Mechanism of Action: Synagis® exhibits neutralizing and fusion-inhibitory activity against RSV. These activities inhibit RSV replication in laboratory experiments. Although resistant RSV strains may be isolated in laboratory studies, a panel of 57 clinical RSV isolates were all neutralized by Synagis® (5). Synagis® serum concentrations of ³40 µg/mL have been shown to reduce pulmonary RSV replication in the cotton rat model of RSV infection by 100-fold (5).The in vivo neutralizing activity of the active ingredient in Synagis® was assessed in a randomized, placebo-controlled study of 35 pediatric patients tracheally intubated because of RSV disease. In these patients, Synagis® significantly reduced the quantity of RSV in the lower respiratory tract compared to control patients (6).

Pharmacokinetics: In pediatric patients <24 months of age without congenital heart disease (CHD), the mean half-life of Synagis® was 20 days and monthly intramuscular doses of 15 mg/kg achieved mean ± SD 30 day trough serum drug concentrations of 37 ± 21 µg/mL after the first injection, 57 ± 41 µg/mL after the second injection, 68 ± 51 µg/mL after the third injection and 72 ± 50 µg/mL after the fourth injection (7). Trough concentrations following the first and fourth Synagis® dose were similar in children with CHD and in non-cardiac patients. In pediatric patients given Synagis® for a second season, the mean ± SD serum concentrations following the first and fourth injections were 61 ± 17 µg/mL and 86 ± 31 µg/mL, respectively.

In 139 pediatric patients ≤24 months of age with hemodynamically significant CHD who received Synagis® and underwentcardio-pulmonary bypass for open-heart surgery, the mean ± SD serum Synagis® concentration was 98 ± 52 µg/mL before bypass and declined to 41 ± 33 µg/mL after bypass, a reduction of 58% (see DOSAGE AND ADMINISTRATION). The clinical significance of this reduction is unknown.

Specific studies were not conducted to evaluate the effects of demographic parameters on Synagis® systemic exposure. However, no effects of gender, age, body weight or race on Synagis® serum trough concentrations were observed in a clinical study with 639 pediatric patients with CHD (≤24 months of age) receiving five monthly intramuscular injections of 15 mg/kg of Synagis® .

Trough serum Synagis® concentrations were comparable between the Synagis® liquid and Synagis® lyophilized formulations administered IM at 15 mg/kg in a cross-over trial in 153 pediatric patients ≤6 months of age with a history of prematurity.

CLINICAL STUDIES: The safety and efficacy of Synagis® were assessed in two randomized, double-blind, placebo-controlled trials of prophylaxis against RSV infection in pediatric patients at high risk of an RSV-related hospitalization. Trial 1 was conducted during a single RSV season and studied a total of 1502 patients ≤24 months of age with bronchopulmonary dysplasia (BPD) or infants with premature birth (≤35 weeks gestation) who were≤6 months of age at study entry (7). Trial 2 wasconducted over four consecutive seasons among a total of 1287 patients ≤24 months of age with hemodynamically significantcongenital heart disease. In both trials participants received 15 mg/kg Synagis® or an equivalent volume of placebo IM monthly for five injections and were followed for 150 days from randomization. In Trial 1, 99% of all subjects completed the study and 93% completed all five injections. In Trial 2, 96% of all subjects completed the study and 92% completed all five injections. The incidence of RSV hospitalization is shown in Table 1.

Table 1: Incidence of RSV Hospitalization by Treatment Group

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