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Infergen (interferon alfacon-1) label revision: combination therapy, weight-based dosing, and label format

On July 2, 2010, FDA approved revised labeling for Infergen (interferon alfacon-1) to include information on combination therapy with weight-based dosing of ribavirin. The label was placed in PLR (Physicians Labeling Rule) format and the major labeling changes include revisions to the following sections :

1) Indications and Usage section to include information describing when patients are unlikely to benefit from retreatment. This section reads as follows:

INFERGEN (interferon alfacon-1) is indicated for treatment of chronic hepatitis C in patients 18 years of age or older with compensated liver disease. This indication is based on clinical trials conducted using INFERGEN as monotherapy prior to the time that combination treatment was the standard of care and on a single trial evaluating INFERGEN in combination with ribavirin in patients who failed to respond to previous treatment with a pegylated interferon and ribavirin.

The following points should be considered when initiating treatment with INFERGEN:

· Use of monotherapy with an interferon such as INFERGEN for the treatment of hepatitis C is not recommended unless a patient is unable to take ribavirin.

· The safety and efficacy of the combination of INFERGEN/ribavirin in treatment-naïve patients or in patients co-infected with HBV or HIV-1 have not been evaluated.

· Patients with the following characteristics are less likely to benefit from retreatment with combination therapy: response of <1 log10 drop HCV RNA on previous treatment, Genotype 1, high viral load (>850,000 IU/mL), African American race, and/or presence of cirrhosis.

· No safety and efficacy data are available for treatment of longer than one year.

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.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration