Labeling Changes Research Articles

Rebound of medication abortion in Texas following updated mifepristone label

BackgroundIn 2013, Texas House Bill 2 (HB 2) placed restrictions on the use of medication abortion, which later were nullified with the 2016 FDA-approved mifepristone label. MethodsUsing data collected directly from Texas abortion facilities, we evaluated changes in the provision and use of medication abortion during three 6-month time periods corresponding to the policy changes: before HB 2, after HB 2 and after the label change. ResultsMedication abortion constituted 28% of all abortions before HB 2, 10% after implementation of the restrictions and 33% after the label change. ConclusionsUse of medication abortion in Texas rebounded after the FDA label change.

Current status of pharmacovigilance regulatory structures, processes, and outcomes in the Asia‐Pacific region: Survey results from 15 countries

Regulatory discrepancies may exist in pharmacovigilance (PV) structure, process, and outcome status worldwide. Our study's objective was to survey the current status of PV in each regulatory body in the Asia-Pacific Economic Cooperation (APEC) region. A modified questionnaire was sent to the PV team heads of 21 PV agencies based in the APEC countries, between June 28 and September 12, 2017, to gather information on the structure, process, and outcome of PV status in these countries. Of the 21 APEC countries, 15 responded. We found harmonized laws and regulations for general PV and risk management systems. However, variations were found in PV structure: for example, 11 out of 15 countries had national regulatory representatives responsible for PV in pharmaceutical companies, while four did not. For PV process, discrepancies were also found in the source type of adverse drug reaction (ADR) reports and reporting of medication errors and therapeutic ineffectiveness in cumulative ADR reports. With respect to PV outcomes, among countries that performed active surveillance, the United States of America was more active, with hundreds of projects including additional pharmacoepidemiological studies etc. Among the nine countries that responded, Japan had the greatest number of product label changes followed by Taiwan, Malaysia, and Korea. We have identified substantial variations in the structures, processes, and outcomes of PV status among the countries of the APEC region. Therefore, efforts to reduce variations in the PV administration and regulation are warranted for harmonization of PV within the APEC region.

Anesthesia Exposure in Children: Practitioners Respond to the 2016 FDA Drug Safety Communication.

In December 2016, the US Food and Drug Administration (FDA) issued a drug safety warning stating that 11 commonly used anesthetic and sedative medications had potential neurotoxic effects when used in children under the age of 3 years and in pregnant women during the third trimester. A panel presentation at the sixth biennial Pediatric Anesthesia Neurodevelopmental Assessment (PANDA) symposium addressed the FDA announcement in a session entitled "Anesthesia Exposure in Children During Surgical and Non-Surgical Procedures: How Do We Respond to the 2016 FDA Drug Safety Communication?" Panelists included representatives from pediatric anesthesiology, obstetrics, pediatric surgery, and several pediatric surgical subspecialties. Each panelist was asked to address the following questions: How has the FDA labelling change affected your clinical practice including patient discussions, timing, and frequency of procedures? Has your professional society provided any guidelines for this discussion? Has there been any discussion of this topic at your national meetings? The panelists provided important perspectives specific to each specialty, which generated a lively discussion and a detailed response from the Deputy Director of the Division of Anesthesia and Addiction of the FDA describing the FDA procedures that led to this drug safety warning.

Remodeling of cholinergic input to the hippocampus after noise exposure and tinnitus induction in Guinea pigs.

Here, we investigate remodeling of hippocampal cholinergic inputs after noise exposure and determine the relevance of these changes to tinnitus. To assess the effects of noise exposure on the hippocampus, guinea pigs were exposed to unilateral noise for 2 hr and 2 weeks later, immunohistochemistry was performed on hippocampal sections to examine vesicular acetylcholine transporter (VAChT) expression. To evaluate whether the changes in VAChT were relevant to tinnitus, another group of animals was exposed to the same noise band twice to induce tinnitus, which was assessed using gap-prepulse Inhibition of the acoustic startle (GPIAS) 12 weeks after the first noise exposure, followed by immunohistochemistry. Acoustic Brainstem Response (ABR) thresholds were elevated immediately after noise exposure for all experimental animals but returned to baseline levels several days after noise exposure. ABR wave I amplitude-intensity functions did not show any changes after 2 or 12 weeks of recovery compared to baseline levels. In animals assessed 2-weeks following noise-exposure, hippocampal VAChT puncta density decreased on both sides of the brain by 20-60% in exposed animals. By 12 weeks following the initial noise exposure, changes in VAChT puncta density largely recovered to baseline levels in exposed animals that did not develop tinnitus, but remained diminished in animals that developed tinnitus. These tinnitus-specific changes were particularly prominent in hippocampal synapse-rich layers of the dentate gyrus and areas CA3 and CA1, and VAChT density in these regions negatively correlated with tinnitus severity. The robust changes in VAChT labeling in the hippocampus 2 weeks after noise exposure suggest involvement of this circuitry in auditory processing. After chronic tinnitus induction, tinnitus-specific changes occurred in synapse-rich layers of the hippocampus, suggesting that synaptic processing in the hippocampus may play an important role in the pathophysiology of tinnitus.

A novel colorimetric indicator based on agar incorporated with Arnebia euchroma root extracts for monitoring fish freshness

This work aimed to develop and characterize a novel indicator film for monitoring fish freshness based on agar incorporated with natural dye extracted from Arnebia euchroma root (AEREs). The Fourier transform infrared spectroscopy results reflected that some new interactions have occurred between polymer matrix and natural dye. And the results of X-ray diffraction and scanning electron microscopy indicated that AEREs were well dispersed in the agar base film. A certain decrease was observed in water solubility, swelling ratio and elongation at break of colorimetric film but tensile strength, Young's modulus, water vapor permeability and water contact angle of colorimetric film were increased by addition of AEREs. The prepared indicator films were used as freshness labels in an application trial, which was conducted to monitor the freshness of Wuchang bream (Megalobrama amblycephala) under refrigeration (4 °C) and at room temperature (25 °C). The total volatile basic nitrogen (TVB-N) and total viable count (TVC) of fish sample were determined periodically, and the color change of freshness labels was recorded simultaneously. The results showed that the indicator film with lower content of AEREs demonstrated more conspicuous color change during fish spoilage. And the color response of freshness label was consistent with the spoilage threshold of TVC and TVB-N content in fish sample. Thus, these colorimetric indicator films could indicate the fish spoilage by visible color change. The developed colorimetric indicator film is expected to provide a convenient, non-destructive and visual method to estimate fish freshness during storage.

Summaries of safety labeling changes approved by FDA-Boxed warnings highlights, July-September 2018.

Summaries of safety labeling changes approved by FDA-Boxed warnings highlights, July-September 2018.

Summaries of safety labeling changes approved by FDA-Boxed warnings highlights, July-September 2018.

As part of FDA’s MedWatch program, important changes to the safety labeling of drugs and therapeutic biologics, including boxed warnings, are posted on the agency’s website. Boxed warnings are ordinarily used to highlight (1) an adverse reaction so serious in proportion to the potential benefit

From the Chief Executive and IFST News

From the Chief Executive and IFST News

Pioglitazone, a PPARγ agonist, reduces cisplatin-evoked neuropathic pain by protecting against oxidative stress.

Painful peripheral neuropathy is a dose-limiting side effect of cisplatin treatment. Using a murine model of cisplatin-induced hyperalgesia, we determined whether a PPARγ synthetic agonist, pioglitazone, attenuated the development of neuropathic pain and identified underlying mechanisms. Cisplatin produced mechanical and cold hyperalgesia and decreased electrical thresholds of Aδ and C fibers, which were attenuated by coadministration of pioglitazone (10 mg/kg, intraperitoneally [i.p.]) with cisplatin. Antihyperalgesic effects of pioglitazone were blocked by the PPARγ antagonist T0070907 (10 mg/kg, i.p.). We hypothesized that the ability of pioglitazone to reduce the accumulation of reactive oxygen species (ROS) in dorsal root ganglion (DRG) neurons contributed to its antihyperalgesic activity. Effects of cisplatin and pioglitazone on somatosensory neurons were studied on dissociated mouse DRG neurons after 24 hours in vitro. Incubation of DRG neurons with cisplatin (13 µM) for 24 hours increased the occurrence of depolarization-evoked calcium transients, and these were normalized by coincubation with pioglitazone (10 µM). Oxidative stress in DRG neurons was considered a significant contributor to cisplatin-evoked hyperalgesia because a ROS scavenger attenuated hyperalgesia and normalized the evoked calcium responses when cotreated with cisplatin. Pioglitazone increased the expression and activity of ROS-reducing enzymes in DRG and normalized cisplatin-evoked changes in oxidative stress and labeling of mitochondria with the dye MitoTracker Deep Red, indicating that the antihyperalgesic effects of pioglitazone were attributed to its antioxidant properties in DRG neurons. These data demonstrate clear benefits of broadening the use of the antidiabetic drug pioglitazone, or other PPARγ agonists, to minimize the development of cisplatin-induced painful neuropathy.

Time Temperature Indicator Label using Black Corn Extract and Chitosan Matrix

Time-temperature indicator (TTI) labels have been widely researched and some have been used commercially due to their ability to provide food product quality information through changes in label color when exposed to temperature over a specified period of time. The TTI label consists of functional dyes and matrices. The purpose of this study was to develop a TTI label that uses natural dyes derived from black corn extract and chitosan as the matrix. Labels were prepared using a simultaneous method then casted on top of PET substrate. Absorption properties of the black corn extract was investigated by using UV-Vis Spectrophotometer. The label colors were characterized using digital photography and analyzed with CIELab color code. The color of the labels were observed over time at temperature conditions of 10, 25 and 40 °C. The extract solution is red at pH 2-3, then pink at pH 4-5, purple at pH 6-7, violet at pH 8, and turned to yellow at pH 9-13 which indicates that the extract contains anthocyanin. Due to time period, the label changes color from purple to blue to yellow, with the fastest color changes occurred at higher temperature of 40 °C and slowest at lower temperature of 10 °C. The shelf life test on different RH conditions shows that the label stored at RH 33% is more stable than at higher RH of 76%. The labels show irreversible properties which is one of the requirements as a time temperature indicator label. These results indicate that the label of black corn extract with chitosan has the potential to be applied on smart packaging.

Summaries of Safety Labeling Changes Approved By FDA: Boxed Warnings Highlights, April-June 2018.

Summaries of Safety Labeling Changes Approved By FDA: Boxed Warnings Highlights, April-June 2018.

Target-Adverse Event Profiles to Augment Pharmacovigilance: A Pilot Study With Six New Molecular Entities.

Clinical trials can fail to detect rare adverse events (AEs). We assessed the ability of pharmacological target adverse‐event (TAE) profiles to predict AEs on US Food and Drug Administration (FDA) drug labels at least 4 years after approval. TAE profiles were generated by aggregating AEs from the FDA adverse event reporting system (FAERS) reports and the FDA drug labels for drugs that hit a common target. A genetic algorithm (GA) was used to choose the adverse event (AE) case count (N), disproportionality score in FAERS (proportional reporting ratio (PRR)), and percent of comparator drug labels with an AE to maximize F‐measure. With FAERS data alone, precision, recall, and specificity were 0.57, 0.78, and 0.61, respectively. After including FDA drug label data, precision, recall, and specificity improved to 0.67, 0.81, and 0.71, respectively. Eighteen of 23 (78%) postmarket label changes were identified correctly. TAE analysis shows promise as a method to predict AEs at the time of drug approval.

Fluoroquinolones: A hot topic for pharmacists and the Food and Drug Administration’s Division of Drug Information

ObjectivesThe Division of Drug Information (DDI) within the U.S. Food and Drug Administration’s (FDA’s) Center for Drug Evaluation and Research receives telephone calls, e-mails, and letters from patients and industry. The consistently high number of contacts about drugs in the fluoroquinolone class indicates an opportunity to increase awareness about the drugs’ evolving safety profile. Data sourcesDatabase used by DDI to summarize inquiries. SummaryInquiries about fluoroquinolones peaked in 2016 and were highest after FDA Drug Safety Communications that were issued that year. Among the first fluoroquinolone, ciprofloxacin, was approved in 1987. Since then, the FDA has required class-wide labeling changes reflecting postmarket benefit-risk assessments of oral and injectable (systemic) fluoroquinolones, including changes in 1990, 2008, 2013, 2016, and 2018. ConclusionPharmacists have a role that is more critical than ever to ensure the safety of patients who are prescribed a systemic fluoroquinolone. Pharmacists should stay informed on this class of drugs, be prepared to suggest alternate therapies, counsel patients on potential benefits and risks, and work with patients to submit Medwatch reports to the FDA if adverse events occur.

Intravoxel Incoherent Motion and Arterial Spin Labeling MRI Analysis of Reversible Unilateral Ureteral Obstruction in Rats.

Renal fibrosis is a common consequence of chronic kidney disease (CKD) and is the mechanism by which various forms of CKD progress to endstage renal failure. Accurate assessment of renal fibrosis is important for treatment. To measure longitudinal changes of intravoxel incoherent motion (IVIM) and arterial spin labeling (ASL) before and after reversible unilateral ureteral obstruction in an animal model. Self-controlled animal study. Surgical obstruction of the ureters was performed and then removed after 5 days. Rats were scanned on Days 0, 1, 3, and 5 after creating the obstruction and on Days 4, 7, and 12 after releasing the obstruction. 3.0T/IVIM/ASL. The apparent diffusion coefficient (ADC), pure molecular diffusion (D), perfusion fraction (f), pseudodiffusion (D*), and renal blood flow (RBF) obtained from the ASL were measured. Using SPSS v. 20.0 software, P < 0.05 were considered statistically significant. The data from each timepoint were compared using one-way analysis of variance and correlation analysis was applied to various parameters. The postobstruction kidneys showed renal tubule swelling and increased collagen fiber content. Renal tubule swelling was relieved after reversing the obstruction, but Masson staining and cell density analysis revealed progressive changes that were primarily localized to the medulla. In general, ADC, D, f, D*, and RBF decreased with time during the 5 days of obstruction, and increased after release of the obstruction. ADC positively correlated with D, f, D*, and RBF (r = 0.415, r = 0.634, r = 0.465 r = 0.586, P < 0.001, respectively) in the cortex in this study. Also, ADC showed a positive correlation with D, f, and D* (r = 0.724, r = 0.749, r = 0.151, P < 0.001, respectively) in the medulla. Kidney perfusion was the major factor affecting ADC. Functional imaging may be useful for following progression of CKD. 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:288-296.

Trends in concomitant clopidogrel and proton pump inhibitor treatment among ACS inpatients, 2000-2016.

The US Food and Drug Administration (FDA) issued three safety announcements between January 2009 and October 2010 warning against concomitant use of clopidogrel and proton pump inhibitors (PPIs) due to a potential drug-drug interaction that may attenuate clopidogrel's antiplatelet activity. This primary objective of this study was to examine trends in concomitant clopidogrel/PPI use among acute coronary syndrome (ACS) inpatients in the US between 2000 and 2016, in relation to the FDA safety communications. Adult inpatients with a primary diagnosis of ACS were identified from the Cerner Health Facts® database. The standardized (age, sex, race, and census region) prevalence of clopidogrel use with PPIs was calculated yearly and quarterly. Findings were stratified by PPIs' potential to inhibit clopidogrel's activity and by age. A total of 204,533 inpatients were identified. In 2008, the prevalence of concomitant clopidogrel and PPI treatment was 34.9%, decreasing to 24.4 and 16.4% in 2009 and 2010, respectively, with the decline being similar across age groups. Treatment with inhibiting PPIs (omeprazole and esomeprazole) and clopidogrel has continued to decrease since 2010, with a prevalence of 0.8% in 2016. A similar reduction was not observed with clopidogrel and non-inhibiting PPIs (pantoprazole, lansoprazole, rabeprazole, and dexlansoprazole). During the FDA warning period, the combined treatment with clopidogrel and H2 receptor antagonists, an alternative to PPIs suggested by the FDA, temporarily increased from 7.8% in 2008 to 12.8 and 14.5% in 2009 and 2010, respectively. Findings suggest that clinical practice recommendations made by the FDA were followed. Further research is needed to determine how changes in drug labels and the availability of new drugs may have influenced the observed trends.

A Comparative Study of Data Mining Algorithms used for Signal Detection in FDA AERS Database

<p style="text-align: justify;"><strong>Objective:</strong> Signal detection is a technique in pharmacovigilance for the early detection of new, rare reactions (desired or undesired) of a drug. This study aims to compare and appraise the performance of data mining algorithms used in signal detection. <strong>Method:</strong> Most commonly used three data mining algorithms (DMAs) (Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR) and Information Component (IC)) were selected and applied retrospectively in USFDA Adverse Event Reporting System database to detect five confirmed Drug Event Combinations. They were selected in such a way that the drug is withdrawn from the market or label change between 2006-2015. A value of ROR-1.96SE&gt;1, PRR&ge;2, &chi;2&gt;4 or IC- 2SD&gt;0 were considered as the positive signal. The data mining algorithms were compared for their sensitivity and early detection. <strong>Result:</strong> Among the three data mining algorithms, Information Component was found to have a maximum sensitivity (100%) followed by Reporting Odds Ratio (60%) and Proportional Reporting Ratio (40%). Sensitivity associated with the number of reports per drug event combination and early signal detection suggested that information component needs comparatively fewer reports to show positive signal than the other two data mining algorithms. ROR and PRR showed comparable results. <strong>Conclusion:</strong> Early detection of a reaction is possible using signal detection technique. Information component was found to be sensitive method compared with other two data mining algorithms in FDA Adverse Event Reporting System database. As the number of reports of drug event combination increased, the sensitivity and comparability of data mining algorithm also increased. <p style="text-align: justify;"><strong>Key words:</strong> Signal Detection, Data mining algorithms, FDA AERS Database, Disproportionality Analysis, Pharmacovigilance.

Transcranial direct-current stimulation (tDCS) improves detection of simple bright stimuli by amblyopic Long Evans rats in the SLAG task and produces an increase of parvoalbumin labelled cells in visual cortices

In this work visual functional improvement of amblyopic Long Evans rats treated with tDCS has been assessed using the “slow angled-descent forepaw grasping” (SLAG) test. This test is based on an innate response that does not requires any memory-learning component and has been used before for measuring visual function in rodents. The results obtained show that this procedure is useful to assess monocular but not binocular deficits, as controls and amblyopic animals showed significant differences during monocular but not during binocular assessment. On the other hand, parvoalbumin labelling was analysed in three areas of the visual cortex (V1M, V1B and V2L) before and after tDCS treatment. No changes in labelling were observed after monocular deprivation. However, tDCS treatment significantly improved vision through the amblyopic eye, and a significant increase of parvoalbumin-positive cells was observed in the three areas, both in the stimulated hemisphere but also in the non-stimulated hemisphere. This effect occurred both in control and amblyopic animals. Thus, tDCS induced changes are similar in controls and amblyopic animals, although only the last one showed a functional improvement.

PRM87 - CRITICAL EVALUATION OF VARIOUS DATA MINING ALGORITHMS USED FOR SIGNAL DETECTION IN FDA ADVERSE EVENT REPORTING SYSTEM DATABASE

Signal detection is a technique in pharmacovigilance for the early detection of new, rare reactions (desired or undesired) of a drug. This study aims to compare and appraise the performance of data mining algorithms used in signal detection. Most commonly used three data mining algorithms (DMAs) (Reporting Odds Ratio, Proportional Reporting Ratio and Information Component) were selected and applied retrospectively in USFDA Adverse Event Reporting System database to detect five confirmed Drug Event Combinations. They were selected in such a way that the drug is withdrawn from the market or label change between 2006-2015. A value of Reporting Odds Ratio-1.96SE>1, Proportional Reporting Ratio≥2, χ2>4 or Information Component- 2SD>0 were considered as the positive signal. The data mining algorithms were compared for their sensitivity and early detection. Among the three data mining algorithms, Information Component was found to have a maximum sensitivity (100%) followed by Reporting Odds Ratio (60%) and Proportional Reporting Ratio (40%). Sensitivity associated with the number of reports per drug event combination and early signal detection suggested that information component needs comparatively fewer reports to show positive signal than the other two data mining algorithms. Reporting Odds Ratio and Proportional Odds Ratio showed comparable results. Early detection of a reaction is possible using signal detection technique. Information component was found to be sensitive method compared with other two data mining algorithms in FDA Adverse Event Reporting System database. As the number of reports of drug event combination increased, the sensitivity and comparability of data mining algorithm also increased.

Dual-calibrated fMRI measurement of absolute cerebral metabolic rate of oxygen consumption and effective oxygen diffusivity

Dual-calibrated fMRI is a multi-parametric technique that allows for the quantification of the resting oxygen extraction fraction (OEF), the absolute rate of cerebral metabolic oxygen consumption (CMRO2), cerebral vascular reactivity (CVR) and baseline perfusion (CBF). It combines measurements of arterial spin labelling (ASL) and blood oxygenation level dependent (BOLD) signal changes during hypercapnic and hyperoxic gas challenges. Here we propose an extension to this methodology that permits the simultaneous quantification of the effective oxygen diffusivity of the capillary network (DC). The effective oxygen diffusivity has the scope to be an informative biomarker and useful adjunct to CMRO2, potentially providing a non-invasive metric of microvascular health, which is known to be disturbed in a range of neurological diseases. We demonstrate the new method in a cohort of healthy volunteers (n = 19) both at rest and during visual stimulation. The effective oxygen diffusivity was found to be highly correlated with CMRO2 during rest and activation, consistent with previous PET observations of a strong correlation between metabolic oxygen demand and effective diffusivity. The increase in effective diffusivity during functional activation was found to be consistent with previously reported increases in capillary blood volume, supporting the notion that measured oxygen diffusivity is sensitive to microvascular physiology.

Electrochemical Enzyme-Linked Sandwich Assay with a Cellulase Label for Ultrasensitive Analysis of Synthetic DNA and Cell-Isolated RNA.

Electrochemical enzyme-linked sandwich assays on magnetic beads (MBs) refer to one of the most sensitive approaches for analysis of nonamplified nucleic acid samples, with redox enzymes being routinely used as labels. Here, we report a sensitive and inexpensive electrochemical nucleic acid sandwich assay on MBs that exploits a hydrolytic enzyme cellulase as a label, while MBs are used for preconcentration and bioseparation of analyzed samples. Binding of target DNA or RNA to capture DNA-modified MB triggers sandwich assembly and its labeling with cellulase. Application of the assembled sandwich to the electrodes covered with insulating nitrocellulose films induces film digestion by the cellulase label and pronounced changes in the electrical properties of the electrodes, the extent of the changes being proportional to the concentration of the analyzed nucleic acids. Down to 1 amol of Lactobacillus brevis specific synthetic DNA and rRNA isolated from L. brevis cells could be detected in 1 mL samples in the overall from 2 to 3 h assay. The assay is universal and can be adapted for point-of-care-testing and for in-field environmental and microbiomic analysis of unamplified samples of any DNA/RNA sequences.