN-alfa and RBV (PR). In the Phase 3 trials, IL28B genotype was a stratification factor.

Overall, SVR rates were lower in subjects with the CT and TT genotypes compared to those with the CC genotype (Tables 10 and 11). Among both treatment-naïve subjects and those who experienced previous treatment failures, subjects of all IL28B genotypes had the highest SVR rates with Olysio-containing regimens (Table 10).

Table 10: SVR12 Rates by IL28B rs12979860 Genotype in Adult Subjects with HCV Genotype 1 Infection Receiving Olysio 150 mg Once Daily with Peg-IFN-alfa and RBV Compared to Subjects Receiving Placebo with Peg-IFN-alfa and RBV (Trials QUEST 1, QUEST 2, PROMISE)
Trial (Population) IL28B rs12979860 Genotype Olysio + PR
% (n/N)
Placebo + PR
% (n/N)
SVR12: sustained virologic response 12 weeks after planned end of treatment (EOT).
QUEST 1 and QUEST 2
(treatment-naïve subjects)
C/C 95 (144/152) 80 (63/79)
C/T 78 (228/292) 41 (61/147)  
T/T 61 (47/77) 21 (8/38)  
PROMISE
(prior relapsers)
C/C 89 (55/62) 53 (18/34)
C/T 78 (131/167) 34 (28/83)  
T/T 65 (20/31) 19 (3/16)  
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)
SVR12: sustained virologic response 12 weeks after planned EOT.
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 80 (8/10) 100 (4/4) 60 (3/5) 39 (7/18)  

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis

Simeprevir was not genotoxic in a series of in vitro and in vivo tests including the Ames test, the mammalian forward mutation assay in mouse lymphoma cells or the in vivo mammalian micronucleus test. Carcinogenicity studies with simeprevir have not been conducted.

If Olysio is administered in a combination regimen containing RBV, refer to the prescribing information for RBV for information on carcinogenesis and mutagenesis.

Impairment of Fertility

In a rat fertility study at doses up to 500 mg/kg/day, 3 male rats treated with simeprevir (2/24 rats at 50 mg/kg/day and 1/24 rats at 500 mg/kg/day) showed no motile sperm, small testes and epididymides, and resulted in infertility in 2 out of 3 of the male rats at approximately 0.2 times the mean AUC in humans.

If Olysio is administered with Peg-IFN-alfa and RBV, refer to the prescribing information for Peg-IFN-alfa and RBV for information on impairment of fertility.

Animal Toxicology and/or Pharmacology

Cardiovascular toxicity consisting of acute endocardial and myocardial necrosis restricted to the left ventricular subendocardial area was seen in 2 out of 6 animals in a 2-week oral dog toxicity study at an exposure approximately 28 times the mean AUC in humans at the recommended daily dose of 150 mg. No cardiac findings were observed in a 6-month and a 9-month oral toxicity study at exposures, respectively, of 11 and 4 times the mean AUC in humans at the recommended daily dose of 150 mg.

If Olysio is administered in a combination regimen containing sofosbuvir, refer to the prescribing information for sofosbuvir for information on animal toxicology.

Clinical Studies

Overview of Clinical Trials

The efficacy of Olysio in combination with sofosbuvir without or with RBV was evaluated in a Phase 2 trial (COSMOS) in HCV genotype 1 infected prior null responders with METAVIR fibrosis score F0–F4 or treatment-naïve subjects with METAVIR fibrosis score F3–F4 and compensated liver disease (see Table 12).

Table 12: Trials Conducted with Olysio in Combination with Sofosbuvir
Trial Population Relevant Study Arms
(Number of Subjects Treated)
GT: genotype; TN: treatment-naïve; TE: treatment-experienced, includes only null responders to prior Peg-IFN/RBV therapy.
COSMOS (open-label) GT 1, TN or TE, with or without cirrhosis
  • Olysio + sofosbuvir (12 weeks) (28)
  • Olysio + sofosbuvir (24 weeks) (31)

The efficacy of Olysio in combination with Peg-IFN-alfa and RBV in patients with HCV genotype 1 infection was evaluated in three Phase 3 trials in treatment-naïve subjects (trials QUEST 1, QUEST 2 and TIGER), one Phase 3 trial in subjects who relapsed after prior interferon-based therapy (PROMISE), one Phase 2 trial in subjects who failed prior therapy with Peg-IFN and RBV (including prior relapsers, partial and null responders) (ASPIRE), and one Phase 3 trial in subjects with HCV genotype 1 and HIV-1 co-infection who were HCV treatment-naïve or failed previous HCV therapy with Peg-IFN and RBV (trial C212), as summarized in Table 13.

The efficacy of Olysio in combination with Peg-IFN-alfa and RBV in patients with HCV genotype 4 infection was evaluated in one Phase 3 trial in treatment-naïve subjects or subjects who failed previous therapy with Peg-IFN and RBV (RESTORE) (see Table 13).

Table 13: Trials Conducted with Olysio in Combination with Peg-IFN-alfa and RBV
Trial Population Relevant Study Arms
(Number of Subjects Treated)
GT: genotype; TN: treatment-naïve; TE: treatment-experienced, includes prior relapsers, partial responders and null responders following prior treatment with Peg-IFN and RBV.
*
Includes only relapsers after prior IFN-based therapy.
QUEST-1
(double-blind)
GT 1, TN, with or without cirrhosis
  • Olysio + Peg-IFN-alfa + RBV (264)
  • Placebo (130)
QUEST-2
(double-blind)
GT 1, TN, with or without cirrhosis
  • Olysio + Peg-IFN-alfa + RBV (257)
  • Placebo (134)
TIGER
(double-blind)
GT 1, TN, with or without cirrhosis
  • Olysio + Peg-IFN-alfa + RBV (152)
  • Placebo (152)
PROMISE
(double-blind)
GT 1, TE*, with or without cirrhosis
  • Olysio + Peg-IFN-alfa + RBV (260)
  • Placebo (133)
ASPIRE
(double-blind)
GT 1, TE, with or without cirrhosis
  • Olysio + Peg-IFN-alfa + RBV (66)
  • Placebo (66)
C212
(open-label)
GT 1, TN or TE, with cirrhosis, HCV/HIV-1 co-infected
  • Olysio + Peg-IFN-alfa + RBV (106)
RESTORE
(open-label)
GT 4, TN or TE, with or without cirrhosis
  • Olysio + Peg-IFN-alfa + RBV (107)

Prior relapsers were subjects who had HCV RNA not detected at the end of prior IFN-based therapy and HCV RNA detected during follow-up; prior partial responders were subjects with prior on-treatment greater than or equal to 2 log10 reduction in HCV RNA from baseline at Week 12 and HCV RNA detected at the end of prior therapy with Peg-IFN and RBV; and null responders were subjects with prior on-treatment less than 2 log10 reduction in HCV RNA from baseline at Week 12 during prior therapy with Peg-IFN and RBV. Subjects in these trials had compensated liver disease (including cirrhosis), HCV RNA of at least 10000 IU/mL, and liver histopathology consistent with chronic HCV infection. In subjects who were treatment-naïve and prior relapsers, the overall duration of treatment with Peg-IFN-alfa and RBV in the Phase 3 trials was response-guided. In these subjects, the planned total duration of HCV treatment was 24 weeks if the following on-treatment protocol-defined response-guided therapy (RGT) criteria were met: HCV RNA lower than 25 IU/mL (detected or not detected) at Week 4 AND HCV RNA not detected at Week 12. Plasma HCV RNA levels were measured using the Roche COBAS® TaqMan® HCV test (version 2.0), for use with the High Pure System (25 IU/mL lower limit of quantification and 15 IU/mL limit of detection). Treatment stopping rules for HCV therapy were used to ensure that subjects with inadequate on-treatment virologic response discontinued treatment in a timely manner. In the Phase 3 trial C212 in HCV/HIV-1 co-infected subjects, the total duration of treatment with Peg-IFN-alfa and RBV in treatment-naïve and prior relapser subjects with cirrhosis was not response-guided; these subjects received a fixed total duration of HCV treatment of 48 weeks. The total duration of treatment with Peg-IFN-alfa and RBV in non-cirrhotic HCV/HIV-1 co-infected treatment-naïve or prior relapser subjects was response-guided using the same criteria.

SVR was defined as HCV RNA lower than 25 IU/mL detected or not detected 12 weeks after the planned end of treatment (SVR12) in the COSMOS and Phase 3 trials and was defined as HCV RNA not detected 24 weeks after planned end of treatment (SVR24) in the ASPIRE trial.

Olysio in Combination with Sofosbuvir

Adult Subjects with HCV Genotype 1 Infection

The COSMOS trial was an open-label, randomized Phase 2 trial to investigate the efficacy and safety of 12 or 24 weeks of Olysio (150 mg once daily) in combination with sofosbuvir (400 mg once daily) without or with RBV in HCV genotype 1-infected prior null responders with METAVIR fibrosis score F0–F2 (Cohort 1), or treatment-naïve subjects and prior null responders with METAVIR fibrosis score F3–F4 and compensated liver disease (Cohort 2).

In this trial, 28 subjects received 12 weeks of Olysio in combination with sofosbuvir (without RBV) and 31 subjects received 24 weeks of Olysio in combination with sofosbuvir (without RBV). These 59 subjects had a median age of 57 years (range 27 to 68 years; with 2% above 65 years); 53% were male; 76% were White, and 24% Black or African American; 46% had a BMI greater than or equal to 30 kg/m2; the median baseline HCV RNA level was 6.75 log10 IU/mL; 19%, 31% and 22% had METAVIR fibrosis scores F0–F1, F2 and F3, respectively, and 29% had METAVIR fibrosis score F4 (cirrhosis); 75% had HCV genotype 1a of which 41% carried Q80K at baseline, and 25% had HCV genotype 1b; 14% had IL28B CC genotype, 64% IL28B CT genotype, and 22% IL28B TT genotype; 75% were prior null responders to Peg-IFN-alfa and RBV, and 25% were treatment-naïve.

Table 14 shows the response rates by combining prior null responders in Cohort 1 and treatment-naïve subjects and prior null responders in Cohort 2. Addition of RBV did not increase response rates in comparison with Olysio in combination with sofosbuvir alone; and therefore these data are not shown in Table 14.

Table 14: Treatment Response by METAVIR Fibrosis Score in Treatment-Naïve Subjects or Prior Null Responders* with HCV Genotype 1 Infection Receiving 12 or 24 Weeks of Olysio with Sofosbuvir (COSMOS Trial; Pooled Data for Cohort 1 and 2)
Olysio + Sofosbuvir
12 weeks
% (n/N)
Olysio + Sofosbuvir
24 weeks
% (n/N)
SVR12: sustained virologic response 12 weeks after planned EOT.
*
Null Responders to prior Peg-IFN-alfa and RBV therapy.
Viral relapse rates are calculated with a denominator of subjects with HCV RNA not detected at EOT and with at least one follow-up HCV RNA assessment. No subjects experienced virologic on-treatment failure.
Overall SVR12 93 (26/28) 97 (30/31)
  F0–3 95 (20/21) 95 (20/21)
  F4 86 (6/7) 100 (10/10)
Viral Relapse 7 (2/28) 0 (0/30)
  F0–3 5 (1/21) 0 (0/20)
  F4 14 (1/7) 0 (0/10)

Olysio in Combination with Peg-IFN-alfa and RBV

Treatment-Naïve Adult Subjects with HCV Genotype 1 Infection

The efficacy of Olysio in treatment-naïve patients with HCV genotype 1 infection was demonstrated in two randomized, double-blind, placebo-controlled, 2-arm, multicenter, Phase 3 trials (QUEST 1 and QUEST 2). The designs of both trials were similar. All subjects received 12 weeks of once daily treatment with 150 mg Olysio or placebo, plus Peg-IFN-alfa-2a (QUEST 1 and QUEST 2) or Peg-IFN-alfa-2b (QUEST 2) and RBV, followed by 12 or 36 weeks of therapy with Peg-IFN-alfa and RBV in accordance with the on-treatment protocol-defined RGT criteria. Subjects in the control groups received 48 weeks of Peg-IFN-alfa-2a or -2b and RBV.

In the pooled analysis for QUEST 1 and QUEST 2, demographics and baseline characteristics were balanced between both trials and between the Olysio and placebo treatment groups. In the pooled analysis of trials (QUEST 1 and QUEST 2), the 785 enrolled subjects had a median age of 47 years (range: 18 to 73 years; with 2% above 65 years); 56% were male; 91% were White, 7% Black or African American, 1% Asian, and 17% Hispanic; 23% had a body mass index (BMI) greater than or equal to 30 kg/m2; 78% had baseline HCV RNA levels greater than 800000 IU/mL; 74% had METAVIR fibrosis score F0, F1 or F2, 16% METAVIR fibrosis score F3, and 10% METAVIR fibrosis score F4 (cirrhosis); 48% had HCV genotype 1a, and 51% HCV genotype 1b; 29% had IL28B CC genotype, 56% IL28B CT genotype, and 15% IL28B TT genotype; 17% of the overall population and 34% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. In QUEST 1, all subjects received Peg-IFN-alfa-2a; in QUEST 2, 69% of the subjects received Peg-IFN-alfa-2a and 31% received Peg-IFN-alfa-2b.

Table 15 shows the response rates in treatment-naïve adult subjects with HCV genotype 1 infection. In the Olysio treatment group, SVR12 rates were lower in subjects with genotype 1a virus with the NS3 Q80K polymorphism at baseline compared to subjects infected with genotype 1a virus without the Q80K polymorphism.

Table 15: Response Rates in Treatment-Naïve Adult Subjects with HCV Genotype 1 Infection (Pooled Data QUEST 1 and QUEST 2)
Response Rate Olysio + PR
N=521
% (n/N)
Placebo + PR
N=264
% (n/N)
Olysio: 150 mg Olysio for 12 weeks with Peg-IFN-alfa-2a or -2b and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg-IFN-alfa-2a or -2b and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT.
*
On-treatment failure was defined as the proportion of subjects with confirmed HCV RNA detected 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 HCV RNA not detected at actual EOT. Includes 4 Olysio-treated subjects who experienced relapse after SVR12.
Overall SVR12 (genotype 1a and 1b) 80 (419/521) 50 (132/264)
Genotype 1a 75 (191/254) 47 (62/131)
  Without Q80K 84 (138/165) 43 (36/83)
  With Q80K 58 (49/84) 52 (23/44)
Genotype 1b 85 (228/267) 53 (70/133)
Outcome for all subjects without SVR12
On-treatment failure* 8 (42/521) 33 (87/264)
Viral relapse 11 (51/470) 23 (39/172)

In the pooled analysis of QUEST 1 and QUEST 2, 88% (459/521) of Olysio-treated subjects were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 88% (405/459).

Seventy-eight percent (78%; 404/521) of Olysio-treated subjects had HCV RNA not detected at Week 4 (RVR); in these subjects the SVR12 rate was 90% (362/404).

SVR12 rates were higher for the Olysio treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype/subtype, baseline HCV RNA load (less than or equal to 800000 IU/mL, greater than 800000 IU/mL), METAVIR fibrosis score, and IL28B genotype. Table 16 shows the SVR rates by METAVIR fibrosis score.

Table 16: SVR12 Rates by METAVIR Fibrosis Score in Treatment-Naïve Adult Subjects with HCV Genotype 1 Infection (Pooled Data QUEST 1 and QUEST 2)
Subgroup Olysio + PR
% (n/N)
Placebo + PR
% (n/N)
Olysio: 150 mg Olysio for 12 weeks with Peg-IFN-alfa-2a or -2b and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg-IFN-alfa-2a or -2b and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT.
F0–2 84 (317/378) 55 (106/192)
F3–4 68 (89/130) 36 (26/72)

SVR12 rates were higher for subjects receiving Olysio with Peg-IFN-alfa-2a or Peg-IFN-alfa-2b and RBV (88% and 78%, respectively) compared to subjects receiving placebo with Peg-IFN-alfa-2a or Peg-IFN-alfa-2b and RBV (62% and 42%, respectively) (QUEST 2).

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 [see Adverse Reactions (6.1), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Adult Subjects with HCV Genotype 1 Infection who Failed Prior Peg-IFN-alfa and RBV Therapy

The PROMISE trial was a randomized, double-blind, placebo-controlled, 2-arm, multicenter, Phase 3 trial in subjects with HCV genotype 1 infection who relapsed after prior IFN-based therapy. All subjects received 12 weeks of once daily treatment with 150 mg Olysio or placebo, 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. Subjects in the control group received 48 weeks of Peg-IFN-alfa-2a and RBV.

Demographics and baseline characteristics were balanced between the Olysio and placebo treatment groups. The 393 subjects enrolled in the PROMISE trial had a median age of 52 years (range: 20 to 71 years; with 3% above 65 years); 66% were male; 94% were White, 3% Black or African American, 2% Asian, and 7% Hispanic; 26% had a BMI greater than or equal to 30 kg/m2; 84% had baseline HCV RNA levels greater than 800000 IU/mL; 69% had METAVIR fibrosis score F0, F1 or F2, 15% METAVIR fibrosis score F3, and 15% METAVIR fibrosis score F4 (cirrhosis); 42% had HCV genotype 1a, and 58% HCV genotype 1b; 24% had IL28B CC genotype, 64% IL28B CT genotype, and 12% IL28B TT genotype; 13% of the overall population and 31% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. The prior IFN-based HCV therapy was Peg-IFN-alfa-2a/RBV (68%) or Peg-IFN-alfa-2b/RBV (27%).

Table 17 shows the response rates for the Olysio and placebo treatment groups in adult subjects with HCV genotype 1 infection who relapsed after prior interferon-based therapy. In the Olysio treatment group, SVR12 rates were lower in subjects infected with genotype 1a virus with the NS3 Q80K polymorphism at baseline compared to subjects infected with genotype 1a virus without the Q80K polymorphism.

Table 17: Response Rates in Adult Subjects with HCV Genotype 1 Infection who Relapsed after Prior IFN-Based Therapy (PROMISE Trial)
Response Rates Olysio + PR
N=260
% (n/N)
Placebo + PR
N=133
% (n/N)
Olysio: 150 mg Olysio for 12 weeks with Peg-IFN-alfa-2a and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg-IFN-alfa-2a and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT.
*
On-treatment failure was defined as the proportion of subjects with confirmed HCV RNA detected 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 HCV RNA not detected at actual EOT and with at least one follow-up HCV RNA assessment. Includes 5 Olysio-treated subjects who experienced relapse after SVR12.
Overall SVR12 (genotype 1a and 1b) 79 (206/260) 37 (49/133)
Genotype 1a 70 (78/111) 28 (15/54)
  Without Q80K 78 (62/79) 26 (9/34)
  With Q80K 47 (14/30) 30 (6/20)
Genotype 1b 86 (128/149) 43 (34/79)
Outcome for all subjects without SVR12
On-treatment failure* 3 (8/260) 27 (36/133)
Viral relapse 18 (46/249) 48 (45/93)

In PROMISE, 93% (241/260) of Olysio-treated subjects were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 83% (200/241).

Seventy-seven percent (77%; 200/260) of Olysio-treated subjects had HCV RNA not detected at Week 4 (RVR); in these subjects the SVR12 rate was 87% (173/200).

SVR12 rates were higher for the Olysio treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype/subtype, baseline HCV RNA load (less than or equal to 800000 IU/mL, greater than 800000 IU/mL), prior HCV therapy, METAVIR fibrosis score, and IL28B genotype. Table 18 shows the SVR rates by METAVIR fibrosis score.

Table 18: SVR12 Rates by METAVIR Fibrosis Score in Adult Subjects with HCV Genotype 1 Infection who Relapsed after Prior IFN-Based Therapy (PROMISE Trial)
Subgroup Olysio + PR
% (n/N)
Placebo + PR
% (n/N)
Olysio: 150 mg Olysio for 12 weeks with Peg-IFN-alfa-2a and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg-IFN-alfa-2a and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT.
F0–2 82 (137/167) 41 (40/98)
F3–4 73 (61/83) 24 (8/34)

The ASPIRE trial was a randomized, double-blind, placebo-controlled, Phase 2 trial in subjects with HCV genotype 1 infection, who failed prior therapy with Peg-IFN-alfa and RBV (including prior relapsers, partial responders or null responders).

In this trial, 66 subjects received 12 weeks of 150 mg Olysio in combination with Peg-IFN-alfa-2a and RBV for 48 weeks, and 66 subjects received placebo in combination with Peg-IFN-alfa-2a and RBV for 48 weeks. These 132 subjects had a median age of 49 years (range: 20 to 66 years; with 1% above 65 years); 66% were male; 93% were White, 3% Black or African American, and 2% Asian; 27% had a BMI greater than or equal to 30 kg/m2; 85% had baseline HCV RNA levels greater than 800000 IU/mL; 64% had METAVIR fibrosis score F0, F1, or F2, 18% METAVIR fibrosis score F3, and 18% METAVIR fibrosis score F4 (cirrhosis); 43% had HCV genotype 1a, and 57% HCV genotype 1b; 17% had IL28B CC genotype, 67% IL28B CT genotype, and 16% IL28B TT genotype (information available for 93 subjects); 27% of the overall population and 23% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. Forty percent (40%) of subjects were prior relapsers, 35% prior partial responders, and 25% prior null responders following prior therapy with Peg-IFN-alfa and RBV. Demographics and baseline characteristics were balanced between the 12 weeks 150 mg Olysio and placebo treatment groups.

Table 19 shows the response rates for the 12 weeks of 150 mg Olysio and placebo treatment groups in prior relapsers, prior partial responders and prior null responders.

Table 19: Response Rates in Prior Partial and Null Responders with HCV Genotype 1 Infection who Failed Prior Peg-IFN-alfa and RBV Therapy (ASPIRE Trial)
Response Rates Olysio + PR
N=66
% (n/N)
Placebo + PR
N=66
% (n/N)
150 mg Olysio: 150 mg Olysio for 12 weeks with Peg-IFN-alfa-2a and RBV for 48 weeks; Placebo: placebo with Peg-IFN-alfa-2a and RBV for 48 weeks. SVR24: sustained virologic response 24 weeks after planned EOT.
*
On-treatment virologic failure was defined as the proportion of subjects who met the protocol-specified treatment stopping rules (including stopping rule due to viral breakthrough) or who had HCV RNA detected at EOT (for subjects who completed therapy).
Viral relapse rates are calculated with a denominator of subjects with HCV RNA not detected at EOT and with at least one follow-up HCV RNA assessment.
SVR24
  Prior relapsers 77 (20/26) 37 (10/27)
  Prior partial responders 65 (15/23) 9 (2/23)
  Prior null responders 53 (9/17) 19 (3/16)
Outcome for all subjects without SVR24
On-treatment virologic failure*
  Prior relapsers 8 (2/26) 22 (6/27)
  Prior partial responders 22 (5/23) 78 (18/23)
  Prior null responders 35 (6/17) 75 (12/16)
Viral relapse
  Prior relapsers 13 (3/23) 47 (9/19)
  Prior partial responders 6 (1/17) 50 (2/4)
  Prior null responders 18 (2/11) 25 (1/4)

SVR24 rates were higher in the Olysio-treated subjects compared to subjects receiving placebo in combination with Peg-IFN-alfa and RBV, regardless of HCV geno/subtype, METAVIR fibrosis score, and IL28B genotype.

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 baseline 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 20 shows the response rates in treatment-naïve, prior relapsers, prior partial responders and null responders.

Table 20: 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)
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.
Overall SVR12 (genotype 1a and 1b) 79 (42/53) 87 (13/15) 70 (7/10) 57 (16/28)
Genotype 1a 77 (33/43) 83 (10/12) 67 (6/9) 54 (13/24)
Genotype 1b 90 (9/10) 100 (3/3) 100 (1/1) 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)

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 21 shows the SVR rates by METAVIR fibrosis scores.

Table 21: 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 at least 200 copies/mL after previous less than 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 baseline 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 22 shows the response rates in treatment-naïve, prior relapsers, prior partial responders and null responders. Table 23 shows the SVR rates by METAVIR fibrosis scores.

Table 22: 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)
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.
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)
Table 23: 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)

How Supplied/Storage and Handling

Olysio 150 mg capsules are white, marked with "TMC435 150" in black ink. The capsules are packaged into a bottle containing 28 capsules (NDC 59676-225-28) or a bottle of 7 capsules (emergency supply; NDC 59676-225-07).

Store Olysio capsules in the original bottle in order to protect from light at room temperature below 30°C (86°F).

Patient Counseling Information

  • Advise patients to read the FDA-approved patient labeling (Patient Information).

Symptomatic Bradycardia when used in combination with Sofosbuvir and Amiodarone

Advise patients to seek medical evaluation immediately for symptoms of bradycardia such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems [see Warnings and Precautions (5.1), Adverse Reactions (6.2) and Drug Interactions (7.3)].

Pregnancy

Advise patients taking Olysio to avoid pregnancy during treatment. In addition, when Olysio is taken with ribavirin, advise patients to avoid pregnancy during treatment and within 6 months of stopping ribavirin and to notify their healthcare provider immediately in the event of a pregnancy [see Use in Specific Populations (8.1)].

Hepatic Decompensation and Failure

Inform patients to watch for early warning signs of liver inflammation, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice and discolored feces, and to contact their healthcare provider immediately if such symptoms occur [see Warnings and Precautions (5.2)].

Photosensitivity

Advise patients of the risk of photosensitivity reactions related to Olysio combination treatment and that these reactions may be severe. Instruct patients to use effective sun protection measures to limit exposure to natural sunlight and to avoid artificial sunlight (tanning beds or phototherapy) during treatment with Olysio.

Advise patients to contact their healthcare provider immediately if they develop a photosensitivity reaction. Inform patients not to stop Olysio due to photosensitivity reactions unless instructed by their healthcare provider [see Warnings and Precautions (5.4)].

Rash

Advise patients of the risk of rash related to Olysio combination treatment and that rash may become severe. Advise patients to contact their healthcare provider immediately if they develop a rash. Inform patients not to stop Olysio due to rash unless instructed by their healthcare provider [see Warnings and Precautions (5.5)].

Administration

Advise patients to use Olysio only in combination with other antiviral drugs for the treatment of chronic HCV infection. Advise patients to discontinue Olysio if any of the other antiviral drugs used in combination with Olysio are permanently discontinued for any reason. Advise patients that the dose of Olysio must not be reduced or interrupted, as it may increase the possibility of treatment failure [see Dosage and Administration (2.1)].

Advise patients to take Olysio every day at the regularly scheduled time with food. Inform patients that it is important not to miss or skip doses and to take Olysio for the duration that is recommended by the healthcare provider. Inform patients not to take more or less than the prescribed dose of Olysio at any one time.

Product of Belgium

Manufactured by:
Janssen-Cilag SpA, Latina, Italy

Manufactured for:
Janssen Therapeutics, Division of Janssen Products, LP
Titusville NJ 08560

Licensed from Medivir AB

Olysio® is a registered trademark of Johnson & Johnson

© Janssen Products, LP 2016

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised February 2016
PATIENT INFORMATION
Olysio® (oh li see oh)

(simeprevir)
Capsules
Read this Patient Information before you start taking Olysio and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.
Important: You should not take Olysio alone. Olysio should be used together with other antiviral medicines to treat chronic hepatitis C virus infection. When taking Olysio in combination with peginterferon alfa and ribavirin you should also read those Medication Guides. When taking Olysio in combination with sofosbuvir, you should also read its Patient Information leaflet.
What is the most important information I should know about Olysio?
  • If you are pregnant, or plan to become pregnant, talk with your healthcare provider before taking Olysio. It is not known if Olysio will harm your unborn baby. Also read the Medication Guides for peginterferon alfa and ribavirin if your healthcare provider prescribes these medications for you in combination with Olysio.
  • Females must use an effective form of birth control during treatment with Olysio. Talk with your healthcare provider about birth control methods that you may use during treatment with Olysio.

Olysio may cause serious side effects, including:

Olysio combination treatment with sofosbuvir (Sovaldi®) may result in slowing of the heart rate (pulse) along with other symptoms when taken with amiodarone (Cordarone®, Nexterone®, Pacerone®), a medicine used to treat certain heart problems.

  • If you are taking Olysio with sofosbuvir and amiodarone and you get any of the following symptoms, or if you have a slow heart rate call your healthcare provider right away:
  • fainting or near-fainting
  • dizziness or lightheadedness
  • weakness, extreme tiredness
  • chest pain, shortness of breath
  • confusion or memory problems

Olysio may cause severe liver problems in some people. These severe liver problems may lead to liver failure or death.

  • Your healthcare provider may do blood tests to check your liver function during treatment with Olysio.
  • Your healthcare provider may tell you to stop taking Olysio if you develop signs and symptoms of liver problems.
  • Tell your healthcare provider right away if you develop any of the following symptoms, or if they worsen during treatment with Olysio:
  • tiredness
  • weakness
  • loss of appetite
  • nausea and vomiting
  • yellowing of your skin or eyes
  • color changes in your stools

Olysio combination treatment may cause rashes and skin reactions to sunlight. These rashes and skin reactions to sunlight can be severe and you may need to be treated in a hospital. Rashes and skin reactions to sunlight are most common during the first 4 weeks of treatment, but can happen at any time during combination treatment with Olysio.

  • Limit sunlight exposure during treatment with Olysio.
  • Use sunscreen and wear a hat, sunglasses, and protective clothing during treatment with Olysio.
  • Avoid use of tanning beds, sunlamps, or other types of light therapy during treatment with Olysio.
  • Call your healthcare provider right away if you get any of the following symptoms:
  • burning, redness, swelling or blisters on your skin
  • mouth sores or ulcers
  • red or inflamed eyes, like "pink eye" (conjunctivitis)
What is Olysio?
  • Olysio is a prescription medicine used with other antiviral medicines to treat chronic (lasting a long time) hepatitis C virus genotype 1 or 4 infection. Olysio should not be taken alone.
  • Olysio is not for people with certain types of liver problems.

It is not known if Olysio is safe and effective in children under 18 years of age.

What should I tell my healthcare provider before taking Olysio?

Before taking Olysio, tell your healthcare provider if you:

  • have liver problems other than hepatitis C virus infection
  • have ever taken any medicine to treat hepatitis C virus infection
  • had a liver transplant
  • are receiving phototherapy
  • have any other medical condition
  • are breastfeeding. It is not known if Olysio passes into your breast milk. You and your healthcare provider should decide if you will take Olysio or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines may interact with Olysio. This can cause you to have too much or not enough Olysio or other medicines in your body, which may affect the way Olysio or your other medicines work, or may cause side effects. Keep a list of your medicines and show it to your healthcare provider and pharmacist.

  • You can ask your healthcare provider or pharmacist for a list of medicines that interact with Olysio.
  • Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take Olysio with other medicines.
How should I take Olysio?
  • Take Olysio exactly as your healthcare provider tells you to take it. Do not change your dose unless your healthcare provider tells you to.
  • Do not stop taking Olysio unless your healthcare provider tells you to. If you think there is a reason to stop taking Olysio, talk to your healthcare provider before doing so.
  • Take 1 Olysio capsule each day with food.
  • Swallow Olysio capsules whole.
  • It is important that you do not miss or skip doses of Olysio during treatment.
  • Do not take two doses of Olysio at the same time to make up for a missed dose.
  • If you take too much Olysio, call your healthcare provider right away or go to the nearest hospital emergency room.
What are the possible side effects of Olysio?

The most common side effects of Olysio when used in combination with peginterferon alfa and ribavirin include:

  • skin rash
  • itching
  • nausea

The most common side effects of Olysio when used in combination with sofosbuvir include:

  • tiredness
  • headache
  • nausea

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of Olysio. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Olysio?
  • Store Olysio at room temperature below 86°F (30°C).
  • Store Olysio in the original bottle to protect it from light.

Keep Olysio and all medicines out of the reach of children.

General information about the safe and effective use of Olysio

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Olysio for a condition for which it was not prescribed. Do not give your Olysio to other people, even if they have the same symptoms that you have. It may harm them.

If you would like more information about Olysio, talk with your pharmacist or healthcare provider. You can ask your pharmacist or healthcare provider for information about Olysio that is written for health professionals.

For more information about Olysio, go to www.Olysio.com or call 1-800-526-7736.

What are the ingredients in Olysio?

Active ingredient: simeprevir

Inactive ingredients: colloidal anhydrous silica, croscarmellose sodium, lactose monohydrate, magnesium stearate, sodium lauryl sulphate. The white capsule contains gelatin and titanium dioxide (E171) and is printed with ink containing iron oxide black (E172) and shellac (E904).

Product of Belgium

Manufactured by: Janssen-Cilag SpA, Latina, Italy

Manufactured for: Janssen Therapeutics, Division of Janssen Products, LP, Titusville NJ 08560

Licensed from Medivir AB

Olysio® is a registered trademark of Johnson & Johnson

© Janssen Products, LP 2016

PRINCIPAL DISPLAY PANEL - 150 mg Capsule Bottle Label

NDC 59676-225-28

28 Capsules

Olysio®
(simeprevir) Capsules
150 mg

Each capsule contains simeprevir sodium
equivalent to 150 mg simeprevir

Rx only

janssen

Olysio 
simeprevir capsule
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:59676-225
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
simeprevir (SIMEPREVIR) SIMEPREVIR 150 mg
Inactive Ingredients
Ingredient Name Strength
SILICON DIOXIDE  
CROSCARMELLOSE SODIUM  
LACTOSE MONOHYDRATE  
MAGNESIUM STEARATE  
SODIUM LAURYL SULFATE  
GELATIN  
TITANIUM DIOXIDE  
FERROSOFERRIC OXIDE  
SHELLAC  
Product Characteristics
Color WHITE Score no score
Shape CAPSULE Size 22mm
Flavor Imprint Code TMC435;150
Contains         
Packaging
# Item Code Package Description
1 NDC:59676-225-28 28 CAPSULE in 1 BOTTLE
2 NDC:59676-225-07 7 CAPSULE in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA205123 11/22/2013
Labeler - Janssen Products LP (804684207)
Establishment
Name Address ID/FEI Operations
Janssen Pharmaceutica NV 374747970 API MANUFACTURE(59676-225)
Establishment
Name Address ID/FEI Operations
Janssen Cilag SpA 542797928 MANUFACTURE(59676-225), ANALYSIS(59676-225), PACK(59676-225)
Establishment
Name Address ID/FEI Operations
AndersonBrecon Inc. 053217022 LABEL(59676-225)
Revised: 03/2016
 
Janssen Products LP
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