(Interferon alfa-2a, recombinant)
Roferon-A (Interferon alfa-2a, recombinant) is a sterile protein product for use by injection. Roferon-A is manufactured by recombinant DNA technology that employs a genetically engineered Escherichia coli bacterium containing DNA that codes for the human protein. Interferon alfa-2a, recombinant is a highly purified protein containing 165 amino acids, and it has an approximate molecular weight of 19,000 daltons. Fermentation is carried out in a defined nutrient medium containing the antibiotic tetracycline hydrochloride, 5 mg/L. However, the presence of the antibiotic is not detectable in the final product. Roferon-A is supplied in prefilled syringes. Each glass syringe barrel contains 0.5 mL of product. In addition, there is a needle, which is ½ inch in length.
Single Use Prefilled Syringes
3 million IU (11.1 mcg/0.5 mL) Roferon-A per syringe — The solution is colorless and each 0.5 mL contains 3 MIU of Interferon alfa-2a, recombinant, 3.605 mg sodium chloride, 0.1 mg polysorbate 80, 5 mg benzyl alcohol as a preservative and 0.385 mg ammonium acetate.
6 million IU (22.2 mcg/0.5 mL) Roferon-A per syringe — The solution is colorless and each 0.5 mL contains 6 MIU of Interferon alfa-2a, recombinant, 3.605 mg sodium chloride, 0.1 mg polysorbate 80, 5 mg benzyl alcohol as a preservative and 0.385 mg ammonium acetate.
9 million IU (33.3 mcg/0.5 mL) Roferon-A per syringe — The solution is colorless and each 0.5 mL contains 9 MIU of Interferon alfa-2a, recombinant, 3.605 mg sodium chloride, 0.1 mg polysorbate 80, 5 mg benzyl alcohol as a preservative and 0.385 mg ammonium acetate.
The route of administration is by subcutaneous injection.
The mechanism by which Interferon alfa-2a, recombinant, or any other interferon, exerts antitumor or antiviral activity is not clearly understood. However, it is believed that direct antiproliferative action against tumor cells, inhibition of virus replication and modulation of the host immune response play important roles in antitumor and antiviral activity.
The biological activities of Interferon alfa-2a, recombinant are species-restricted, i.e., they are expressed in a very limited number of species other than humans. As a consequence, preclinical evaluation of Interferon alfa-2a, recombinant has involved in vitro experiments with human cells and some in vivo experiments.1 Using human cells in culture, Interferon alfa-2a, recombinant has been shown to have antiproliferative and immunomodulatory activities that are very similar to those of the mixture of interferon alfa subtypes produced by human leukocytes. In vivo, Interferon alfa-2a, recombinant has been shown to inhibit the growth of several human tumors growing in immunocompromised (nude) mice. Because of its species-restricted activity, it has not been possible to demonstrate antitumor activity in immunologically intact syngeneic tumor model systems, where effects on the host immune system would be observable. However, such antitumor activity has been repeatedly demonstrated with, for example, mouse interferon-alfa in transplantable mouse tumor systems. The clinical significance of these findings is unknown.
The metabolism of Interferon alfa-2a, recombinant is consistent with that of alpha-interferons in general. Alpha-interferons are totally filtered through the glomeruli and undergo rapid proteolytic degradation during tubular reabsorption, rendering a negligible reappearance of intact alfa interferon in the systemic circulation. Small amounts of radiolabeled Interferon alfa-2a, recombinant appear in the urine of isolated rat kidneys, suggesting near complete reabsorption of Interferon alfa-2a, recombinant catabolites. Liver metabolism and subsequent biliary excretion are considered minor pathways of elimination for alfa interferons.
The serum concentrations of Interferon alfa-2a, recombinant reflected a large intersubject variation in both healthy volunteers and patients with disseminated cancer.
In healthy people, Interferon alfa-2a, recombinant exhibited an elimination half-life of 3.7 to 8.5 hours (mean 5.1 hours), volume of distribution at steady-state of 0.223 to 0.748 L/kg (mean 0.400 L/kg) and a total body clearance of 2.14 to 3.62 mL/min/kg (mean 2.79 mL/min/kg) after a 36 MIU (2.2×108pg) intravenous infusion. After intramuscular and subcutaneous administrations of 36 MIU, peak serum concentrations ranged from 1500 to 2580 pg/mL (mean 2020 pg/mL) at a mean time to peak of 3.8 hours and from 1250 to 2320 pg/mL (mean 1730 pg/mL) at a mean time to peak of 7.3 hours, respectively. The apparent fraction of the dose absorbed after intramuscular injection was greater than 80%.
The pharmacokinetics of Interferon alfa-2a, recombinant after single intramuscular doses to patients with disseminated cancer were similar to those found in healthy volunteers. Dose proportional increases in serum concentrations were observed after single doses up to 198 MIU. There were no changes in the distribution or elimination of Interferon alfa-2a, recombinant during twice daily (0.5 to 36 MIU), once daily (1 to 54 MIU), or three times weekly (1 to 136 MIU) dosing regimens up to 28 days of dosing. Multiple intramuscular doses of Interferon alfa-2a, recombinant resulted in an accumulation of two to four times the single dose serum concentrations. There is no pharmacokinetic information in patients with chronic hepatitis C, hairy cell leukemia, and chronic myelogenous leukemia.
Serum neutralizing activity, determined by a highly sensitive enzyme immunoassay, and a neutralization bioassay, was detected in approximately 25% of all patients who received Roferon-A.2 Antibodies to human leukocyte interferon may occur spontaneously in certain clinical conditions (cancer, systemic lupus erythematosus, herpes zoster) in patients who have never received exogenous interferon.3 The significance of the appearance of serum neutralizing activity is not known.
Studies have shown that Roferon-A can normalize serum ALT, improve liver histology and reduce viral load in patients with chronic hepatitis C. Other studies have shown that Roferon-A can produce clinically meaningful tumor regression or disease stabilization in patients with hairy cell leukemia.4,5 In Ph-positive Chronic Myelogenous Leukemia, Roferon-A supplemented with intermittent chemotherapy has been shown to prolong overall survival and to delay disease progression compared to patients treated with chemotherapy alone.6 In addition, Roferon-A has been shown to produce sustained complete cytogenetic responses in a small subset of patients with CML in chronic phase. The activity of Roferon-A in Ph-negative CML has not been determined.
Effects On Chronic Hepatitis C
The safety and efficacy of Roferon-A was evaluated in multiple clinical trials involving over 2000 patients 18 years of age or older with hepatitis, with or without cirrhosis, who had elevated serum alanine aminotransferase (ALT) levels and tested positive for antibody to hepatitis C. Roferon-A was given three times a week (tiw) by subcutaneous (SC) or intramuscular (IM) injection in a variety of dosing regimens, including dose escalation and de-escalation regimens. Normalization of serum ALT was defined in all studies as two consecutive normal serum ALT values at least 21 days apart. A sustained response (SR) was defined as normalization of ALT both at the end of treatment and at the end of at least 6 months of treatment-free follow-up.
In trials in which Roferon-A was administered for 6 months, 6 MIU, 3 MIU, and 1 MIU were directly compared. Six MIU was associated with higher SR rates but greater toxicity (see ADVERSE REACTIONS). In studies in which the same dose of Roferon-A was administered for 6 or 12 months, the longer duration was associated with higher SR rates and adverse events were no more severe or frequent in the second 6 months than in the first 6 months. Based on these data, the recommended regimens are 3 MIU for 12 months or 6 MIU for the first 3 months followed by 3 MIU for the next 9 months (see Table 1 and DOSAGE AND ADMINISTRATION). There are no direct comparisons of these two regimens.
Younger patients (e.g., less than 35 years of age) and patients without cirrhosis on liver biopsy were more likely to respond completely to Roferon-A than those patients greater than 35 years of age or patients with cirrhosis on liver biopsy.
In the two studies in which Roferon-A was administered subcutaneously three times weekly for 12 months, 20/173 (12%) patients experienced a sustained response to therapy (see Table 1). Of these patients, 15/173 (9%) maintained this sustained response during continuous follow-up for up to four years. Patients who have ALT normalization but who fail to have a sustained response following an initial course of therapy may benefit from retreatment with higher doses of Roferon-A (see DOSAGE AND ADMINISTRATION).
A subset of patients had liver biopsies performed both before and after treatment with Roferon-A. An improvement in liver histology as assessed by Knodell Histology Activity Index was generally observed.
A retrospective subgroup analysis of 317 patients from two studies suggested a correlation between improvement in liver histology, durable serum ALT response rates, and decreased viral load as measured by the polymerase chain reaction (PCR).
Table 1ALT Normalization in Patients Receiving Therapy With Roferon-A for 12 Months
|Study No.||Dose (MIU)||N||End of Treatment|
[% (95% CI)]
|End of Observation|
(Sustained Response SR)
[% (95% CI)]All patients were followed for 6 months after end of treatment.
|1EOT and SR rates for Placebo (study 1) were 0.||3||56||23||11|
|1 and 2 Combined||3||173||23 (17-30)||12 (7-17)|
|3||6-3||210||25 (19-31)||19 (14-25)|
Effects on Ph-Positive Chronic Myelogenous Leukemia (CML)
Roferon-A was evaluated in two trials of patients with chronic phase CML. Study DM84-38 was a single center phase II study conducted at the MD Anderson Cancer Center, which enrolled 91 patients, 81% were previously treated, 82% were Ph positive, and 63% received Roferon-A within 1 year of diagnosis. Study MI400 was a multicenter randomized phase III study conducted in Italy by the Italian Cooperative Study Group on CML in 335 patients; 226 Roferon-A and 109 chemotherapy. Patients with Ph-positive, newly diagnosed or minimally treated CML were randomized (ratio 2:1) to either Roferon-A or conventional chemotherapy with either hydroxyurea or busulfan. In study DM84-38, patients started Roferon-A at 9 MIU/day, whereas in study MI400, it was progressively escalated from 3 to 9 MIU/day over the first month. In both trials, dose escalation for insufficient hematologic response, and dose attenuation or interruption for toxicity was permitted. No formal guidelines for dose attenuation were given in the chemotherapy arm of study MI400. In addition, in the Roferon-A arm, the MI400 protocol allowed the addition of intermittent single agent chemotherapy for insufficient hematologic response to Roferon-A alone. In this trial, 44% of the Roferon-A treated patients also received intermittent single agent chemotherapy at some time during the study.
The two studies were analyzed according to uniform response criteria. For hematologic response: complete response (WBC <9×109/L, normalization of the differential with no immature forms in the peripheral blood, disappearance of splenomegaly), partial response (>50% decrease from baseline of WBC to <20%×109/L). For cytogenetic response: complete response (0% Ph-positive metaphases), partial response (1% to 34% Ph-positive metaphases).
In study DM84-38, the median survival from initiation of Roferon-A was 47 months. In study MI400, the median survival for the patients on the interferon arm was 69 months, which was significantly better than the 55 months seen in the chemotherapy control group (48 patients in study MI400 proceeded to BMT and in study DM84-38, 15 patients proceeded to BMT). Roferon-A treatment significantly delayed disease progression to blastic phase as evidenced by a median time to disease progression of 69 months to 46 months with chemotherapy.
By multivariate analysis of prognostic factors associated with all 335 patients entered into the randomized study, treatment with Roferon-A (with or without intermittent additional chemotherapy; p=0.006), Sokal index7 (p=0.006) and WBC (p=0.023) were the three variables associated with an improved survival, independent of other baseline characteristics (Karnofsky performance status and hemoglobin being the other factors entered into the model).
In study MI400, overall hematologic responses, [complete responses (CR) and partial responses (PR)], were observed in approximately 60% of patients treated with Roferon-A (40% CR, 20% PR), compared to 70% with chemotherapy (30% CR, 40% PR). The median time to reach a complete hematologic response was 5 months in the Roferon-A arm and 4 months in the chemotherapy arm. The overall cytogenetic response rate (CR+PR), in patients receiving Roferon-A, was 10% and 12% in studies MI400 and DM84-38, respectively, according to the intent-to-treat principle. In contrast, only 2% of the patients in the chemotherapy arm of study MI400 achieved a cytogenetic response (with no complete responses). Cytogenetic responses were observed only in patients who had complete hematologic responses. In study DM84-38, hematologic and cytogenetic response rates were higher in the subset of patients treated with Roferon-A within 1 year of diagnosis (76% and 17%, respectively) compared to the subset initiating Roferon-A therapy more than 1 year from diagnosis (29% and 4%, respectively). In an exploratory analysis, patients who achieved a cytogenetic response lived longer than those who did not.
Severe adverse events were observed in 66% and 31% of patients on study DM84-38 and MI400, respectively. Dose reduction and temporary cessation of therapy was required frequently. Permanent cessation of Roferon-A, due to intolerable side effects, was required in 15% and 23% of patients on studies DM84-38 and MI400, respectively (see ADVERSE REACTIONS).
Limited data are available on the use of Roferon-A in children with Ph-positive, adult-type CML. A published report on 15 children with CML suggests a safety profile similar to that seen in adult CML; clinical responses were also observed8 (see DOSAGE AND ADMINISTRATION).
Effects on Hairy Cell Leukemia
A multicenter US phase II study (N2752) enrolled 218 patients; 75 were evaluable for efficacy in a preliminary analysis; 218 patients were evaluable for safety. Patients were to receive a starting dose of Roferon-A up to 6 MIU/m2/day, for an induction period of 4 to 6 months. Responding patients were to receive 12 months maintenance therapy.
During the first 1 to 2 months of treatment of patients with hairy cell leukemia, significant depression of hematopoiesis was likely to occur. Subsequently, there was improvement in circulating blood cell counts. Of the 75 patients who were evaluable for efficacy following at least 16 weeks of therapy, 46 (61%) achieved complete or partial response. Twenty-one patients (28%) had a minor remission, 8 (11%) remained stable, and none had worsening of disease. All patients who achieved either a complete or partial response had complete or partial normalization of all peripheral blood elements including hemoglobin level, white blood cell, neutrophil, monocyte and platelet counts with a concomitant decrease in peripheral blood and bone marrow hairy cells. Responding patients also exhibited a marked reduction in red blood cell and platelet transfusion requirements, a decrease in infectious episodes and improvement in performance status. The probability of survival for 2 years in patients receiving Roferon-A (94%) was statistically increased compared to a historical control group (75%).