| Background: Off-label drug use in children is one of the public health issues of great concern.Children’s growth and development are immature,and they absorb and metabolize medications very differently from adults,making safety problems like side effects and drug poisoning much more likely to occur.Chinese patent medicine(CPM),one of the drugs frequently used in pediatric diseases,makes up a greater percentage of pediatric-specialty drugs than Western drugs.However,there is a dearth of comprehensive data on the prevalence of off-label use of CPM for children,as well as evidence-based studies on the effectiveness and safety of this practice.Objectives: 1)Systematic synthesis of studies on the prescription reviews and offlabel drug use of CPM for children was conducted,to provide overall data on the prevalence of irrational prescriptions and off-label drug use of CPM for children in China.2)To conduct an investigation into the prevalence and contributing factors of off-label use of CPM for children in the Gansu Province and to serve as a resource for medical institutions and the appropriate administrators in developing management standards for off-label use of CPMs for children.3)Consider one of the most frequently prescribed and off-label used CPM and one of the related diseases as an example to assess the quality of pertinent evidence on the application of the CPM,provide references for sensible drug use in the clinic,and establish an evidence-based medicine database for the off-label use of CPM for children.Methods: 1)To find cross-sectional studies relating to prescription reviews and off-label drug use of CPM for children,systematic searches of the China National Knowledge Infrastructure(CNKI),Wan Fang Data Knowledge Service Platform(Wanfang Data),the China Biology and Medicine Database(CBM),Pub Med,Embase,and Web of Science(WOS)were conducted.The risk of bias of included studies was also assessed and the usage rate of CPM and the prevalence of irrational prescription and off-label drug use were estimated using Meta-analysis.2)The medical orders of CPM for children were screened from the outpatient and emergency prescriptions in the first week of March and September 2020 in all secondary and tertiary hospitals in Gansu province.Two pharmacists conducted a review of off-label drug use according to the drug instructions and the Pharmacopoeia of the People’s Republic of China:Clinical Medication Instructions(Traditional Chinese Medicine Prescription Volume)2015 Edition,to investigate the prevalence of off-label use of CPM for children in Gansu province.The chi-square test was used to compare the difference in the prevalence of off-label drug use by region,gender,age,hospital level,visit time,visit type,department type,disease type,physician title,and prescription amount.The binary logistic regression analysis was further used to explore the potential factors that may contribute to the occurrence of off-label drug use.3)To identify relevant studies on the most commonly used and off-label drug used in CPM for the treatment of the related disease,systematic searches of CNKI,Wanfang Data,CBM,Pub Med,the Cochrane Library,Embase,and WOS were carried out,and these searches were evaluated for methodological quality.The quality of the evidence of effectiveness and safety was also graded using the GRADE(Grading of Recommendations Assessment,Development,and Evaluation)method.Results: 1)A total of 76 studies were included,of which 39 studies reported data related to the use of CPM for children,and the results of the Meta-analysis showed that the use of CPM for children in medical orders and prescriptions was 22.1%(95%CI[17.7%,26.6%];37 studies)and 36.0%(95%CI [19.4%,52.6%];2 studies),respectively.Meta-analysis of 34 studies on prescription reviews showed that the prevalence of irrational prescriptions of CPM for children was 9.2%(95%CI [6.4%,11.9%]),among which the highest prevalence is for abnormal dosage(2.6%,95%CI[1.0%,4.2%];26 studies).Meta-analysis of 41 studies on off-label drug use showed that the prevalence of off-label use of CPM in children was 42.0%(95%CI [35.6%,48.5%];39 studies)and 43.9%(95%CI [19.1%,68.7%];3 studies)for medical orders and prescriptions,respectively.2)A total of 20,539 medical orders of CPM for children were included.The study found that the prevalence of off-label drug use in medical orders was 40.24%.Of the 527 CPM,69.83% have used an off-label medication at least once.The prevalence of over-frequency(18.13%)was highest among the off-label uses of CPM for children,followed by over-dosing(16.94%).The results of the logistic regression analysis demonstrated that a variety of variables,including age,medical insurance type,hospital level,visit time,prescription amount,and the GDP ranking of the visit area,may influence the occurrence of off-label drug use.Xiao’er Chiqiao Qingre Granule(XCQG),which is frequently used to treat upper respiratory tract infections,a condition with the highest number of off-label drug uses,was the most widely used and most off-label used CPM in Gansu Province.3)There were 73 included studies for the treatment of upper respiratory tract infection with XCQG in children.The results of the methodological quality evaluation showed that two guidelines for the use of XCQG in the treatment of upper respiratory tract infection were determined to be generally recommended;one of the three systematic reviews was of high quality,and two were of moderate quality;a total of 68 randomized controlled trials were included,and only one was of high quality,while 13 were of low quality and the rest of the studies were of unclear quality.The results of the GRADE evaluation showed that the quality of evidence for the therapeutic effectiveness and incidence of adverse effects of XCQG as a treatment for upper respiratory tract infection were of low or very low quality,and that there was insufficient evidence to support its use.Conclusions: 1)Prescription audits must be strengthened in order to decrease the frequency of irrational prescriptions of CPM for children,which are still relatively common in China.The prevalence of off-label use of CPM for children is high,but the current study has paid less attention to different types of off-label drug use,and further large sample and multi-center studies are needed to obtain more information.2)In Gansu Province,the percentage of children using CPM off-label is comparable to the national average in China,with over-frequency and over-dosing being the most frequent behaviors.It is recommended to formulate the management regulations for off-label drug use,promote the research and development of special pediatric medication and update the drug instructions,to reduce non-essential off-label drug use.3)More high-quality and focused clinical trials are required to confirm the effectiveness and safety of the treatment for upper respiratory tract infection with XCQG in children.The quality of the clinical evidence for this treatment needs to be improved.It is also advised that,in order to effectively support clinical decision-making,medical institutions establish a standardized evidence-based evaluation procedure,as well as a medical database on the off-label use of CPM for children. |
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