Wednesday, October 30, 2013

Hepatitis C - Changes to Incivek (telaprevir) product labeling

Changes to Incivek (telaprevir) product labeling

Source FDA 10/29/2013 Changes to Incivek (telaprevir) product labeling

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

In 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 of fentanyl.
  • Section 12 Clinical Pharmacology was updated with information regarding the twice daily dosing regimen.

Telaprevir 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:
In 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 as follows:
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.

rs12979860 Genotype
SVR, n/N (%)
C211 (treatment-naïve)
T12 Twice Daily/PR
T12 q8h/PR
97/105 (92%)
92/106 (87%)
139/206 (67%)
141/208 (68%)
38/58 (66%)
37/57 (65%)

  • Section 14 Clinical Studies was updated to include results from Trial C211 (OPTIMIZE)
Trial C211 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.

The 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.

Table 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; 270/371], respectively.  

Table 11:               Response Rates: Trial C211 
Treatment outcome
T12 (twice daily)/PR
N = 369
% (n/N)
T12 (q8h)/PR
N = 371
% (n/N)
74% (274/369)
73% (270/371)
Undetectable HCV RNA (target not detected) at week 4a
69% (256/369)
67% (250/371)
SVR in subjects with undetectable HCV RNA (target not detected) at week 4
86% (221/256)
85% (213/250)
SVR in subjects who did not have undetectable HCV RNA at week 4
47% (53/113)
47% (57/121)
Outcome for Subjects without SVR 
26% (95/369)
27% (101/371)
On‑treatment virologic failureb 
10% (38/369) 
10% (36/371) 
8% (23/300)
6% (19/293)
9% (34/369)
12% (46/371)

T12 (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.
b   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 breakthrough.
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 window.
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 planned follow-up.

 SVR 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. 

Fifty-four 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.

Thirty-five 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. 

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

Kimberly Struble
Division of Antiviral Products
Food and Drug Administration

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