Safety of a novel parenteral formulation of diclofenac after major orthopedic or abdominal/pelvic surgery in a population including anticoagulated, elderly or renally insufficient patients: an open-label, multiday, repeated dose clinical trial.

OBJECTIVE: Decisions to use or avoid nonsteroidal anti-inflammatory drugs (NSAIDs) for postsurgical pain are often influenced by concerns about bleeding and renal adverse effects. The objective of this study was to evaluate the safety of a novel parenteral NSAID, hydroxypropyl-ß-cyclodextrin (HPßCD) diclofenac, in a large postsurgical patient population, with particular focus on bleeding and renal effects. METHODS: This was a large open-label study in adult patients with acute moderate-to-severe pain following major surgery. Patients received ≥2 days of continuous treatment with HPßCD diclofenac, administered as a small-volume bolus injection every 6 hours. Few exclusion criteria were applied in order to reflect surgical patient populations commonly managed in clinical practice. Adverse events (AEs) were recorded throughout the study. The incidences of bleeding- and renal-related AEs were examined in patient subpopulations with known risk factors for NSAID-induced complications: advanced age, pre-existing renal insufficiency, concomitant anticoagulant use, prolonged exposure, elevated dosage, and major surgeries. RESULTS: Of the total 971 patients studied, 38% were ≥65 years old (12% >75 years), 62% received concomitant anticoagulants, and 6% had pre-existing renal insufficiency. HPßCD diclofenac was well tolerated by the patient population. AE rates are presented by risk factor to enable clinicians to better describe renal- or bleeding-related AEs. CONCLUSIONS: In addition to its previously demonstrated efficacy, this study provides evidence of HPßCD diclofenac's safety in a large postsurgical population including anticoagulated, elderly or renally insufficient patients. Because study exclusion criteria were minimal, these findings may be broadly generalizable to populations commonly treated in clinical practice.

Phase II study to evaluate the safety and efficacy of the oral neurokinin-1 receptor antagonist casopitant (GW679769) administered with ondansetron for the prevention of postoperative and postdischarge nausea and vomiting in high-risk patients.

BACKGROUND: In recent years, there has been an increased interest in using a multimodal approach with combined agents to treat postoperative nausea and vomiting. This study evaluated whether the addition of an oral dose of the neurokinin-1 receptor antagonist casopitant improved the antiemetic efficacy of an intravenous dose of ondansetron hydrochloride. METHODS: The authors enrolled 702 premenopausal or perimenopausal, nonsmoking, female patients aged 18-55 yr with a history of postoperative nausea and vomiting and/or motion sickness undergoing a laparoscopic or laparotomic gynecologic surgical procedure or laparoscopic cholecystectomy with general anesthesia. Subjects were randomized to one of five treatment arms: standard ondansetron 4 mg with casopitant at 0, 50, 100, or 150 mg, or 0 mg ondansetron with casopitant at 150 mg (the latter arm was considered an exploratory study group and was included in the safety analysis but not in the efficacy analysis). RESULTS: A significantly greater proportion of patients in all of the active casopitant plus ondansetron groups achieved a complete response (i.e., no vomiting, retching, rescue medication, or premature withdrawal) during the first 24 h postoperatively versus those in the ondansetron-alone group (59-62% vs. 40%, respectively; P = 0.0006). All active doses seemed to be well tolerated; headache, dizziness, and constipation were the most frequently reported adverse events. CONCLUSIONS: Compared with ondansetron alone, the casopitant and ondansetron combination results in superior emesis prevention during the first 24 h postoperatively in female patients with known risk factors for postoperative nausea and vomiting.

Safety of multiple-dose intravenous acetaminophen in adult inpatients.

BACKGROUND: Intravenous (IV) acetaminophen provides rapid and effective analgesia in the postoperative and inpatient settings. The utility and efficacy of acetaminophen is well established; however, due to chronic excessive dosing of over-the-counter acetaminophen products and prescription opioid combination products resulting in the potential for hepatic toxicity, concerns remain about acetaminophen safety. In order to evaluate the safety of IV acetaminophen 1,000mg q6h or 650mg q4h with repeated dosing for 5 days, a randomized, open-label study assessed the safety and tolerability of repeated doses used to treat acute pain or fever in 213 adult inpatients was conducted. METHODS: Subjects were randomized (3:3:1) to receive IV acetaminophen (1,000mg q6h or 650mg q4h) or standard-of-care treatment for pain or fever. Safety was assessed according to spontaneous reports of adverse events (AEs) and clinically meaningful changes from baseline laboratory parameters. RESULTS: Overall, IV acetaminophen was shown to be safe and well tolerated in adult inpatients when given as repeated doses for up to 5 days. Owing to the comorbidities in the study population, the frequency of AEs reported was high. However, the majority of treatment-emergent adverse events (TEAEs) were unrelated to treatment, and only 8% of the study population withdrew because of TEAEs. No major hepatic issues associated with IV acetaminophen warranted concern, and most hepatic events were likely related to underlying medical conditions or recent trauma/surgery. CONCLUSIONS: Consistent with the tolerability and safety results, both treatment groups (1,000mg q6h and 650mg q4h) demonstrated statistically significantly better ratings for the Subject Global Evaluations for the level of satisfaction with side effects related to study treatments as compared with the control group. The findings from this trial support the use of IV acetaminophen as a safe therapy in adult patients.