Benchmarking iron dextran sensitivity: reactions requiring resuscitative medication in incident and prevalent patients.

BACKGROUND: Reliable information on the incidence of severe reactions to iron dextran is limited. Administration of agents of resuscitation in acute anaphylaxis may serve as a marker to quantify life-threatening adverse drug reactions. METHODS: To determine the incidence of the most serious reactions to intravenous (i.v.) iron dextran, we searched the Gambro Healthcare US medical database for evidence of same-day administration of both i.v. iron dextran and parenteral adrenaline, corticosteroids or antihistamines. We confirmed each case as an iron dextran sensitivity reaction by direct inquiry. We also determined the total reported number of suspected adverse iron dextran reactions. RESULTS: During the 16 month study period, we determined that 1,066,099 doses of i.v. iron dextran were given to 48,509 patients, including 20,213 patients who had not previously received iron dextran (iron dextran na?ve). We identified seven patients who experienced reactions requiring resuscitative agents, all in response to a test dose (five patients) or first therapeutic dose (two patients), and therefore all in the iron-na?ve (incident) group. Thus, we found the incidence of iron dextran reactions requiring resuscitative agents to be 0.035% (7 out of 20,213). No reaction was fatal. In a combined group of incident and prevalent patients, we found 337 total reports of suspected adverse reactions to iron dextran, without regard to severity of reaction, yielding an overall per patient adverse drug event (ADE) rate of 0.69% (337 out of 48,509) and per exposure rate of 0.03% (337 out of 1,066,099). CONCLUSIONS: The incidence of reactions to iron dextran requiring resuscitative medications, per exposure or per patient, is approximately 0.035%. Reactions of this severity occur after either the test dose or first dose of iron dextran.     

Safety Data of Injectable Nonanimal Stabilized Hyaluronic Acid Gel for Soft Tissue Augmentation

BACKGROUND: Nonanimal hyaluronic acid gel was recently developed for soft tissue augmentation and volume expansion and has been shown to offer several advantages in comparison to other augmentation materials. There are rare reports of adverse events believed to be secondary to trace amounts of proteins in the hyaluronic acid raw material. OBJECTIVE: To determine the safety profile of nonanimal stabilized hyaluronic acid gel (Restylane, Perlane, Restylane Fine Lines, Q-Med AB, Uppsala, Sweden) for soft tissue augmentation using a retrospective review of all adverse events data from Europe, Canada, Australia, South American, and Asia from 1999 and 2000. RESULTS: Data from an estimated 144,000 patients treated in 1999 indicated the major reaction to injectable hyaluronic acid was localized hypersensitivity reactions, occurring in approximately 1 of every 1400 patients treated. In 1999 there was an adverse event reported for 1 of every 650 patients (0.15%) treated. These were temporary events that included redness, swelling, localized granulomatous reactions, bacterial infection, as well as acneiform and cystic lesions. For 2000 there was an estimated 262,000 patients treated with hyaluronic acid gel. The total number of adverse events was 144, corresponding to one adverse event for every 1800 patients (0.06%) treated. The major adverse event was again hypersensitivity, occurring in 1 of every 5000 patients treated. CONCLUSION: According to the reported worldwide adverse events data, hypersensitivity to nonanimal hyaluronic acid gel is the major adverse event and is most likely secondary to impurities of bacterial fermentation. According to data from 2000, the incidence of hypersensitivity appears to be declining after the introduction of a more purified hyaluronic acid raw material.     

Osteonecrosis in protease inhibitor-treated patients

The introduction of protease inhibitors has proven a watershed in human immunodeficiency virus infection therapy and has initiated an era of highly active antiretroviral therapy. However, the numerous data on the effectiveness of these therapeutic regimens have been cited with an ever-growing number of communications concerning adverse reactions. In particular, the widescale use of protease inhibitors has underlined a series of events not evidenced in the controlled clinical studies that permitted the registration of these drugs. We are conducting a cohort multicenter study to evaluate the incidence of adverse events during treatment with protease inhibitors. To date, 4 cases of bilateral osteonecrosis of the femoral head have been reported out of 1073 person-years. While the pathogenesis of this event is unclear, it may be a long-term complication of protease inhibitor treatment.     

Efficacy and safety of tamsulosin hydrochloride compared to doxazosin in the treatment of Indonesian patients with lower urinary tract symptoms due to benign prostatic hyperplasia

AIM: The objective of the study was to compare the efficacy and safety of tamsulosin hydrochloride and doxazosin in patients with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). METHODS: The safety and efficacy of tamsulosin (0.2 mg) and doxazosin (2 mg) was determined after once daily administration for 6 weeks in an open-label, randomized, multicenter study of 101 men with BPH. The International Prostatic Symptom Score (IPSS), maximal urinary flow rates (Qmax), average urinary flow rates (Qave) and residual urine were determined at baseline and again at 6 weeks as efficacy parameters. The primary parameters used for safety evaluation were vital signs (blood pressure and heart rate) and adverse events. The number of patients with a clinically significant response to treatment with tamsulosin or doxazosin was determined and defined as those with >20% improvement from the baseline Qmax or >20% decrease in total IPSS. RESULTS: The total IPSS decreased significantly in both the tamsulosin and doxazosin groups compared to baseline. There was a significant difference in the decrease in total IPSS between two groups. Qmax, Qave and residual urine significantly improved only in the tamsulosin group. There were no significant differences in systolic blood pressure, diastolic blood pressure or heart rate profile in the tamsulosin group; however, doxazosin resulted in a significant difference in systolic and diastolic blood pressure. Tamsulosin was well tolerated; only three patients (6%) in the tamsulosin group reported an adverse event (dizziness) while 11 patients (22%) in the doxazosin group reported an adverse event (dizziness), one of whom withdrew from the study. CONCLUSIONS: Tamsulosin was shown to be more effective than doxazosin in the treatment of LUTS due to BPH.     

Rocuronium and anaphylaxis – a statistical challenge

Drug induced anaphylaxis is frequently attributed to the use of muscle relaxants during anaesthesia. Recently The Norwegian Medicines Agency recommended that rocuronium bromide (Esmeron) be withdrawn from routine practice due to frequent reports of anaphylaxis. Over a period of two and a half years approximately 150,000 patients received rocuronium as part of their anaesthesia. In this period the Norwegian drug authorities received 29 reports of anaphylaxis or anaphylactoid reactions in patients treated with rocuronium. This is in stark contrast to the situation in other Nordic countries where a total of only seven cases of anaphylaxis in approximately 800,000 patients treated with rocuronium had been recorded by December 2000. This situation highlights the many potential problems of the surveillance of adverse drug reactions: reporting bias may lead to an over-estimate of the risk of one drug compared to another, and the possibility of under-reporting of adverse events (due to a weak reporting culture) further limit the validity of such comparisons. The surveillance of adverse drug reactions also represents a statistical challenge. While adverse event reports may help us to estimate the anaphylaxis rate we need to appreciate the uncertainty of such estimates. Adverse reactions are rare, random, and mostly independent events, resulting from the successive exposure of patients to a low risk intervention. The frequency distribution of adverse events will therefore conform to that of a Poisson process. The resulting Poisson distribution may inform us about the variability of adverse event data. An understanding of these methodological problems and statistical challenges will allow anaesthesiologists to make informed decisions concerning the use of muscle relaxants and other drugs associated with severe adverse reactions.     

盐酸坦索罗辛治疗伴有下尿路症状的BPH有效性和安全性研究

目的 评价长期服用盐酸坦索罗辛治疗伴有下尿路症状(LUTS)的BPH的有效性和安全性.方法 2005-2007年LUTS/BPH患者113例,经4周安慰剂导入期,进入60周开放性研究,每天早餐前口服盐酸坦索罗辛0.2 mg.Ⅰ期治疗(0～12周)结束时对盐酸坦索罗辛的有效性和安全性进行评价,IPSS改善≥25%者行Ⅱ期(13～60周)治疗;IPSS改善＜25%者Ⅱ期联合使用非那雄胺治疗.Ⅱ期治疗结束时行有效性和安全性评价.受试者随访期间监测症状、体征、实验室检查和不良事件.IPSS和Qmax为主要有效性评价参数.结果 113例患者完成Ⅰ期治疗111例,IPSS由治疗前19.5降为15.4,平均改善率21.2%;平均Qmax由治疗前11.2 ml/s提高1.7 ml/s,平均改善率16.5%,治疗前后比较差异均有统计学意义(P＜0.05).完成Ⅱ期治疗95例,其中联合使用非那雄胺25例、未联合使用非那雄胺者70例(P＞0.05),IPSS由治疗前19.0±4.7降为12.6±3.2,改善率30.3%; Qmax由治疗前(11.6±2.3)ml/s提高3.0 ml/s;生活质量评分(QOL)由4.3±0.8降为2.6±0.7,治疗前后比较差异均有统计学意义(P＜0.05).治疗前后IIEF-5评分、前列腺体积和血压差异无统计学意义(P＞0.05).治疗期间共发生13例24次不良事件,其中头晕5例8次、腹泻2例2次、乏力2例5次、口干1例6次,头痛、恶心及皮肤瘙痒各1例1次.无严重不良事件.结果 盐酸坦索罗辛治疗伴有LUTS的BPH患者安全有效,疗效持久,耐受性好,可以作为有效的常规治疗药物.     

Efficacy and safety of two doses (10 and 15 mg) of alfuzosin or tamsulosin (0.4 mg) once daily for treating symptomatic benign prostatic hyperplasia

OBJECTIVE: To evaluate the efficacy and safety of two doses (10 and 15 mg) of alfuzosin once daily and tamsulosin (0.4 mg) once daily, compared with placebo, in men with benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: In this randomized, double-blind, placebo-controlled, multicentre study, 625 patients were randomized to receive alfuzosin 10 or 15 mg once daily, tamsulosin 0.4 mg once daily (active reference), or matching placebo for 12 weeks, with no initial dose titration. The study was designed to compare each of the three active treatments with the placebo group. Primary outcome measures were mean changes from baseline in the International Prostate Symptom Score (IPSS) and peak urinary flow rate (Qmax) at 12 weeks, compared with placebo, using one-way analysis of variance. Because Qmax data were not normally distributed, median changes from baseline were also compared for Qmax. Pair-wise comparisons were conducted using the Dunnett correction for quantitative variables and Bonferroni-Holm correction for categorical variables, allowing for multiple treatment group comparisons. RESULTS: Alfuzosin 10 mg significantly improved urinary tract symptoms compared with placebo, with a mean (sd) change from baseline in the IPSS of -6.5 (5.2) vs -4.6 (5.8) for placebo (adjusted P = 0.007); there was a trend toward a difference between alfuzosin 15 mg, with a mean (sd) change from baseline in IPSS of -6.0 (5.6), and placebo (adjusted P = 0.050). The mean change from baseline in IPSS with tamsulosin 0.4 mg, at -6.5 (5.6), vs placebo was also significant (adjusted P = 0.014). The median change from baseline in Qmax was significantly increased with both alfuzosin doses and with tamsulosin (all adjusted P = 0.02 vs placebo). Both doses of alfuzosin were well tolerated, with dizziness the most frequent adverse event (placebo, 4%; alfuzosin 10 mg, 6%; 15 mg, 7%; tamsulosin, 2%); the respective incidence rates of sexual function adverse events were 0%, 3%, 1% and 8%. CONCLUSION: Treatment with alfuzosin 10 mg significantly improved urinary symptoms and Qmax compared with placebo and was well tolerated. There were also significant improvements over placebo with the active reference, tamsulosin 0.4 mg. The incidence of sexual function adverse events was higher with tamsulosin than with placebo. The benefit-to-risk profile of alfuzosin 10 mg once daily appeared to be reduced with a higher dose (15 mg).     

Silodosin, a new alpha1A-adrenoceptor-selective antagonist for treating benign prostatic hyperplasia: results of a phase III randomized, placebo-controlled, double-blind study in Japanese men

OBJECTIVE: To verify the efficacy and safety of the new alpha1A-adrenoceptor-selective antagonist silodosin compared with tamsulosin and placebo in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled study was conducted at 88 centres in Japan. Men aged > or = 50 years with an International Prostate Symptom Score (IPSS) of > or = 8, a quality-of-life (QoL) score of > or = 3, a maximum urinary flow rate (Qmax) of < 15 mL/s, a prostate volume of > or = 20 mL and a postvoid residual urine volume of < 100 mL were eligible for enrolment. Patients were randomized to receive silodosin 4 mg twice daily, tamsulosin 0.2 mg once daily, or placebo, for 12 weeks. The primary endpoint was the change in IPSS from baseline. Safety was assessed by adverse events, physical examination, vital signs and laboratory tests. RESULTS: In all, 457 patients were randomized (silodosin 176, tamsulosin 192 and placebo 89). The change in the total IPSS from baseline in the silodosin, tamsulosin and placebo groups was -8.3, -6.8 and -5.3, respectively. There was a significant decrease in the IPSS vs placebo in the silodosin group from 1 week. In the early-stage comparison, silodosin showed a significant decrease in IPSS vs tamsulosin at 2 weeks. The change in QoL from baseline was -1.7, -1.4 and -1.1 in the silodosin, tamsulosin and placebo groups, respectively; silodosin showed a significant improvement in the QoL score vs placebo. In the subgroup of patients with severe symptoms (IPSS > or = 20) silodosin also gave a significantly better improvement than placebo (-12.4 vs -8.7). The incidence rates of adverse events and drug-related adverse events were, respectively, 88.6%, 82.3% and 71.6% and 69.7%, 47.4% and 36.4%, respectively. The most common adverse event in the silodosin group was abnormal ejaculation, which occurred more often in the silodosin than in the tamsulosin group (22.3% vs 1.6%). However, only five men (2.9%) discontinued treatment for abnormal ejaculation. CONCLUSION: Silodosin was generally effective in the absence of obtrusive side-effects. This study suggests that silodosin is clinically useful for treating LUTS associated with BPH.     

Doxazosin in the treatment of benign prostatic hyperplasia. A review of the safety profile in older patients

The objective of this paper is to review the safety of doxazosin in older patients (>/=65 y) with benign prostatic hyperplasia (BPH) as reported in seven international clinical trials. Data from seven double-blind, placebo-controlled, phase III trials, in both normotensive and hypertensive patients with BPH were collated and analysed. Data on doxazosin were available for 341 men 65 y and over. Even though older patients can be at particular risk of adverse drug reactions, there was no apparent evidence of poor tolerability with doxazosin in older patients with BPH. The percentages of younger normotensive BPH patients (<65 y) experiencing at least one adverse event were 47 and 44% for doxazosin and placebo groups, respectively; for older normotensive BPH patients (>/=65 y) the corresponding values were 42 and 38%. For the younger hypertensive BPH patients the incidence rates for adverse events were 55% (doxazosin) and 42% (placebo) and for older hypertensive BPH patients 43 and 30%, respectively. The most commonly reported adverse events for all groups were dizziness, headache and fatigue and few serious adverse effects were reported throughout these trials. It can be concluded that doxazosin is well tolerated in young and old, normotensive and hypertensive patients with BPH.     

A morbidity and mortality conference-based classification system for adverse events: surgical outcome analysis: part I

BACKGROUND: We hypothesized that an archive database in conjunction with Morbidity and Mortality (M&M) review could be used to define a systematic list of post-surgical adverse events and identify areas for performance improvement. STUDY DESIGN: Adverse event data following surgery were prospectively collected at the Beth Israel Medical Center in NYC from academic, specialty, community hospital, and ambulatory care settings over a 5-year period from September 2000 through April 2005. A classification system and analysis methodology was developed to guide and maximize the effectiveness of M&M review. RESULTS: A total of 1618 adverse events, including 219 deaths, were analyzed following 29,237 operative procedures according to the analysis method described. A list of 245 adverse events was classified among 15 groups, and a subgroup of 25 adverse events accounted for over 80% of total adverse events. Five categories of adverse events were associated with death in surgical patients and 4 of 5 categories were post-operative events. Used in conjunction with M&M review, data derived from this analysis highlighted those adverse events with the greatest clinical frequency to the department's quality profile. CONCLUSIONS: We present a classification system for surgical adverse events and propose a specific analysis method which may be used in conjunction with Morbidity and Mortality Conference to standardize the profiling of surgical performance.     

Outcomes and complications of naftopidil versus tamsulosin for elderly men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: A systematic review and meta-analysis

We conducted a systematic review and meta-analysis to assess the outcomes and complications of naftopidil in treating elderly men with lower urinary tract symptoms secondary to benign prostatic hyperplasia and compared them with those administered with tamsulosin. A literature review was performed to identify the available randomised controlled trials concerning the comparison between naftopidil and tamsulosin for men with LUTS/BPH. We searched the following databases: the Cochrane Library Database, PubMed, Embase and Web of Science. Eleven publications involving 1,114 men (557 in the naf group and 557 in the tam group) were pooled in our analysis. We found no significant differences in the total IPSS, IPSS storage score, IPSS voiding score, quality of life index, peak urinary flow rate, average flow rate and post-void residual volumes. We assessed cardiovascular and sexual adverse events, acute urinary retention, surgical intervention, withdrawals due to any reason and withdrawals due to adverse events. The incidence of adverse events was similar among patients in naf and tam groups. In conclusion, naftopidil shared comparable efficacy and similar incidence of adverse events with tamsulosin and appears to be a promising agent for and alternative to tam. However, more prospective trials with high quality and long-term treatment duration are needed to verify this observation.     

Short‐term effects of crossover treatment with silodosin and tamsulosin hydrochloride for lower urinary tract symptoms associated with benign prostatic hyperplasia

Objectives: To compare the efficacy and safety of silodosin and tamsulosin in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) by a randomized crossover method. Methods: BPH patients with the complaint of LUTS were included in this study, and were randomly divided into two groups: a silodosin‐preceding group (4 weeks of twice‐daily administration of silodosin at 4 mg, followed by 4 weeks of once‐daily administration of tamsulosin at 0.2 mg) or a tamsulosin‐preceding group (4 weeks' administration of tamsulosin, followed by 4 weeks' administration of silodosin). No drug withdrawal period was provided when switching the drug. Results: In the first treatment period, both drugs significantly improved the International Prostate Symptom Score total score, but the improvement by silodosin was significantly superior to that by tamsulosin. After crossover treatment, significant improvement was observed only with silodosin treatment. Moreover, intergroup comparison of changes revealed that silodosin showed significant improvement of straining and nocturia with first and crossover treatments, respectively, compared with tamsulosin. Silodosin also significantly improved quality of life (QOL) score in both treatment periods, while tamsulosin significantly improved QOL score only in the first treatment period. The most frequent adverse drug reaction was ejaculatory disorder with silodosin; however, the incidence of dizziness with silodosin was similar to that with tamsulosin. Conclusions: In BPH/LUTS patients, silodosin exhibits excellent efficacy in improving subjective symptoms in both initial and crossover treatment, and it appears to improve the QOL of patients.     

Efficacy and safety of dutasteride, tamsulosin and their combination in a subpopulation of the CombAT study: 2-year results in Asian men with moderate-to-severe BPH

Although ethnicity-based differences in prostate size and physiology have been reported, results of benign prostatic hyperplasia (BPH) treatment trials in predominantly Caucasian patients are assumed to be applicable to non-Caucasian populations. This post hoc analysis investigated whether an Asian subpopulation of men with moderate-to-severe BPH in the CombAT study achieves treatment responses in line with those of the overall study population. In this double-blind, randomized, parallel-group trial, 325 Asian men were assigned to treatment with 0.5 mg dutasteride once daily, 0.4 mg tamsulosin once daily or the combination. Decrease in international prostate symptom score (IPSS) at month 24 from baseline (the primary endpoint) was significantly greater with combination treatment compared with tamsulosin (P<0.05), and numerically, but not statistically significantly, greater compared with dutasteride. Mean IPSS was reduced from baseline by 7.5 (+/-0.84) in the combination group, by 6.3 (+/-0.86) in the dutasteride group and by 4.5 (+/-0.78) in the tamsulosin group, resulting in respective mean IPSS at months 24 of 11.4 (+/-0.60), 12.7 (+/-0.70) and 14.3 (+/-0.74). The adverse event profile was similar to that observed in the overall CombAT population, and drug-related adverse events were more common with combination therapy (26%) than with tamsulosin (15%) or dutasteride (9%). No unexpected adverse events emerged. In conclusion, in Asian men with moderate-to-severe lower urinary tract symptoms and an enlarged prostate, combination therapy achieved significantly greater improvements from baseline BPH symptoms, flow rate, quality of life, reduced prostate volume and improved treatment satisfaction compared with tamsulosin monotherapy.     

Tamsulosin 0.4 mg once daily: effect on sexual function in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction.

OBJECTIVE: To evaluate the effect of tamsulosin, 0.4 mg once daily, on sexual function in comparison with placebo and alfuzosin, 2.5 mg three times daily, in patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO). METHODS: Data from 830 patients randomized into three European multicenter studies with similar protocols were analyzed. In two studies, patients were randomized to receive either tamsulosin, 0.4 mg once daily, or placebo, and in the third, patients were randomized to receive either a fixed dose of tamsulosin, 0.4 mg once daily, or alfuzosin, titrated to 2.5 mg three times daily. The studies employed a 2-week placebo run-in period, followed by a 12-week study period. Sexual function was assessed by related adverse events and by a sexual function score determined from a life-style questionnaire. RESULTS: Abnormal ejaculation occurred significantly more frequently in patients treated with tamsulosin than in those receiving placebo (p = 0.045); however, the incidence of abnormal ejaculation was similar in patients receiving tamsulosin or alfuzosin in the comparative study. Abnormal ejaculation was not perceived as a major problem by the patients since it resulted in few treatment discontinuations (n = 3). It was also reversible on drug withdrawal. There was no difference between tamsulosin and placebo or alfuzosin with regard to the occurrence of decreased libido or impotence. In addition, there was no significant difference in the change in sexual function score between patients treated with tamsulosin and those treated with alfuzosin. Compared with patients receiving placebo, there was, however, a significant improvement in total sexual function score in patients receiving tamsulosin (p = 0.042). CONCLUSIONS: Tamsulosin, 0.4 mg once daily, is well tolerated and has no overall negative impact on sexual function compared with placebo or alfuzosin. Compared with placebo, tamsulosin may even improve sexual function.