CAMPATH Solution for injection Ref.[50384] Active ingredients: Alemtuzumab

Cardiac Electrophysiology

The effect of multiple doses of alemtuzumab (12 mg/day for 5 days) on the QTc interval was evaluated in a single-arm study in 53 patients without malignancy. No large changes in the mean QTc interval (i.e., >20 ms) were detected in the study. A mean increase in heart rate of 22 to 26 beats/min was observed for at least 2 hours following the initial infusion of alemtuzumab. This increase in heart rate was not observed with subsequent doses.

CAMPATH pharmacokinetics were characterized in a study of 30 previously treated B-CLL patients in whom CAMPATH was administered at the recommended dose and schedule. After 12 weeks of dosing, patients exhibited a 7-fold increase in mean AUC.

Distribution

After the last 30 mg dose, the mean volume of distribution at steady-state was 0.18 L/kg (range 0.1 to 0.4 L/kg).

Elimination

CAMPATH pharmacokinetics displayed nonlinear elimination kinetics. Systemic clearance decreased with repeated administration due to decreased receptor-mediated clearance (i.e., loss of CD52 receptors in the periphery). Mean half-life was 11 hours (range 2 to 32 hours) after the first 30 mg dose and was 6 days (range 1 to 14 days) after the last 30 mg dose.

Specific Populations

The effects of renal or hepatic impairment on the pharmacokinetics of CAMPATH have not been studied.

Studies to assess the carcinogenic or genotoxic potential of CAMPATH have not been conducted.

In fertility studies, alemtuzumab (3 or 10 mg/kg intravenously) was administered to huCD52 transgenic male mice on 5 consecutive days prior to cohabitation with untreated wild-type females. No effect on fertility or reproductive performance was observed. However, adverse effects on sperm parameters (including abnormal morphology [detached/no head] and reduced total count and motility) were observed at both doses tested.

When alemtuzumab (3 or 10 mg/kg intravenously) was administered to huCD52 transgenic female mice for 5 consecutive days prior to cohabitation with untreated wild-type males, there was a decrease in the average number of corpora lutea and implantation sites and an increase in postimplantation loss, resulting in fewer viable embryos at the higher dose tested.

14.1 Previously Untreated B-CLL Patients

CAMPATH was evaluated in an open-label, randomized (1:1) active-controlled study in previously untreated patients with B-CLL, Rai Stage I–IV, with evidence of progressive disease requiring therapy. Patients received either CAMPATH 30 mg intravenously 3 times per week for a maximum of 12 weeks or chlorambucil 40 mg/m² orally once every 28 days for a maximum of 12 cycles.

Of the 297 patients randomized, the median age was 60 years, 72% were male, 99% were Caucasian, 96% had a WHO performance status 0–1, 23% had maximum lymph node diameter ≥5 cm, 34% were Rai Stage III/IV, and 8% were treated in the U.S.

Patients randomized to receive CAMPATH experienced longer progression free survival (PFS) compared to those randomized to receive chlorambucil (median PFS 14.6 months vs. 11.7 months, respectively). The overall response rates were 83% and 55% (p <0.0001) and the complete response rates were 24% and 2% (p<0.0001) for CAMPATH and chlorambucil arms, respectively. The Kaplan-Meier curve for PFS is shown in Figure 1.

Figure 1. Progression Free Survival in Previously Untreated B-CLL Patients^*:

14.2 Previously Treated B-CLL Patients

CAMPATH was evaluated in three multicenter, open-label, single-arm studies of 149 patients with B-CLL previously treated with alkylating agents, fludarabine, or other chemotherapies. Patients were treated with the recommended dose of CAMPATH 30 mg intravenously 3 times per week for up to 12 weeks. Partial response rates of 21% to 31% and complete response rates of 0% to 2% were observed.