Background: The objective of this trial was to demonstrate the clinical efficacy and safety of topical cocaine as part of the effort to gain regulatory approval from the United States Food and Drug Administration. Methods: This phase III, randomized, prospective, double-blind, multicenter, single-dose, placebo-and dosecontrolled, parallel-group study aimed to evaluate the safety and efficacy of topical intranasal cocaine (RX0041-002). A total of 925 subjects were screened and a total of 648 subjects were randomized: 95 to placebo; 275 to 4% RX0041-002; and 278 to 8% RX0041-002. Efficacy was assessed with subjective pain intensity scores using the visual numeric rating scale and objectively using the von Frey filament test. Adverse events (AEs), vital signs, Holter monitoring, nasal irritation on visual examination, and smell assessment were recorded. The placebo and experimental groups were compared using a two-tailed Fisher's exact test. Results: Topical 4% and 8% cocaine achieved significant subject analgesia, the primary efficacy endpoint. Both doses were safe and well-tolerated, with a safety profile similar to placebo. In the 4% and 8% groups, headache (1.5% and 2.5%, respectively), epistaxis (0.7% and 1.1%), and anxiety (0.7% and 0%) were the only AEs reported by >1 subject. No cardiovascular AEs, serious AEs, or deaths occurred. A higher percentage of subjects in the 4% and 8% groups compared with the placebo group had a modest increase in either systolic or diastolic blood pressure. Conclusion: Topical 4% and 8% cocaine is an effective anesthetic that can be safely administered for nasal procedures.
Background Topical cocaine is currently available for local anesthesia of the upper airway mucous membranes. Objective The objective of this study was to define the safety and efficacy of topical intranasal cocaine for a subsequent phase II clinical trial. Methods This study was a single-dose, single-center, and open-label study of the plasma and urinary pharmacokinetics (PK) of 4% topical cocaine and its major metabolites, benzoylecgonine (BE) and ecgonine methyl ester (EME), in 30 healthy subjects. Subjects received the topical solution on cotton pledgets containing 4 mL of 4% topical cocaine applied for 20 minutes, which was equivalent to 160 mg of cocaine hydrochloride. Results A total of 30 subjects (14 males and 16 females) were enrolled, treated, and provided PK data for analysis. Mean plasma concentrations of cocaine rose rapidly during the intranasal exposure period, with peak levels (Cmax, 37.0 ± 17.3 ng/mL) observed at the time of pledget removal (Tmax, 0.43 ± 0.34 h). Mean plasma concentrations then fell rapidly and monoexponentially for the remainder of the study, with a mean half-life (t1/2) of 1.04 ± 0.35 hours. Following a 20-minute topical intranasal exposure to a 160 mg dose of cocaine 4% solution, the mean 0 to 12 hours recoveries of cocaine, BE, and EME were 117 ± 67 μg, 816 ± 440 μg, and 275 ± 113 μg, respectively. Plotting urinary recovery by collection interval showed that urinary excretion of cocaine closely followed the time course of plasma cocaine. Conclusions Cocaine was rapidly but incompletely absorbed and then rapidly eliminated. Only 4% of the administered cocaine dose appeared to be absorbed in this study. Cocaine appeared in the urine with a time course similar to that in plasma.
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