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For more than a decade, US laboratories have failed to implement solutions to help their clinicians in managing complex situations or patients on direct oral anticoagulants (DOACs). The problem may find different origins, among which is the position of the Food and Drug Administration, which categorized these drugs as monitoring- and measurement-free, whereas other regulatory bodies like the European Medicines Agency or the Therapeutic Goods Administration in Australia were more conservative on the principle that the absence of proof (of monitoring/measurement benefits) is not proof of an absence (of monitoring/measurement needs). Pivotal clinical studies that led to the approval of DOACs were presented as devoid of such testing, although some companies considered monitoring as a solution to improve their benefit/risk ratio. In this JTH In Clinics issue, we report more than a decade of development that has permitted the activation of smart laboratory solutions to qualify or quantify DOACs and discuss myths and misconceptions around technical and regulatory requirements that support the current reluctance of implementing these technologies in most US laboratories. Use of DOACs is ever expanding, with DOAC prescriptions now exceeding those of other anticoagulants, including vitamin K antagonists, in some geographies. As this use increases, the likely need to measure DOAC exposure will also increase. Measurement of DOACs does not represent any technical difficulty. That these laboratory tests are not available in some locations suggests disparities in patient care, and we suggest it is time to address such inequalities.

Background The Prescribing Information (PI) is the US Food and Drug Administration (FDA)'s primary tool for communicating a summary of the essential scientific information needed for the safe and effective use of a prescription drug to healthcare providers.[1] One challenge with this type of communication is balancing the need to be thorough with the need to be concise. Objectives This study aimed to explore physicians' preferences for and understanding of specific content and formatting in the PI. This study also explored physicians’ use of and perceptions of the PI. Methods Seventy semi-structured qualitative interviews were conducted with primary care physicians (n = 35) and physicians from a wide range of specialties (n = 35) using web conferencing technology. Using fictitious PI examples, the guide assessed physicians’ interpretation of language and preferences for how certain information is organized and communicated in select sections of the PI. The interview guide also included questions about the resources physicians use to find information about prescription drugs, when and how physicians access the PI, and their perceptions of the PI. Results The findings suggest that of the content and formatting items surveyed, physicians had the greatest preference for: (1) uniformly specifying the age group for which the drug is indicated in the INDICATIONS AND USAGE section, even for medical conditions that are highly associated with only one particular age group (e.g., adult patients), and (2) uniformly including administration information in relation to food (e.g., “with or without food”) in the DOSAGE AND ADMINISTRATION section for drugs with oral dosing. The findings also suggest that including a long list of interacting drug examples in the DRUG INTERACTIONS section may be misinterpreted to be a comprehensive list. Conclusion This qualitative research suggests physicians may prefer more clarity in some sections of the PI.

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., publishedVersion

BackgroundAdjunctive metformin is the most well-studied intervention in the pharmacological management of antipsychotic-induced weight gain (AIWG). Although a relatively unaddressed area, among guidelines recommending consideration of metformin, prescribing information that would facilitate its applied use by clinicians, for example, provision of a dose titration schedule is absent. Moreover, recommendations differ regarding metformin’s place in the hierarchy of management options. Both represent significant barriers to the applied, evidence-based use of metformin for this indication.ObjectiveTo produce a guideline solely dedicated to the optimised use of metformin in AIWG management, using internationally endorsed guideline methodology.MethodsA list of guideline key health questions (KHQs) was produced. It was agreed that individual recommendations would be ‘adopted or adapted’ from current guidelines and/or developed de novo, in the case of unanswered questions. A systematic literature review (2008–2020) was undertaken to identify published guidelines and supporting (or more recent) research evidence. Quality appraisal was undertaken using the Appraisal of Guidelines Research and Evaluation II tool, A Measurement Tool to Assess Systematic Reviews (AMSTAR) assessment,and the Cochrane Risk of Bias 2 tool, where appropriate. Assessment of evidence certainty and recommendation development was undertaken using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.FindingsWe confirmed that no published guideline—of appropriate quality, solely dedicated to the use of metformin to manage AIWG was available. Recommendations located within other guidelines inadequately addressed our KHQs.ConclusionAll 11 recommendations and 7 supporting good practice developed here were formulated de novo.Clinical implicationsThese recommendations build on the number and quality of recommendations in this area, and facilitate the optimised use of metformin when managing AIWG.

BACKGROUND: Real-world safety of bevacizumab in cancer patients is limited. OBJECTIVE: To review the adverse drug reactions (ADRs) due to bevacizumab in cancer patients, in published case reports. METHODS: PubMed was searched; case reports of patients with any type of cancer, administered with bevacizumab (monotherapy/combination) and reported ADRs were included. Causality of ADRs was presented as reported in individual papers. ADRs were classified using the information in the USFDA-approved prescribing information (PI) of bevacizumab as ‘Serious’, ‘Common’, and ‘Post-marketing surveillance’ ADRs; ADRs not mentioned in the bevacizumab PI were termed as ‘Non-label ADRs’. RESULTS: A total of 130 published papers comprising 154 cases from 22 different countries were included. Most papers (102/130; 78.46%) had moderate methodological quality. Age range of patients was 9-77 years. Off-label use of bevacizumab was found in 34/154 cases (22.08%). Ninety-six unique ADRs were found among 154 ADRs; most reported ADRs affected circulatory, digestive, and respiratory systems (33, 32, and 26 cases respectively). Most commonly reported ADRs were posterior leukoencephalopathy, fistulae, and gastrointestinal perforation (17, 17, and 16 cases respectively). Twenty-eight unique non-label ADRs (29.17%) were found. CONCLUSION: Bevacizumab is associated with more ADRs in the real world among cancer patients than those reported during clinical trials.

Aducanumab (aducanumab-avwa; Aduhelm™) is a human, immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid β. It has been co-developed by Biogen and Eisai under license from Neurimmune for the treatment of Alzheimer's disease. In June 2021, aducanumab received its first approval in the USA for the treatment of Alzheimer's disease. According to the US FDA prescribing information, treatment should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied. Aducanumab is under regulatory review in Japan and in Europe. Its long-term safety and tolerability is being evaluated in a multinational phase 3b clinical study in patients with early Alzheimer's disease (mild cognitive impairment and mild Alzheimer's disease). This article summarizes the milestones in the development of aducanumab leading to this first approval for Alzheimer's disease.

Aims A substantial number of Summaries of Product Characteristics (SmPCs)/Prescribing Information (PI) have warnings or contraindications on QT interval prolongation. The goal of this work was to quantify usage of QT interval prolonging drugs according to the CredibleMeds® database of the German outpatient drug prescription market and to evaluate discrepancies between German SmPCs/US PI and CredibleMeds® . Methods Drugs listed on CredibleMeds® with known, possible or conditional risk for torsade de pointes were evaluated from 2000 to 2020. The German drug prescription report was used as source for defined daily dose- (DDD-) based prescriptions of the German outpatient drug prescription market of the public health insurance system. German SmPCs and US PI of 253 CredibleMeds® -listed drugs were evaluated for contents regarding QT interval prolongation. Results Of the drugs currently listed on CredibleMeds® , 59.7% (95% confidence interval [CI] 53.5-65.5%) were listed after 2012. Due to newly listed drugs, the proportion of DDDs of CredibleMeds® drugs among all prescriptions increased from 4.6% in 2013 to 21.1% in 2019. DDD-based usage of the CredibleMeds® drugs already listed in 2013 was similar in 2019. Among the drugs with known QT risk according to CredibleMeds® , 7.5% (95% CI 2.6-19.9%) of German SmPCs and 21.1% (95% CI 11.1-36.3%) of US PI had no mention of QT issues whatsoever. Conclusion A significant proportion of all drugs prescribed in the outpatient sector is associated with QT risks according to CredibleMeds® . SmPCs and PI should systematically be evaluated for concordance with the widely used CredibleMeds® database to increase medication safety.

Antibody-drug conjugates (ADCs) are new treatment options for certain cancers, especially those in advanced states with limited treatment options. Their unique design provides targeted therapy with toxins that otherwise would not be available, but they manifest toxicities that require risk minimization interventions to optimize their tolerability. We summarize selected toxicities for ADCs that have been approved through the end of 2020 and three investigational ADCs, which include both payload and linker, as described in the US Prescribing Information, the European Summary of Product Characteristics, and study protocols. These toxicities include peripheral neuropathy; pulmonary, skin, hepatic, and ocular toxicities; hyperglycemia; left ventricular dysfunction; and fluid-related events. We also review the risk minimization approaches to managing these toxicities as described in the product labels and study protocols. Our general observation suggests that the selected toxicities of the approved ADCs are primarily associated with off-target effects of the drug payloads. We also observed that the risk minimization approaches used to manage the selected toxicities are similar across product labels and study protocols. ADCs provide a unique treatment approach that is currently focused on advanced or refractory cancers. The risk minimization approaches for the selected toxicities for the approved ADCs per product label, or the study protocol for those in clinical investigation, are similar to those of standard chemotherapy agents and other pharmaceutical agents for the treatment of advanced malignancies. These risk minimization measures align with standard medical practice and are likely familiar to and feasible for physicians who prescribe for, and to other healthcare practitioners who care for, patients treated with ADCs.

Introduction In 2000, the FDA began issuing advice about treatments for hypoactive sexual desire disorder (HSDD) in women. How its recommendations have evolved has not been reviewed. Its consistent preference for self-rating by patients over evaluation by an examining clinician has not been addressed. Objectives Recount the changes in FDA’s proposals about patient-reported outcomes and diagnostics. Compare the value of patient-reported measures and clinical interviews. Methods Historical review is based on draft guidances, publications, meetings, and prescribing information. Results The FDA has avoided clinician input into diagnosis and evaluation of the severity of HSDD in women. It abandoned its initial (2000) insistence on counts of satisfying sexual events to define efficacy in favor of symptom-related scales to evaluate desire and distress with daily self-ratings. By 2015, the FDA accepted the self-rated Female Sexual Function Index-Desire Domain (FSFI-D) to measure desire and the most relevant item of the Female Sexual Distress Scale-Revised (FSDS-R) to measure distress; retrospection for both is one month. The FDA rejected the one clinician-rated broad measure of HSDD, the Sexual Interest and Desire Inventory (SIDI-F), although well-validated and treatment-sensitive. Since 2005, the FDA has accepted the Decreased Sexual Desire Screener (DSDS) to diagnose HSDD by non-expert clinicians using self-ratings and exploring them in more depth in a clinical interview. Conclusion FDA’s decisions on how to measure HSDD in women may have stabilized on accepting 2 co-primary measures: the FSFI-D and the FSDS-R item on bother about low desire, and on accepting the DSDS for diagnosis. FDA’s rejection of clinician ratings of severity through interviews in clinical trials seems unsound because interviews can give broader assessments than (brief) self-ratings, although the agency’s logic was to avoid diagnostic controversies and help avoid overcommercialization. Semistructured clinical interviews for diagnosis (DSDS) and severity-rating (SIDI-F) are well validated and are recommended for clinical practice. Pyke RE. FDA Decisions on Measures of Hypoactive Sexual Desire Disorder in Women: A History, With Grounds to Consider Clinical Judgment. Sex Med Rev 2021;9:186–193.

Background Patient-reported outcomes (PROs) can provide valuable information about drug benefit-risk tradeoffs from the patient perspective and are particularly important to patients with breast cancer due to its symptoms and adverse events from breast cancer treatments. The United States Food and Drug Administration (U.S. FDA) has acknowledged PROs as important approval endpoints used in clinical trials of cancer drugs. However, previous studies found that PROs are rarely mentioned in cancer drug labels, a widely used and trusted source of information about drugs. Our objectives were to compare PRO data reported in FDA labeling versus FDA medical review documents for breast cancer drugs approved in the U.S. between 2000 and 2019 to identify possible causes for PRO-data labeling exclusions. Methods We included new molecular entities (NMEs) and biologic license applications (BLAs) initially approved for breast cancer treatment by the FDA between 1/1/2000 and 12/31/2019. Product labeling and FDA medical review documents were collected from the FDA-Approved Drugs database (Drugs@FDA). From these resources, details on PRO measures used in trials, design of trials using PRO measures, PRO-endpoint status, analytical methods, and FDA reviewer comments regarding PRO measurement were extracted. Results Of 633 FDA-approved drugs, 13 were indicated for breast cancer treatment; none of their prescribing information contained information about PROs. However, 11 of 13 (85%) included PRO measures and endpoint information in FDA medical review documents. PRO measures were used in 14 different clinical trials, and FDA reviewers’ comments regarding PRO measurement were related to lack of meaningfulness and clinical significance, lack of content validity, and inadequate analytical methods. Conclusions Despite the importance of PROs to patients with breast cancer, PRO measures were only described in FDA medical review documents of breast cancer drugs, but not in drug product labeling. Therefore, it appears that PRO data are often collected in breast cancer trials, but have not been methodologically acceptable to FDA reviewers. Collaborative efforts between the FDA and industry are warranted to increase the number of breast cancer drug applications with appropriate use of PRO measures and endpoints.

Introduction: Regulatory agencies are responsible for defining the use of off-label (OL) and unlicensed (UL) drug prescription in neonatal intensive care. However, these regulatory criteria may differ between agencies in different countries. The aim of this study was to establish the frequency of OL and UL drug prescription in a sample of patients in a neonatal intensive care unit applying the criteria of the Food and Drug Administration (FDA) of the United States and the Agência Nacional de Vigilância Sanitária (ANVISA) of Brazil, analysing the differences observed in the results based on the applied criteria. Methods: Prospective cohort study in neonates admitted for more than 24 h to the NICU of a teaching maternity hospital between August 2017 and July 2018. We obtained information concerning the drugs included in the analysis of OL and UL prescriptions from the DrugDex-Micromedex® and official information on pharmaceutical products in Brazil. We used the kappa correlation coefficient to assess the agreement between the FDA and ANVISA criteria. We defined disagreement as a kappa value of less than 0.200. Results: We evaluated 220 neonates admitted to the NICU and 17,421 items prescribed during the study period. We did not find a difference in the proportion of neonates in which at least 1 drug was prescribed under OL conditions applying the FDA versus the ANVISA criteria (96.4% vs. 98.6%). We found differences between the FDA and ANVISA in the OL classification based on the authorized age of use and indications for prescription, mainly in systemic antimicrobials and cardiovascular drugs. When we compared the prescribing information provided by the FDA and the ANVISA, we found that the criteria of the ANVISA were less specific. Conclusion: Off-label and unlicensed drug prescription are frequent in neonatal intensive care applying the criteria of either agency, although the FDA has established more detailed criteria in terms of the ages and indications for which prescription is authorized. Resumen: Introducción: Las agencias reguladoras son responsables de enmarcar la prescripción de fármacos en condiciones off-label (OL) y unlicensed (UL) en los cuidados intensivos neonatales. No obstante, los criterios de aprobación establecidos pueden variar entre las agencias de distintos países. El objetivo del estudio fue determinar la frecuencia de la prescripción de fármacos OL y UL en una muestra de pacientes en cuidados intensivos neonatales según los criterios establecidos por la Food and Drug Administration (FDA) de Estados Unidos y la Agência Nacional de Vigilância Sanitária (ANVISA) de Brasil, analizando las diferencias en los resultados obtenidos con los criterios de cada agencia. Métodos: Estudio prospectivo de cohortes en neonatos ingresados más de 24 horas en la unidad de cuidados intensivos neonatales (UCIN) de un hospital universitario materno infantil entre agosto de 2017 y julio de 2018. Se obtuvo información sobre los fármacos incluidos en el análisis de prescripción OL y UL de las bases de datos DrugDex-Micromedex® y de la información oficial sobre fármacos de Brasil. La concordancia entre los criterios de la FDA y de la ANVISA se evaluó por medio del índice kappa. Los valores de kappa < 0,200 se consideraron indicativos de discordancia. Resultados: Se evaluó a 220 neonatos ingresados en la UCIN y 17 421 prescripciones de fármacos individuales en el período de estudio. No hubo diferencias en la proporción de pacientes que recibieron al menos una prescripción OL según se aplicasen los criterios de la FDA o los de la ANVISA (96,4% vs. 98,6%). En cambio, se encontraron diferencias en el motivo de clasificación como OL en base a la edad o a la indicación entre las dos agencias reguladoras, principalmente en la prescripción de antiinfecciosos sistémicos y agentes cardiovasculares. Al comparar las condiciones de prescripción aprobadas por la FDA y la ANVISA, se observó que los criterios de la ANVISA eran menos específicos. Conclusiones: La prescripción de fármacos off-label y unlicensed es frecuente en los cuidados intensivos neonatales aplicando los criterios de cualquiera de las dos agencias, los criterios de la FDA son más específicos en cuanto a los grupos de edad y las indicaciones para los que se autoriza el uso de los fármacos.

Objectives Omnitrope® (somatropin, Sandoz Inc.) is one of several recombinant human growth hormones (rhGH) approved in the United States (US) for use in pediatric indications, including growth hormone deficiency (GHD) and idiopathic short stature (ISS). We report data on the effectiveness and safety of Omnitrope® in the US cohort of the PATRO Children (international, longitudinal, non-interventional) study. Methods All visits and assessments are carried out according to routine clinical practice, and doses of Omnitrope® are given according to country-specific prescribing information. Results By September 2018, 294 US patients were recruited; the two largest groups were GHD (n=193) and ISS (n=62). Across all indications, HSDS improvement (ΔHSDS) from baseline at three years was +1.0 (rhGH-naïve, +1.2; pre-treated, +0.7). In pre-pubertal patients, ΔHSDS from baseline at three years was +0.94 (rhGH-naïve, +1.3; pre-treated, +0.7). Following three years of treatment, ΔHSDS from baseline was +1.3 in rhGH-naïve GHD patients and +1.1 in rhGH-naïve ISS patients. In pre-pubertal rhGH-naïve patients, ΔHSDS from baseline was +1.3 and +1.2 in GHD and ISS patients, respectively. Overall, 194 patients (66.0%) experienced adverse events (AEs; n=886 events); most were of mild-moderate intensity. Five patients (1.7%) had AEs that were suspected to be treatment-related (n=5 events). All reported neoplasms were benign, non-serious, and considered unrelated to rhGH therapy. No AEs of diabetes mellitus or hyperglycemia were reported. Conclusions Omnitrope® appears to be well tolerated and effective in the majority of patients, without evidence of an increased risk of developing unexpected AEs, diabetes mellitus, or new malignancies during treatment.

BackgroundPsychotropics are overprescribed for adults with intellectual disabilities; there are few studies in children and young people.AimsTo investigate antipsychotic and antidepressant prescribing in children and young people with and without intellectual disabilities, and prescribing trends.MethodScotland's annual Pupil Census, which identifies pupils with and without intellectual disabilities, was record-linked to the Prescribing Information System. Antidepressant and antipsychotic data were extracted. Logistic regression was used to analyse prescribing between 2010 and 2013.ResultsOf the 704 297 pupils, 16 142 (2.29%) had a record of intellectual disabilities. Antipsychotic and antidepressant use increased over time, and was higher in older pupils; antipsychotic use was higher in boys, and antidepressant use was higher in girls. Overall, antipsychotics were prescribed to 281 (1.74%) pupils with intellectual disabilities and 802 (0.12%) without (adjusted odds ratio 16.85, 95% CI 15.29–18.56). The higher use among those with intellectual disabilities fell each year (adjusted odds ratio 20.19 in 2010 v. 14.24 in 2013). Overall, 191 (1.18%) pupils with intellectual disabilities and 4561 (0.66%) without were prescribed antidepressants (adjusted odds ratio 2.28, 95% CI 2.03–2.56). The difference decreased each year (adjusted odds ratio 3.10 in 2010 v. 2.02 in 2013).ConclusionsSignificantly more pupils with intellectual disabilities are prescribed antipsychotics and antidepressants than are other pupils. Prescribing overall increased over time, but less so for pupils with intellectual disabilities; either they are not receiving the same treatment advances as other pupils, or possible overprescribing in the past is changing. More longitudinal data are required.

Background Recombinant human follitropin alfa (r-hFSH) is used for ovarian stimulation as part of medically assisted reproduction. There is a risk for ovarian hyperstimulation syndrome (OHSS) with r-hFSH treatment, and an increased risk for thromboembolic events in the presence of pregnancy with OHSS. Objectives To report the frequency of OHSS and thromboembolism with originator follitropin alfa (GONAL-f) based on the Global Safety Database of Merck KGaA, Darmstadt, Germany and a systematic review of published data. Data Sources Reports of OHSS and thromboembolism were obtained from the Global Safety Database of Merck KGaA, Darmstadt, Germany from 20 October 1995 to 19 October 2018. The systematic review was based on MEDLINE and Embase searches from inception to 19 October 2018. Study Eligibility Criteria Patients receiving GONAL-f for ovulation induction or ART, with a starting dose within the range included in the prescribing information and providing information on the occurrence of OHSS and/or thromboembolism. Study Appraisal and Synthesis Matches In the Global Safety Database of Merck KGaA, Darmstadt, Germany there were an estimated 16,525,975 treatment cycles since 20 October 1995; 1110 reported cases of OHSS and 80 reported cases of thromboembolic events (reporting rates 6.7 and 0.48 per 100,000 treatment cycles, respectively). The systematic review identified 45 studies (5186 patients exposed to GONAL-f; 5240 treatment cycles). There were 272 reports of OHSS (5190 [5.19%] per 100,000 treatment cycles), including 10 cases of severe OHSS (191 [0.19%] per 100,000 treatment cycles). Limitations There may be the potential for under-reporting of safety outcomes in the literature, and under-reporting is a well-known phenomenon in spontaneous reporting databases. Conclusion and Implications of Key Findings Our analyses demonstrate low rates of OHSS and thromboembolism with GONAL-f. Electronic Supplementary Material The online version of this article (10.1007/s12325-020-01512-w) contains supplementary material, which is available to authorized users.

Background: Selection of optimal tracer activity for 82Rb PET is based on a trade-off between necessary count-statistics in the late static phase and detector saturation in the early blood-pool phase. Administered tracer activity recommended in prescribing information differs substantially from recommendations in current literature. The present study examines the effect on both absolute myocardial blood flow (MBF), myocardial flow reserve (MFR) and relative myocardial perfusion imaging (MPI) of reducing dose.Methods: Forty patients were scanned twice on a PMT-based PET/CT (GE D690): At recommended activity (1110 MBq) and at either 740 or 370 MBq. MBF, MFR, total perfusion deficit (TPD) and ejection fractions (EF) were quantified. Results were compared using linear regression and Bland–Altman plots.Results: Linear correlation between MBF at 1110 MBq at either reduced activity had an R2 > 0.98. A small bias (± 5%-9%) was observed with opposite signs for 1110/740 and 1110/370. Limits of agreement for MBF were larger for 1110/370. MFR had a lower linear correlation (R2 = 0.96), but wide limits of agreement especially for 1110/370. TPD and EF correlated well at 1110/740 (R2 = 0.96 and 0.99, respectively), but large scatter was observed for 1110/370.Conclusion: Reduction of the tracer activity to 740 MBq, significantly reduced dead-time correction factors, while still producing reliable static and gated images. However, despite large dead-time at 1110 MBq, no systematic bias on absolute MBF was observed compared to reduced activities.

Background Sublingual immunotherapy (SLIT) is administered via tablets (SLIT-T) or liquid drops (SLIT-D). In North America, currently 4 SLIT-T formulations are approved by the US Food and Drug Administration for allergy immunotherapy, and SLIT-D is an off-label use of subcutaneous immunotherapy (SCIT) extracts. Objective To compare and contrast aspects of SLIT-T and SLIT-D, including physical characteristics, mechanism of action, dosing, efficacy, safety, adherence, and cost. Data Sources PubMed literature review (no limits), product prescribing information, and manufacturer websites. Study Selections Publications related to physical characteristics, mechanism of action, dosing, efficacy, safety, and adherence. Results Published evidence indicates that tablet and drop formulations differ in regard to physical characteristics, dosing, and strength of evidence for efficacy. Whether there are any differences in absorption and mechanism of action between the 2 formulations is currently unknown. Optimal dosing, efficacy, and safety have been established for SLIT-T. In contrast, in North America there is little support for efficacy of SLIT-D from randomized double-blind, placebo-controlled trials, and dose ranges have not been appropriately evaluated. SLIT-T treats a single allergen, whereas in the United States SLIT-D often contains multiple allergens to treat polysensitization. The safety profiles of SLIT-T and SLIT-D appear similar, and both formulations are considered safer than SCIT. Conclusion Professional guidelines should make a clear distinction between SLIT-T and SLIT-D in their recommendations to minimize confusion with the umbrella term SLIT.

The prevalence of cutaneous adverse events attributable to newly approved anti-cancer drugs has been well reviewed in the dermatologic literature. In contrast, over 75% of US Food and Drug Administration approvals in the past 5 years have been for non-cancer drugs and indications. This represents multiple other categories of approved medications associated with cutaneous adverse reactions. To investigate the cutaneous adverse events associated with these potentially neglected medications, a systematic review was conducted. Two hundred and forty-one medications approved by the Food and Drug Administration between 2013 and 2018 were reviewed and 180 non-oncologic drugs were identified. The prescribing information for each medication was reviewed for the presence of cutaneous adverse events and a supplemental literature search was performed to better characterize any adverse events outlined within the prescribing information. Most reactions were classified as morbilliform, macular, popular, or maculopapular. Fortunately, only a few severe cutaneous adverse reactions were reported, namely in benznidazole, cannabidiol, and sofosbuvir. This review summarizes available data drawn from clinical trials and case reports involving cutaneous adverse events from the 21 non-oncologic medications associated with cutaneous adverse events.

Zusammenfassung Hintergrund Die Fachinformationen (FI) wirkstoffgleicher Arzneimittel konnen inhaltliche Unterschiede aufweisen. Dies kann bei Verordnungen von Arzneimitteln im Rahmen der Aut-idem-Regelung zu Schwierigkeiten fur die arztliche Aufklarung fuhren. Zur Beurteilung des Nutzungsverhaltens von FI, der zur Informationsbeschaffung uber Arzneimittel herangezogenen Quellen und der Kenntnis von der Existenz von Unterschieden zwischen FI wirkstoffgleicher Arzneimittel wurde eine Befragung von Hausarzten (HA) und Apothekern (AP) durchgefuhrt. Methode Es wurde ein explorative/nicht-reprasentative, fragenbogengestutzte, telefonbasierte, semistrukturierte Querschnittsbefragung durchgefuhrt (Juni bis August 2018). Ergebnisse Die Teilnahmequoten lagen bei 29,8% (34/114) der HA bzw. 73,0% (73/100) der AP. Im letzten Monat hatten alle AP und 82,4% der HA mindestens einmal eine FI genutzt (p = 0,001). Die HA gaben an, FI monatlich 6,4 ± 4,9 Mal zu nutzen, AP 65,0 ± 52,5 Mal (p Diskussion Die Ergebnisse der vorliegenden Befragung ergaben Hinweise auf eine geringe Nutzung von FI durch HA sowie geringe Kenntnis von der Existenz von Unterschieden zwischen FI wirkstoffgleicher Handelspraparate in dieser Berufsgruppe. Beide Aspekte konnen zu einer nicht ordnungsgemasen Aufklarung fuhren, insbesondere bei der Aut-idem-Verordnung von Substanzen, fur die zahlreiche wirkstoffgleiche Handelspraparate mit unterschiedlichen FI verfugbar sind. Schlussfolgerung Arzte sollten FIs regelmasig nutzen und uber Unterschiede zwischen FIs wirkstoffgleicher Handelspraparate informiert sein.

Objectives: Fear of opioid withdrawal syndrome (OWS) often dissuades opioid discontinuation. Lofexidine is an FDA-approved, alpha2-adrenergic receptor agonist for treatment of OWS. Pivotal trial results from the per-protocol statistical analyses have been published. However, the FDA prescribing information presents these efficacy results using a different, standardized statistical approach that does not transform data or impute missing values. This analysis is easier to interpret and allows comparison across studies. This reanalysis is presented here. Methods: Studies were double-blind, placebo-controlled for 7 days in Study 1 and 5 days in Study 2. Opioid-dependent adults received placebo or lofexidine; efficacy was assessed using the Short Opioid Withdrawal Scale of Gossop (SOWS-G) daily. Results: Study 1 (N = 602) mean SOWS-G scores were 6.1 (SE: 0.35), 6.5 (SE: 0.34), and 8.8 (SE: 0.47) over Days 1–7 for lofexidine 2.88 mg/day, 2.16 mg/day, and placebo, respectively (for 2.88, p

Liver disease is a common condition worldwide that can cause alterations in drug disposition and susceptibility to drug toxicities, with increased risk of adverse drug reactions. European Summaries of Product Characteristics (SmPCs) and United States Prescribing Information (US PI) should therefore be comprehensible to prescribers regarding their liver-associated contraindications to ensure safe prescribing. This study aimed to evaluate the ambiguity of terminology used in communicating liver-associated absolute contraindications in SmPCs/PI of commonly prescribed drugs in four major drug markets (Germany, Switzerland, the United Kingdom, and the United States) by assigning wordings to different categories and analyzing their clinical comprehensibility. For US PI, 79% did not contain liver-related contraindications, compared to 2, 13, and 6% of German, Swiss, and British SmPCs, respectively. Study findings indicate that out of 228 examined SmPCs/PI containing liver-related contraindications, 77, 79, 76, and 52% contained unclear wording in the German, Swiss, British, and American drug market, respectively. Only 40% (German), 52% (Swiss), 39% (British), and 29% (American) of SmPCs/PI included terms with explicit wording. Including more precise statements in SmPCs/PI based on laboratory parameters (such as albumin) or scores (e.g., the Child–Pugh score) to objectify the severity of liver disease may improve the clarity of SmPCs/PI and the safety of drug prescription.

We report a 59-year-old male with left leg osteomyelitis caused by an XDR Pseudomonas aeruginosa strain following a road traffic accident. Limited treatment options and adverse antimicrobial reaction led to consideration of cefiderocol together with appropriate surgical intervention. Improved bony remodelling over the tibia and fibula was observed with good bony alignment and no adverse features. Physiotherapy support was continued for 4 months following treatment, which resulted in good functional mobility, improved proprioception and full ability to bear weight. This case also adds to multiple reports that describe safe and successful use of cefiderocol to treat MDR, aerobic Gram-negative infections. The prescribing information for cefiderocol is available at: https://shionogi-eu-content.com/gb/fetcroja/pi.

Objectives To review the availability of information specific to older people in the product labeling for novel US Food and Drug Administration drug approvals in 2019. Design Descriptive report. Methods Product labeling for the 48 novel new drugs approved by the US Food and Drug Administration in 2019 were analyzed for the presence of information specific to older people. The “Geriatric Use” section, Section 8.5 in the product labeling, was categorized based on the information available. Each product label was further searched using the terms “geriatric,” “elderly,” “old,” and “year.” Searches of the term “old” and “year” focused on information that mentioned adults 65 years of age or older. The sections of the product label that contained additional information related to older people was identified. Results Information was available in the “Geriatric Use” section (Section 8.5) for 46 of the 48 novel new drugs approved in 2019; 2 did not include a “Geriatric Use” section. Four product labels indicated that the drugs were not used in older people. One of the 2 medications whose labeling omitted the “Geriatric Use” section was also not indicated for use in older people. These labels were excluded from analysis.Of the remaining 42 drugs, there was insufficient numbers of patients 65 years of age and older to determine whether older patients responded differently than younger patients for 18 medications. Labeling for 15 medications indicated that there was no difference in safety and/or efficacy between younger and older persons. Product information for 6 medications indicated that the incidence of adverse events was higher for older people. The product label for 2 medications indicated that no dosage adjustment was required in older patients. One medication’s product labeling indicated that there were insufficient numbers of patients 65 years of age or older for 1 indication but that there was no difference in safety and/or efficacy for the medication’s second indication. Additional sections that referred to people 65 years of age and older included warnings and precautions, clinical trial experience, pharmacokinetics for special populations, and clinical studies. The “Geriatric Use” section of 1 product label referred to the dosage recommendations in patients with renal impairment. Conclusion Despite efforts to increase the enrollment of older people in clinical trials, 43% of the novel new drugs approved in 2019 lacked information on differences in response between older and younger populations because of insufficient numbers of study subjects. This paucity of information translates into therapeutic uncertainty regarding the safety and efficacy of these new medications in older people. An additional concern is that 14% of novel new drug labels indicated that older people are at greater risk for adverse events. Limited information specific to older people is available in other parts of the product labeling. More useful information related to older persons needs to be included in new drug labeling.

Introduction Dissemination of generic drug (GD) use could provide significant savings on drug expenditures and contribute to the long-term sustainability of healthcare. We aimed to exhibit the nationwide trend of GD use in primary care and investigate potentially relevant drug and patient factors. Methods Prescriptions written by primary care physicians in Turkey between 2013 and 2016 were analysed using the National Prescribing Information System. We determined the ratio of GD prescriptions with all prescriptions in terms of quantity and cost. In addition, we analysed the use of GD in terms of demographic characteristics of the patients, the most frequently prescribed preparations and frequent indications. Results In the 4-year period, we identified 518,335,821 prescriptions, those with at least one GD constituted 54.0% (n = 786,972,813) with a total cost-share of 36.9%-37.8%. GD use was the highest in 2016 (54.4%) and lowest in 2014 (53.6%). GD prescribing was higher in women than men every year (P < .001 for each), with the highest difference in 2016 as 54.7% vs 54.0%. GD utilisation decreased as the age group increased, which was 64.0%-64.5% in = 75-year-old group. Among the top ten encountered indications, the highest and lowest GD prescribing was detected in acute tonsillitis (68.1%) and hypertension (33.9%). Metformin had the highest percentage of GD prescribing (96.1%-97.7%), whereas esomeprazole showed the lowest GD prescribing (4.5%-14.8%) among the most frequently used preparations in primary care. Conclusion This study shows a modest upward trend of GD utilisation in primary care, though its share appears to be lower than expected. GD use revealed a consistent reduction towards older age groups. GDs were more likely to be prescribed for acute conditions, particularly infectious diseases.

We report the methods, results, and some implications of an experiment to provide API access to reorganized, re-represented content from a current U.S. Food and Drug Administration (FDA) Structured Product Label (SPL). Using a question-and-answer pattern and current technical approach, we demonstrate that prescribing information in SPLs can be converted to a more granular, highly computable, API-accessible format. Our results suggest that computable prescribing information can be systematically published in drug product-specific modules, deployed and widely distributed via APIs, and integrated with downstream client apps to answer key questions about medications and compute patient-specific advice.

Dong-Jin Yi,1 Seongjin Hwang,2 JunHyuk Son,3 Irina Yushmanova,4 Krystal Anson Spenta,5 Suzanne St.Rose6 1BLS Clinic, Seoul, Republic of Korea; 2Fulore Clinic, Seoul, Republic of Korea; 3Department of Ophthalmology, Yeungnam University College of Medicine, Daegu, Republic of Korea; 4Global Patient Safety and Epidemiology, Allergan plc, Irvine, CA, USA; 5Global Medical Trial Management, Allergan plc, Irvine, CA, USA; 6Global Patient Safety and Epidemiology, Allergan Holdings Ltd, Marlow, Buckinghamshire, UKCorrespondence: Suzanne St.RoseAllergan Holdings, Ltd., Marlow International, The Parkway, Marlow, Buckinghamshire SL7 1YL, UKTel +44 16 2849 4299Email Suzanne.strose@allergan.comPurpose: OnabotulinumtoxinA is approved in the Republic of Korea for the treatment of moderate-to-severe crow’s feet lines (CFL) and glabellar lines (GL), separately or in combination. We assessed safety and effectiveness of onabotulinumtoxinA in real-world clinical practice.Patient and methods: This 4-year postmarketing surveillance study was conducted in the Republic of Korea in subjects with moderate-to-severe CFL. Subjects aged 18 to 75 years received onabotulinumtoxinA injections for CFL alone or in combination with GL. Safety assessments included adverse events (AEs), serious AEs (SAEs), and unexpected AEs (not noted in Korean prescribing information). Investigators assessed effectiveness via change from baseline in CFL.Results: The full analysis set comprised 695 subjects; 667 were in the safety set and 376 in the effectiveness set. In the safety set, mean ± SD age was 40.9±13.0 years; most subjects (87.3%) were female. More subjects were treated for CFL (69.9%) than CFL and GL simultaneously (30.1%). Eleven subjects experienced 14 AEs; 12 were mild in severity and 11 resolved without sequelae. Two cases of injection site pain in 2 subjects each were deemed possibly related to onabotulinumtoxinA. One unexpected SAE (acute renal failure) occurred in 1 subject (0.15%). All unexpected AEs (n=4) were mild and considered unrelated to treatment. Overall change from baseline showed CFL was improved in 375 subjects (99.7%) and unchanged in 1 subject (0.3%).Conclusion: OnabotulinumtoxinA was well tolerated and effective for treatment of CFL with or without GL in a real-world Korean population. No new safety concerns were identified.Keywords: aesthetics, Botox, botulinum toxins, type A, skin aging

Recently, pharmaceutical companies have increased their focus on engaging with patients, following trends toward patient centricity and delivering services around individual drugs. Meanwhile, the U.S. Food and Drug Administration has released draft guidance on disclosing risk information in consumer-directed materials that recommends against verbatim presentations of the risk-related sections within prescribing information, as this may be of limited value to consumers who lack medical or scientific training. In this context, Bristol-Myers Squibb set out to build an organizational capability to communicate complex health topics to patients called the Universal Patient Language™, or UPL. In this report, the authors explore health literacy considerations within the pharmaceutical industry; introduce the UPL; explain how human-centered service design methods were deployed to build the UPL; and present two UPL case studies.

This chart is an update to the 2012 article published in Hospital Pharmacy on injectable drugs to be used with a filter. To update the chart, drugs approved from December 2011 to April 2019 were reviewed to determine if they require filtration and drugs included in the 2012 table were reviewed for accuracy. Readers are urged to review national standards of practice for information about clinical situations that warrant the use of a filter for medication preparation or administration, independent of the drug being given, and the reader should consult the Food and Drug Administration (FDA)-approved prescribing information for the most up-to-date information.

To develop a comprehensive open-source measurement guide of the most prevalent chronic conditions among persons aged 65+ based on registry data of both diagnoses and prescribed drugs [“The Chronic Condition Measurement Guide (CCMG)]. Based on the Danish population aged 65 years and older we developed the CCMG identifying 83 different chronic conditions based on registry data of both diagnoses and prescribed drugs. By applying the CCMG to a large national cohort of all Danish citizens aged 65 or above, we found that the prevalence of multimorbidity ranged from 10 to 69% using different years of history and in- or excluding information about drug prescribing. The CCMG is easily implemented using registry data and we recommend using 10 years of history and drug prescribing information. The aim of the study was to develop a comprehensive open-source measurement guide of the most prevalent chronic conditions among persons aged 65+ based on registry data of both diagnoses and prescribed drugs [the chronic condition measurement guide (CCMG)]. Furthermore, to investigate proof of concept of the measurement guide, different years of history and in- and excluding data on prescribed drugs. Finally, to investigate the measurement guide with other measurement guides designed to identify chronic conditions in persons aged 65+. The measurement guide was based on the 200 most prevalent chronic ICD10 codes in the Danish population 65+ years in 2015; the 200 most prevalent chronic ICD10 codes and causes of death in a cohort of 209,337 people who died of non-traumatic causes (January 2011–January 2016). Prescribed drugs were included in the measurement guide based on a literature review and specialist opinions. We identified 83 different chronic conditions based on 1241 unique ICD-10 codes. Multimorbidity prevalence ranged from 10% (1-year history, excluding prescribing information) to 69% (15-year history, including prescribing information). We identified 95% of the persons with multimorbidity using the 29 most prevalent chronic conditions. Inclusion of these 29 conditions affected the prevalence of multimorbidity and 1-year mortality when the CCMG was compared with other measurement guides. The CCMG is easily implemented using registry data. When implementing the measurement guide 10 years of history and drug prescribing information should be used. Using the CCMG to study multimorbidity, we recommend using at least the 29 most prevalent chronic conditions.

OBJECTIVE This retrospective study aimed at identifying opiate prescribing practices, the number of morphine milligram equivalents (MMEs) prescribed by orthopaedic and nonorthopaedic providers in patients with operatively treated isolated lower extremity fractures, and provide opiate prescribing recommendations. METHODS Patients older than 18 years with isolated lower extremity (unicondylar, bicondylar, tibial shaft, pilon, and ankle) fractures between 2005 and 2016 were identified. Prescribing information was obtained from the State Controlled Substance Monitoring Database. Descriptive statistics were calculated for each injury and plotted for MME use. Mann-Whitney and Wilcoxon tests were used for data analysis. To aid in clinical relevance, MMEs were converted to number of pills of oxycodone 10 mg (OC 10 mg). RESULTS Three hundred forty-one patients met our inclusion criteria. Mean age was 45 years; 56% (192/341) were men. Forty-seven percent (159/341) were prescribed opiates before their injury. Orthopaedic providers prescribed more opiates to patients with pilon fractures compared with unicondylar (P = 0.010), tibial shaft (P < 0.001), and ankle (P < 0.001) fractures. Bicondylar plateau fracture patients also received more opiates when compared with unicondylar (P = 0.001), tibial shaft (P < 0.001), and ankle (P < 0.001) fractures. Nonorthopaedic providers prescribed more opiates to patients with pilon fractures when compared with unicondylar (P = 0.006), bicondylar (P < 0.001), tibial shaft (P < 0.001), and ankle fractures (P = 0.006). Differences between orthopaedic and nonorthopaedic MMEs prescribed are significantly different for each injury type (

The aim was to analyze safety data associated with the maternal use of antiepileptic drugs in pregnancy and to assess the risk of cleft lip and/or palate (CL/P) as an outcome in the neonate. A parallel objective was to assess the completeness of the safety information concerning pregnancy exposures in the Summary of Product Characteristics (SmPCs) and the Patient Information (PI) in the USA and the UK.We analyzed individual case safety reports of CL/P associated with antiepileptic drugs in the FDA Adverse Event Reporting System. For the antiepileptic drugs with signals (EB05 ≥ 2), we reviewed Drug Analysis Prints for CL/P cases in the UK Medicines and Healthcare products Regulatory Agency (MHRA). We performed descriptive analyses of relevant SmPCs and PIs in the UK and the USA using a checklist of recommendations collected from the literature.In total 817 CL/P reports were identified for 12 antiepileptic drugs in the FDA Adverse Event Reporting System. Ten of the 12 antiepileptic drugs were associated with 156 CL/P cases in the MHRA Sentinel. Safety information concerning pregnancy was found to be more comprehensive in UK SmPCs than in the US equivalents.There is statistical disproportionality in individual case safety reports indicative of an increased risk of CL/P with 12 antiepileptic drugs studied. More studies are required to explore the association between in utero exposure to antiepileptic drugs and the risk of CL/P. There are inconsistencies between the UK and US safety labels. CL/P associated with antiepileptic drugs is an important topic and requires providing inclusive, unbiased, up-to-date information to prescribers and women of childbearing age.

As the liver is vital for the metabolism of many anticancer drugs, determining the correct starting doses in cancer patients with liver impairment is key to safe prescription and prevention of unnecessary adverse effects. Clinicians typically use liver function tests when evaluating patients; however, prescribing information and summaries of product characteristics often suggest dosing of anticancer drugs in patients with liver impairment based on the Child-Pugh criteria, even though the criteria were not developed for this purpose. In this review, we assessed all the oncological small molecule and cytotoxic drugs approved by the United States Food and Drug Administration (FDA) over a 5-year period from 2014 to 2018. The various entry criteria related to these drugs—with respect to hepatic function—in key pivotal studies were compared with their approved dosing recommendations found in prescribing information and summaries of product characteristics. We found that 46% of drugs have dosing recommendations based on Child-Pugh criteria alone, despite the fact that only 8% of these drugs were tested within studies that used the Child-Pugh criteria as entry criteria. Moreover, we note that the data used to make recommendations based on Child-Pugh criteria are typically from small studies that may lack an appropriate patient population. We propose that these findings, along with details surrounding the development of the Child-Pugh criteria, call into question the validity and appropriateness of using Child-Pugh criteria for dosing recommendations of anticancer drugs., Highlights • Dosing information for anticancer drugs in patients with liver impairment is often based on the Child-Pugh criteria. • Clinical trials and clinicians typically use liver function tests when evaluating patients. • Of the 39 oncologic drugs examined, almost half (46%) had dosing recommendations based on Child-Pugh criteria alone. • We question whether using Child-Pugh criteria for dosing recommendations of anticancer drugs is the best approach.

Objective: To review the efficacy and safety of crizanlizumab (Adakveo) in the prevention of vaso-occlusive pain crises in sickle cell disease. Data Sources: An English-language literature search of PubMed, MEDLINE, and Ovid (1946 to January 2021) was completed using the terms crizanlizumab, SEG101, SelG1, and sickle cell disease. Manufacturer prescribing information, article bibliographies, and data from clinicaltrials.gov were incorporated in the reviewed data. Study Selection/Data Extraction: All studies registered on clinicaltrials.gov were incorporated in the reviewed data. Data Synthesis: Crizanlizumab is the first monoclonal antibody approved for sickle cell disease to reduce the frequency of vaso-occlusive crises. One phase 2 clinical trial and a post hoc analysis of the trial have been published. Relevance to Patient Care and Clinical Practice: Crizanlizumab is a monthly intravenous infusion approved by the Food and Drug Administration for patients with sickle cell disease 16 years of age and older to reduce the frequency of vaso-occlusive crises. Conclusion: Crizanlizumab appears to be an efficacious therapy for patients with sickle cell disease to reduce the frequency of vaso-occlusive crises. Concerns include drug cost and administration. Long-term benefits and risks have not been determined.