Accuracy of Labeling of Galantamine Generic Drugs and Dietary Supplements.

This study examines the accuracy of labeling for galantamine products formulated as both generic drugs and dietary supplements, as well as tests for contamination with microorganisms.

Inconsistencies of absolute drug-drug contraindication reports: Analysis of Summaries of Product Characteristics of commonly prescribed drugs.

AIMS: Prescribing information should follow a defined structure to help prescribers easily find required information. Often information appears in different sections of Summaries of Product Characteristics (SmPCs) in an inconsistent way. Still unknown is how this inconsistency affects absolute contraindications and how it can be improved. Thisstudy aimed to evaluate the structure of absolute contraindications in SmPCs based on absolute drug-drug contraindications (DDCI) in the section 'contraindications' and references to sections 'special warnings and precautions for use' (here as 'warnings') and 'interaction with other medicinal products and other forms of interaction' (here as 'interactions'). METHODS: SmPCs of 693 commonly prescribed drugs were analysed regarding absolute DDCI in 'contraindications' sections. References to sections on 'warnings' and 'interactions' were evaluated to characterize information provided about DDCI. RESULTS: Of 693 analysed SmPCs, 138 (19.9%) contained ≥1 absolute DDCI. Of 178 SmPCs that referred to sections on 'warnings' or 'interactions', 131 (73.6%) did not contain further information on absolute DDCI, whereas 47 (26.4%) did. Such additional information was found in sections on 'interactions' and 'warnings' in 41 (87.2%) and 9 (19.1%) SmPCs, respectively. CONCLUSIONS: Information regarding absolute DDCI was found not only in sections on 'contraindications' but also in sections on 'warnings' and 'interactions'. Information was not given with consistently straightforward phrasing and structure and so can leave uncertainty for prescribers. To improve drug safety, clear definitions and wording for absolute and relative contraindications should be provided, ideally in tables.

Comparative analysis of PIM criteria and drug labels in the elderly.

PURPOSE: By discussing the corresponding situation of PIM criteria and labels, it provides a reference for the formulation and update of the criteria and the content of the section of "medications for the elderly" in the labels, so as to realize rational drug use for the elderly. METHODS: Extract the four indicators of Beers criteria, STOPP criteria, and the EU(7)-PIM list that involve dosage, duration, age, and mortality, and compare them with the latest labels for drugs marketed in the USA and the EU. RESULTS: There are 148 drugs involving four indicators in the criteria, and 85.14% of the drugs are found in at least one region. In terms of dose, there are 28 drugs with inconsistent descriptions in the labels of the two regions, accounting for 47.46% of the 59 drugs found in both regions. A total of 42.37% of the drugs are consistent in both regions with the criteria (25/59), 28.81% of the drugs are inconsistent in both regions with the criteria (17/59), and 28.81% of the drugs are inconsistent in only one region with the criteria (17/59). The doses of 50 drugs found in F/D labels are consistent with the criteria, accounting for 54.35% of the 92 drugs found in F/D labels, and of 41 drugs found in E/H SmPC are consistent with the criteria, accounting for 60.29% of the 68 drugs found in E/H SmPC. Only the duration of omeprazole in the labels in both regions is consistent with the criteria, and only the age of prasugrel in both regions is consistent with the criteria. Five drugs whose labels mentioned increased mortality, accounting for 38.46% of the 13 drugs found in both regions. CONCLUSION: There are certain differences between PIM criteria and PIM criteria, labels and labels, and PIM criteria and labels, which will affect the use of drugs in the elderly. Therefore, the unity between the criteria and labels should be strengthened to provide more instructive guidance for the elderly, so as to jointly realize rational drug use in the elderly.

Harmonization of summaries of product characteristics (SmPCs) of drugs with the same active ingredients: an evaluation of SmPCs of the most frequently prescribed active substances.

PURPOSE: In aut-idem or generic substitution, discrepancies between summaries of product characteristics (SmPCs) referring to the same active substance (AS) may cause difficulties regarding informed consent and medical liability. The qualitative and quantitative characteristics of such discrepancies are insufficiently studied, impeding harmonization of same-substance SmPCs and compromising safe drug treatment. METHODS: SmPCs of the one hundred most frequently prescribed ASs in Germany were analyzed for discrepancies in the presentation of indications (Inds) and contraindications (CInds). Inclusion and exclusion criteria of drugs/SmPCs were chosen according to the standards of the aut-idem substitution in Germany. RESULTS: According to the study protocol, we identified 1486 drugs, of which 1426 SmPCs could be obtained. 41% respectively 65% of the ASs had same-substance SmPCs that differed from the respective reference SmPC in the number of listed Inds respectively CInds. The number of listed Inds/CInds varied considerably between same-substance SmPCs with maximum ranges in Inds of 7 in amoxicillin, and in CInds of 11 in lisinopril. Many ASs had large proportions (> 50%) of associated same-substance SmPCs that differed from the respective reference SmPC. A considerable proportion of ASs had same-substance SmPCs with formal and content-related differences other than the discrepancy in the number of Inds/CInds. CONCLUSION: This evaluation of same-substance SmPCs shows a clear lack of harmonization of same-substance SmPCs. Considering that generic substitution has become the rule and that physicians usually do not know which drug the patient receives in the pharmacy, these discrepancies raise several questions, that require a separate legal evaluation.

A systematic comparison of hepatobiliary adverse drug reactions in FDA and EMA drug labeling reveals discrepancies.

Drug labeling informs physicians and patients on the safe and effective use of medication. However, recent studies suggested discrepancies in labeling of the same drug between different regulatory agencies. Here, we evaluated the hepatic safety information in labeling for 549 medications approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Limited discrepancies were found regarding risk for hepatic adverse drug reactions (ADRs) (8.7% in hepatic ADR warnings and 21.3% in contraindication for liver disease), while caution should be exercised over drugs with inconsistencies in contraindications for liver disease and evidence for hepatotoxicity (4.9%). Most discrepancies were attributable to less-severe hepatic events and low-frequency hepatic ADR reports and had limited implication on clinical outcomes.

HDRS - Hybrid Diffuse Reflectance Spectroscopy: Non-Erythemal In Vivo Driven SPF and UVA-PF Testing.

BACKGROUND/AIMS: In order to define a label SPF of topically applied sunscreens, in vivo test methods like ISO 24444, FDA Guideline, and the Australian Standard are used worldwide. The basis of all these methods is to induce an erythemal skin reaction by UV irradiation to find the level of MEDu and MEDp (Minimal Erythmal Dose unprotected and protected). In vitro methods replacing the human skin by any kind of nonhuman material are still not available. Thus, offering the new hybrid diffuse reflectance spectroscopy (HDRS) technique that can maintain an in vivo level for SPF testing while neglecting the UV-dose-related erythemal skin reaction is a perfect combination to take care of sun protection and any ethical concerns in SPF testing nowadays. METHODS: HDRS is a combination of in vivo diffuse reflectance spectroscopy measurements on the skin and in vitro transmission measurements of a sunscreen on a roughened polymethylmethacrylate plate. By this technique, the in vivo behavior of the investigated sunscreen on the skin is measured as well as the UVB absorption, which is still nonvisible in the reflectance technique. In order to establish an alternative method for in vivo SPF and UVA-PF testing, a huge number of sunscreens (250 samples) were measured by HDRS and compared with the worldwide accepted standards ISO 24444, ISO 24442, and ISO 24443. The variety of sunscreens measured reflect a wide range of different types of formulations as well as a wide range of SPFs (5-120) to validate this new alternative SPF testing procedure. RESULTS: Far-reaching statistical data analyses show an excellent link between the new nonerythemal-driven HDRS-SPF technique and ISO 24444 results. In the same way, HDRS-UVA-PF results can be correlated with UVA-PF values calculated from ISO 24442 as well as from ISO 24443. The importance of the inclusion of a spectral ratio of photodegradation is shown in the comparison of photostable and photounstable products. CONCLUSION: Owing to the elimination of any erythemal-relevant UVB and UVA doses, absolutely no skin reaction occurs during the HDRS experiment. Consequently, there is no need to define an MED anymore. For the first time, an alternative way to arriving at SPF and UVA-PF values is shown, without any ethical concerns of SPF testing in vivo and/or any restriction of SPF testing in vitro. Regardless of the type of formulation or the level of protection, an excellent correlation between SPFHDRSand SPF24444as for sunscreen labeling could be found. By this new alternative nonerythemal technique, not only SPF values can be measured but also UVA-PF values can be calculated with a linear correlation to ISO 24442 as well as to ISO 24443 from the same set of data. By this a robust alternative test method of SPF and UVA-PF values is described, taking into account the interaction of sunscreen formulation and skin.

Quality assessment of selected co-trimoxazole suspension brands marketed in Nairobi County, Kenya.

INTRODUCTION: Quality of medicines in both developed and developing countries is sometimes compromised due to infiltration of counterfeit, substandard or degraded medicines into the markets. It is a public health concern as poor quality medicines endanger public health where patients are exposed to chemical toxins and/or sub-therapeutic doses. This could lead to reduced treatment efficacy and promote development of drug resistance. Co-trimoxazole, a fixed dose combination of sulfamethoxazole and trimethoprim, is a broad spectrum for bacterial diseases and is also used as a prophylaxis for opportunistic infections in HIV infected individuals. This study evaluated quality of selected co-trimoxazole suspension brands marketed in Nairobi County, Kenya. METHODS: A total of 106 samples were collected, categorized into 15 brands and evaluated for active pharmaceutical ingredient content (API) and pH following United States Pharmacopeia. Assay for API was conducted using High Performance Liquid Chromatography. Results were compared with pharmacopeia references. Visual examination of labels and confirmation of retention status of the brands with Pharmacy and Poisons Board retention register was carried out. RESULTS: The samples were primarily of local origin (86.7%). On October 23, 2019, retention status of six of the fifteen brands documented were no longer listed in the Pharmacy and Poisons Board retention register. Of the 106 samples tested 70.6% and 86.8% were compliant with United States Pharmacopeia (USP) specifications for pH and API respectively while 84.0% adhered to packaging and labelling requirements. CONCLUSION: This study has demonstrated that majority of co-trimoxazole suspensions tested were compliant with USP requirements. Additionally, it has provided evidence of poor quality co-trimoxazole medicines that could compromise treatment of infectious diseases in children. This emphasizes the need for regular quality assurance tests to ensure only quality medicines are in the market.

An Evidence-Based Framework for Evaluating Pharmacogenomics Knowledge for Personalized Medicine.

Clinical annotations are one of the most popular resources available on the Pharmacogenomics Knowledgebase (PharmGKB). Each clinical annotation summarizes the association between variant-drug pairs, shows relevant findings from the curated literature, and is assigned a level of evidence (LOE) to indicate the strength of support for that association. Evidence from the pharmacogenomic literature is curated into PharmGKB as variant annotations, which can be used to create new clinical annotations or added to existing clinical annotations. This means that the same clinical annotation can be worked on by multiple curators over time. As more evidence is curated into PharmGKB, the task of maintaining consistency when assessing all the available evidence and assigning an LOE becomes increasingly difficult. To remedy this, a scoring system has been developed to automate LOE assignment to clinical annotations. Variant annotations are scored according to certain attributes, including study size, reported P value, and whether the variant annotation supports or fails to find an association. Clinical guidelines or US Food and Drug Administration (FDA)-approved drug labels which give variant-specific prescribing guidance are also scored. The scores of all annotations attached to a clinical annotation are summed together to give a total score for the clinical annotation, which is used to calculate an LOE. Overall, the system increases transparency, consistency, and reproducibility in LOE assignment to clinical annotations. In combination with increased standardization of how clinical annotations are written, use of this scoring system helps to ensure that PharmGKB clinical annotations continue to be a robust source of pharmacogenomic information.

Drug Safety in Labeling for Pediatric Drug Development and Dose Selection in Submissions to the US Food and Drug Administration.

Pediatric safety evaluations are an essential part of a pediatric drug development program. Communication of the results of these safety evaluations is primarily accomplished by labeling of the drug either during the initial pediatric drug development program, or during the postmarketing period after drug approval for pediatric patients. During drug development, the dose-adverse drug event (ADE) relationship is an important part of the evaluation, but a consideration for pediatric ADEs that are unrelated to drug dosage must be maintained. Examples of dose-related and non-dose-related ADEs are presented. The failure to label a product for pediatric use has been safety related for a number of development programs. The US Food and Drug Administration's Pediatric Advisory Committee is a primary source of the pediatric postmarketing safety review and has been associated with a number of labeling changes through its ongoing review process. Pediatric drug safety remains a critical part of the assessment of dose-effect relationship in the pediatric patient population during the drug development and postmarketing surveillance process.

The impact of textual elements on the comprehensibility of drug label instructions (DLIs): A systematic review.

INTRODUCTION: Correct interpretation of drug labels instructions (DLIs) is needed for safe use and better adherence to prescribed drugs. DLIs are often too difficult for patients, especially for those with limited health literacy. What is yet unknown, is how specific textual elements in DLIs (e.g., the presentation of numbers, or use of medical jargon) and patients' health literacy skills are related to the comprehension of DLIs. In order to provide concrete directions for health professionals on how to optimize drug prescriptions, we performed a systematic review to summarize the available research findings on which textual elements facilitate or hinder the correct interpretation of DLIs in relation to patients' health literacy. METHOD: A systematic search was performed in PubMed, EMBASE, PsychINFO, and Smartcat (until April 2019) to identify studies investigating textual elements that facilitate or hinder the correct interpretation of DLIs in relation to patients' health literacy. RESULTS: A total of 434 studies were identified of which 28 studies met our inclusion criteria. We found that textual elements contributing to the correct interpretation of DLIs were: using explicit time periods in dosage instructions, using plain language, presenting numbers in a numerical format, and providing DLIs in patients' native language. Multistep instructions per instruction line, using abbreviations and medical jargon seem to hinder the correct interpretation of DLIs. Although health literacy was taken into account in a majority of the studies, none of them assessed the effectiveness of specific textual elements on patients' comprehensibility of DLIs. CONCLUSION: Based on our findings, we provide an overview of textual elements that contribute to the correct interpretation of DLIs. Optimizing the textual instruction on drug labels may increase the safety and adherence to prescribed drugs, taking into account that a significant proportion of patients has low health literacy.

Labeling Changes for Vinca Alkaloid Chemotherapies.

The labeling for vinca alkaloid chemotherapy drugs is being revised to remove instructions for their administration with use of a syringe. This revision is in response to inadvertent intrathecal administration of vinca alkaloids, which is normally fatal.

A retrospective analysis of actionable pharmacogenetic/genomic biomarker language in FDA labels.

The primary goal of precision medicine is to maximize the benefit-risk relationships for individual patients by delivering the right drug to the right patients at the right dose. To achieve this goal, it has become increasingly important to assess gene-drug interactions (GDIs) in clinical settings. The US Food and Drug Administration (FDA) periodically updates the table of pharmacogenetic/genomic (PGx) biomarkers in drug labeling on their website. As described herein, an effort was made to categorize various PGx biomarkers covered by the FDA-PGx table into certain groups. There were 2 major groups, oncology molecular targets (OMT) and drug-metabolizing enzymes and transporters (DMETs), which constitute ~70% of all biomarkers (~33% and ~35%, respectively). These biomarkers were further classified whether their labeling languages could be actionable in clinical practice. For OMT biomarkers, ~70% of biomarkers are considered actionable in clinical practice as they are critical for the selection of appropriate drugs to individual patients. In contrast, ~30% of DMET biomarkers are considered actionable for the dose adjustments or alternative therapies in specific populations, such as CYP2C19 and CYP2D6 poor metabolizers. In addition, the GDI results related to some of the other OMT and DMET biomarkers are considered to provide valuable information to clinicians. However, clinical GDI results on the other DMET biomarkers can possibly be used more effectively for dose recommendation. As the labels of some drugs already recommend the precise doses in specific populations, it will be desirable to have clear language for dose recommendation of other (or new) drugs if appropriate.

An International Comparison of the Information in the Regulatory-Approved Drug Labeling and Prescribing Guidelines for Pediatric Depression.

Objectives: To determine the differences in information between prescribing guidelines and drug labeling, as well as to compare the approval of psychotropic medicines for major depression in pediatric patients ("pediatric depression") across countries. Methods: The recommendations of The Maudsley Prescribing Guidelines in Psychiatry (MPGP) for the treatment of pediatric depression (<18 years) were compared against the regulatory-approved drug-labeling documents from the United Kingdom, Australia, New Zealand, Canada, and the United States. The use of medicines outside of their regulatory approval is defined as off-label use, so differences between the drug labeling and MPGP were characterized according to unapproved age, indication, dosage, or route of administration. Information in the drug labeling was also compared across countries. Results: MPGP provides recommendations for 6 medicines for the treatment of pediatric depression, for which, 30 drug labeling were retrieved. Three of 30 drug labeling were consistent with MPGP recommendations (fluoxetine in the United Kingdom, fluoxetine and escitalopram in the United States). Differences in information between MPGP and the drug labeling were identified in 26 of 30 drug labeling analyzed, most often due to age (24/26) followed by indication (2/26). No differences pertaining to dosage or route of administration information were identified. The number of approved psychotropic medicines varied across the studied countries and we found cross-country discrepancies in information in the drug labeling. Conclusion: Significant differences in information exists between MPGP and the drug labeling for psychotropic medicines for pediatric depression, due to unapproved ages or indications. Additionally, approval information in the drug labeling are not consistent across countries. Further research into reasons for variability and impact on practice may be warranted.