Associated Adverse Events Research Articles

Evaluation of progression-free survival by blinded independent central review in patients with progressive, well-differentiated pancreatic neuroendocrine tumors treated with sunitinib or placebo.

249 Background: Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor with antiangiogenic activity. In a phase III, double-blind, placebo-controlled, randomized trial in patients with advanced, well-differentiated progressive pancreatic neuroendocrine tumors (NET), sunitinib 37.5 mg continuous daily dosing significantly improved investigator-assessed progression-free survival (PFS) compared with placebo (median, 11.4 months vs. 5.5 months; hazard ratio [HR] 0.418; 95% CI: 0.263, 0.662; P=0.0001). To evaluate the possibility that recognizable treatment- associated adverse events (AEs) might have impacted the efficacy results by unblinding the investigators, we conducted a retrospective blinded independent central review (BICR) of the tumor imaging scans. Methods: PFS was defined as the time from randomization to the first objective progression of disease or death due to any cause, whichever occurred first. Baseline and on-study CT/MRI scans were evaluated independently according to a two-reader, two-time point lock, followed by a sequential locked read, batch mode paradigm, by independent, third party radiologists. Reading radiologists were blinded to investigator tumor assessments and AEs; discrepancies were adjudicated by a similarly blinded and independent third radiologist. Results: Overall, 171 patients were randomized to treatment (sunitinib, n=86, placebo, n=85). Scans were collected retrospectively for 170 (99.4%) patients. Complete scan sets/time points were available for 160 patients (93.6%). Median PFS based on BICR of scans was 12.6 months for sunitinib and 5.8 months for placebo with an HR of 0.315 (95% CI: 0.181, 0.546; p=0.000015), consistent with the investigator- assessed PFS results. Conclusions: This BICR of tumor scans confirms the investigator-assessed, clinically meaningful PFS benefit of sunitinib in patients with pancreatic NET, and provides evidence against the presence of any systematic bias favoring sunitinib. [Table: see text]

Tolerability of a New 10% Liquid Immunoglobulin for Intravenous Use, Privigen®, at Different Infusion Rates

The tolerability of L-proline-stabilized Privigen, a new 10% liquid immunoglobulin for intravenous administration, was assessed at high infusion rates in a Phase III, open-label, single-arm, multicenter study in 45 patients with primary immune deficiencies. Maximum infusion rates were not assigned prospectively. For analysis, patients were grouped according to maximum infusion rate in a low infusion rate group (8 mg/kg/min) and high infusion rate group (12 mg/kg/min). Twenty-three patients, selected at the investigators' discretion for the high infusion rate group based on their good tolerability, tolerated Privigen at 12 mg/kg/min with no increase in temporally associated adverse events (AEs) above the level they had experienced at 8 mg/kg/min. The proportion of infusions with temporally associated AEs in these patients was 0.079 [97.5% confidence interval (CI) 0.114] compared to 0.211 (97.5% CI 0.267) in the low infusion rate group. The most frequent AE was headache. Thus, selected patients tolerate Privigen at high infusion rates.

Abdominal Aortitis after Use of Granulocyte Colony-Stimulating Factor

Granulocyte colony-stimulating factor (G-CSF) is a recombinant human glycoprotein that promotes proliferation and differentiation of granulocytic-committed progenitors. It is commonly used to treat neutropenia and is generally well tolerated. Occurrences of rare but serious adverse events in association with the use of G-CSF have been described. We report the case of a 54-year-old male with squamous cell carcinoma of the lung who developed abdominal aortitis following the use of G-CSF. Other possible aetiological conditions were excluded based on laboratory and radiological evaluations. To our knowledge, this represents the second case report demonstrating an association between aortitis and the use of G-CSF.

Effect of Dexmedetomidine IV on the Duration of Spinal Anesthesia with Prilocaine: A Double-Blind, Prospective Study in Adult Surgical Patients

Background: The duration of spinal anesthesia with prilocaine has been poorly documented and no English-language study has been published regarding the effects of dexmedetomidine on the duration of anesthesia with spinal prilocaine. Objective: The aim of this study was to assess the effects of dexmedetomidine IV on the duration of action of prilocaine and its associated adverse events (AEs) in spinal anesthesia. Methods: In this double-blind, prospective study, patients classified as American Society of Anesthesiologists grade I to II who were to undergo lower abdominal, anorectal, or extremity surgery with a spinal anesthetic were assigned to 1 of 2 groups. All patients were administered prilocaine 2% for spinal anesthesia. Within 10 minutes after spinal anesthesia was initiated, group 1 received a loading dose of dexmedetomidine 1 μg/kg IV, followed by a maintenance dose of 0.4 μg/kg · h for 50 minutes; group 2 (control) received the same amount of physiologic saline in the same time frame. Mean arterial pressure (MAP), heart rate (HR), duration of sensory and motor blockade, and sedation scores were tracked. Patients were observed for 4.5 hours after surgery, with follow-ups occurring up to 96 hours after surgery. Results: Eighty-three patients were assessed for study inclusion, 23 of whom were excluded. Sixty patients (42 men, 18 women; mean [SD] age, 40.56 [16.86] years) were included in the study. MAP was similar in the 2 groups throughout the study. Mean (SD) HR was significantly lower in group 1 compared with group 2 at 20 minutes (70.43 [19.28] vs 77.63 [18.14] beats per minute, respectively; P = 0.02). The mean (SD) duration of the persistence of sensory anesthesia (ie, the time required for the maximal level of anesthesia to regress 2 dermatomes) was significantly longer in group 1 compared with group 2 (148.33 [21.18] vs 122.83 [18.73] minutes; P < 0.001). The mean (SD) time to complete abolishment of motor blockade was also significantly longer in group 1 than in group 2 (215.16 [25.10] vs 190.83 [18.57] minutes; P < 0.001). The average sedation score in group 1 was significantly higher than in group 2 ( P < 0.001) during anesthesia. Significantly more patients in group 1 required atropine than those in group 2 (9 vs 2 patients; P < 0.001) to treat bradycardia. There was no significant between-group difference in the number of patients who received ephedrine to treat hypotension. One patient in each group reported waist and back pain; 2 patients in each group reported nausea. Shivering occurred in 0 and 5 patients in groups 1 and 2, respectively; the between-group difference in AEs was not statistically significant. Paresthesia, postdural puncture headache, allergic reactions, total spinal anesthesia, urinary retention, or vomiting—AEs commonly associated with spinal anesthesia—were not observed or reported by either group. Conclusions: The results of this study suggest that dexmedetomidine IV significantly prolonged the duration of spinal anesthesia and provided a significantly higher level of sedation compared to placebo in this group of adult surgical patients. The treatment was generally well tolerated in all patients.

The calcium-channel blocker controversy: historical perspective and important lessons for future pharmacotherapies. An international society of pharmacoepidemiology ?hot topic?

Reports of adverse events in association with calcium-channel blockers led to heated controversy over the safety and efficacy of these drugs, as well as to panic among the general public. At the 1998 International Conference of Pharmacoepidemiology, four experts were asked to summarize, and draw lessons from, the controversy's development. We conducted our own review in order to provide a broader historical perspective on the subject and to present the discussants' views within the framework of additional published opinions. Several years after the controversy's onset, many uncertainties still remain about the merits of CCBs. Yet the media scare generated by a few studies might have been prevented had investigators placed greater emphasis, particularly in their reports to the media, on the limitations of their observational and meta-analytic designs. These studies, however, did call attention to the persistent use of CCBs for off-label indications, and the imperative to improve clinician prescribing practices. Moreover, they showed the pitfalls of reliance on surrogate endpoints, stressing the need for data on major clinical outcomes-with funding a responsibility of the pharmaceutical industry-before approving drugs destined for widespread, long-term use. Attention to these lessons will do us well as we evaluate emerging pharmacotherapies. Copyright (c) 2000 John Wiley & Sons, Ltd.

Safety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study experience.

The National Cooperative Growth Study has monitored the safety of recombinant human GH (rhGH) since 1985. Data have been collected from more than 19,000 children representing over 47,000 patient-years of rhGH treatment. Children receiving GH for renal disease were more likely to develop problems such as intracranial hypertension than those with GH deficiency (P < 0.01). Children with idiopathic short stature were less likely to develop slipped capital femoral epiphysis than those with GH deficiency or Turner's syndrome (P < 0.01). There was no evidence of an increased recurrence of leukemia or central nervous system tumors. There were 3 new cases of leukemia in children without known risk factors for developing leukemia and 5 cases in children with known risk factors. Growth deceleration associated with high affinity, high capacity antibodies to GH was found in only 2 of 5039 subjects tested (0.04%). Major adverse events in association with rhGH treatment have been rare, and preexisting medical conditions such as renal insufficiency may affect their frequency.

Safety database on fluvoxamine: analysis and report.

A review was conducted of the safety and tolerability of fluvoxamine in 54 worldwide marketing studies that enrolled 24,624 patients, the majority of whom were treated with fluvoxamine in uncontrolled studies in depression. In accordance with the general epidemiologic distribution of depressive disorder, female patients and patients aged between 30 and 50 years predominated. The majority of patients were treated for 6 weeks, the most frequent, or modal, total daily dose being 100 mg. Overall, 57.4% of the patients exposed to fluvoxamine did not have any adverse experiences. The greatest proportion of adverse experiences, as defined using COSTART body systems, affected the digestive system (24.1%), the nervous system (23.7%), and the body as a whole (15.3%). The only adverse experience with an incidence greater than 10% was nausea (15.7%); somnolence (6.9%) and asthenia (6.2%) were the next most frequent adverse experiences. Notably, the rates of agitation and anxiety were only 1.4% and 1.3%, respectively. The incidences of adverse experiences generally increased with age and were slightly higher in females than in males. In total, 15.1% of patients discontinued treatment prematurely as a result of adverse experiences, principally nausea, dizziness, vomiting, somnolence, abdominal pain, and headache. The overall incidence of serious adverse events in association with fluvoxamine treatment was 2.5% when U.S. Food and Drug Administration criteria and the most conservative approach, without causality judgments, were used.(ABSTRACT TRUNCATED AT 250 WORDS)