Toxicological evaluation of Norpace after intravenous administration to rat and dog

Norpace (disopyramide phosphate) is a drug for treating cardiac arrhythmias. It has been evaluated for potential toxicological effects in albino rats and Beagle dogs, to provide safety support for clinical studies involving intravenous infusion. The compound was dissolved in Sodium Chloride for Injection, U.S.P. and administered daily by continuous intravenous infusion to groups of rats and dogs. Dose levels to 4.95 mg/kg/h for 14 and 28 consecutive days, respectively were employed. Rats received the formulation for 6--12 h daily; dogs were infused for 6 h daily. Conventional physical, cardiovascular, hematology, clinical chemistry and postmortem gross and microscopic examinations were performed. No compound-related changes were observed in the physical examinations (including ophthalmic), blood pressure (rat), ECG (dog), body weight, or clinical lab parameters evaluated; Food consumption was unontinuous restraining procedure employed during infusions reduced food consumption in all dogs, however, Postmortem examination did not reveal any lesions unique to treated animals. Some dogs exhibited intravenous fibrin thrombi at the site of injection. Organizing blood clots were occasionally present in the thoracic cavity of the rat. These findings were considered related to the infusion technique employed, rather than the drug administered. It was concluded that daily intravenous infusions of Norpace at doses up to 4.65 mg/kg/h to rats and dogs for 14 and 28 consecutive rays respectively, cause no biologically meaningful detrimental effects.