兒童抗組織胺處方型態研究與用藥安全分析

Abstract

研究背景 抗組織胺用於臨床已逾一甲子，是兒童常用藥品之一。然而，由於上市早或臨床試驗倫理及執行考量等因素，多數抗組織胺缺乏理想之兒童臨床試驗評估，遑論抗組織胺於兒童之使用劑量、療效及安全性等實證資料。兒童處方因而常見off-label使用，其所潛藏之危險性不容小覷，值得探討。 研究目的 瞭解國內兒童之抗組織胺處方型態，並探討抗組織胺之使用與神經、精神及心臟方面之藥品不良反應相關性。 研究方法 利用全民健康保險研究資料庫2007年之百萬歸人檔，探討18歲以下兒童門診使用抗組織胺之處方型態，主要以人次表現，分別就病人、醫事人員及醫療院所分析抗組織胺之使用頻次、類別頻次、重複使用處方及劑型等藥品相關特性。此外，將2007年18歲以下兒童隨機簡單抽樣1/10進行回溯性抗組織胺使用安全性研究，排除2006年有事件相關疾病史之群體，另外排除2007年於分析心律不整事件有心臟病史群體，於動作不正常事件則另排除曾用抗癲藥品及就醫科別為神經或精神科之群體，利用time-dependent Cox’s proportional hazard model，放入藥品、病人、醫療院所等相關變項進行存活分析，探討兒童使用抗組織胺與神經、精神（失眠、精神異常、動作不正常和癲癇）及心律不整等不良事件之相關性。 研究結果 本研究共納入205841位18歲以下兒童，其中達86.6%曾用過抗組織胺，最常被處方予抗組織胺的群體為2~12歲兒童（76.77%）。總處方張數為2165173張，其中1323084張處方（61.1%）含抗組織胺，口服固體劑型為主要使用劑型（83.4%），抗組織胺複方型態比例佔37.0%。第一代抗組織胺佔87.3%總使用人次，依抗組織胺使用人次排序前10名依次為chlorpheniramine、cyproheptadine、dexchlorpheniramine、carbinoxamine、triprolidine、mequitazine、cetirizine、loratadine、buclizine及brompheniramine等藥品，抗組織胺最常被用於急性呼吸道感染疾病（ICD-9-CM codes：460-466；74.5%）診斷，惟第二代抗組織胺常被開立於慢性呼吸道疾病（例如：過敏性鼻炎，ICD-9-CM codes：477）及皮膚炎（ICD-9-CM codes：690-709）等診斷。就醫科別以小兒科佔41.85%、耳鼻喉科佔23.84%使用抗組織胺人次較高。抗組織胺處方中，抗組織胺重複用藥處方佔31.1%，以小兒科（48.68%）比例較高；醫療院所層級方面，以基層診所（66.13%）最常見。有關抗組織胺使用安全性之研究上，共抽樣19000位18歲以下兒童，平均年齡為10.7 ± 5.0歲。在失眠事件中，使用第一代抗組織胺相對於未使用者發生事件的hazard ratio（HR）為3.72（95% CI = 1.21-11.44；p = 0.022），使用第一代抗組織胺液體複方劑型亦有較高事件發生風險（HR = 4.17，95% CI=1.09-16.00；p = 0.0377）；在動作不正常事件中，使用第一代抗組織胺相較未使用者發生事件之HR為9.56（95% CI = 4.72-19.38；p < 0.0001）；在意識改變事件中，使用第一代抗組織胺相對於未使用者有較高風險（HR = 1.45，95% CI = 1.10-1.92；p = 0.0089）；在癲癇、心律不整事件之討論中，則抗組織胺使用與否未有顯著差異。 結論 兒童抗組織胺主要使用之年齡群體為2~12歲，平均每10張處方中，有6張含抗組織胺。抗組織胺之使用八成以上為第一代，且以口服固體劑型為主，最常見者為chlorpheniramine、cyproheptadine、dexchlorpheniramine及carbinoxamine等藥品。含抗組織胺處方中有31.1%為抗組織胺重複用藥處方，易有劑量過量之危險性，臨床使用上應特別注意。有關失眠、動作不正常及意識改變事件之分析中，發現皆與第一代抗組織胺之使用相關，另液體複方劑型會增高失眠事件之風險，6歲以下為主要使用群體須小心。本研究未發現第二代抗組織胺與各類事件之顯著相關性。此外，癲癇及心律不整事件與抗組織胺之使用未達顯著相關。未來可以考慮延長分析時間或利用抗組織胺之化學結構分類進行分析或直接以問卷方式直接瞭解病人用藥情況，以期得到更多兒童抗組織胺使用之藥品資訊。

Background Although H1-antihistamines, one of the common drugs used in children, have been introduced to clinical use for more than 60 years, many of them were deficient of appropriate clinical trial evaluations. Additionally, based on ethic and practical factors, it’s difficult to promote a clinical trial to children, which makes it insufficient information to prove efficacy and safety of antihistamines and makes pediatric drug are prescribed ”off-label” excessively which may increase potential risk of adverse drug reactions in children. Therefore, it is worth to analyze current status of antihistamine usage in children. Objective We focus the study on analyzing the prescribing patterns of antihistamines by clinicians for children, and investigate the risk of adverse drug reactions including neurological-, psychological-, and cardiac-related events related to antihistamines. Methods The study used the National Health Insurance Research Database (NHIRD) in 2007 and extracted data of patients aged below 18, focusing on prescriptions containing antihistamines to analyze prescribing patterns in Taiwan. Antihistamine prescriptions were quantified as person-time to analyze the prescription pattens associated with different settings of hospital and prescribers. Bseides, we make use of a retrospective study to analyze antihistamine-related adverse events, including insomnia, movement disorders, psychosis, seizures, consciousness changes and arrhythmia. The analyses were done by using sampling data (one tenth of original data) from patients aged below 18 in 2007 with exclusion of data from those with underlying disorders of neurologic, psychotic, and cardiovascular system in 2006. We constructed time-dependent Cox’s proportional hazard models for each variable. Results Among a total of 205841 out-patients aged under 18 from the NHIRD in 2007, 86.6% of children received at least one antihistamine during visits and 61.1% prescriptions contained some antihistamines. Children aged between 2 to 12 (76.77%) were the major age group receiving antihistamines and 87.3% of antihistamine usages were 1st-generation antihistamines. The top 10 frequently used antihistamines were chlorpheniramine, cyproheptadine, dexchlorpheniramine, carbinoxamine, triprolidine, mequitazine, cetirizine, loratadine, buclizine and brompheniramine. Oral solid form (83.4%) was the major dose form of antihistamine, and multi form was 37.0%. Most antihistamines were used for acute respiractory infection, and a high percentage of 2nd-generation antihistamines were used in chronic respiractory disease and dermatitis. Pediatric and E.N.T. departments were the major medical utilizations of antihistamines. More than one antihistamine were used in 31.1% of prescriptions, especially for pediatricians (48.68%) and private clinics (66.13%). We sampled one tenth of original data to get 19000 patients whose ages was 10.7 ± 5.0 years in average for analysis of drug-associated adverse events. Patients exposed to 1st-generation antihistamines are more likely to experience insomnia than those who did not (HR = 3.72, 95% CI=1.21-11.44, p = 0.022), and 1st -generation antihistamines in multi liquid form were more likely to be associated with insomnia (HR = 4.17, 95% CI = 1.09-16.00, p = 0.0377). Patients exposed to 1st -generation antihistamines were more likely to have movement disorders than those who didn’t (HR = 9.56, 95% CI = 4.72-19.38, p < 0.0001). Patients used 1st -generation antihistamines were more likely to have consciousness changes than those who didn’t (HR = 1.45, 95% CI = 1.10-1.92, p = 0.0089). The occurrence of seizures and arrhythmia did not significantly related to any variables in the analysis. Conclusions Children aged between 2 to 12 were the major age group receiving antihistamines. Antihistamines were used in 6 out of every 10 prescriptions. Most antihsitamines were 1st -generation antihistamines, and the major dose forms were oral solid form. Chlorpheniramine, cyproheptadine, dexchlorpheniramine, carbinoxamine were most commonly used. More than one antihistamine were used in 31.1% of prescriptions. Insomnia, movement disorders, and consciousness changes were releated to the use of 1st -generation antihistamine, but not 2nd-generation antihistamines. Otherwise, using the multi liquid form of 1st -antihistamines has a higher hazard ratio to induce insomnia. Events of seizures and arrythmeia were not related to the use of antihistamines in our study. Further studies may use different strategies to delineate the drug safety of antihistamine use in children, including correlating different categories of antihistamine’s structures and adverse events, using questionnaires to obtain direct information from patients, and prolonging the duration of study to increase the sample size.