On November 5, 2014, FDA approved changes to the Olysio (simeprevir) label to include use of Olysio in combination with sofosbuvir for the treatment of patients with chronic hepatitis C virus genotype 1 infection.
Highlights of the label changes are summarized below.
INDICATIONS AND USAGE
OLYSIO® is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection as a component of a combination antiviral treatment regimen.
Limitations of Use:
- OLYSIO monotherapy is not recommended.
- OLYSIO efficacy 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. Screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended. Alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism.
- OLYSIO is not recommended in patients with severe hepatic impairment (Child Pugh Class C) due to substantial increases in simeprevir exposures, which have been associated with increased frequency of adverse reactions.
- OLYSIO is not recommended in patients who have previously failed therapy with a treatment regimen that included OLYSIO or other HCV protease inhibitors.
DOSAGE AND ADMINISTRATION
2.1 OLYSIO Combination Treatment
Administer OLYSIO in combination with other antiviral drugs for the treatment of CHC infection. For specific dosing recommendations for the antiviral drugs used in combination with OLYSIO, refer to their respective prescribing information. OLYSIO monotherapy is not recommended. Administer OLYSIO in combination with either:
- Peg‑IFN‑alfa and RBV: Table 1 displays the recommended dosage regimen and treatment duration of OLYSIO in combination with Peg‑IFN‑alfa and RBV. Refer to Table 3 for treatment stopping rules for OLYSIO combination therapy with Peg‑IFN‑alfa and RBV; or
- Sofosbuvir: Table 2 displays the recommended dosage regimen and treatment duration of OLYSIO in combination with sofosbuvir.
The recommended dosage of OLYSIO is one capsule taken orally once daily with food. The capsule should be swallowed as a whole.
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Table 1: Recommended Dosage Regimens and Treatment Duration for OLYSIO, Peg‑IFN‑alfa, and RBV Combination Therapy for Treatment of CHC Infection |
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Patient Population* |
Treatment Regimen and Duration |
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Treatment‑naïve patients and prior relapsers† |
12 weeks of OLYSIO in combination with Peg‑IFN‑alfa and RBV followed by an additional 12 weeks of Peg‑IFN‑alfa and RBV (total treatment duration of 24 weeks)‡ |
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Prior non‑responders (including partial# and null responders§) |
12 weeks of OLYSIO in combination with Peg-IFN-alfa and RBV followed by an additional 36 weeks of Peg‑IFN‑alfa and RBV (total treatment duration of 48 weeks)‡ |
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* Includes patients with or without cirrhosis. † Prior relapser: HCV RNA not detected at the end of prior IFN‑based therapy and HCV RNA detected during follow‑up [see Clinical Studies (14)]. ‡ Recommended duration of treatment if patient does not meet stopping rules (see Table 3). # Prior partial responder: prior on-treatment ≥ 2 log10 IU/mL reduction in HCV RNA from baseline at Week 12 and HCV RNA detected at end of prior IFN‑based therapy [see Clinical Studies (14)]. § Prior null responder: prior on‑treatment < 2 log10 reduction in HCV RNA from baseline at Week 12 during prior IFN‑based therapy [see Clinical Studies (14)]. |
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Table 2: Recommended Dosage Regimen and Treatment Duration for OLYSIO and Sofosbuvir Combination Therapy for Treatment of CHC Infection |
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Patient Population |
Treatment Regimen and Duration |
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Treatment‑naïve and treatment‑experienced* patients without cirrhosis |
12 weeks of OLYSIO + sofosbuvir |
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Treatment‑naïve and treatment‑experienced* patients with cirrhosis |
24 weeks of OLYSIO + sofosbuvir |
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* Treatment‑experienced patients include prior relapsers, prior partial responders and prior null responders who failed prior IFN‑based therapy. |
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2.2 Testing Prior to Initiation of OLYSIO in HCV Genotype 1a‑Infected Patients
Prior to initiation of treatment with OLYSIO 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. Prior to initiation of treatment with OLYSIO with sofosbuvir, screening patients infected with HCV genotype 1a for the presence of virus with the NS3 Q80K polymorphism is not strongly recommended but may be considered. [See Indications and Usage (1)].
2.3 Discontinuation of Dosing
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 ≥ 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.
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Table 3: Treatment Stopping Rules in Patients Receiving OLYSIO in Combination with Peg‑IFN‑alfa and RBV with Inadequate On‑Treatment Virologic Response |
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Treatment Week |
HCV RNA |
Action |
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Week 4 |
≥ 25 IU/mL |
Discontinue OLYSIO, Peg‑IFN‑alfa, and RBV |
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Week 12 |
Discontinue Peg‑IFN‑alfa, and RBV (treatment with OLYSIO is complete at Week 12) |
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Week 24 |
Discontinue Peg‑IFN‑alfa, and RBV (treatment with OLYSIO is complete at Week 12) |
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Use with Sofosbuvir
No treatment stopping rules apply to the combination of OLYSIO with sofosbuvir [see Clinical Studies (14.)].
ADVERSE REACTIONS
Adverse Reactions when Used with Sofosbuvir
In the COSMOS trial, the most common (> 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.
Microbiology
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.
Failure to achieve SVR with simeprevir does not select virus that is cross‑resistant to sofosbuvir or vice versa.
CLINICAL STUDIES
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).
The 80 enrolled subjects without advanced hepatic fibrosis in Cohort 1 had a median age of 56 years (range 27 to 70 years; with 8% above 65 years); 61% were male; 71% were White, 29% Black or African American, and 25% were Hispanic; 30% had a BMI greater than or equal to 30 kg/m2; 98% had HCV RNA levels greater than 800,000 IU/mL; 41% had METAVIR fibrosis score F0 or F1 and 59% had METAVIR fibrosis score F2; 78% had HCV genotype 1a, and the remaining patients had HCV genotype 1b; 39% of the overall population and 50% of the subjects with genotype 1a had the NS3 Q80K polymorphism at baseline; 6% had IL28B CC genotype, 70% IL28B CT genotype, and 24% IL28B TT genotype. All subjects were prior null responders to Peg‑IFN‑alfa and RBV.
The 87 enrolled subjects with advanced hepatic fibrosis in Cohort 2 had a median age of 58 years (range 28 to 70 years; with 3% above 65 years); 67% were male; 91% were White, 9% Black or African American, and 17% were Hispanic; 44% had a BMI greater than or equal to 30 kg/m2; 84% had HCV RNA levels greater than 800,000 IU/mL; 53% had METAVIR fibrosis score F3 and 47% had METAVIR fibrosis score F4 (cirrhosis); 78% had HCV genotype 1a, and 22% HCV genotype 1b; 31% of the overall population and 40% of the subjects with genotype 1a had the NS3 Q80K polymorphism at baseline; 21% had IL28B CC genotype, 56% IL28B CT genotype, and 23% IL28B TT genotype. Fifty-four percent of subjects were prior null responders to Peg‑IFN‑alfa and RBV and 46% were treatment‑naïve.
Table 16 shows the response rates by combining prior null responders in Cohort 1 and treatment‑naïve subjects and prior null responders in Cohort 2. When treatment arms with and without ribavirin were combined, the overall SVR12 rate was 95% (61/64) in subjects with METAVIR fibrosis score F0-F3 who received 12 weeks treatment of OLYSIO in combination with sofosbuvir with/without RBV when pooling both cohorts. The overall SVR12 rate was 96% (22/23) in subjects with METAVIR fibrosis score F4 who received 24 weeks treatment of OLYSIO in combination with sofosbuvir with/without RBV when pooling both cohorts. 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 16.
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Table 16: 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 (Pooled Data for Cohort 1 and 2) |
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OLYSIO + Sofosbuvir 12 weeks % (n/N) |
OLYSIO + Sofosbuvir 24 weeks % (n/N) |
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Overall SVR12 |
93 (26/28) |
97 (30/31) |
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F0-3 |
95 (20/21) |
95 (20/21) |
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F4 |
86 (6/7) |
100 (10/10) |
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Viral Relapse† |
7 (2/28) |
0 (0/30) |
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F0-3 |
5 (1/21) |
0 (0/20) |
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F4 |
14 (1/7) |
0 (0/10) |
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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. |
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The complete product label will be available soon at DailyMed or at Drugs@FDA.
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
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