ROFERON-A- interferon alfa-2a injection, solution
Alpha-interferons, including Interferon alfa-2a, 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 Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many, but not all cases, these disorders resolve after stopping Interferon alfa-2a therapy (see WARNINGS and ADVERSE REACTIONS).
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.
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 (2.2×108 pg) 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.
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).
|Study No.||Dose (MIU)||N||End of Treatment |
[% (95% CI)]
|End of Observation |
(Sustained Response SR)
[% (95% CI)]*
|1 and 2 Combined||3||173||23 (17-30)||12 (7-17)|
|3||6-3||210||25 (19-31)||19 (14-25)|
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