ranged from 9.4 mL/min•kg

-1

to 28.9 mL/min•kg

-1

and were independent of dose. Mean terminal elimination half-life

values ranged from 8 minutes to 4.3 hours and mean steady-state volume of distribution values ranged from 0.25 L/kg to

2.88 L/kg. Three-times-a-week intravenous dosing for two weeks resulted in no accumulation of interferon beta-1b in sera

of patients. Pharmacokinetic parameters after single and multiple intravenous doses of BETASERON were comparable.

Following every other day subcutaneous administration of 0.25 mg BETASERON in healthy volunteers, biologic

response marker levels (neopterin, β

- microglobulin, MxA protein, and the immunosuppressive cytokine, IL-10)

increased significantly above baseline six-twelve hours after the first BETASERON dose. Biologic response marker levels

peaked between 40 and 124 hours and remained elevated above baseline throughout the seven-day (168-hour) study. The

relationship between serum interferon beta-1b levels or induced biologic response marker levels and the clinical effects of

interferon beta-1b in multiple sclerosis is unknown.

Drug Interaction Studies

No formal drug interaction studies have been conducted with BETASERON.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

BETASERON has not been tested for its carcinogenic potential in animals.

Mutagenesis

BETASERON was not genotoxic in the in vitro Ames bacterial test or the in vitro chromosomal aberration assay in

human peripheral blood lymphocytes. BETASERON treatment of mouse BALBc-3T3 cells did not result in increased

transformation frequency in an in vitro model of tumor transformation.

Impairment of Fertility

Administration of BETASERON (doses of up to 0.33 mg/kg/day) to normally cycling female rhesus monkeys had no

apparent adverse effects on either menstrual cycle duration or associated hormonal profiles (progesterone and estradiol)

when administered over three consecutive menstrual cycles. The highest dose tested is approximately 30 times the

recommended human dose of 0.25 mg on a body surface area (mg/m

) basis. The potential for other effects on fertility or

reproductive performance was not evaluated.

14 CLINICAL STUDIES

The clinical effects of BETASERON were studied in four randomized, multicenter, double-blind, placebo-controlled

studies in patients with multiple sclerosis (Studies 1, 2, 3, and 4).

Patients with Relapsing-Remitting Multiple Sclerosis

The effectiveness of BETASERON in relapsing-remitting MS (RRMS) was evaluated in a double-blind, multiclinic,

randomized, parallel, placebo controlled clinical study of two years duration (Study 1). The study enrolled MS patients,

aged 18 to 50, who were ambulatory [Kurtzke Expanded Disa

bility Status Scale (EDSS) of ≤ 5.5 –

score 5.5 is ambulatory

for 100 meters, disability precludes full daily activities], exhibited a relapsing-

remitting clinical course, met Poser’s

criteria for clinically definite and/or laboratory supported definite MS and had experienced at least two exacerbations over

two years preceding the trial without exacerbation in the preceding month. The EDSS score is a method of quantifying