Phase IV, Open-Label, Safety Study Evaluating the Use of Dexmedetomidine in Pediatric Patients Undergoing Procedure-Type Sedation.

Dexmedetomidine (Precedex™) may be used as an alternative sedative in children, maintaining spontaneous breathing, and avoiding tracheal intubation in a non-intubated moderate or deep sedation (NI-MDS) approach. This open-label, single-arm, multicenter study evaluated the safety of dexmedetomidine in a pediatric population receiving NI-MDS in an operating room or a procedure room, with an intensivist or anesthesiologist in attendance, for elective diagnostic or therapeutic procedures expected to take at least 30 min. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Patients received one of two doses dependent on age: patients aged ≥28 weeks' gestational age to <1 month postnatal received dose level 1 (0.1 µg/kg load; 0.05-0.2 µg/kg/h infusion); those aged 1 month to <17 years received dose level 2 (1 µg/kg load; 0.2-2.0 µg/kg/h infusion). Sedation efficacy was assessed and defined as adequate sedation for at least 80% of the time and successful completion of the procedure without the need for rescue medication. In all, 91 patients were enrolled (dose level 1, n = 1; dose level 2, n = 90); of these, 90 received treatment and 82 completed the study. Eight patients in dose level 2 discontinued treatment for the following reasons: early completion of diagnostic or therapeutic procedure (n = 3); change in medical condition (need for intubation) requiring deeper level of sedation (n = 2); adverse event (AE; hives and emesis), lack of efficacy, and physician decision (patient not sedated enough to complete procedure; n = 1 each). Sixty-seven patients experienced 147 TEAEs. The two most commonly reported AEs were respiratory depression (bradypnea; reported per protocol-defined criteria, based on absolute respiratory rate values for age or relative decrease of 30% from baseline) and hypotension. Four patients received glycopyrrolate for bradycardia and seven patients received intravenous fluids for hypotension. SpO2 dropped by 10% in two patients, but resolved without need for manual ventilation. All other reported AEs were consistent with the known safety profile of dexmedetomidine. Two of the 78 patients in the efficacy-evaluable population met all sedation efficacy criteria. Dexmedetomidine was well-tolerated in pediatric patients undergoing procedure-type sedation.

A Pooled Analysis Evaluating Renal Safety in Placebo- and Active Comparator-Controlled Phase III Trials of Multiple-Dose Injectable HPßCD-Diclofenac in Subjects with Acute Postoperative Pain.

OBJECTIVE : While injectable nonsteroidal anti-inflammatory drugs (NSAIDs) are a key component of postoperative multimodal analgesia, renal safety concerns may limit use in some patients. This study examined the renal safety of injectable HPßCD-diclofenac when given for ≤ 5 days following orthopedic or abdominal/pelvic surgery. METHODS : Pooled analysis of data from two randomized, placebo- and active comparator-controlled phase III trials in 608 total patients was conducted. Renal safety was assessed by examining treatment-emergent adverse events (AEs) and postoperative blood urea nitrogen (BUN) and serum creatinine shifts. RESULTS : There were three renal AEs each in the HPßCD-diclofenac (n = 318 patients) and placebo (n = 148 patients) groups, and two renal AEs in the ketorolac group (n = 142 patients). No significant difference in renal AE risk was detected for patients receiving HPßCD-diclofenac (RR: 1.40 [0.15,13.3]; P = 0.75) or ketorolac (RR: 2.08 [0.19,22.7]; P = 0.56) versus placebo. All renal AEs were mild or moderate in severity, and a single renal AE (acute renal failure in a patient receiving HPßCD-diclofenac) was treatment-related. One incidence of postoperative shift to high (> upper limit of normal) serum creatinine occurred in the HPßCD-diclofenac group (n = 2 in the ketorolac group). Mean changes in serum creatinine or BUN did not differ significantly between patients receiving HPßCD-diclofenac and placebo. CONCLUSIONS : While this analysis examined relatively brief exposure typical for parenterally administered analgesics in the postoperative setting in patients with largely normal renal function, the results suggest that HPßCD-diclofenac use for acute postoperative pain may not be associated with added renal safety risks over placebo in this patient population.

Cardiovascular safety of hydroxypropyl-ß-cyclodextrin-diclofenac in the management of acute postsurgical pain: a pooled analysis of 2 randomized, double-blind, placebo- and active comparator-controlled phase III clinical trials.

STUDY OBJECTIVE: Long-term use of nonsteroidal anti-inflammatory drugs, including selective and nonselective cyclooxygenase inhibitors, has been suggested to be associated with cardiovascular (CV) safety risks. Data are limited regarding CV risks associated with short-term nonsteroidal anti-inflammatory drug use, including injectable formulations, although it has been suggested that even a single dose may increase CV adverse event (AE) risk. The objective of this study was to examine the CV safety of an injectable diclofenac formulation solubilized with hydroxypropyl-ß-cyclodextrin (HPßCD) when given for ≤5days postoperatively. DESIGN: A pooled analysis of CV AEs from 2 pivotal phase III clinical trials examining the efficacy and safety of intravenous (IV) HPßCD-diclofenac vs placebo and the active comparator ketorolac was conducted. SETTING: Postoperative, with treatment initiated in the postanesthesia care unit ≤6hours postsurgery. PATIENTS: Overall, 608 abdominal/pelvic and orthopedic surgery patients met inclusion criteria and received ≥1 study medication dose. INTERVENTIONS: Patients received either HPßCD-diclofenac, ketorolac, or placebo via IV bolus injection every 6hours, for ≤5days postsurgery. MEASUREMENTS: CV AEs, reported by study investigators, were evaluated through the treatment period and follow-up (≤37days after last study medication dose), and relative CV AE risks were estimated. MAIN RESULTS: IV HPßCD-diclofenac was not associated with increased treatment-emergent CV AE incidence vs placebo (11.6% vs 12.2%; relative risk, 0.96 [95% confidence interval, 0.56-1.62]). Serious CV AEs as well as treatment-related AEs were uncommon, and there were no reports of myocardial infarction or cerebrovascular accident. CV AEs were uncommon during the follow-up period, occurring in 1.3%, 0%, and 1.4% of patients in the HPßCD-diclofenac, ketorolac, and placebo groups, respectively. CONCLUSIONS: Although a longer duration follow-up study in a larger patient population would expand our understanding of potential CV risks, the present analysis suggests that postoperative use of HPßCD-diclofenac does not present an added CV safety risk over placebo.