Source: European Medicines Agency (EU) Revision Year: 2008 Publisher: SP Europe, 73, rue de Stalle, B-1180 Bruxelles, Belgium
Pharmacotherapeutic group: Immunostimulants, cytokines and immunomodulators, interferons, interferon alfa-2b
ATC code: L03AB05
Viraferon is a sterile, stable, formulation of highly purified interferon alfa-2b produced by recombinant DNA techniques. Recombinant interferon alfa-2b is a water-soluble protein with a molecular weight of approximately 19,300 daltons. It is obtained from a clone of E. coli, which harbours a genetically engineered plasmid hybrid encompassing an interferon alfa-2b gene from human leukocytes.
The activity of Viraferon is expressed in terms of IU, with 1 mg of recombinant interferon alfa-2b protein corresponding to 2.6 x l08 IU. International Units are determined by comparison of the activity of the recombinant interferon alfa-2b with the activity of the international reference preparation of human leukocyte interferon established by the World Health Organisation.
The interferons are a family of small protein molecules with molecular weights of approximately 15,000 to 21,000 daltons. They are produced and secreted by cells in response to viral infections or various synthetic and biological inducers. Three major classes of interferons have been identified: alpha, beta and gamma. These three main classes are themselves not homogeneous and may contain several different molecular species of interferon. More than 14 genetically distinct human alpha interferons have been identified. Viraferon has been classified as recombinant interferon alfa-2b.
Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface. Human interferon receptors, as isolated from human lymphoblastoid (Daudi) cells, appear to be highly asymmetric proteins. They exhibit selectivity for human but not murine interferons, suggesting species specificity. Studies with other interferons have demonstrated species specificity. However, certain monkey species, eg, rhesus monkeys, are susceptible to pharmacodynamic stimulation upon exposure to human type 1 interferons.
The results of several studies suggest that, once bound to the cell membrane, interferon initiates a complex sequence of intracellular events that include the induction of certain enzymes. It is thought that this process, at least in part, is responsible for the various cellular responses to interferon, including inhibition of virus replication in virus-infected cells, suppression of cell proliferation and such immunomodulating activities as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells. Any or all of these activities may contribute to interferon’s therapeutic effects.
Recombinant interferon alfa-2b has exhibited antiproliferative effects in studies employing both animal and human cell culture systems as well as human tumour xenografts in animals. It has demonstrated significant immunomodulatory activity in vitro.
Recombinant interferon alfa-2b also inhibits viral replication in vitro and in vivo. Although the exact antiviral mode of action of recombinant interferon alfa-2b is unknown, it appears to alter the host cell metabolism. This action inhibits viral replication or if replication occurs, the progeny virions are unable to leave the cell.
Current clinical experience in patients who remain on interferon alfa-2b for 4 to 6 months indicates that therapy can produce clearance of serum HBV-DNA. An improvement in liver histology has been observed. In adult patients with loss of HBeAg and HBV-DNA, a significant reduction in morbidity and mortality has been observed.
Interferon alfa-2b (6 MIU/m² 3 times a week for 6 months) has been given to children with chronic active hepatitis B. Because of a methodological flaw, efficacy could not be demonstrated. Moreover children treated with interferon alfa-2b experienced a reduced rate of growth and some cases of depression were observed.
In adult patients receiving interferon in combination with ribavirin, the achieved sustained response rate is 47%. Superior efficacy has been demonstrated with the combination of pegylated interferon with ribavirin (sustained response rate of 61% achieved in a study performed in naïve patients with a ribavirin dose >10.6 mg/kg, p <0.01).
Adult patients: Viraferon alone or in combination with ribavirin has been studied in 4 randomised Phase III clinical trials in 2,552 interferon-naïve patients with chronic hepatitis C. The trials compared the efficacy of Viraferon used alone or in combination with ribavirin. Efficacy was defined as sustained virologic response, 6 months after the end of treatment. Eligible patients for these trials had chronic hepatitis C confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (>100 copies/ml), a liver biopsy consistent with a histologic diagnosis of chronic hepatitis with no other cause for the chronic hepatitis, and abnormal serum ALT.
Viraferon was administered at a dose of 3 MIU 3 times a week as monotherapy or in combination with ribavirin. The majority of patients in these clinical trials were treated for one year. All patients were followed for an additional 6 months after the end of treatment for the determination of sustained virologic response. Sustained virologic response rates for treatment groups treated for one year with Viraferon alone or in combination with ribavirin (from two studies) are shown in Table 3.
Co-administration of Viraferon with ribavirin increased the efficacy of Viraferon by at least two fold for the treatment of chronic heptatitis C in naïve patients. HCV genotype and baseline virus load are prognostic factors which are known to affect response rates. The increased response rate to the combination of Viraferon + ribavirin, compared with Viraferon alone, is maintained across all subgroups. The relative benefit of combination therapy with Viraferon + ribavirin is particularly significant in the most difficult to treat subgroup of patients (genotype 1 and high virus load) (Table 3).
Response rates in these trials were increased with compliance. Regardless of genotype, patients who received Viraferon in combination with ribavirin and received ≥ 80% of their treatment had a higher sustained response 6 months after 1 year of treatment than those who took < 80% of their treatment (56% vs. 32% in trial C/I98-580).
Table 3. Sustained virologic response rates with Viraferon + ribavirin (one year of treatment) by genotype and viral load:
| HCV Genotype | I N=503 C95-132/I95-143 | I/R N=505 C95-132/I95-143 | I/R N=505 C/I98-580 |
|---|---|---|---|
| All Genotypes | 16% | 41% | 47% |
| Genotype 1 | 9% | 29% | 33% |
| Genotype 1 ≤2 million copies/ml | 25% | 33% | 45% |
| Genotype 1 >2 million copies/ml | 3% | 27% | 29% |
| Genotype 2/3 | 31% | 65% | 79% |
I Viraferon (3 MIU 3 times a week)
I/R Viraferon (3 MIU 3 times a week) + ribavirin (1,000/1,200 mg/day)
Two trials have been conducted in patients co-infected with HIV and HCV. Overall, in both studies, patients who received Viraferon plus ribavirin, were less likely to respond than patients who received pegylated interferon alfa-2b with ribavirin. The response to treatment in both of these trials is presented in Table 4. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either pegylated interferon alfa-2b (1.5 μg/kg/week) plus ribavirin (800 mg/day) or Viraferon (3 MIU TIW) plus ribavirin (800 mg/day) for 48 weeks with a follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either pegylated interferon alfa-2b (100 or 150 μg /week based on weight) plus ribavirin (800-1,200 mg/day based on weight) or Viraferon (3 MIU TIW) plus ribavirin (800-1,200 mg/day based on weight). The duration of therapy was 48 weeks with a follow-up period of 6 months except for patients infected with genotypes 2 or 3 and viral load <800,000 IU/ml (Amplicor) who were treated for 24 weeks with a 6-month follow-up period.
Table 4. Sustained virological response based on genotype after Viraferon in combination with ribavirin versus pegylated interferon alfa-2b in combination with ribavirin in HCV/HIV co-infected patients:
| Study 11 | Study 22 | |||||
|---|---|---|---|---|---|---|
| pegylated interferon alfa-2b (1.5 μg/kg/week) + ribavirin (800 mg) | Viraferon (3 MIU TIW) + ribavirin (800 mg) | p valuea | pegylated interferon alfa-2b (100 or 150c μg/week) + ribavirin (800-1,200 mg)d | Viraferon (3 MIU TIW) + ribavirin (800-1,200 mg)d | p valueb | |
| All | 27% (56/205) | 20% (41/205) | 0.047 | 44% (23/52) | 21% (9/43) | 0.017 |
| Genotype 1,4 | 17% (21/125) | 6% (8/129) | 0.006 | 38% (12/32) | 7% (2/27) | 0.007 |
| Genotype 2,3 | 44% (35/80) | 43% (33/76) | 0.88 | 53% (10/19) | 47% (7/15) | 0.730 |
MIU = million international units; TIW = three times a week.
a p value based on Cochran-Mantel Haenszel Chi square test.
b p value based on chi-square test.
c subjects <75 kg received 100 μg/week pegylated interferon alfa-2b and subjects ≥75 kg received 150 μg/week pegylated interferon alfa-2b.
d ribavirin dosing was 800 mg for patients <60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients >75 kg.
1 Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848.
2 Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36.
Relapse patients: A total of 345 interferon alpha relapse patients were treated in two clinical trials with Viraferon monotherapy or in combination with ribavirin. In these patients, the addition of ribavirin to Viraferon increased by as much as 10-fold the efficacy of Viraferon used alone in the treatment of chronic hepatitis C (48.6% vs. 4.7%). This enhancement in efficacy included loss of serum HCV (<100 copies/ml by PCR), improvement in hepatic inflammation, and normalisation of ALT, and was sustained when measured 6 months after the end of treatment.
In a large study, 1,071 patients were enrolled after treatment in a prior non pegylated interferon alfa-2b or non pegylated interferon alfa-2b/ribavirin study to evaluate the durability of sustained virologic response and assess the impact of continued viral negativity on clinical outcomes. 462 patients completed at least 5 years of long-term follow-up and only 12 sustained responders' out of 492 relapsed during this study. The Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 97% with a 95% Confidence Interval of [95%, 99%].
SVR after treatment of chronic HCV with non pegylated interferon alfa-2b (with or without ribavirin) results in long-term clearance of the virus providing resolution of the hepatic infection and clinical ‘cure’ from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma).
Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in two multicentre trials and received Viraferon 3 MIU/m² 3 times a week plus ribavirin 15 mg/kg per day for 1 year followed by 6 months follow-up after-treatment. A total of 118 patients were enrolled: 57% male, 80% Caucasian, and 78% genotype 1,64% ≤12 years of age. The population enrolled mainly consisted in children with mild to moderate hepatitis C. Sustained virological response rates in children and adolescents were similar to those in adults. Due to the lack of data in children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of ribavirin and interferon alfa-2b needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8).
Study results are summarized in Table 5.
Table 5. Virological response in previously untreated paediatric patients:
| Viraferon 3 MIU/m² 3 times a week + ribavirin 15 mg/kg/day | |
|---|---|
| Overall Response1 (n=118) | 54 (46%)* |
| Genotype 1 (n=92) | 33 (36%)* |
| Genotype 2/3/4 (n=26) | 21 (81%)* |
* Number (%) of patients
1 Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period
The pharmacokinetics of Viraferon were studied in healthy volunteers following single 5 million IU/m² and 10 million IU doses administered subcutaneously, at 5 million IU/m² administered intramuscularly and as a 30-minute intravenous infusion. The mean serum interferon concentrations following subcutaneous and intramuscular injections were comparable. Cmax occurred three to 12 hours after the lower dose and six to eight hours after the higher dose. The elimination half-lives of interferon injections were approximately two to three hours, and six to seven hours, respectively. Serum levels were below the detection limit 16 and 24 hours, respectively, post-injection. Both subcutaneous and intramuscular administration resulted in bioavailabilities greater than 100%.
After intravenous administration, serum interferon levels peaked (135 to 273 IU/ml) by the end of the infusion, then declined at a slightly more rapid rate than after subcutaneous or intramuscular administration of medicinal product, becoming undetectable four hours after the infusion. The elimination half-life was approximately two hours.
Urine levels of interferon were below the detection limit following each of the three routes of administration.
Children and adolescents: Multiple-dose pharmacokinetic properties for Viraferon injection and ribavirin capsules in children and adolescents with chronic hepatitis C, between 5 and 16 years of age, are summarized in Table 6. The pharmacokinetics of Viraferon and ribavirin (dose-normalized) are similar in adults and children or adolescents.
Table 6. Mean (% CV) multiple-dose pharmacokinetic parameters for Viraferon and ribavirin capsules when administered to children or adolescents with chronic hepatitis C:
| Parameter | Ribavirin 15 mg/kg/day as 2 divided doses (n = 17) | Viraferon 3 MIU/m² 3 times a week (n = 54) |
|---|---|---|
| Tmax (hr) | 1.9 (83) | 5.9 (36) |
| Cmax (ng/ml) | 3,275 (25) | 51 (48) |
| AUC* | 29,774 (26) | 622 (48) |
| Apparent clearance l/hr/kg | 0.27 (27) | Not done |
* AUC12 (ng.hr/ml) for ribavirin; AUC0-24 (IU.hr/ml) for Viraferon
Interferon neutralising factor assays were performed on serum samples of patients who received Viraferon in Schering-Plough monitored clinical trials. Interferon neutralising factors are antibodies which neutralise the antiviral activity of interferon. The clinical incidence of neutralising factors developing in cancer patients treated systemically is 2.9% and in chronic hepatitis patients is 6.2%. The detectable titres are low in almost all cases and have not been regularly associated with loss of response or any other autoimmune phenomenon. In patients with hepatitis, no loss of response was observed apparently due to the low titres.
Although interferon is generally recognised as being species specific, toxicity studies in animals were conducted. Injections of human recombinant interferon alfa-2b for up to three months have shown no evidence of toxicity in mice, rats, and rabbits. Daily dosing of cynomolgus monkeys with 20 × 10^6^ IU/kg/day for 3 months caused no remarkable toxicity. Toxicity was demonstrated in monkeys given 100 × 10^6^ IU/kg/day for 3 months.
In studies of interferon use in non-human primates, abnormalities of the menstrual cycle have been observed (see section 4.4).
Results of animal reproduction studies indicate that recombinant interferon alfa-2b was not teratogenic in rats or rabbits, nor did it adversely affect pregnancy, foetal development or reproductive capacity in offspring of treated rats. Interferon alfa-2b has been shown to have abortifacient effects in Macaca mulatta (rhesus monkeys) at 90 and 180 times the recommended intramuscular or subcutaneous dose of 2 million IU/m². Abortion was observed in all dose groups (7.5 million, 15 million and 30 million IU/kg), and was statistically significant versus control at the mid- and high-dose groups (corresponding to 90 and 180 times the recommended intramuscular or subcutaneous dose of 2 million IU/m² ). High doses of other forms of interferons alpha and beta are known to produce dose-related anovulatory and abortifacient effects in rhesus monkeys.
Mutagenicity studies with interferon alfa-2b revealed no adverse events.
No studies have been conducted in juvenile animals to examine the effects of treatment with interferon alfa- 2b on growth, development, sexual maturation, and behaviour (see section 4.4 and Rebetol SPC if Viraferon is to be administered in combination with ribavirin).
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