Pentosan associated retinal pigmentary changes: FDA's perspective on an emerging postmarketing safety finding.

INTRODUCTION AND HYPOTHESIS: Recent publications describe pigmentary changes in the retina associated with the use of pentosan polysulfate sodium, the only FDA-approved oral agent for relief of bladder pain or discomfort associated with interstitial cystitis. METHODS: To evaluate this association, we reviewed data from the FDA Adverse Event Reporting System and published case reports and observational studies. RESULTS: The totality of clinical and epidemiology evidence does not resolve the question of causation between pentosan use and retinal pigmentary changes; however, several elements support a potential association. CONCLUSION: Here, we provide our perspective on the available evidence the agency weighed when retinal pigmentary changes were added to pentosan labeling. It is important for urogynecologists prescribing pentosan to be aware of this potential association and be vigilant about assessing eye health in pentosan users.

Information Visualization Platform for Postmarket Surveillance Decision Support.

INTRODUCTION: The US FDA receives more than 2 million postmarket reports each year. Safety Evaluators (SEs) review these reports, as well as external information, to identify potential safety signals. With the increasing number of reports and the size of external information, more efficient solutions for data integration and decision making are needed. OBJECTIVES: The aim of this study was to develop an interactive decision support application for drug safety surveillance that integrates and visualizes information from postmarket reports, product labels, and biomedical literature. METHODS: We conducted multiple meetings with a group of seven SEs at the FDA to collect the requirements for the Information Visualization Platform (InfoViP). Using infographic design principles, we implemented the InfoViP prototype version as a modern web application using the integrated information collected from the FDA Adverse Event Reporting System, the DailyMed repository, and PubMed. The same group of SEs evaluated the InfoViP prototype functionalities using a simple evaluation form and provided input for potential enhancements. RESULTS: The SEs described their workflows and overall expectations around the automation of time-consuming tasks, including the access to the visualization of external information. We developed a set of wireframes, shared them with the SEs, and finalized the InfoViP design. The InfoViP prototype architecture relied on a javascript and a python-based framework, as well as an existing tool for the processing of free-text information in all sources. This natural language processing tool supported multiple functionalities, especially the construction of time plots for individual postmarket reports and groups of reports. Overall, we received positive comments from the SEs during the InfoViP prototype evaluation and addressed their suggestions in the final version. CONCLUSIONS: The InfoViP system uses context-driven interactive visualizations and informatics tools to assist FDA SEs in synthesizing data from multiple sources for their case series analyses.

Comparison of Antithrombin III Products in Pediatric Patients Receiving Extracorporeal Membrane Oxygenation.

The study investigated the safety and efficacy of two antithrombin III (ATIII) products in pediatric patients receiving extracorporeal membrane oxygenation (ECMO) by performing a retrospective analysis of patients who received either recombinant ATIII (rATIII) or human-derived ATIII (hATIII). Twenty-two patients were included in the study from January 2014 to September 2015 and all received unfractionated heparin (UFH) as anticoagulation during ECMO. In total, 86 doses of ATIII were included in the analysis in which 37 doses (43%) were rATIII and 49 doses (57%) were hATIII. Unfractionated heparin rates were also evaluated for all cases (n = 86) at 24 hours post-ATIII supplementation. The UFH rate decreased after the administration of both types of ATIII. However, neither the reduction in UFH rate between the two ATIII products (p = 0.52) nor the UFH rates pre- and post-ATIII supplementation at 24 hours (p = 0.08) reached statistical significance. There was a significant difference in cost favoring the rATIII product (p < 0.0001). An ad-hoc estimation of waste associated with ATIII supplementation showed >$100,000 in financial loss of unused drug. Future studies are warranted to evaluate the efficacy of ATIII supplementation in pediatric ECMO.

Antipsychotic Treatment of Delirium in Critically Ill Children: A Retrospective Matched Cohort Study.

OBJECTIVE: To describe the use of pharmacologic treatment in critically ill children treated according to a delirium protocol and compare those treated with antipsychotics to those treated non-pharmacologically. METHODS>: The study included a retrospective matched cohort describing patients who were pharmacologically treated for delirium compared to those with delirium but not treated in a PICU from December 2013 to September 2015, using a delirium management protocol. Patients were matched by age, sex, diagnosis, mechanical ventilation (MV), and presence of delirium. RESULTS: Of 1875 patients screened, 188 (10.03%) were positive for delirium. Of those, 15 patients (8%) were treated with an antipsychotic for delirium. Patients with delirium treated with antipsychotics were younger, had more delirium days (6 vs. 3, p=0.022), longer MV days (14 vs. 7, p=0.017), and longer PICU length of stay (34 vs. 16 days, p=0.029) than in the untreated group. Haloperidol, risperidone, and quetiapine were used in 9, 6, and 2 patients, respectively. Two patients were treated with multiple antipsychotics. Antipsychotic treatment was initiated on day 2 of delirium for 8 of 15 patients (53.3%). Ten patients in the treatment group had improved delirium scores by day 2 of treatment. No significant differences in sedation exposure between groups. No significant adverse effects were reported. CONCLUSIONS: No significant adverse events seen in this small cohort of critically ill pediatric patients with delirium treated with antipsychotic therapy. Patients with early-onset delirium refractory to non-pharmacologic treatment may have a more effective response to antipsychotic therapy than patients with late-onset refractory delirium.

N-Acetylcysteine for Gastric Lactobezoars in a 1-Month-Old.

Gastric lactobezoars are a result of the inability to digest milk and mucous. Formulas that contain high casein concentrations, medium triglyceride oils, or high caloric density can increase the risk of bezoar formation by decreasing gastric secretion or delaying gastric emptying. N-acetylcysteine (NAC) is used to clear thick mucus secretions and is hypothesized to be effective in the treatment of gastric lactobezoars due to the cleavage of disulfide bonds in mucoproteins. We describe the use of NAC in a 1-month-old full term male (4.5 kg) who was diagnosed with a gastric lactobezoar following an upper gastrointestinal series that showed a large persistent filling defect in the distal body, which was suggestive of a gastric lactobezoar. A dose of 45 mg (10 mg/kg) of 10% NAC was diluted in 50 mL of normal saline and given every 6 hours via a nasogastric (NG) tube. Administration was followed by clamping of the NG tube for 2 hours and aspiration of the stomach contents. NAC was discontinued when aspirates were a clear mucus consistency. The patient's gastric lactobezoar was successfully treated with a 10 mg/kg/dose of NAC that was given every 6 hours for a total of 4 doses.

Serious Adverse Events Associated with Off-Label Use of Azithromycin or Fentanyl in Children in Intensive Care Units: A Retrospective Chart Review.

OBJECTIVES: Half of prescription drugs commonly given to children lack product labeling on pediatric safety, efficacy, and dosing. Two drugs most widely used off-label in pediatrics are azithromycin and fentanyl. We sought to determine the risk of serious adverse events (SAEs) when oral azithromycin or intravenous/intramuscular fentanyl are used off-label compared to on-label in pediatric intensive care units (ICUs). STUDY DESIGN: Six pediatric hospitals participated in a retrospective chart review of patients administered oral azithromycin (n = 241) or intravenous/intramuscular fentanyl (n = 367) between January 5, 2013 and December 26, 2014. Outcomes were SAEs by drug and labeling status: off-label compared to on-label by Food and Drug Administration (FDA)-approved age and/or indication. Statistical analysis was performed using logistic regression to estimate odds ratios (ORs) and Cox regression to estimate hazard ratios (HRs). RESULTS: Twenty-one (9%) children receiving azithromycin experienced SAEs. Off-label use of azithromycin was not associated with a higher risk of SAE (OR 0.87, 95% CI 0.27-2.71, p = 0.81). Ninety-five (26%) children receiving fentanyl experienced SAEs. Fentanyl off-label use by both age and indication was not associated with a higher risk of overall SAEs compared to on-label use (OR 1.99, 95% CI 0.94-4.19, p = 0.07). However, the risk of the SAE respiratory depression was significantly greater when fentanyl was used off-label by both age and indication (OR 5.05, 95% CI 1.08-23.56, p = 0.044). Results based on HRs were similar. CONCLUSIONS: Azithromycin off-label use in pediatric ICUs does not appear to be associated with an increased risk of SAEs. Off-label use of fentanyl appears to be more frequently associated with respiratory depression when used off-label by both age and indication in pediatric ICUs. Prospective studies should be undertaken to assess the safety and efficacy of fentanyl in the pediatric population so that data can be added to the FDA labeling.

Pharmacist and Pediatrician Knowledge of Codeine Use in Children.

OBJECTIVES: In 2011, approximately 1.7 million pediatric patients had a codeine-containing prescription filled at a US retail pharmacy. Numerous cases involving serious adverse effects or fatalities have been reported in children who have been prescribed codeine. In 2013, the US Food and Drug Administration added a boxed warning to avoid codeine in children after a tonsillectomy. The purpose of this study is to determine pharmacists' and pediatricians' knowledge of the boxed warning for codeine in children. METHODS: Two separate surveys were administered to community pharmacists in Maryland, pediatricians, and pediatric residents at a single institution in Maryland. Both surveys consisted of questions regarding knowledge of the boxed warning for codeine in children. RESULTS: There was no difference in the awareness of the boxed warning between pharmacists (48.9%, n = 43) and pediatricians (51.3%, n = 41, p = 0.88). More pharmacists knew that ultrarapid metabolizers have the risk for increased adverse events from codeine (39.5% pharmacists vs. 20% pediatricians, p = 0.01). In addition, 36% of pharmacists and 33% of pediatricians noted that it was never appropriate to use codeine in a child (p = 0.73). CONCLUSIONS: Only half of pharmacists and pediatricians surveyed were aware of the boxed warning for codeine. One third of pharmacists and pediatricians in this study would never use codeine in a child. Therefore, more education is needed for pharmacists and pediatricians regarding the dangers of using codeine in children.

Implementation and assessment of a naloxone-training program for first-year student pharmacists.

BACKGROUND AND PURPOSE: Develop a naloxone training activity and assess the activity's impact on increasing student pharmacist knowledge and confidence to counsel about management of opioid overdose and naloxone administration. EDUCATIONAL ACTIVITY AND SETTING: First-year student pharmacists participated in a naloxone training activity in an abilities laboratory course. The students completed pre-lab questions, received a brief lecture about responding to an opioid overdose, and then practiced counseling and administering intranasal and intramuscular naloxone using training kits. An Objective Structured Clinical Examination (OSCE) was conducted to assess students' ability to counsel on intranasal naloxone use in response to opioid overdose. Students completed self-assessments about their confidence in counseling patients about management of opioid overdose and naloxone administration following the OSCE and at course end. FINDINGS: 158 students participated and the average OSCE score was 82%. In the post-encounter self-assessment, 93% of students agreed or completely agreed that the OSCE improved their confidence in counseling about management of an opioid overdose and intranasal naloxone administration. Fifty-nine students completed the end-of-course survey and >90% of respondents reported they were somewhat or very confident in their ability to administer intranasal or intramuscular naloxone, recognize the opioid overdose symptoms, and counsel about intranasal naloxone use. Confidence in counseling about use of intramuscular naloxone was slightly lower. SUMMARY: Further study of training programs to increase future healthcare professionals' ability to respond to opioid overdoses is warranted. Incorporation of a short training activity can increase student pharmacists' knowledge and confidence in counseling patients about opioid overdose and naloxone administration.

Voriconazole: Poor Oral Bioavailability and Possible Renal Toxicity in an Infant With Invasive Aspergillosis.

Voriconazole is the recommended agent of choice for treatment of invasive aspergillosis; however, achieving therapeutic serum concentrations while avoiding toxicity, both with intravenous and oral formulations, is challenging in infants. We report the case of an infant with confirmed invasive aspergillosis who developed renal toxicity possibly associated with IV voriconazole. Renal function improved upon withdrawal of the IV agent and switch to the oral formulation. The infant subsequently required large oral weight-based dosing to achieve therapeutic voriconazole serum concentrations. This case illustrates a rare side effect associated with voriconazole as well as the issues surrounding the pharmacokinetic profile of voriconazole in a pediatric patient.

Implementation of an ICU Bundle: An Interprofessional Quality Improvement Project to Enhance Delirium Management and Monitor Delirium Prevalence in a Single PICU.

OBJECTIVES: To examine the impact of an ICU bundle on delirium screening and prevalence and describe characteristics of delirium cases. DESIGN: Quality improvement project with prospective observational analysis. SETTING: Nineteen-bed PICU in an urban academic medical center. PATIENTS: All consecutive patients admitted from December 1, 2013, to September 30, 2015. INTERVENTIONS: A multidisciplinary team implemented an ICU bundle consisting of three clinical protocols: delirium, sedation, and early mobilization using the Plan-Do-Study-Act cycles as part of a quality improvement project. The delirium protocol implemented in December 2013 consisted of universal screening with the Cornell Assessment of Pediatric Delirium revised instrument, prevention and treatment strategies, and case conferences. The sedation protocol and early mobilization protocol were implemented in October 2014 and June 2015, respectively. MEASUREMENTS AND MAIN RESULTS: One thousand eight hundred seventy-five patients were screened using the Cornell Assessment of Pediatric Delirium revised tool. One hundred forty patients (17%) had delirium (having Cornell Assessment of Pediatric Delirium revised scores ≥ 9 for 48 hr or longer). Seventy-four percent of delirium positive patients were mechanically ventilated of which 46% were younger than 12 months and 59% had baseline developmental delays. Forty-one patients had emerging delirium (having one Cornell Assessment of Pediatric Delirium revised score ≥ 9). Statistical process control was used to evaluate the impact of three ICU bundle process changes on monthly delirium rates over a 22-month period. The delirium rate decreased with the implementation of each phase of the ICU bundle. Ten months after the delirium protocol was implemented, the mean delirium rate was 19.3%; after the sedation protocol and early mobilization protocols were implemented, the mean delirium rate was 11.84%. CONCLUSIONS: Implementation of an ICU bundle along with staff education and case conferences is effective for improving delirium screening, detection, and treatment and is associated with decreased delirium prevalence.

Vancomycin AUC/MIC and Corresponding Troughs in a Pediatric Population.

OBJECTIVES: Adult guidelines suggest an area under the curve/minimum inhibitory concentration (AUC/MIC) > 400 corresponds to a vancomycin trough serum concentration of 15 to 20 mg/L for methicillin-resistant Staphylococcus aureus infections, but obtaining these troughs in children are difficult. The primary objective of this study was to assess the likelihood that 15 mg/kg of vancomycin every 6 hours in a child achieves an AUC/MIC > 400. METHODS: This retrospective chart review included pediatric patients >2 months to <18 years with a positive S aureus blood culture and documented MIC who received at least two doses of vancomycin with corresponding trough. Patients were divided into two groups: group 1 initially receiving ≥15 mg/kg every 6 hours, and group 2 initially receiving any other dosing ranges or intervals. AUCs were calculated four times using three pharmacokinetic methods. RESULTS: A total of 36 patients with 99 vancomycin trough serum concentrations were assessed. Baseline characteristics were similar between groups. For troughs in group 1 (n = 55), the probability of achieving an AUC/MIC > 400 ranged from 16.4% to 90.9% with a median trough concentration of 11.4 mg/L, while in group 2 (n = 44) the probability of achieving AUC/MIC > 400 ranged from 15.9% to 54.5% with mean trough concentration of 9.2 mg/L. The AUC/MICs were not similar between the different pharmacokinetic methods used; however, a trapezoidal equation (Method A) yielded the highest correlation coefficient (r2 = 0.59). When dosing every 6 hours, an AUC/MIC of 400 correlated to a trough serum concentration of 11 mg/L. CONCLUSIONS: The probability of achieving an AUC/MIC > 400 using only a trough serum concentration and an MIC with patients receiving 15 mg/kg every 6 hours is variable based on the method used to calculate the AUC. An AUC/MIC of 400 in children correlated to a trough concentration of 11 mg/L using a trapezoidal Method to calculate AUC.

Abuse and Misuse of Selected Dietary Supplements Among Adolescents: a Look at Poison Center Data.

OBJECTIVE: The use of dietary supplements has increased and is associated with adverse effects. Indications for use include recreation, body image concerns, mood enhancement, or control of medical conditions. The risk of adverse effects may be enhanced if agents are used improperly. The objective of this study was to determine the frequency of abuse and misuse of 4 dietary substances among adolescents reported nationally to poison centers. Secondary outcomes included an assessment of medical outcomes, clinical effects, location of treatments provided, and treatments administered. METHODS: This descriptive retrospective review assessed data concerning the use of garcinia (Garcinia cambogia), guarana (Paullinia cupana), salvia (Salvia divinorum), and St John's wort (Hypericum perforatum) among adolescents reported nationally to poison centers from 2003 to 2014. Adolescents with a singlesubstance exposure to one of the substances of interest coded as intentional abuse or misuse were included. Poison center calls for drug information or those with unrelated clinical effects were excluded. Data were collected from the National Poison Data System. RESULTS: There were 84 cases: 7 cases of Garcinia cambogia, 28 Paullinia cupana, 23 Salvia divinorum, and 26 Hypericum perforatum. Garcinia cambogia was used more frequently by females (100% versus 0%), and Paullinia cupana and Salvia divinorum were used more frequently by males (61% versus 36% and 91% versus 9%, respectively). Abuse, driven by Salvia divinorum, was more common overall than misuse. Abuse was also more common among males than females (p <0.001). Use of these agents fluctuated over time. Overall, use trended down since 2010, except for Garcinia cambogia use. In 62 cases (73.8%), the medical outcome was minor or had no effect or was judged as nontoxic or minimally toxic. Clinical effects were most common with Paullinia cupana and Salvia divinorum. Treatment sites included emergency department (n = 33; 39.3%), non-healthcare facility (n = 24; 28.6%), admission to a health care facility (n = 8; 9.5%), and other/unknown (n = 19; 22.6%). CONCLUSIONS: Abuse and misuse of these dietary supplements was uncommon, and outcomes were mild. Further research should be performed to determine use and outcomes of abuse/misuse of other dietary supplements in this population.

Safe and Effective Use of Pharmacologic and Device Therapy for Peripartum Cardiomyopathy.

Peripartum cardiomyopathy (PPCM) is an uncommon, idiopathic complication of pregnancy associated with significant (10-30%) mortality. The disease occurs late in pregnancy or in the months following delivery, resulting in reduced systolic function and heart failure (HF) symptoms. Limited direction is provided for the management of PPCM, and the safe and effective use of medications in pregnant and breastfeeding women with PPCM presents a unique challenge. Although several HF therapies in pregnant and lactating women are supported by robust evidence, evidence to support the use of other therapies is significantly lacking. Current guidelines recommend treatment as in other forms of HF with reduced left ventricular ejection fraction (LVEF) but with consideration for the important nuances in this population as well as the unique and potential teratogenic effects of these therapies. Since most patients with PPCM recover their LVEF, the duration of therapy is currently unknown and warrants further study. We review the available literature surrounding pharmacologic and device therapy for PPCM and provide insight into managing patients with the condition.

Appropriate Use of Vancomycin in NICU Despite Free-for-All Policy.

OBJECTIVES: Because of increases in antimicrobial resistance, the use of vancomycin in late-onset sepsis has come under scrutiny. The primary outcome of this study was to determine if vancomycin for the treatment of late-onset sepsis in the neonatal intensive care unit (NICU) was being discontinued within 72 hours according to the existing protocol. Secondary outcomes included the appropriateness of therapeutic drug monitoring associated with vancomycin, and renal dysfunction associated with the use of vancomycin in the NICU outside of the 72-hour policy. METHODS: A retrospective chart review was completed for patients in the NICU who received vancomycin for the treatment of late-onset sepsis between the dates of January 1, 2014, and July 1, 2014. RESULTS: There were 125 vancomycin treatment courses, of which 97 were included. Appropriate use of vancomycin, per policy, occurred in a total of 87 of 97 courses (89.6%). Therapeutic drug monitoring was evaluated by the number of appropriate troughs, determined using renal function and previous trough concentrations. There was not a statistically significant difference in the number of inappropriate troughs drawn between those that were continued on vancomycin appropriately (n = 17 courses; 4 of 44 inappropriate troughs) versus inappropriately (n = 10 courses; 1 of 22 inappropriate troughs; p = 0.66), despite the large number of troughs drawn. Adverse renal outcomes were not statistically significant in patients continued inappropriately on vancomycin (p = 1.0). CONCLUSIONS: Vancomycin use in the NICU for late-onset sepsis is appropriate per the existing antibiotic policy. Therapeutic drug monitoring could be improved, and adverse renal outcomes due to inappropriate continuation of vancomycin are rare.

Effects of Clonidine on Withdrawal From Long-term Dexmedetomidine in the Pediatric Patient.

OBJECTIVE: To compare withdrawal symptoms among pediatric intensive care patients receiving clonidine to those not receiving clonidine while being weaned from long-term dexmedetomidine. METHODS: This retrospective analysis evaluated Withdrawal Assessment Tool-1 (WAT-1) scores and hemodynamic parameters in pediatric patients on dexmedetomidine for 5 days or longer between January 1, 2009, and December 31, 2012. The primary objective was to compare withdrawal symptoms based on the number of elevated WAT-1 scores among patients on clonidine to those not on clonidine, while being weaned from long-term dexmedetomidine. The secondary objective was to describe withdrawal symptoms associated with long-term dexmedetomidine use. RESULTS: Nineteen patients (median age, 1.5 years; interquartile range [IQR], 0.67-3.3) received 20 treatment courses of dexmedetomidine for at least 5 days. Clonidine was received by patients during 12 of the treatment courses. The patients in the clonidine group had an average of 0.8 (range, 0-6) elevated WAT-1 scores 24 hours post wean compared to an average of 3.2 (0-8) elevated WAT-1 scores in the no clonidine group (p = 0.49). There were no significant difierences between prewean and postwean systolic or diastolic blood pressures among the 2 groups. The average heart rate during the postwean period was 112 beats per minute (bpm) (range, 88.5-151.5) in the clonidine group compared to 138.4 bpm (range, 117.8-168.3) in the no clonidine group (p = 0.003). In the clonidine group, the mean change in heart rate postwean compared to prewean was an increase of 3.6 bpm (range, -39.6 to 47.5), compared to a mean increase of 29.9 bpm (range, 5.5-74.7) in the no clonidine group (p = 0.042). CONCLUSIONS: There was no difierence in WAT-1 scores between groups, with the clonidine group displaying a trend towards fewer elevated WAT-1 scores during the 24 hours post dexmedetomidine wean. Patients who received clonidine had significantly lower heart rates than the no clonidine group.

Acute care clinical pharmacy practice: unit- versus service-based models.

This commentary from the 2010 Task Force on Acute Care Practice Model of the American College of Clinical Pharmacy was developed to compare and contrast the "unit-based" and "service-based" orientation of the clinical pharmacist within an acute care pharmacy practice model and to offer an informed opinion concerning which should be preferred. The clinical pharmacy practice model must facilitate patient-centered care and therefore must position the pharmacist to be an active member of the interprofessional team focused on providing high-quality pharmaceutical care to the patient. Although both models may have advantages and disadvantages, the most important distinction pertains to the patient care role of the clinical pharmacist. The unit-based pharmacist is often in a position of reacting to an established order or decision and frequently is focused on task-oriented clinical services. By definition, the service-based clinical pharmacist functions as a member of the interprofessional team. As a team member, the pharmacist proactively contributes to the decision-making process and the development of patient-centered care plans. The service-based orientation of the pharmacist is consistent with both the practice vision embraced by ACCP and its definition of clinical pharmacy. The task force strongly recommends that institutions pursue a service-based pharmacy practice model to optimally deploy their clinical pharmacists. Those who elect to adopt this recommendation will face challenges in overcoming several resource, technologic, regulatory, and accreditation barriers. However, such challenges must be confronted if clinical pharmacists are to contribute fully to achieving optimal patient outcomes.