2)
Dosage and Administration section was updated to include dose
recommendations for retreatment in combination with weight-based
dosing of ribavirin for the treatment of chronic hepatitis C
as follows:
Combination
Treatment with INFERGEN/Ribavirin Dosing
The
recommended dose of INFERGEN is 15 mcg daily administered as
a single subcutaneous injection in combination with weight-based
ribavirin at 1,000 mg-1,200 mg (< 75 kg and >75
kg) orally in two divided doses for up to 48 weeks. [see Clinical
Studies (14.3), Medication Guide for instructions].
Ribavirin
should be taken with food. INFERGEN/ribavirin should not be
used in patients with creatinine clearance < 50 mL/min [see
CONTRAINDICATIONS (4)].
Dose
Modifications
If
a serious adverse reaction develops during the course of treatment
[see WARNINGS and PRECAUTIONS (5)] discontinue or modify the
dosage of INFERGEN and/or ribavirin until the adverse event
abates or decreases in severity. If persistent or recurrent
serious adverse events develop despite adequate dosage adjustment,
discontinue treatment. Upon resolution or improvement of the
adverse reaction, resuming INFERGEN and/or ribavirin may be
considered.
INFERGEN/Ribavirin
Combination Therapy Dose Modifications
Stepwise
dose reduction from 15 mcg to 9 mcg and from 9 mcg to 6 mcg
may be necessary for serious adverse reactions.
Please
refer to updated label for complete guidelines for dose modifications
and discontinuation of INFERGEN and/or ribavirin based on depression
or laboratory parameters.
3)
The WARNINGS and PRECAUTIONS section was updated and placed
in the order of importance of each toxicity of concern. Many
of the toxicities are considered class labeling among the interferon
products.
4)
The Adverse Event section was updated to remove antiquated information
and to include information about safety from the INFERGEN/RBV
study (DIRECT Trial/IRHC-001 and IRHC-002).
5)
Clinical Studies section was updated to include information
regarding study IRHC-001/IRHC-002/DIRECT Trial. Specifically,
Subsequent
Treatment with Combination INFERGEN/Ribavirin
This
study (DIRECT Trial/ IRHC-001 and IRHC-002) was a randomized,
open-label, multi-center, US-based study comparing the safety
and efficacy of two doses of INFERGEN (9 mcg or 15 mcg) administered
daily plus ribavirin (1000 mg or 1200 mg weight based dosed)
administered daily for 48 weeks to subjects who were nonresponders
to previous pegylated interferon plus ribavirin (Peg-IFN/ribavirin)
therapy. Prior non-response was defined as a < 2 log10 decline
in viral load (VL) while undergoing at least 12 weeks of previous
Peg-IFN/ribavirin therapy with > 80% adherence or
a detectable VL at end-of-treatment after completing at least
24 weeks of therapy. Study subjects had a mean age of 50 yrs,
70% were male, mean weight of 89 kg, 19% were African Americans,
65% were Caucasians, 66% had high VL (> 850,000 IU/mL),
95% were infected with genotype 1, 54% had evidence of bridging
fibrosis, 25% had evidence of cirrhosis on biopsy, and 50% had
steatosis. Approximately 80% of the patients were null responders
(< 2 log10 drop in viral load during their previous Peg-IFN/ribavirin
therapy). The median washout period between previous treatment
and day 1 of INFERGEN therapy was 448 days (15 months) and 506
days (16.8 months) for the 9 mcg and 15 mcg groups, respectively.
The use of hematopoietic growth factors was not permitted in
the DIRECT Trial.
In
study IRHC-001, 515 subjects were randomized to INFERGEN 9 mcg
plus ribavirin (n=171), INFERGEN 15 mcg plus ribavirin (n=172),
or no treatment (n=172). In study IRHC-002, 144 patients in
the no treatment arm of study IRHC-001 were re-randomized to
either INFERGEN 9 mcg plus ribavirin (n=74) or INFERGEN 15 mcg
plus ribavirin (n=70).
Subjects
were treated for up to 48 weeks. The primary endpoint was sustained
virological response (SVR), defined as undetectable HCV RNA
24 weeks after the end of treatment using a sensitive qualitative
assay (TMA LOD <10 IU/mL). None of the subjects in the no-treatment
arm of study IRHC-001 achieved an SVR.
Combined
SVR results from IRHC-001 and IRHC-002 according to baseline
characteristics are shown in Table 8 of the package insert.
The overall SVR rate for INFERGEN 9 mcg/ribavirin was 5% (13/245)
compared to 95 (21/242) for INFERGEN 15 mcg/ribavirin. Based
on these results, INFERGEN 15 mcg is the recommended starting
dose.
6)
The Contraindications, and the Animal Toxicology and/or Pharmacology
section was also updated.
Additionally
the Medication Guide was revised to provide information on combination
therapy with weight-based dosing of ribavirin and to provide
information on the risk associated with interferon therapy.
The
complete revised label can be accessed at the FDA
web site.
Infergen
is a product of Three Rivers Pharmaceuticals, Warrendale, PA.
7/9/10
Source
R
Klein and K Struble, U.S.Food and Drug Administration. Infergen
(interferon alfacon-1) label revision: combination therapy,
weight-based dosing, and label format. Hepatitis Update.
July 7, 2010.
