FDA approved changes to the Incivek (telaprevir) product labeling to
include results from trial C211 (OPTIMIZE) to support a twice daily
dosing regimen. In addition new contraindications were added for
anticonvulsant medications (carbamazepine, phenobarbital and phenytoin)
and other revisions to the section 7 Drug Interactions. Below is a summary of the changes
- Section 2: Dosage and Administration of telaprevir were updated throughout the label: from 750 mg three times a day to 1125 mg twice daily.
- The anticonvulsant medications carbamazepine, phenobarbital, and phenytoin were moved from the Drug Interaction section (Section 7, Table 5) to the Contraindications section (Section 4, Table 3)
- Section 6: Adverse Reactions was updated as follows:
Additional Data from Clinical Trials
the analysis of an additional study (Trial C211), the safety profile
of combination treatment with INCIVEK 1125 mg twice daily was similar
to the safety profile for patients receiving combination treatment with
INCIVEK 750 mg every 8 hours (q8h) [see Clinical Studies (14.2)]. No
new safety findings were identified.
- The analgesic medications alfentanil and fentanyl were added in section 7 Drug Interactions
Table 5 as potential drug interaction drugs when used with
telaprevir. Specifically, careful monitoring of therapeutic and
adverse effects (including respiratory depression) is recommended
when telaprevir is co-administered with alfentanil or fentanyl,
including extended-release transdermal or transmucosal preparations
- Section 12 Clinical Pharmacology was updated with information regarding the twice daily dosing regimen.
total exposure (AUC24h,ss) was similar regardless of whether the total
daily dose of 2250 mg was administered as 750 mg every 8 hours or 1125
mg twice daily.
Additionally the data from interaction trials with carbamazepine and phenytoin were included.
- Section 12.4 Microbiology was updated as follows:
the C211 Phase 3 clinical trial, there were no differences in the
types of emerging variants between subjects receiving telaprevir 1125
mg twice daily and subjects receiving telaprevir 750 mg every 8 hours.
Similar proportions of subjects in both treatment groups had
telaprevir-resistant variants at the time of failure.
- Section 12.5 Pharmacogenomics
was updated to include the sustained virologic response rates at
12 weeks post treatment (SVR12) for the twice daily dosing regimen
In Trial C211, all subjects were
prospectively tested for IL28B variants; there were no clinically
relevant differences in SVR12 responses between q8h and twice-daily
dosing within the genetic subgroups.
||SVR, n/N (%)
||T12 Twice Daily/PR
- Section 14 Clinical Studies was updated to include results from Trial C211 (OPTIMIZE)
was a randomized, open-label, Phase 3 trial conducted in
treatment‑naïve subjects. Enrolled subjects received 12 weeks of either
INCIVEK 750 mg every 8 hours [T12 (q8h)/PR] or INCIVEK 1125 mg twice
daily [T12 (twice daily)/PR] in combination with peginterferon alfa‑2a
and ribavirin. The trial was designed to compare twice-daily dosing [T12
(twice daily)/PR] versus q8h dosing [T12 (q8h)/PR] of INCIVEK. At
week 12, INCIVEK dosing ended and subjects continued on peginterferon
alfa‑2a and ribavirin treatment. The total treatment duration was
determined based on the subjects’ individual on-treatment viral
response. If a subject achieved undetectable HCV RNA < 25 IU/mL
(target not detected) at week 4, the total treatment duration was
24 weeks. Otherwise, the total treatment duration was 48 weeks.
740 enrolled subjects had a median age of 51 years (range: 18 to 70);
60% of the subjects were male; 21% had a body mass index ≥ 30 kg/m2;
5% were Black; 2% were Asian; 85% had baseline HCV RNA levels
≥ 800,000 IU/ml; 15% had bridging fibrosis; 14% had cirrhosis; 57% had
HCV genotype 1a; and 43% had HCV genotype 1b.
11 shows the response rates for the T12 (twice daily)/PR group and the
T12 (q8h)/PR groups by treatment outcomes. The overall SVR rates were
similar at 74% [T12 (twice daily)/PR; 274/369] and 73% [T12 (q8h)/PR;
(twice daily)/PR: INCIVEK 1125 mg twice daily for 12 weeks with
peginterferon alfa‑2a and ribavirin for 24 or 48 weeks; T12 (q8h)/PR:
INCIVEK 750 mg every 8 hours for 12 weeks with peginterferon alfa‑2a
and ribavirin for 24 or 48 weeks
a Subjects with planned total treatment duration of 24 weeks.
On‑treatment‑virologic failure includes subjects who met a
protocol‑defined virologic stopping rule and/or who had detectable
HCV RNA at the time of their last dose of study drug and had viral
c Relapse was defined as having
less than 25 IU/mL at the planned end of treatment followed by HCV RNA
≥ 25 IU/ml at the last observation within the SVR follow-up visit
d Other includes subjects with detectable
HCV RNA at the planned end of treatment but who did not have viral
breakthrough, and subjects with a missing SVR assessment during
rates were similar for the T12 (twice daily)/PR and T12 (q8h)/PR
groups across subgroups determined by sex, age, race, ethnicity, body
mass index, HCV genotype subtype, IL28B genotype, baseline HCV RNA
(less than 800,000, greater than or equal to 800,000 IU per mL), and
extent of liver fibrosis. However, there were small numbers of subjects
enrolled in some key subgroups.
and 49 subjects in T12 (twice daily)/PR and T12 (q8h)/PR groups,
respectively, had cirrhosis at baseline. The SVR rate in these subjects
was 54% (29/54) in the T12 (twice daily)/PR group and 49% (24/49) in
the T12 (q8h)/PR group. In the T12 (twice daily)/PR group, 52% (28/54)
of subjects with cirrhosis achieved undetectable HCV RNA (target not detected) at week 4; their SVR rate was 68% (19/28). In the T12 (q8h)/PR group, 59% (29/49) achieved undetectable
HCV RNA (target not detected) at week 4; their SVR was 59% (17/29).
The SVR rate for subjects assigned 48 weeks of treatment was 38%
(10/26) in the T12 (twice daily)/PR group and 35% (7/20) in the T12 (q8h)/PR.
subjects were Black/African Americans. The overall SVR among
Black/African American subjects was 50% (10/20) in the T12 (twice
daily)/PR group and 60% (9/15) in the T12 (q8h)/PR group. Among these
subjects, 46% (16/35) were assigned to 24 weeks of treatment and of
those 88% (14/16) achieved SVR.
Office of Health and Constituent Affairs
Food and Drug Administration
Division of Antiviral Products
Food and Drug Administration
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