Drug Package Inserts Research Articles

Ontological Organization and Bioinformatic Analysis of Adverse Drug Reactions From Package Inserts: Development and Usability Study.

BackgroundLicensed drugs may cause unexpected adverse reactions in patients, resulting in morbidity, risk of mortality, therapy disruptions, and prolonged hospital stays. Officially approved drug package inserts list the adverse reactions identified from randomized controlled clinical trials with high evidence levels and worldwide postmarketing surveillance. Formal representation of the adverse drug reaction (ADR) enclosed in semistructured package inserts will enable deep recognition of side effects and rational drug use, substantially reduce morbidity, and decrease societal costs.ObjectiveThis paper aims to present an ontological organization of traceable ADR information extracted from licensed package inserts. In addition, it will provide machine-understandable knowledge for bioinformatics analysis, semantic retrieval, and intelligent clinical applications.MethodsBased on the essential content of package inserts, a generic ADR ontology model is proposed from two dimensions (and nine subdimensions), covering the ADR information and medication instructions. This is followed by a customized natural language processing method programmed with Python to retrieve the relevant information enclosed in package inserts. After the biocuration and identification of retrieved data from the package insert, an ADR ontology is automatically built for further bioinformatic analysis.ResultsWe collected 165 package inserts of quinolone drugs from the National Medical Products Administration and other drug databases in China, and built a specialized ADR ontology containing 2879 classes and 15,711 semantic relations. For each quinolone drug, the reported ADR information and medication instructions have been logically represented and formally organized in an ADR ontology. To demonstrate its usage, the source data were further bioinformatically analyzed. For example, the number of drug-ADR triples and major ADRs associated with each active ingredient were recorded. The 10 ADRs most frequently observed among quinolones were identified and categorized based on the 18 categories defined in the proposal. The occurrence frequency, severity, and ADR mitigation method explicitly stated in package inserts were also analyzed, as well as the top 5 specific populations with contraindications for quinolone drugs.ConclusionsOntological representation and organization using officially approved information from drug package inserts enables the identification and bioinformatic analysis of adverse reactions caused by a specific drug with regard to predefined ADR ontology classes and semantic relations. The resulting ontology-based ADR knowledge source classifies drug-specific adverse reactions, and supports a better understanding of ADRs and safer prescription of medications.

Characteristics on Drug Safety Measures in Japan Stratified by System Organ Classes and Therapeutic Categories in Relation to the Approval Date.

Revisions of drug package inserts (PIs) may be made immediately after approval or after considerable clinical experience; however, it is unclear whether there is a relationship between the characteristics of these safety measures and the period since drug approval. Here, we analyzed 209 cases of safety measures (revisions of the PIs) taken in Japan over 5years (FY2014 to FY2018). The median, minimum, and maximum period from approval date in Japan to PI revision date was 6.29years (interquartile range 2.68-15.53years), 0.16years, and 59.69years, respectively. The cases were classified into four groups depending on types of adverse reaction and therapeutic category in relation to the national approval date and international birth date, resulting in the grouping together of particular adverse reactions and therapeutic drugs. For example, "Hepatobiliary disorders", "Blood and lymphatic system disorders", "Respiratory, thoracic and mediastinal disorders", "Antineoplastics", "Chemotherapeutics", and "Other agents affecting metabolism" were associated with the group of safety measures taken early after approval of a drug soon after the international birth date, suggesting that careful attention at an earlier stage after approval is necessary for these adverse reactions and drugs. Understanding such features of PI revisions makes pharmacovigilance planning more appropriate, contributing to the implementation of rapid and proper safety measures after drug approval.

Trends in FDA cancer registration trial design over time, 1969-2020.

2060 Background: The FDA has issued hundreds of cancer drug indications, with many new drugs, expanded indications, and biosimilars approved in recent years. While the gold standard for regulatory approval is the randomized controlled trial (RCT), RCT design including selection of control arms can differ considerably. We sought to investigate trends and patterns in RCT trial design used to support FDA approvals in oncology. Methods: We reviewed the available FDA package inserts of oncology drugs (N=258) for RCTs cited to support initial and expanded indication approvals as of January 2020; biosimilars were excluded. RCTs were linked to the HemOnc ontology, which contains trial-level metadata including publication year, endpoints, and trial design. Log-linear regression was performed to evaluate trends in approvals over time by endpoint. Study drugs were categorized as cytotoxic therapy, targeted therapy, or immunotherapy. RCTs were categorized by four designs: escalation (adding a drug or increasing the drug dose in an established regimen), in-class comparison (comparing two drugs in the same therapeutic class), out-of-class switch (comparing drugs in distinct therapeutic classes), and de-escalation (removing a drug or reducing the drug dose in an established regimen). Results: We identified 556 registration trials, 372 (67%) of which were RCTs. Approvals have been increasing exponentially over time (R2 0.9, p<0.001), both for RCTs reporting overall survival (OS) endpoints (R2 0.77, p<0.001), and non-OS endpoints (R2 0.67, p<0.001). Of the three most common trial designs (Table), in-class comparisons were least likely to report OS (28%; escalations 47%; out-of-class switches 43%, p=0.01 by Chi-squared). Class switches were common in immunotherapy trials compared to targeted or cytotoxic therapy. Conclusions: Despite growth in FDA approvals, a minority of registration trials report paradigmatic shifts in therapeutic approach (out-of-class switches), with the relative exception of immunotherapy trials. Escalation is the most common route to FDA approval, even though this design inevitably increases cost and toxicity. This suggests that new oncology drug approvals are not alone a useful metric of practice-changing innovation. [Table: see text]

The Clinical Pharmacology Sections in Drug Package Inserts: Do We Need to Reexamine the Basis?

The Clinical Pharmacology Sections in Drug Package Inserts: Do We Need to Reexamine the Basis?

DESCRIPTIVE ANALYSIS OF QUALITY OF INFORMATION OF DRUGS ON ANDROID-BASED INDIAN ONLINE PHARMACY APPLICATIONS: A PRELIMINARY ANALYSIS

Objectives: The objectives of the study were as follows: 1) To analyze the completeness of drug-related information of various Indian pharmacy online android applications and its readability. 2)To analyze the ease of availability of drugs and barriers to access them on these apps.
 Methods: A total of five popular pharmacy android apps in India (1mg, Netmeds, MedPlus, Pharmeasy, and Medikova) were chosen to analyze the prescribing information (PI) regarding five drugs, metformin, atenolol, ranitidine, ibuprofen, and alprazolam. Display of PI in these apps was compared with standard sources, i.e., National Formulary of India, Current Index of Medical Specialties, and package inserts of respective drugs. Drug-related information under 11 categories (indication, dose, contraindications, adverse events, etc.) was analyzed in these apps as complete/ incomplete. Readability of information was assessed using Flesch Reading Ease Score (FRES). These five drugs were ordered from all the apps to know the exact process to access them.
 Results: Categories such as indication and dose were mentioned in most apps. While, precautions and adverse events were given for few drugs in few apps. Least score was for categories like precautions in special population. FRES was minimum in Pharmeasy (30.82) and maximum in MedPlus (70.51). Valid prescriptions were demanded by all apps while one app had the facility of providing prescription from their own consultant. Only one app provided “Ask a Pharmacist” option.
 Conclusion: We found lots of inconsistency in the information provided by these apps. Our results are based on only five apps and provide a framework for future studies to scrutinize online apps.

Recent Social Background and Consumer Views on Over-the-counter Drugs and Self-medication

Recently, because the marked rise in medical expenses in Japan has become a major social problem, self-medication using OTC drugs in cases of minor health problems has attracted increasing attention. When people use OTC drugs for self-medication, they need support and/or advice from pharmacists on their proper use. This paper outlines recent revisions in the legal sales system of OTC drugs, the social background of self-medication, characteristics of OTC drugs and role of the pharmacists in providing consultation on OTC preparations. Next, consumers' views of self-medication and the OTC drug sales system are described based on the results of surveys performed after they attended an educational event on the proper use of OTC drugs. The survey of consumer views on the legal sales system of OTC drugs revealed that they were the most concerned about safety and convenience. From the survey of consumer views on self-medication, a significant percentage of the group who understood the meaning of the term "self-medication" practiced it in cases of minor health problems. Although no significant difference was seen between the groups who understood the term "self-medication" and those who did not in regard to the reading the drug package label and/or insert, a significant difference was found in their understanding of "The System for Sufferers from Adverse Drug Reactions". Therefore, it was clear that the consumers familiar with "self-medication" not only practiced it, but also understood the contents of drug package labels and/or inserts.

A study on the evaluation of drug package inserts: a prospective observational study

Background: The package inserts are an important source of information for the patient and the prescribers which are often incomplete in terms of information. Not many of them are patient friendly, usage of technical terms further complicates the scenario amidst inadequate doctor-patient ratio. Aim of the study was to evaluate the completeness of package inserts.Methods: Hundred package inserts were collected from June 2018 to September 2018 from nearby pharmacies and drug store of a tertiary care hospital, Government Medical College, Akola and evaluated in terms of completeness as per guidelines mentioned in the section D of Drug and Cosmetics Act 1945, language used and addressed to whom. Each guideline followed under section D was given a score of 1 and absence 0 depending upon which grouped as Grade A (>15), Grade B (10-15), Grade C (<10). Result was analysed in Microsoft Excel 2010 expressed in percentage and whole numbers.Results: Out of the 100 package inserts evaluated the guidelines like mentioning of special circumstances like pregnancy was present in (98%), undesirable effects in 98%. All of them used English with 3% having combination with regional language, 70% had no mention as to whom it is addressed. Grades allotted after evaluation A, B, C, 24%, 74%, 2%.Conclusions: The present study showed though improvement occurred deficiencies should be corrected and properly scrutinised for better compliance of the patient and effective drug use and to step up the healthcare services in society.

Analysis of individual case safety reports of drug-induced anaphylaxis to the Korea Adverse Event Reporting System

Purpose: To identify causative agents of the drug-induced anaphylaxis (DIA) by using the Korea Institute of Drug Safety & Risk Man agement-Korea Adverse Event Reporting System (KIDS-KAERS) database (Ministry of Food and Drug Safety) in Korea and to check their labeling information regarding anaphylaxis. Methods: Among Individual Case Safety Reports from January, 2008 to December 2017, cases of DIA were analyzed for demo graphics, causative agents and fatal cases resulting in death. The domestic drug labeling, Micromedex and U.S. Food and Drug Ad ministration (FDA) drug package insert, were reviewed to check if the labeling information on suspected causative agents contains anaphylaxis. Results: A total of 4,700 cases of DIA were analyzed. The mean age was 49.85±18.32 years, and 2,642 patients (56.2%) were females. Among 8,664 drugs reported as causative agents, antibiotics (27.4%) accounted for the largest portion. There were 18 fatal cases: antibiotics (7 cases), antineoplastic agents (4 cases) were the major causative drugs for the mortality cases. Of 513 drugs reported as suspected causative agents, 103 (20.1%) did not list anaphylaxis as an adverse effect on domestic drug labeling and 16 (3.1%) did not reflect anaphylaxis in any of 3 adverse drug information. Conclusion: Analysis of 10-year data showed that antibiotics were the main cause of DIA and the mortality rate was 0.7%. In 3.1% of suspected drugs, there was no description of anaphylaxis in any of the drug labeling. (Allergy Asthma Respir Dis 2020;8:30-35)

Investigation and Analysis of the Information Available for Pregnant Women in 1102 Antibiotic Package Inserts

Objective To understand the current status of information on use by pregnant women in antibiotic package inserts. Methods Information related to use by pregnant women, was obtained from the package inserts of 66 commercially available antibiotics and was investigated and analyzed. The drugs were classified as follows according to their pharmacological effects: penicillins; first-, second-, third-, and fourth-generation cephalosporins; cephamycins; aminoglycosides; macrolides; tetracyclines; lincosamides; glycopeptide antibiotics; carbapenems; third- and fourth-generation quinolones; sulfonamides; and nitroimidazoles. Results A total of 1102 package inserts of 66 common commercially available antibiotics were obtained. Among them, 72.14% (795) package inserts included labels with advice for pregnant women, backed by relevant research data, whereas 23.23% (256) included labeling on the use by pregnant women without such experimental or relevant research data. In addition, 2.00% (22) of these inserts included unclear information, whereas the information was missing in 2.63% (29). Finally, 10.60% (7) of the package inserts contained contradictory information across manufacturers. Package inserts of some antibiotics are either not standardized or lack relevant information for use of these drugs by pregnant women, making it difficult to meet the needs of users and ensure medication safety. Conclusion Standardized management of drug package inserts must thus be enhanced.

A Neural Network Architecture for Information Extraction in Chinese Drug Package Insert

There is a lot of useful information in the medical photocopying materials. The correct extraction and identification of this information are of great significance for the construction of digital medical. In most previous research, researchers have been working on clinical data, and there is little discussion on the extraction of information from Chinese drug package insert. To settle this issue, a neural network model is proposed in this paper. This model uses OCR's post-document as the data source, which can not only correct these data but also classify sentences. It is mainly composed of three layers: the first layer is employed to correct the data using the language model and the seq2seq model, the second layer is defined by convolution neural network (CNN) aiming to enrich the processed sentences, and another layer is used to determine the label of each sentence. The quantitative experimental results verify the feasibility and validity of the proposed model. In addition, the comparing experiments demonstrate that our method outperforms the regular rule-based approaches, which indicated 4%-6% higher in F1 score.

EP1.15-20 Good Control by Re-Administration of Carboplatin and Paclitaxel Against Unresectable Thymic Carcinoma

Many chemotherapy regimens have been administered for unresectable and recurrent thymic carcinoma. However, hightly effective standard regimens have not yet been developed. Although carboplatin-based chemotherapy is considered one of the effective options for thymic carcinoma, carboplatin can be used to treat thymic carcinoma up to only 4–6 cycles following guidelines. In addition, there is no scientific evidence for the usefulness of chemotherapy when thymic carcinoma relapses. A 48-year-old man who had an abnormal shadow on a chest radiograph obtained during a medical checkup was referred to our hospital. Chest computed tomography (CT) showed a mass measuring 9.3 cm in the anterior mediastinum. Positron emission tomography (PET)-CT showed significant abnormal uptake with a standardized uptake value of 24.5, and there was no evidence of metastasis. We performed median sternotomy, but found pleural dissemination in the right thoracic cavity. We then only obtained a biopsy. Pathologically he was diagnosed with thymic carcinoma. We administered carboplatin and paclitaxel for up to 6 cycles, combined with radiotherapy (60 Gy/30 fr). Six months later, abnormal uptake on PET-CT almost disappeared. However, one year after the chemoradiotherapy, PET-CT showed recurrence of thymic carcinoma. Therefore, we decided to administer the same regimen again for up to 13 cycles. After re-administration, PET-CT showed markedly decreased accumulation and regression of thymic carcinoma. No severe adverse effects were observed. We have subsequently continued monotherapy containing paclitaxel, and until currently there is no evidence of relapse 23 months after surgery. Carboplatin has no limitations on its cumulative dose according to its drug package insert, unlike in the case of anthracycline, and the total dose is only limited on the basis of increased side effects regardless of its antineoplasmatic effect. We herein report a case of re-administering carboplatin against unresectable thymic carcinoma beyond the dose suggested by guidelines and achieving good progress.

Readability Evaluation of Drug Package Inserts for Children with Asthma in China

Readability Evaluation of Drug Package Inserts for Children with Asthma in China

Do drug package inserts meet the rules and regulations of Iran's Food and Drug Administration in terms of informing patients?

Background: Drug package inserts (PIs) are the most accessible source of information for users and are designed to aid the safe use of medicines and avert adverse events. This study measured the conformity of PIs with the health communications standards of Iran’s Food and drug Administration (FDA). Methods: This descriptive cross-sectional study evaluated 92 PIs related to 22 best-selling neurological and psychiatric drugs in Iran based on criteria approved by Iran’s FDA. Six categories of criteria were considered in evaluating the extent of conformity: I) writing and formatting, II) references, III) drug description, IV) warnings and precautions, V) interactions, and VI) side effects. Each PI was scored based on observation of standards; data was analyzed using Microsoft Excel pivot tables. Results: In total, 2929 items from 92 PIs were evaluated, of which 37 (40.2%) were related to antidepressants, 31 (33.7%) to sedatives and hypnotics, and 24 (26%) to anticonvulsant drugs. The PI content was insufficient in various aspects of conformity with standards in each category. Among the six categories, the best match was found in warnings and precautions with 667items (72.5%), followed by writing and formatting with 663 (69.1%). The lowest conformity was found in the reference category with 194 (26.4%) items. Conclusion: The PIs of Iranian neurological drugs do not fully meet Iran’s FDA standards. It is strongly recommended that smart PIs be developed using mobile apps to overcome this problem.

Does Industry-Conducted All-Case Surveillance of Newly Approved Oncology Drugs Contribute to the Revision of Package Inserts in Japan?

In Japan, the Pharmaceuticals and Medical Devices Agency requires all‐case surveillance studies (ACSS) for many novel oncology drugs as a condition for approval. However, this is a major burden on the pharmaceutical industry and clinicians. The objective of this analysis was to investigate whether ACSS can contribute essential new information on severe adverse drug reactions, which are necessary to revise the package inserts of drugs. All oncology drugs for which ACSS were required from January 2006–September 2015 found on the Pharmaceuticals and Medical Devices Agency website were reviewed, and the influence of ACSS on the package insert content was evaluated. Most of the package insert revisions regarding serious treatment‐related adverse events were based on spontaneous reports from clinicians. The contribution of ACSS results to the revision of package inserts is limited and comes at the cost of financial resources and labor. An alternative, more efficient adverse‐event reporting system is necessary.

Auto-Generated Physiological Chain Data for an Ontological Framework for Pharmacology and Mechanism of Action to Determine Suspected Drugs in Cases of Dysuria.

Patients often take several different medications for multiple conditions concurrently. Therefore, when adverse drug events (ADEs) occur, it is necessary to consider the mechanisms responsible. Few approaches consider the mechanisms of ADEs, such as changes in physiological states. We proposed that the ontological framework for pharmacology and mechanism of action (pharmacodynamics) we developed could be used for this approach. However, the existing knowledge base contains little data on physiological chains (PCs). We aimed to investigate a method for automatically generating missing PC from the viewpoint of anatomical structures. This study was conducted to determine dysuria-related adverse events more likely to occur during multidrug administration. We adopted a systematic approach to determine drugs suspected to cause adverse events and incorporated existing data and data generated in our newly developed method into our ontological framework. The performance of automated data generation was evaluated using this newly developed system. Suspected drugs determined by the system were compared with those derived from adverse events databases. Of the 242 drugs involving suspected drug-induced urinary retention or dysuria, 26 suspected drugs were determined. Of these, five were drugs with side effects not listed in drug package inserts. The system derived potential mechanisms of action, PCs, and suspected drugs. Our method is novel in that it generates PC data from anatomical structural properties and could serve as a knowledge base for determining suspected drugs by potential mechanisms of action.

ODAE: Ontology-based systematic representation and analysis of drug adverse events and its usage in study of adverse events given different patient age and disease conditions

BackgroundDrug adverse events (AEs), or called adverse drug events (ADEs), are ranked one of the leading causes of mortality. The Ontology of Adverse Events (OAE) has been widely used for adverse event AE representation, standardization, and analysis. OAE-based ADE-specific ontologies, including ODNAE for drug-associated neuropathy-inducing AEs and OCVDAE for cardiovascular drug AEs, have also been developed and used. However, these ADE-specific ontologies do not consider the effects of other factors (e.g., age and drug-treated disease) on the outcomes of ADEs. With more ontological studies of ADEs, it is also critical to develop a general purpose ontology for representing ADEs for various types of drugs.ResultsOur survey of FDA drug package insert documents and other resources for 224 neuropathy-inducing drugs discovered that many drugs (e.g., sirolimus and linezolid) cause different AEs given patients’ age or the diseases treated by the drugs. To logically represent the complex relations among drug, drug ingredient and mechanism of action, AE, age, disease, and other related factors, an ontology design pattern was developed and applied to generate a community-driven open-source Ontology of Drug Adverse Events (ODAE). The ODAE development follows the OBO Foundry ontology development principles (e.g., openness and collaboration). Built on a generalizable ODAE design pattern and extending the OAE and NDF-RT ontology, ODAE has represented various AEs associated with the over 200 neuropathy-inducing drugs given different age and disease conditions. ODAE is now deposited in the Ontobee for browsing and queries. As a demonstration of usage, a SPARQL query of the ODAE knowledge base was developed to identify all the drugs having the mechanisms of ion channel interactions, the diseases treated with the drugs, and AEs after the treatment in adult patients. AE-specific drug class effects were also explored using ODAE and SPARQL.ConclusionODAE provides a general representation of ADEs given different conditions and can be used for querying scientific questions. ODAE is also a robust knowledge base and platform for semantic and logic representation and study of ADEs of more drugs in the future.

Incidence of kampo medicine‐induced interstitial pneumonia: 10 year retrospective study at a university hospital kampo medicine department

ABSTRACTAimAt present, traditional Japanese medicines, termed kampo medicines, are integrated into the Japanese national health‐care system. In Japan, interstitial pneumonia is described as an adverse drug event in the drug package insert of some prescription kampo formulations. Additionally, many of the kampo formulas that induce interstitial pneumonia contain Scutellariae Radix (SR). The incidence of kampo medicine‐induced interstitial pneumonia has not been sufficiently studied. The aim of the present study was therefore to assess the incidence of kampo medicine‐induced interstitial pneumonia in the kampo medicine department of a clinical institution.MethodsWe selected patients who had developed interstitial pneumonia due to kampo formulas on the basis of the medical records of the Department of Japanese Oriental Medicine, Toyama University Hospital, from 2008 to 2017. Moreover, we investigated the number of patients who were prescribed kampo formulas and the number of patients who were prescribed kampo formulas containing SR during the study period.ResultsOf the 3590 patients who received kampo medications in the 10 year survey period, three patients developed kampo medicine‐induced interstitial pneumonia (incidence, 0.08%). The causal kampo formulas in all three of these cases contained SR. For the 1111 patients who were prescribed SR‐containing formulas, the incidence of kampo medicine‐induced interstitial pneumonia was 0.27%.ConclusionAlthough the incidence is not high, physicians should keep in mind that kampo formulas, particularly SR‐containing formulas, might cause kampo medicine‐induced interstitial pneumonia.

Oral oncolytic and antiretroviral therapy administration: dose adjustments, drug interactions, and other considerations for clinical use.

The rise in non-AIDS defining cancers (NADCs) is emerging as a leading cause of death for HIV and cancer patients. To address this, current literature and guidelines suggest the continuation of antiretroviral therapy (ART) with oral oncolytic agents to prevent adverse complications associated with HIV disease progression. However, such an approach has the potential for drug–drug interactions and adverse events for patients on such therapy. Further, recommendations on how to adjust these medications, when used concomitantly, are limited. As such, our purpose is to evaluate existing literature through such means as drug databases (e.g. Micromedex, Lexi-Comp, etc.) and package inserts along with PubMed/Medline, Embase, and Google Scholar databases to develop a reference tool for providers to utilize when there is a decision to treat a patient with ART and oral oncolytic agents concurrently. Our findings suggest that there are many drug interactions that should be taken into consideration with dual therapy. Metabolism is a key determinant of dose adjustment, and many oncolytic agents and ART agents must have their dose adjusted as such. Most notably, several tyrosine kinase inhibitors require dose increases when used with non-nucleoside reverse transcriptase inhibitors (NNRTIs) but must be decreased when used concomitantly with protease inhibitors (PIs) and cobicistat. Further findings suggest that certain agents should not be used together, which include, but are not limited to, such combinations as bosutinib with NNRTIs, cobicistat, or PIs; idelalisib with maraviroc or PIs; neratinib with NNRTIs, cobicistat, or PIs; and venetoclax with NNRTIs. Overall, the most prominent oncolytic drug interactions were discovered when such agents were used concomitantly with PIs, cobicistat-boosted elvitegravir, or NNRTIs. Future studies are necessary to further evaluate the use of these agents together in disease therapy to generate absolute evidence of such findings. However, from the studies evaluated, much evidence exists to suggest that concomitant therapy is not without drug interactions. As such, clinical decisions regarding concomitant therapy should be evaluated in which the risk and benefit of dual therapy are assessed. Dose adjustments must be made accordingly and in consultation with both HIV and oncology clinicians and pharmacists to reduce the risk for adverse outcomes and disease progression for those with cancer and HIV/AIDS.

Protocol for the development and validation of a driving simulator for evaluating the influence of drugs on driving performance.

Introduction:Although automobile driving is often necessary in daily life, most package inserts for psychotropic drugs in Japan prohibit patients from driving under the influence of medication. This may be partially because no system to evaluate the influence of drugs on driving performance has been established. Standardized evaluation methods have been established in the Netherlands and the United States, but these cannot be implemented in Japan because of differences in road situations, traffic laws, and ethnicities. Therefore, to establish a method to evaluate the influence of drugs on driving performance in Japan, we planned a validation study using alcohol and a driving simulator (DS) and set a clinically meaningful threshold involving the standard deviation of lateral position (SDLP), which is a criterion standard evaluation item.Methods:This study was designed as a double-blind, placebo-controlled, randomized, 4-way, fourth-order crossover trial (Williams design). Twenty-four healthy Japanese men aged 21 to 64 years will be recruited through advertisements. The participants will be required to drive daily for over 3 years and to carry the active-type aldehyde dehydrogenase (ALDH) gene polymorphism (ALDH 2∗1/∗1). Participants will be randomly assigned to 4 groups based on blood alcohol concentration (BAC): 0% (placebo), 0.025%, 0.05%, and 0.09%. The amount of alcohol intake will be calculated based on Widmark formula using a beverage that is a mixture of 40% vodka and orange juice. After a practice period, each examination period will be set with 6-day intervals. The primary outcome is SDLP in a 60-minute road-tracking test using the DS. The secondary outcomes are other evaluation items in the DS tasks and DS sickness and sleepiness according to questionnaire responses. The estimated difference in SDLP between BAC levels of 0.05% and 0% will be calculated using a linear model.Ethics and dissemination:Ethics approval was obtained from the Ethics Committee at Hakata Clinic and the Nagoya University Medical School Hospital Bioethics Review Committee. The trial results will be disseminated through peer-reviewed publications and international conferences.Trial registration:This study was registered at ClinicalTrials.gov NCT 03572985 on June 28, 2018.

Use of antidepressants during breastfeeding: evaluating drug package inserts conformity with science-based bibliographical sources

This article sought to evaluate the conformity between recommendations regarding antidepressant use during breastfeeding found in drug package inserts with recommendations from science-based bibliographic sources. We evaluated the standard drug package inserts of 23 antidepressants with active registration in Brazil. The presence of contraindications of antidepressant use during breastfeeding was compared with information present in the Brazilian Ministry of Health technical manual, the book Medications and Mothers' Milk and on the databases LactMed, Micromedex and UpToDate. In most drug package inserts (62.5%), antidepressants are contraindicated during breastfeeding. Among bibliographical sources, that percentage varied between 0% and 25%. The study shows a low conformity between drug package inserts and bibliographical sources, alerting to the need for revising the content and presentation of information present in antidepressant drug package inserts in Brazil.