Infergen: Package Insert and Label Information

INFERGEN- interferon alfacon-1 injection
Valeant Pharmaceuticals, Inc.

Alpha interferons, including Interferon alfacon-1, cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders.
Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening symptoms of these conditions should be withdrawn from therapy. In many but not all cases, these disorders resolve after stopping Interferon alfacon-1 therapy.
See WARNINGS and ADVERSE REACTIONS.

DESCRIPTION

Interferon alfacon-1 is a recombinant non-naturally occurring type-I interferon. The 166-amino acid sequence of Interferon alfacon-1 was derived by scanning the sequences of several natural interferon alpha subtypes and assigning the most frequently observed amino acid in each corresponding position.1 Four additional amino acid changes were made to facilitate the molecular construction, and a corresponding synthetic DNA sequence was constructed using chemical synthesis methodology. Interferon alfacon-1 differs from interferon alfa-2b at 20/166 amino acids (88% homology), and comparison with interferon-beta shows identity at over 30% of the amino acid positions. Interferon alfacon-1 is produced in Escherichia coli (E. coli) cells that have been genetically altered by insertion of a synthetically constructed sequence that codes for Interferon alfacon-1. Prior to final purification, Interferon alfacon-1 is allowed to oxidize to its native state, and its final purity is achieved by sequential passage over a series of chromatography columns. This protein has a molecular weight of 19,434 daltons.

INFERGEN is a sterile, clear, colorless, preservative-free liquid formulated with 100 mM sodium chloride and 27 mM sodium phosphate at pH 7.0 ± 0.2. The product is available in single-use vials containing 9 mcg and 15 mcg Interferon alfacon-1 at a fill volume of 0.3 mL and 0.5 mL, respectively. INFERGEN vials contain 0.03 mg/mL Interferon alfacon-1, 5.9 mg/mL sodium chloride, and 3.8 mg/mL sodium phosphate in Water for Injection, USP. INFERGEN is to be administered undiluted by subcutaneous (SC) injection.

CLINICAL PHARMACOLOGY

General

Interferons are a family of naturally occurring, small protein molecules with molecular weights of 15,000 to 21,000 daltons that are produced and secreted by cells in response to viral infections or to various synthetic and biological inducers. Two major classes of interferons have been identified (i.e., type-I and type-II). Type-I interferons include a family of more than 25 alpha interferons as well as beta interferon and omega interferon. While all alpha interferons have similar biological effects, not all the activities are shared by each alpha interferon and, in many cases, the extent of activity varies substantially for each interferon subtype.

All type-I interferons share common biological activities generated by binding of interferon to the cell-surface receptor, leading to the production of several interferon-stimulated gene products. Type-I interferons induce pleiotropic biologic responses which include antiviral, antiproliferative, and immunomodulatory effects, regulation of cell surface major histocompatibility antigen (HLA class I and class II) expression and regulation of cytokine expression. Examples of interferon-stimulated gene products include 2’5′ oligoadenylate synthetase (2’5′OAS) and β-2 microglobulin.

The antiviral, antiproliferative, natural killer (NK) cell activation, and gene-induction activities of INFERGEN have been compared with other recombinant alpha interfereons in in vitro assays and have demonstrated similar ranges of activity. INFERGEN exhibited at least 5 times higher specific activity in vitro than Interferon alfa-2a and Interferon alfa-2b.2 Comparison of INFERGEN with a WHO international potency standard for recombinant alpha interferon (83/514) revealed that the specific activity of INFERGEN in both an in vitro antiviral cytopathic effect assay and an antiproliferative assay was 1 x 109 U/mg. However, correlation between in vitro activity and clinical activity of any interferon is unknown.

Pharmacokinetics and Pharmacodynamics

The pharmacokinetic properties of INFERGEN have not been evaluated in patients with chronic hepatitis C. Pharmacokinetic profiles were evaluated in normal, healthy volunteer subjects after SC injection of 1, 3, or 9 mcg INFERGEN. Plasma levels of INFERGEN after SC administration of any dose were too low to be detected by either enzyme-linked immunosorbent assay (ELISA) or by inhibition of viral cytopathic effect. However, analysis of INFERGEN-induced cellular products (induction of 2’5′ OAS and β-2 microglobulin) after treatment in these subjects revealed a statistically significant, dose-related increase in the area under the curve (AUC) for the levels of 2’5′ OAS or β-2 microglobulin induced over time (p < 0.001 for all comparisons). Concentrations of 2’5′ OAS were maximal at 24 hours after dosing, while serum levels of β-2 microglobulin appeared to reach a maximum 24 to 36 hours after dosing. The dose-response relationships observed for 2’5′ OAS and β-2 microglobulin were indicative of biological activity after SC administration of 1 to 9 mcg INFERGEN.

Preclinical Experience

All interferons have been shown to be highly species-specific. Antiviral activity of INFERGEN was observed in the rhesus monkey LLC cell line and golden Syrian hamster BHK cell line. Antiviral activity of INFERGEN in the golden Syrian hamster was confirmed further in vivo. 3 Pharmacokinetic studies of INFERGEN in golden Syrian hamsters and rhesus monkeys demonstrated rapid absorption following SC injection. Peak serum concentrations of INFERGEN were observed at 1 hour and 4 hours in golden Syrian hamsters and in rhesus monkeys, respectively. Subcutaneous bioavailability was high in both species, averaging 99% in golden Syrian hamsters and 83% to 104% in rhesus monkeys. Clearance of INFERGEN, averaging 1.99 mL/minute/kg in golden Syrian hamsters and 0.71 to 0.92 mL/minute/kg in rhesus monkeys, was due predominantly to catabolism and excretion by the kidneys. The terminal half-life of INFERGEN following SC dosing was 1.3 hours in golden Syrian hamsters and 3.4 hours in rhesus monkeys. Upon 7-day multiple SC dosing, no accumulation of serum levels was observed in golden Syrian hamsters.

In preclinical toxicology studies in golden Syrian hamsters and rhesus monkeys, administration of INFERGEN at doses of up to 100 mcg/kg/day was associated with decreased body weight, decreased food consumption, and bone marrow suppression. High-dose chronic exposure at doses of 10 to 100 mcg/kg/day (50- to 500-fold higher than the maximum clinical dose given daily) in rhesus monkeys was not tolerated for greater than 1 month, due to the development of vascular leak syndrome.

Reproductive toxicity studies in pregnant rhesus monkeys and golden Syrian hamsters demonstrated an increase in fetal loss in hamsters treated with INFERGEN at doses of > 150 mcg/kg/day and in rhesus monkeys at doses of 3 and 10 mcg/kg/day. The INFERGEN toxicity profile described is consistent with the known toxicity profile of other alpha interferons.4

CLINICAL EXPERIENCE: RESPONSE TO INFERGEN

Initial Treatment

INFERGEN was studied in an open-label dose-escalation study using 3, 6, 9, 12, or 15 mcg administered three times per week (TIW) to patients with compensated liver disease secondary to chronic hepatitis C virus (HCV) infection. The 15 mcg dose was the maximum tolerated dose. All doses demonstrated an acceptable safety profile and preliminary evidence of efficacy.

The efficacy of 3 and 9 mcg doses of INFERGEN in the treatment of chronic HCV infection was examined in a randomized, double-blind clinical trial involving 704 patients previously untreated with alpha interferon.5 Patients were 18 years or older, had compensated liver disease, tested positive for HCV RNA, and had elevated serum alanine aminotransferase (ALT) averaging greater than 1.5 times the upper limit of normal. Staging of chronic liver disease was confirmed by a liver biopsy taken within 1 year prior to enrollment. Other causes of chronic liver disease were ruled out prior to randomization. Notable exclusion criteria were decompensated liver disease, thyroid abnormality, or history of depression.

Efficacy of INFERGEN therapy was assessed on an intent-to-treat basis and was determined by measurement of serum ALT at the end of therapy (24 weeks) and following 24 weeks of observation after the end of treatment (sustained response rate). Serum HCV RNA was also assessed using a research-based quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay with a lower limit of sensitivity of 100 copies/mL. Liver histology was assessed by comparing the histology activity index (HAI) score6 of a pretreatment biopsy specimen with the HAI score from a specimen obtained 24 weeks after cessation of interferon therapy.

Patients enrolled in the study were randomized to 1 of 3 treatment groups: INFERGEN at a dose of 3 mcg (n = 232), INFERGEN at a dose of 9 mcg (n = 232), or Interferon alfa-2b recombinant (IFN α-2b, Intron® A [Intron® is a registered trademark of the Schering Corporation]) at a dose of 3 million international units (MIU) (approximately 15 mcg) (n = 240). All patients were scheduled to receive their respective interferons SC TIW for 24 weeks (end of treatment). Following treatment, patients were observed for an additional 24 weeks to assess durability of ALT normalization (end of posttreatment observation). In all patients, a complete response was defined as a decrease in serum ALT to, at, or below the upper limit of normal (48 U/L) at the end of the posttreatment observation period, even if ALT normalization had not been observed at the end of treatment. Complete response was dependent on 2 consecutive normal serum ALT values determined 4 weeks apart. Reduction of HCV RNA to less than 100 copies/mL was measured as a secondary efficacy endpoint (2 consecutive measurements).

Sustained response rates by ALT normalization and HCV RNA reductions to below detectable limits for patients who received initial treatment are included in Table 1. Among the INFERGEN treatment groups in this study, the 9 mcg dosage arm demonstrated a similar efficacy profile when compared to the IFN α-2b dosage arm. The 3 mcg INFERGEN dosage arm had lesser efficacy; 3% of patients receiving 3 mcg INFERGEN had sustained reductions in their ALT to within the normal range and 3% had sustained reductions in HCV RNA to below detectable limits.

Table 1. Rates (95% Cla) of ALT Normalization and HCV RNA Reductions to Below Detectable Limits in Previously Untreated Patients
End of 24-week End of Observation
Treatment (Sustained Response Rate)
INFERGEN IFN α-2b INFERGEN IFN α-2b
9 mcg 3 MIUb 9 mcg 3 MIUb
n = 232 n = 240 n = 232 n = 240
a. Cl = Confidence Interval.
b. 3 MIU IFN α-2b is equivalent to approximately 15 mcg IFN α-2b.
Normalized ALT 39% 35% 17% 17%
(33%, 46%) (29%, 41%) (12%, 22%) (13%, 22%)
HCV RNA 33% 25% 9% 8%
Negative (27%, 39%) (19%, 31%) (6%, 14%) (5%, 13%)

In this study, liver biopsies were taken at baseline and at the end of posttreatment observation. Similar improvement in liver histology, assessed by HAI score, was observed in the 9 mcg INFERGEN (68%), 3 mcg INFERGEN (63%), and IFN α-2b (65%) dosage arms.

Subsequent Treatment

Subsequent treatment with 15 mcg of INFERGEN for 24 and 48 weeks was evaluated in an open-label clinical trial in 208 patients who had failed initial therapy for 24 weeks with either 9 mcg INFERGEN or 3 MIU (approximately 15 mcg) IFN α-2b.7 Of these patients, 133/208 had failed to normalize ALT during the initial treatment period. Seventy-five of 208 achieved normal ALT during initial treatment, but experienced relapse (return of abnormal ALT) during posttreatment observation. Patients were assessed for normalization of ALT (ALT response rate) and HCV RNA reduction to less than 100 copies/mL (HCV response rate) at the end of 24 weeks of observation following discontinuation of therapy. Sustained response rates measured by ALT normalization and HCV RNA reductions to below detectable limits for patients who received subsequent treatment with 15 mcg of INFERGEN are included in Table 2.

Patients who received 48 weeks of interferon therapy were more likely to experience a sustained response than were those who received 24 weeks of therapy. Similarly, patients who normalized their serum ALT but subsequently relapsed following initial therapy were more likely to experience a sustained response than those who were refractory to initial therapy.

Table 2. Sustained Response Rates (95% Cl) of ALT Normalization and HCV RNA Reductions to Below Detectable Limits After Subsequent Treatmenta with 15 mcg INFERGEN
All Patients Prior Nonresponders Prior Relapsers
24 Weeks 48 Weeks 24 Weeks 48 Weeks 24 Weeks 48 Weeks
n =107 n =101 n =74 n =59 n =33 n =42
a. Subsequent treatment data are presented for patients initially treated with 9 mcg INFERGEN or 3 MIU IFN α-2b in the initial treatment study; patients initially treated with 3 mcg INFERGEN were excluded from this analysis
b. P value = 0.01.
End of Observation
Normalized ALT
13% 19% 7% 7% 27% 36%
(7.3%, 21.0%) (11.7%, 27.8%) (2.2%, 15.1%) (1.9%, 16.5%) (13.3%, 45.5%) (21.6%, 52.0%)
End of Observation
HCV RNA Negative
9% 22%b 4% 12% 21% 36%
(4.6%, 16.7%) (13.4%, 30.0%) (0.9%, 11.5%) (4.9%, 22.9%) (9.0%, 38.9%) (21.6%, 52.0%)

Serum antibody levels were measured in all patients using both an INFERGEN-binding radioimmunoassay and an IFN α-2b-binding ELISA. A patient was considered to have developed binding antibodies if, using serum samples from 2 consecutive time points, a positive response was detected in either assay. The number of patients developing positive binding antibody responses in either assay was similar in the 9 mcg INFERGEN (11%) and 3 MIU IFN α-2b groups (15%). The titer of neutralizing antibodies to interferon was not measured. Sustained ALT response rates in patients treated with INFERGEN who developed binding antibodies (4/25) were similar to sustained ALT response rates in patients who did not develop detectable antibody titers (40/195). The most frequently observed time to first antibody response was week 16 of interferon treatment. Following cessation of interferon therapy, the number of patients with a positive antibody response declined during posttreatment observation.

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