-2a reflected a large intersubject variation in both healthy volunteers and patients with disseminated cancer. The pharmacokinetics of Roferon-A in animals (monkey, dog and mouse) were similar to those seen in man. The pharmacokinetics of Roferon-A in man were linear over a 3 million to 198 million IU dose range. In healthy man, interferon alfa-2a exhibited an elimination half-life of 3.7 - 8.5 hours (mean: 5.1 hours), a volume of distribution at steady state of 0.223 - 0.748 l/kg (mean: 0.4 l/kg) and a total body clearance of 2.14 - 3.62 ml/min/kg (mean: 2.79 ml/min/kg) after a 36 million IU intravenous infusion. After intramuscular administration of 36 million IU, 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 after subcutaneous administration of 36 million IU from 1250 to 2320 pg/ml (mean: 1730 pg/ml) at a mean time to peak of 7.3 hours.
The apparent fraction of the dose absorbed after intramuscular or subcutaneous injection is greater than 80%.
The pharmacokinetics of interferon alfa-2a after single intramuscular doses to patients with disseminated cancer and chronic hepatitis B were similar to those found in healthy volunteers. Dose-proportional increases in serum concentrations were observed after single doses up to 198 million IU. There were no changes in the distribution or elimination of interferon alfa-2a during twice daily (0.5 - 36 million IU), once daily (1 - 54 million IU), or three times weekly (1 - 136 million IU) dosing regimens up to 28 days of dosing. Renal catabolism is the major pathway for Roferon-A elimination. Biliary excretion and liver metabolism are considered to be minor pathways of elimination of Roferon-A.
Intramuscular administration of Roferon-A one or more times daily for up to 28 days to some patients with disseminated cancer resulted in peak plasma concentrations of two to four times greater than those seen after single doses. However, multiple dosing caused no changes in its distribution or elimination parameters during several dosage regimens studied.
For other information on pharmacokinetic properties please refer to the SmPC for Ribavirin.
5.3 Preclinical safety data
Because of species specificity of human interferon, only limited toxicological studies have been carried out with Roferon-A. The acute parenteral toxicity of Roferon-A has been studied in mice rats, rabbits and ferrets at doses up to 30 million IU/kg intravenously, and 500 million IU/kg intramuscularly. No treatment-related mortality was noted in any species studied given Roferon-A by any of the routes of administration. With doses greatly exceeding the recommended clinical dose no significant adverse effects were observed except for an abortifacient effect when administered to pregnant rhesus monkeys in the early to mid-foetal period and transient menstrual cycle irregularities including prolonged menstrual periods in non-pregnant monkeys. The relevance of these findings in man has not been established.
Mutagenic effects of Roferon-A have not been observed experimentally.
For other information on preclinical safety data please refer to the SmPC for Ribavirin.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Ammonium acetate
Sodium Chloride
Benzyl alcohol (10mg/1ml)
Polysorbate 80
Glacial Acetic acid
Sodium Hydroxide
Water for Injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not b
