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Aim: To elicit preferences for pharmacogenomic (PGx) testing in polypharmacy patients. Materials & methods: A face-to-face discrete choice experiment survey was designed and administered to adult polypharmacy patients recruited at a local retail pharmacy in Albuquerque (NM, USA). Results: A total of 128 eligible polypharmacy patients completed the discrete choice experiment survey and significantly preferred a PGx test with lower cost, better confidentiality and higher certainty of identifying best medication/dose and side effects and one that can be used to advocate for their treatment needs (all p

Introduction The purpose of this study was to evaluate whether a public health (PH) micro-level case-based learning exercise increased pharmacy students' self-perceived understanding and confidence in their role as PH pharmacists. Methods Three PH micro-level case-based learning exercises in community pharmacy settings were developed and integrated into the third professional year PH course. Students enrolled in the PH course from January 2012 – May 2015 completed a pre- and post-activity survey consisting of 22 statements with Likert scale responses. Survey questions were grouped into domains: perceptions of pharmacist roles (ROLES) in PH, confidence in ability to identify and address PH problems (CONF), pharmacist impact on improving PH outcomes for patients with human immunodeficiency virus (IMPACT-HIV), diabetes (IMPACT-DM), or alcoholism (IMPACT-AL), perceiving pharmacists as role models in PH (MODEL), and whether PH is beyond the scope of pharmacy practice (SCOPE). Within each domain, paired t-tests were performed on summated scores (pre- vs. post-, alpha = 0.05). Results Both surveys were completed by 271 of 336 students (80.7%). Baseline scores were lowest in the CONF and MODEL domains. The activity resulted in significant changes in 21 out of 24 survey questions. Significantly higher scores were found for domains of ROLES (+1.22), CONF (+1.60), IMPACT-HIV (+0.65), IMPACT-DM (+0.42), IMPACT-AL (+0.70), and MODEL (+1.50). Cronbach's alpha ranged from 0.73 to 0.93 for each domain. Conclusion A PH case-based learning session increased students' scores on a pre- and post-activity survey regarding PH challenges at the micro-level. The activity improved students' perceptions and confidence in providing PH interventions.

Biosimilar filgrastims are primarily indicated for chemotherapy-induced neutropenia prevention. They are less expensive formulations of branded filgrastim, and biosimilar filgrastim was the first biosimilar oncology drug administered in European Union (EU) countries, Japan, and the U.S. Fourteen biosimilar filgrastims have been marketed in EU countries, Japan, the U.S., and Canada since 2008, 2012, 2015, and 2016, respectively. We reviewed experiences and policies for biosimilar filgrastim markets in EU countries and Japan, where uptake has been rapid, and in the U.S. and Canada, where experience is rapidly emerging. U.S. regulations for designating biosimilar interchangeability are under development, and such regulations have not been developed in most other countries. Pharmaceutical substitution is allowed for new filgrastim starts in some EU countries and in Canada, but not Japan and the U.S. In EU countries, biosimilar adoption is facilitated with favorable hospital tender offers. U.S. adoption is reportedly 24%, while the second filgrastim biosimilar is priced 30% lower than branded filgrastim and 20% lower than the first biosimilar filgrastim approved by the U.S. Food and Drug Administration. Utilization is about 60% in EU countries, where biosimilar filgrastim is marketed at a 30%–40% discount. In Japan, biosimilar filgrastim utilization is 45%, primarily because of 35% discounts negotiated by Central Insurance and hospital-only markets. Overall, biosimilar filgrastim adoption barriers are small in many EU countries and Japan and are diminishing in Canada in the U.S. Policies facilitating improved U.S. adoption of biosimilar filgrastim, based on positive experiences in EU countries and Japan, including favorable insurance coverage; larger price discount relative to reference filgrastim pricing; closing of the “rebate trap” with transparent pricing information; formal educational efforts of patients, physicians, caregivers, and providers; and allowance of pharmaceutical substitution of biosimilar versus reference filgrastim, should be considered. Implications for Practice We reviewed experiences and policies for biosimilar filgrastims in Europe, Japan, Canada, and the U.S. Postmarketing harmonization of regulatory policies for biosimilar filgrastims has not occurred. Acceptance of biosimilar filgrastims for branded filgrastim, increasing in the U.S. and in Canada, is commonplace in Japan and Europe. In the U.S., some factors, accepted in Europe or Japan, could improve uptake, including acceptance of biosimilars as safe and effective; larger cost savings, decreasing “rebate traps” where pharmaceutical benefit managers support branded filgrastim, decreased use of patent litigation/challenges, and allowing pharmacists to routinely substitute biosimilar for branded filgrastim.

Background Patients with chronic obstructive pulmonary diseases (COPD) suffer from impaired Health-Related Quality of Life (HRQoL). Having an adequate social/emotional support may improve the quality of life of COPD patients. Objective To study the relationships between social/emotional support and HRQoL, depression and disability among patients with COPD. Methods We applied a propensity score model using data from a large U.S. population-based health survey to match COPD patients who reported rarely/never receiving social/emotional support with those who received that support. Social/emotional support and all dependent variables were dichotomized into yes/no responses. For HRQoL domains, number of days of poor physical or mental health and activity limitations, “yes” indicated ≥14 unhealthy days in the last 30 days. McNemar’s test was used to compare the matched groups. Results Social/emotional support was rarely/never received by 37% of responders. Standardized differences between matched groups, after propensity score matching, were less than 10% indicating successful matching. COPD patients who rarely/never receive social/emotional support were more likely to report: depression (n = 321 pairs, odds ratio (OR) = 2.2, 95% confidence interval (CI): 1.56–3.14, p < .001), ≥14 poor mental HRQoL days (n = 310 pairs, OR = 3.12, 95% CI: 2.1–4.73, p < .001) and ≥14 poor physical HRQoL days (n = 307 pairs, OR = 1.5, 95% CI: 1.06–2.13, p = .02). There were no significant differences in general health, disability, or activity limitations. Conclusion Among COPD patients, lower levels of social/emotional support are associated with depression and deterioration of mental and physical HRQoL. The importance of social/emotional support should be emphasized by policy makers, healthcare providers, and family members, to improve functioning among COPD patients.

Background Influenza virus is responsible for substantial morbidity and mortality. Specific populations are at higher risk for exacerbations from influenza virus, such as patients with chronic obstructive pulmonary disease (COPD). Influenza vaccination coverage among COPD patients is low. Pharmacists can improve influenza vaccination among COPD patients by recognizing factors that influence vaccination and addressing these factors. Objectives To (1) determine the recent influenza vaccination coverage among patients with COPD, (2) identify factors that were associated with immunization, and (3) interpret the results based upon Andersen's healthcare utilization model. Methods The 2012 Behavioral Risk Factor Surveillance System (BRFSS) was accessed for the study. Among respondents age ≥ 25 years with COPD, presence of influenza vaccination was captured along with demographic, provider, insurance, and clinical variables. Weighted multiple logistic regression was used to identify significant factors associated with receiving influenza vaccination. The findings were interpreted according to predisposing, enabling, and need factors relevant to Anderson's model. Results Influenza vaccination rate was 53% among COPD patients. Older age was a significant predisposing factor that increased vaccination (adjusted odds ratio [AOR] = 2.4; 95% CI:2.02–2.88). Predisposing factors that decreased vaccination were being Black or Hispanic (AOR = 0.72, 95% CI:0.59–0.86, and AOR = 0.78, 95% CI:0.61–0.98 respectively), and being a non smoker (former and never smokers had higher vaccination rates [AOR = 1.53, 95% CI = 1.3–1.72, and AOR = 1.36, 95% CI = 1.19–1.55 respectively]). Significant enabling factors included having health insurance (AOR = 1.68, 95% CI = 1.37–2.06), a primary physician (AOR = 1.63, 95% CI = 1.30–2.02), and the ability to see a physician regardless of cost (AOR = 1.33, 95% CI = 1.17–1.52). Significant need factors included the presence of comorbidities such as asthma (AOR = 1.18, 95% CI = 1.1–1.3), or diabetes (AOR = 1.36, 95% CI = 1.20–1.53), activity limitation (AOR = 1.16, 95% CI = 1.04–1.29), and having the last medical checkup within less than one year (AOR = 1.49, 95% CI = 1.31–1.70). Conclusion Influenza vaccination coverage among COPD patients is far below the Healthy People 2020 national goal. Several predisposing, enabling, and need factors influenced vaccination rate among COPD patients. Pharmacists can improve vaccination rate among COPD patients by recognizing these influencing factors and by acting as advocates, counselors, and administrators of influenza vaccine. Ultimately, with the collaborative efforts of other healthcare providers and public health initiatives, pharmacists can help achieve Healthy People 2020 objectives related to influenza vaccination.

A 43‐year‐old female with multiple sclerosis developed urethral melanoma. The only potential risk factor was treatment with natalizumab, a humanized monoclonal antibody against α4 integrins. To investigate the risk‐exposure relationship, we reviewed this case, all other published cases, and cases of natalizumab‐associated melanoma reported to regulatory agencies. Data sources included the Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) (2004–2014), a FDA Advisory Committee Meeting Report, and peer‐reviewed publications. In the United States, the manufacturer maintains an FDA‐mandated Tysabri Safety Surveillance Program (part of the Tysabri Outcomes Unified Commitment to Health (TOUCH)) of natalizumab‐treated patients. We statistically compared reporting completeness for natalizumab‐associated melanoma cases in FAERs for which information was obtained entirely from the TOUCH program versus cases where FAERS information was supplemented by TOUCH program information. FAERS included 137 natalizumab‐associated melanoma reports in patients with multiple sclerosis. Median age at melanoma diagnosis was 45 years (range: 21–74 years). Changes in preexisting nevi occurred in 16%, history of cutaneous nevi occurred in 22%, diagnosis within 2 years of beginning natalizumab occurred in 34%, and 74% had primary surgical treatment. Among seven natalizumab‐treated MS patients who developed biopsy‐confirmed melanoma on treatment and reported in the literature, median age at diagnosis was 41 years (range: 38–48 years); and the melanoma diagnosis occurred following a median of 12 natalizumab doses (range: 1–77 doses). A history of mole or nevi was noted in four patients and a history of prior melanoma was noted in one patient. Completeness scores for reports were significantly lower for FAERS cases reported from the TOUCH program versus FAERS cases supplemented by TOUCH information (median score of 2 vs. 4 items out of 8‐possible items, P

Although the availability of generic oncology drugs allows access to contemporary care and reduces costs, there is international variability in the safety of this class of drugs. In this Series paper, we review clinical, policy, safety, and regulatory considerations for generic oncology drugs focusing on the USA, Canada, the European Union (EU), Japan, China, and India. Safety information about generic formulations is reviewed from one agent in each class, for heavy metal drugs (cisplatin), targeted agents (imatinib), and cytotoxic agents (docetaxel). We also review regulatory reports from Japan and the USA, countries with the largest pharmaceutical expenditures. Empirical studies did not identify safety concerns in the USA, Canada, the EU, and Japan, where regulations and enforcement are strong. Although manufacturing problems for generic pharmaceuticals exist in India, where 40% of all generic pharmaceuticals used in the USA are manufactured, increased inspections and communication by the US Food and Drug Administration are occurring, facilitating oversight and enforcement. No safety outbreaks among generic oncology drugs were reported in developed countries. For developing countries, oversight is less intensive, and concerns around drug safety still exist. Regulatory agencies should collaboratively develop procedures to monitor the production, shipment, storage, and post-marketing safety of generic oncology drugs. Regulatory agencies for each country should also aim towards identical definitions of bioequivalence, the cornerstone of regulatory approval.

Objectives: To examine agreement between the FDA Adverse Event Reporting System (FAERS) and observational studies in common infections for tumor necrosis factor inhibitors (TNFi’s).Methods: Using M...

Objective In a pilot study, our group showed that an internet-based self-management program improves self-efficacy in systemic sclerosis (SSc). The objective of the current study was to compare an internet-based self-management program to a patient-focused educational book developed to assess measures of self-efficacy and other patient-reported outcomes in patients with SSc. Methods We conducted a 16-week randomized, controlled trial. Results Of the 267 participants who completed baseline questionnaires and were randomized to the intervention (internet: www.selfmanagescleroderma.com) or control (book) group, 123 participants (93%) in the internet group and 124 participants (94%) in the control group completed the 16-week randomized controlled trial (RCT). The mean ± SD age of all participants was 53.7 ± 11.7 years, 91% were women, and 79.4% had some college or a higher degree. The mean ± SD disease duration after diagnosis of SSc was 8.97 ± 8.50 years. There were no statistical differences between the 2 groups for the primary outcome measure (Patient-Reported Outcomes Measurement Information System Self-Efficacy for Managing Symptoms: mean change of 0.35 in the internet group versus 0.94 in the control group; P = 0.47) and secondary outcome measures, except the EuroQol 5-domain instrument visual analog scale score (P = 0.05). Internet group participants agreed that the self-management modules were of importance to them, the information was presented clearly, and the website was easy to use and at an appropriate reading level. Conclusion Our RCT showed that the internet-based self-management website was not statistically superior to an educational patient-focused book in improving self-efficacy and other measures. The participants were enthusiastic about the content and presentation of the self-management website.

Background The 3 fluoroquinolone (FQ) antibiotics - ciprofoxacin, levofoxacin, and moxifoxacin - are commonly administered to oncology patients. Although these oral antibiotics are approved by the US Food and Drug Administration (FDA) for treatment of urinary tract infections, acute bacterial sinusitis, or bacterial infection in patients with chronic obstructive pulmonary disease, they are commonly prescribed off-label to neutropenic cancer patients for the prevention and treatment of infections associated with febrile neutropenia. New serious FQ-associated safety concerns have been identified through novel collaborations between FQ-treated persons who have developed long-term neuropsychiatric (NP) toxicity, pharmacovigilance experts, and basic scientists. Objective To conduct basic science and clinical investigations of a newly identified adverse drug reaction, termed FQ-associated disability. Methods 5 groups of C57BL/6 mice receiving the antibiotic ciprofoxacin in 10-mg increments (10 mg/kg-50 mg/kg) and 1 group of control mice were evaluated. The Southern Network on Adverse Reactions (SONAR) and a social network of FQ-treated persons with long-term NP toxicity (the Floxed Network) conducted a web-based survey. The clinical toxicity manifestations reported by 94 respondents to the web-based survey of persons who had received 1 or more doses of an FQ prescribed for any indication (generally at FDA-approved dosages) and who subsequently experienced possible adverse drug reactions were compared with adverse event information included on the product label for levofoxacin and with FQ-associated adverse events reported to the FDA's MedWatch program. Results Mice treated with ciprofoxacin had lower grip strengths, reduced balance, and depressive behavior compared with the controls. For the survey, 93 of 94 respondents reported FQ-associated events including anxiety, depression, insomnia, panic attacks, clouded thinking, depersonalization, suicidal thoughts, psychosis, nightmares, and impaired memory beginning within days of FQ initiation or days to months of FQ discontinuation. The FDA Adverse Event Reporting System (FAERS) included 210,705 adverse events and 2,991 fatalities for FQs. Levofoxacin and ciprofoxacin toxicities were neurologic (30% and 26%, respectively), tendon damage (8% and 6%), and psychiatric (10% and 2%). In 2013, an FDA safety review reported that FQs affect mammalian topoisomerase II, especially in mitochondria. In 2013 and 2014, SONAR fled citizen petitions requesting black box revisions identifying neuropsychiatric toxicities and mitochrondrial toxicity as serious levofoxacin-associated adverse drug reactions. In 2015, FDA advisors recommended that FQ product labels be revised to include information about this newly identified disability syndrome termed "FQ-associated disability" (FQAD). Limitations Basic science studies evaluated NP toxicity for only 1 FQ, ciprofoxacin. Conclusion Pharmacovigilance investigators, a social network, and basic scientists can collaborate on pharmacovigilance investigations. Revised product labels describing a new serious adverse drug reaction, levofoxacin-associated long-term disability, as recommended by an FDA advisory committee, are advised.

To review and summarize reports of tendon rupture associated with each fluoroquinolone (FQ) currently marketed in the United States (US), as reported to the FDA's Adverse Event Reporting System (FAERS).FAERS data were reviewed for reports of tendon rupture associated with each FQ from their respective approval date through September 2012. Disproportional reporting signal detection was estimated using empirical Bayes geometric mean (EBGM) with 95% confidence intervals (CI).There were 2495 FAERs reports of tendon rupture associated with currently approved FQs. Most FAERS reports were associated with levofloxacin (n = 1555) followed by ciprofloxacin (n = 606) and moxifloxacin (n = 230). Signal detection results for FQs were as follows: levofloxacin (EBGM = 55.2, 95% CI = 52.3 - 58.0), ciprofloxacin (EBGM = 20.0, 95% CI = 18.2 - 21.6), moxifloxacin (EBGM = 13.3, 95% CI = 11.7 - 15.1), norfloxacin (EBGM = 9.6, 95% CI = 6.5 - 13.5), ofloxacin (EBGM = 8.2, 95%CI = 6.3 - 10.2) and gemifloxacin (EBGM = 1.9, 95% CI = 0.7 - 4.5). The mean age of affected individuals was 59.6 ± 5.1 years. Corticosteroids were administered concomitantly with FQs in 21.2% of cases.As noted in boxed warnings, FQ use is associated with increased tendon rupture risk. Risk factors for FQ associated tendon rupture include use in the elderly, and in patients with concomitant corticosteroids. Further monitoring may be needed due to antibiotic overuse and marketing of newer FQs.

Objective Results from three observational methods for assessing effectiveness of long-acting bronchodilator therapies for reducing severe exacerbations of chronic obstructive pulmonary disease (COPD) were compared: intent-to-treat (ITT), as protocol (AP), and an as-treated analysis that utilized a marginal structural model (MSM) incorporating time-varying covariates related to treatment adherence and moderate exacerbations. Study Design and Setting Severe exacerbation risk was assessed over a 2-year period using claims data for patients aged ≥40 years who initiated long-acting muscarinic antagonist (LAMA), inhaled corticosteroid/long-acting beta-agonist (ICS/LABA), or triple therapy (LAMA + ICS/LABA). Results A total of 5475 COPD patients met inclusion criteria. Six months post-initiation, 53.5 % of patients discontinued using any therapy. The ITT analysis found an increased severe exacerbation risk for triple therapy treatment (hazard ratio [HR] 1.24; 95 % confidence interval [CI] 1.00–1.53). No increased risk was found in the AP (HR 1.00; 95 % CI 0.73–1.36), or MSM analyses (HR 1.11; 95 % CI 0.68–1.81). The MSM highlighted important associations among post-index events. Conclusion Neglecting to adjust for treatment discontinuation may produce biased risk estimates. The MSM approach is a promising tool to compare chronic disease management by illuminating relationships between treatment decisions, adherence, patient choices, and outcomes. Electronic supplementary material The online version of this article (doi:10.1007/s40801-015-0025-6) contains supplementary material, which is available to authorized users.

Inhaled corticosteroids (ICS) are widely used in the management of asthma. Prior research suggests that access to ICS among patients with asthma may vary by ethnicity.Study objectives were to determine if there is a difference in the proportion of Hispanic and non-Hispanic white patients with asthma in the receipt of an ICS prescription and to determine independent predictors for the receipt of an ICS prescription for asthma.The 2009 U.S. Medical Expenditure Panel Survey data were used to compare the receipt of ICS prescription among patients with asthma with the following inclusion criteria: Hispanic and non-Hispanic white ethnicity, age over 4 years, and diagnostic codes for asthma. Multiple logistic regression was used to determine the influence of race/ethnicity and other significant factors on the receipt of an ICS prescription.There were 1,469 patients with asthma, corresponding to a weighted sample of 14,401,069 U.S. patients with asthma who met the inclusion criteria, represented by 16.1% Hispanic, 59.5% female, and mean age of 39.9 years. Among non-Hispanic white patients with asthma, 39.7% (35% children and 41% adults) had a receipt of an ICS prescription compared with 22.2% of Hispanic patients (23.9% children and 21.2% adults); P 0.001. In the multiple regression model, Hispanic patients aged 18 years or older had 43% lower odds (odds ratio, 0.6; 95% confidence interval, 0.3-0.9) of having a receipt of an ICS prescription compared with non-Hispanic white patients, independent of other factors. There was no significant difference in receipt of an ICS prescription between Hispanic and non-Hispanic white children with asthma (aged 4-17 yr).The disparity in the receipt of ICS prescription between Hispanic and non-Hispanic white adult patients with asthma could result in suboptimal asthma management, a higher rate of exacerbations, and higher health care costs in this growing minority population. The differences and potential disparities in the receipt of an ICS prescription between Hispanic and non-Hispanic white patients with asthma warrant further investigation to better understand the reasons for such disparities, along with their impact on the U.S. health care burden and interventions that can be undertaken to reduce these disparities.

Summary Biological oncology products are integral to cancer treatment, but their high costs pose challenges to patients, families, providers, and insurers. The introduction of biosimilar agents—molecules that are similar in structure, function, activity, immunogenicity, and safety to the original biological drugs—provide opportunities both to improve health-care access and outcomes, and to reduce costs. Several international regulatory pathways have been developed to expedite entry of biosimilars into global marketplaces. The first wave of oncology biosimilar use was in Europe and India in 2007. Oncology biosimilars are now widely marketed in several countries in Europe, and in Australia, Japan, China, Russia, India, and South Korea. Their use is emerging worldwide, with the notable exception of the USA, where several regulatory and cost barriers to biosimilar approval exist. In this Review, we discuss oncology biosimilars and summarise their regulatory frameworks, clinical experiences, and safety concerns.

Introduction Preference elicitation methods help to increase patient-centred medical decision making (MDM) by measuring benefit and value. Preferences can be applied in decisions regarding reimbursement, including health technology assessment (HTA); market access, including benefit–risk assessment (BRA); and clinical care. These three decision contexts have different requirements for use and elicitation of preferences. Objectives This systematic review identified studies using preference elicitation methods and summarized methodological and practical characteristics within the requirements of the three contexts. Methods The search terms included those related to MDM and patient preferences. Only articles with original data from quantitative preference elicitation methods were included. Results The selected articles (n = 322) included 379 preference elicitation methods, comprising matching methods [MM] (n = 71, 18.7 %), discrete choice experiments [DCEs] (n = 96, 25.3 %), multi-criteria decision analysis (n = 12, 3.2 %) and other methods (n = 200, 52.8 %; i.e. rating scales, which provide estimates inconsistent with utility theory). Most publications of preference elicitation methods had an intended use in clinical decisions (n = 134, 40 %). Fewer preference studies had an intended use in HTA (n = 68, 20 %) or BRA (n = 12, 4 %). In clinical decisions, rating, ranking, visual analogue scales and direct choice are used most often. In HTA, DCEs and MM are both used frequently, and elicitation of preferences in BRA was limited to DCEs. Conclusion Relatively simple preference methods are often adequate in clinical decisions because they are easy to administer and have a low cognitive burden. MM and DCE fulfil the requirements of HTA and BRA but are complex for respondents. No preference elicitation methods with a low cognitive burden could adequately inform HTA and BRA decisions.

Tobacco use causes hundreds of thousands of deaths in the United States each year. Pharmacists are available in the community to provide tobacco cessation interventions. Between 2004 and 2010, the New Mexico Pharmaceutical Care Foundation (NMPCF) provided a pharmacist-led tobacco cessation program to residents in New Mexico.To (a) obtain point prevalence quit rates at 1 month, 3 months, and 6 months follow-up for participants enrolled in the NMPCF program; (b) differentiate between the quitting patterns of enrolled participants; and (c) identify predictors associated with the quitting patterns.Seven-year data were combined for the pattern analysis. Four quitting patterns were defined, including immediate quitters, delayed quitters, once quitters, and never quitters. Multinomial logistic regression was used to identify characteristics of participants with different quitting patterns.The analysis included 1,437 participants. The average point prevalence quit rate at 1 month, 3 months, and 6 months was 29.3%, 23.3%, and 18.0%, respectively. Based on our definition for quitting patterns, the study sample consisted of 145 (10.1%) immediate quitters, 113 (7.9%) delayed quitters, 298 (20.7%) once quitters, and 881 (61.3%) never quitters. Multinomial logistic regression identified associations between quitting patterns and demographics, tobacco use and restrictions, baseline confidence in successful quitting, and pharmacotherapy aids used to quit. Relationships varied between quitting patterns.The study findings showed that having community pharmacists provide smoking cessation interventions resulted in quitting success rates similar to other health care professionals, which ranged from 9.9% to 26.0%. Since pharmacists are a widely available resource for their patients, managed care organizations may be able to improve the health, and avoid subsequent tobacco-related adverse health outcomes, of their members by implementing a program similar to the NMPCF Tobacco Cessation Program.

Purpose Brentuxiumab vedotin (BV) is an anti-CD30 monoclonal antibody-drug conjugate approved in 2011 for treating anaplastic large cell and Hodgkin lymphomas. The product label indicates that three BV-treated patients developed progressive multifocal leukoencephalopathy (PML), a frequently fatal JC-virus induced central nervous system infection. Prior immunosuppressive therapy and compromised immune systems were postulated risk factors. We report 5 patients who developed BV-associated PML, including two immunocompetent patients.

Nephrogenic systemic fibrosis is a fibrosing disorder associated with exposure to gadolinium-based contrast agents in people with severely compromised renal function.The purpose of this study was to determine the reported number of cases of nephrogenic systemic fibrosis in children using three distinct publicly available data sources.We conducted systematic searches of the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), the International Center for Nephrogenic Systemic Fibrosis Research (ICNSFR) registry and published literature from January 1997 through September 2012. We contacted authors of individual published cases to obtain follow-up data. Data sets were cross-referenced to eliminate duplicate reporting.We identified 23 children with nephrogenic systemic fibrosis. Seventeen had documented exposure to gadolinium-based contrast agents. Six children had been reported in both the FAERS and the literature, four in the FAERS and the ICNSFR registry and five in all three data sources.Nephrogenic systemic fibrosis has been rarely reported in children. Although rules related to confidentiality limit the ability to reconcile reports, active pharmaco-vigilance using RADAR (Research on Adverse Drug events And Reports) methodology helped in establishing the number of individual pediatric cases within the three major data sources.

To summarize reports of anaphylaxis associated with gadolinium-based contrast agents (GBCAs) reported to the Food and Drug Administrations Adverse Event Reporting System (FAERS), examine the safety signals of anaphylaxis from GBCAs, and perform a literature review of relevant case reports.FAERS (1/1988-8/2012) was searched using groups of preferred event terms for anaphylaxis combined with all drug names for GBCAs Signal detection involved determination of proportional reporting ratios (PRRs) and empirical Bayes geometric means (EBGM). Published case reports were identified through a Medline search (1/1988-7/2013).There were 614 GBCA FAERS reports of anaphylaxis, resulting in a safety signal (PRR = 6.2, 95% confidence interval (CI) = 5.7 - 6.7; EBGM = 5.1 CI = 5.6 - 6.6). Among GBCAs, 43% were associated with gadopentetate dimeglumine (PRR = 4.9, CI = 4.3 - 5.5; EBGM = 4.8, CI = 4.3 - 5.4), 29% with gadobenate dimeglumine (PRR = 17.5, CI = 15.2 - 20.2; EBGM = 17.1, CI = 14.6 - 19.8) , and 17% with gadoteridol (PRR = 5.7, CI = 4.7 - 6.8; EBGM = 5.6, CI = 4.6 - 56.7). There were 14 anaphylaxis case reports in the literature.GBCAs used as medical imaging agents, can cause life-threatening or fatal anaphylaxis. There were differences in disproportionality of reporting between between agents. Although differences in numbers of reports of anaphylaxis reflect relative utilization rates of the various agents, disproportionality analyses (PRR, EBGM) disclose significant safety signals of anaphylaxis associated with most GBCAs.

Background The U.S. population of racial/ethnic minorities continues to increase; however, health disparities and poor health outcomes among many of them continue to be a major public health problem confronting the U.S. health care system. Objectives The objective of this review was to summarize published pharmaceutical care services literature reporting economic, clinical, and/or humanistic outcomes (ECHOs) among racial/ethnic minorities. Studies that reported differences by race/ethnicity and studies where most participants were from multiracial/ethnic minorities were included. Methods PubMed and International Pharmaceutical Abstracts databases were searched for articles that reported the effects of pharmaceutical care on ECHOs among racial/ethnic minorities published between January 1980 and November 2010. The literature review was focused on racial groups that included black/African-American, Native American, Indian American Asian, Alaska Native, Native Hawaiian, and Pacific Islander patients, and ethnic group that was non-white Hispanic/Latino patients. Results There were 24 articles that studied the impact of pharmaceutical care on ECHOs by race/ethnicity or where most participants were from multiracial/ethnic minorities. Twenty-three studies reported that pharmaceutical care has a positive impact on health outcomes of the studied populations. About half of the studies meeting inclusion criteria evaluated only 1 type of patient outcome, primarily clinical outcomes. Education/consultation and medication/therapy management were the most commonly evaluated types of pharmaceutical care services throughout the studied groups. Comprehensive disease management was evaluated mainly in multiracial/ethnic populations and blacks/African-Americans. Few studies adopted randomized controlled designs, which make it difficult to attribute changes in patient outcomes to the provision of pharmaceutical care. Nine studies that involved cooperation between pharmacists and other medical professionals reflect an increased tendency for interprofessional collaboration in the current health care system. Conclusion This review shows that there is a positive relationship between pharmaceutical care and ECHOs in patients from racial/ethnic minority groups. However, more studies are needed to document the effects of pharmaceutical care on reducing racial/ethnic health disparities and to determine which interventions are most effective among certain groups with health disparities.

In 1998, a multidisciplinary team of investigators initiated the Research on Adverse Drug events And Reports (RADAR) project, a post-marketing surveillance effort that systematically investigates and disseminates information describing serious and previously unrecognized serious adverse drug and device reactions (sADRs).Herein, we describe the findings, dissemination efforts, and lessons learned from the first decade of the RADAR project.After identifying serious and unexpected clinical events suitable for further investigation, RADAR collaborators derived case information from physician queries, published and unpublished clinical trials, case reports, US FDA databases and manufacturer sales figures.All major RADAR publications from 1998 to the present are included in this analysis.For each RADAR publication, data were abstracted on data source, correlative basic science findings, dissemination and resultant safety information.RADAR investigators reported 43 serious ADRs. Data sources included case reports (17 sADRs), registries (5 sADRs), referral centers (8 sADRs) and clinical trial reports (13 sADRs). Correlative basic science findings were reported for ten sADRs. Thirty-seven sADRS were described as published case reports (5 sADRs) or published case-series (32 sADRs). Related safety information was disseminated as warnings or boxed warnings in the package insert (17 sADRs) and/or 'Dear Healthcare Professional' letters (14 sADRs).An independent National Institutes of Health-funded post-marketing surveillance programme can supplement existing regulatory and pharmaceutical manufacturer-supported drug safety initiatives.

Purpose: To determine whether acute kidney injury (AKI) is identified within the US Food and Drug Administration’s Adverse Events and Reporting System (FDA AERS) as an adverse event resulting from bisphosphonate (BP) use in cancer therapy. Methods: A search of the FDA AERS records from January 1998 through June 2009 was performed; search terms were “renal problems” and all drug names for BPs. The search resulted in 2,091 reports. We analyzed for signals of disproportional association by calculating the proportional reporting ratio for zoledronic acid (ZOL) and pamidronate. Literature review of BP-associated renal injury within the cancer setting was conducted. Results: Four hundred eighty cases of BP-associated acute kidney injury (AKI) were identified in patients with cancer. Two hundred ninety-eight patients (56%) were female; mean age was 66 10 years. Multiple myeloma (n 220, 46%), breast cancer (n 98, 20%), and prostate cancer (n 24, 5%) were identified. Agents included ZOL (n 411, 87.5%), pamidronate (n 8, 17%), and alendronate (n 36, 2%). Outcomes included hospitalization (n 304, 63.3%) and death (n 68, 14%). The proportional reporting ratio for ZOL was 1.22 (95% CI, 1.13 to 1.32) and for pamidronate was 1.55 (95% CI, 1.25 to 1.65), reflecting a nonsignificant safety signal for both drugs. Conclusion: AKI was identified in BP cancer clinical trials, although a safety signal for BPs and AKI within the FDA AERS was not detected. Our findings may be attributed, in part, to clinicians who believe that AKI occurs infrequently; ascribe the AKI to underlying premorbid disease, therapy, or cancer progression; or consider that AKI is a known adverse drug reaction of BPs and thus under-report AKI to the AERS.

Background Accurate confirmation of prenatal alcohol exposure (PAE) is required as a diagnostic criterion for the majority of children adversely affected by PAE who do not manifest the physical features associated with fetal alcohol syndrome. A number of ethanol biomarkers have been used to assess PAE, often with suboptimal results. The purpose of this study was to evaluate the feasibility and cost of PAE screening in newborns by measuring phosphatidylethanol (PEth) in dried blood spot (DBS) cards. Methods The feasibility of collecting an additional DBS card during routine newborn screening and the background prevalence of PAE were evaluated in a de-identified sample of newborn children delivered at the University of New Mexico Hospital. Electronic orders to collect DBS cards from newborns who continue to bleed after the routine newborn screen, glucose, or hematocrit testing were initiated for all infants delivered during a 4-week time frame. Specimens were sent to a contract laboratory for PEth analysis by liquid chromatography–tandem mass spectrometry. A cost analysis was conducted to compare the cost of PAE screening by PEth in DBS versus PEth in conventional blood specimens and by meconium fatty acid ethyl esters. Results From 230 collected cards, 201 (87.4%) had at least 1 full blood spot (amount sufficient for PEth analysis), and 6.5% had PEth >20 ng/ml indicative of potential PAE in late pregnancy. PAE screening by PEth in DBS is logistically simpler and less expensive compared with 2 other screening approaches. Conclusions These results indicate that screening for PAE in DBS cards is a feasible procedure and that a majority of infants have enough blood after the routine heel prick to fill an additional card. Moreover, screening by PEth analysis from DBS cards is cost-efficient. The acceptability of such screening by parents and corresponding ethical issues remain to be investigated.

To our knowledge, no previous study has examined state-level geographic variability and its predictors in clinical practice patterns to screen for prostate cancer in the United States.We used the Behavioral Risk Factor Surveillance System 2010 data set to analyze geographic variability (by state) and its associated predictors in receiving a PSA test and/or a digital rectal examination (DRE). The study population consisted of men aged ≥50 years who responded as yes/no when asked about having a PSA test or DRE performed during the last year. We build two multilevel logistic regression models, differing in dependent variables, that is, (1) any prostate cancer screening (PCS) (either PSA and/or DRE), and (2) PCS based on PSA testing (PSAT). Individual characteristics (age, education, employment, marriage, income, race/ethnicity, self-reported health status, obesity, alcohol consumption, smoking status, personal physician presence, and health insurance coverage) were treated as level-1 variables and state characteristics (number of doctors per 100 000 persons per state, US regions and metropolitan statistical area (MSA) codes) were treated as level-2 variables.We found significant geographic variability in receiving PCS and PSAT screening in the United States. For PCS, MSA code was an independent predictor, with men living in urban areas having lower odds of screening (odds ratio (OR)=0.8, 95% confidence interval (CI)=0.7-0.9). In PSAT, the number of doctors per 100 000 persons per state was an independent predictor, with lowest quartile states (0-25% quartile) having lower odds of PSA-based screening (OR=0.78, 95% CI=063-0.94). In both models, all level-1 variables were independent predictors (P0.05) of PCS, except self-reported health status.Men living in urban areas and states with lower prevalence of doctors have lower odds of screening for prostate cancer and PSAT, respectively, after adjusting for individual variables. Future studies should examine the reasons for these health disparities.

Background: In the United States, hip fracture rates have declined by 30% coincident with bisphosphonate use. However, bisphosphonates are associated with sporadic cases of atypical femoral fracture. Atypical femoral fractures are usually atraumatic, may be bilateral, are occasionally preceded by prodromal thigh pain, and may have delayed fracture-healing. This study assessed the occurrence of bisphosphonate-associated nonhealing femoral fractures through a review of data from the U.S. FDA (Food and Drug Administration) Adverse Event Reporting System (FAERS) (1996 to 2011), published case reports, and international safety efforts. Methods: We analyzed the FAERS database with use of the proportional reporting ratio (PRR) and empiric Bayesian geometric mean (EBGM) techniques to assess whether a safety signal existed. Additionally, we conducted a systematic literature review (1990 to February 2012). Results: The analysis of the FAERS database indicated a PRR of 4.51 (95% confidence interval [CI], 3.44 to 5.92) for bisphosphonate use and nonhealing femoral fractures. Most cases (n = 317) were attributed to use of alendronate (PRR = 3.32; 95% CI, 2.71 to 4.17). In 2008, international safety agencies issued warnings and required label changes. In 2010, the FDA issued a safety notification, and the American Society for Bone and Mineral Research (ASBMR) issued recommendations about bisphosphonate-associated atypical femoral fractures. Conclusions: Nonhealing femoral fractures are unusual adverse drug reactions associated with bisphosphonate use, as up to 26% of published cases of atypical femoral fractures exhibited delayed healing or nonhealing.

Objective 1) To compare the Food and Drug Administration's (FDA's) Risk Evaluation and Mitigation Strategies (REMS) and European Medicines Agency's (EMA's) Risk Management Plan (RMP) guidances and 2) to compare REMS and RMPs for specific chemical entities and biological products. Methods FDA, EMA, and pharmaceutical company Web sites were consulted for details pertaining to REMS and RMPs. REMS requirements include medication guides, communication plans, elements to ensure safe use, implementation systems, and specified assessment intervals. RMP requirements are increased pharmacovigilance and risk minimization activities. We compared these requirements for drugs requiring both REMS and RMPs. Results We identified 95 drugs on FDA's REMS list as of March 2010. Of these, there were 29 drugs (11 biologics and 18 new chemical entities) with EMA RMPs. REMS and RMPs are similar in objectives, with comparable toolkits. Both allow flexibility in product-specific actions, recognizing adverse effects of potential concern. Of the 29 drugs reviewed, REMS requirements not included in RMPs were patient medication guides (100% of the drugs), provider communication plans (38%), and routine monitoring of REMS (66%). RMP requirements not included in REMS were specific adverse event reporting (45% of the drugs), prospective registry studies (34%), prospective epidemiology studies (24%), additional trial data (28%), and Summary of Product Characteristics contraindications (76%). Conclusions Both REMS and RMPs provide positive guidance for identification, monitoring, and minimization of risk to patient safety. Currently, neither agency provides specific guidance on how risk should be related to benefit either qualitatively or quantitatively.

Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.

OBJECTIVE Depression affects up to 20–25% of adults with type 2 diabetes and may increase all-cause mortality, but few well-designed studies have examined the effects of depression on the full range of cardiovascular disease outcomes in type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 2,053 participants in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) Health-Related Quality of Life substudy completed the Patient Health Questionnaire (PHQ)-9 measure of depression symptoms at baseline and 12, 36, and 48 months. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) (95% CI) for the time-varying impact of depression on protocol-defined clinical outcomes with and without adjustment for demographic, trial-related, clinical, and behavioral variables. RESULTS In fully adjusted models, depression was not significantly related to the ACCORD primary composite outcome (cardiovascular death, nonfatal heart attack, or stroke) (HR 1.53 [95% CI 0.85–2.73]) or to the ACCORD microvascular composite outcome (0.93 [0.53–1.62]), but all-cause mortality was significantly increased both in those with PHQ-assessed probable major depression (2.24 [1.24–4.06]) and PHQ score of ≥10 (1.84 [1.17–2.89]). The effect of depression on all-cause mortality was not related to previous cardiovascular events or to assignment to intensive or standard glycemia control. Probable major depression (by PHQ-9) had a borderline impact on the ACCORD macrovascular end point (1.42 [0.99–2.04]). CONCLUSIONS Depression increases the risk of all-cause mortality and may increase the risk of macrovascular events among adults with type 2 diabetes at high risk for cardiovascular events.

IN BRIEF Our study demonstrates strong associations of diabetes symptoms and distress with female sex, higher BMI, history of neuropathy, and current depressive symptoms. Many diabetes-specific symptoms may be significantly shaped by factors such as depression and obesity.

Although amiodarone is the most commonly prescribed anti-arrhythmic drug, its use is limited by serious toxicities, including optic neuropathy. Current reports of amiodarone-associated optic neuropathy identified from the Food and Drug Administration's Adverse Event Reporting System and published case reports were reviewed. A total of 296 reports were identified: 214 from the Adverse Event Reporting System, 59 from published case reports, and 23 from adverse events reports for patients enrolled in clinical trials. Mean duration of amiodarone therapy before vision loss was 9 months (range 1-84 months). Insidious onset of amiodarone-associated optic neuropathy (44%) was the most common presentation, and nearly one third were asymptomatic. Optic disk edema was present in 85% of cases. Following drug cessation, 58% had improved visual acuity, 21% were unchanged, and 21% had further decreased visual acuity. Legal blindness (

Purpose: Counterfeit pharmaceuticals pose risks domestically. Because of their cost, cancer pharmaceuticals are vulnerable. We review findings from a domestic counterfeiting episode involving erythropoietin and outline anticounterfeiting recommendations for policy makers, patients, and health care professionals. Materials and Methods: Information was obtained on patients who received counterfeit erythropoietin, its distribution, and criminal investigations into counterfeiting networks. Interview sources included a physician, an attorney, employees of the Florida Department of Health and Human Services and the US Food and Drug Administration’s (FDA) Office of Criminal Investigation, manufacturers, and wholesalers. Other sources included the book “Dangerous Doses,” LexisNexis (search terms “counterfeit” and “erythropoietin”) and the FDA database. Results: Counterfeit product consisted of 2,000 U vials with counterfeit labels denoting 40,000 U. The counterfeiters, in collaboration with a Miami pharmacy, purchased 110,000 erythropoietin 2,000 U vials and affixed counterfeit labels to each vial. Products werethensoldviathepharmaceutical“graymarket”towholesalers, then pharmacy chains. Investigations by Florida government officials implicated 17 persons, all of whom were found guilty of trafficking in counterfeit pharmaceuticals. Despite the large size of the operation, the FDA received reports of only 12 patients who had received counterfeit erythropoietin and detailed information for only two individuals. A 17-year-old liver transplant recipient and a 61year-oldpatientwithbreastcancerexperiencedlossofefficacyafter receiving counterfeit erythropoietin. Conclusion: Wider use of FDA anticounterfeit initiatives, limiting pharmaceutical suppliers to reputable distributors, and educating providers and patients about signs of counterfeit drugs can improve the safety of cancer pharmaceuticals.

Background Assessment of adherence to study medications is a common challenge in clinical research. Counting unused study medication is the predominant method by which adherence is assessed in outpatient clinical trials but it has limitations that include questionable validity and burdens on research personnel. Purpose To compare capsule counts, patient questionnaire responses, and plasma drug levels as methods of determining adherence in a clinical trial that had 2056 participants and used centralized drug distribution and patient follow-up. Methods Capsule counts from study medication bottles returned by participants and responses to questions regarding adherence during quarterly telephone interviews were averaged and compared. Both measures were compared to plasma drug levels obtained at the 3-month study visit of patients in the treatment group. Counts and questionnaire responses were converted to adherence rates (doses taken divided by days elapsed) and were categorized by stringent (≥85.7%) and liberal (≥71.4%) definitions. We calculated the prevalence-adjusted bias-adjusted kappa to assess agreement between the two measures. Results Using a pre-paid mailer, participants returned 76.0% of study medication bottles to the central pharmacy. Both capsule counts and questionnaire responses were available for 65.8% of participants and were used to assess adherence. Capsule counts identified more patients who were under-adherent (18.8% by the stringent definition and 7.5% by the liberal definition) than self-reports did (10.4% by the stringent definition and 2.1% by the liberal definition). The prevalence-adjusted bias-adjusted kappa was 0.58 (stringent) and 0.83 (liberal), indicating fair and very good agreement, respectively. Both measures were also in agreement with plasma drug levels determined at the 3-month visit (capsule counts: p = 0.005 for the stringent and p = 0.003 for the liberal definition; questionnaire: p = 0.002 for both adherence definitions). Limitations Inconsistent bottle returns and incomplete notations of medication start and stop dates resulted in missing data but exploratory missing data analyses showed no reason to believe that the missing data resulted in systematic bias. Conclusions Depending upon the definition of adherence, there was fair to very good agreement between questionnaire results and capsule counts among returned study bottles, confirmed by plasma drug levels. We conclude that a self-report of medication adherence is potentially comparable to capsule counts as a method of assessing adherence in a clinical trial, if a relatively low adherence threshold is acceptable, but adherence should be confirmed by other measures if a high adherence threshold is required.

This article examines the relationship among diabetes-related stress, appraisal, coping and depressive symptoms in patients with type 2 diabetes mellitus (T2DM) using the transactional model of stress and coping (TMSC) as the theoretical framework. In this cross-sectional study, a convenience sample of 201 patients with T2DM was recruited from three outpatient clinics. Patients with depressive symptoms reported significantly more diabetes-related stress than patients without depressive symptoms. The results of path analysis suggest that patients who experience greater diabetes-related stress or greater depressive symptoms have a negative appraisal of their diabetes. Negative appraisal is, in turn, associated with greater use of avoidance, passive resignation and diabetes integration coping and lesser use of problem-focused coping. Avoidance, passive resignation and diabetes integration coping are, in turn, related to greater depressive symptoms or greater diabetes-related stress. Overall, the results of this study support the TMSC as a framework to elucidate the relationships among diabetes-related stress, appraisal, coping and depressive symptoms in patients with T2DM. However, given the cross-sectional nature of the study, we are unable to elucidate the directionality of the relationship between stress and depressive symptoms. Implications of the findings and the need for longitudinal studies to evaluate these relationships are discussed.

Background: Rituximab has been associated with hepatitis B virus reactivation (HBV-R). However, the characteristics and scope of this association remain largely undefined. Methods: We completed a comprehensive literature search of all published rituximab-associated HBV-R cases and from the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) MedWatch database. Literature and FDA cases were compared for completeness, and a meta-analysis was completed. Results: One hundred and eighty-three unique cases of rituximab-associated HBV-R were identified from the literature (n = 27 case reports, n = 156 case series). The time from last rituximab to reactivation was 3 months (range 0–12), although 29% occurred >6 months after last rituximab. Within FDA data (n = 118 cases), there was a strong signal for rituximab-associated HBV-R [proportional reporting ratio = 28.5, 95% confidence interval (CI) 23.9–34.1; Empiric Bayes Geometric Mean = 26.4, 95% CI 21.4–31.1]. However, the completeness of data in FDA reports was significantly inferior compared with literature cases (P < 0.0001). Among HBV core antibody (HBcAb(+)) series, the pooled effect of rituximab-based therapy showed a significantly increased risk of HBV-R compared with nonrituximab-treated patients (odds ratio 5.73, 95% CI 2.01–16.33; Z = 3.33, P = 0.0009) without heterogeneity (χ2 = 2.12, P = 0.5473). Conclusions: The FDA AERS provided strong HBV-R safety signals; however, literature-based cases provided a significantly more complete description. Furthermore, meta-analysis of HBcAb(+) series identified a more than fivefold increased rate of rituximab-associated HBV-R.

Summary Background Tumour necrosis factor-α inhibitors (TNFαIs) are used for treatment of inflammatory disorders. There is evidence linking these agents with occurrence of malignancies. For four out of five TNFαIs the Food and Drug Administration (FDA) label states, ‘melanoma has been reported in patients treated with these agents’. Objectives To determine whether a statistically significant association exists between administration of TNFαIs and development of malignant melanoma. Methods We searched the FDA Adverse Event Reporting System (FAERS) database for terms related to melanoma and TNFαIs for detection of safety signals. We also searched a large urban academic electronic medical record (EMR) database for which we calculated the relative risk (RR) of melanoma in subjects exposed to TNFαIs vs. nonexposed subjects. Results There were 972 reports of melanoma associated with a TNFαI identified in the FAERS database, with 69 reports among individuals using more than one TNFαI. A safety signal was detected for infliximab, golimumab, etanercept and adalimumab, but not certolizumab pegol. For TNFαIs as a class of drugs, a safety signal was detectable in the FAERS database, and RR was significant in the EMR database. For the EMR cohort, 6045 patients were exposed to TNFαIs and 35 cases of melanoma were detected. Significance for RR was detected for adalimumab (RR 1·8, P = 0·02) and etanercept (RR 2·35, P = 0·0004 < 0·001). Conclusions We identified a significant association between exposure to TNFαIs and malignant melanoma in two different analyses. Our findings add to existing evidence linking these agents with the occurrence of malignant melanoma. Additional investigations are required to explore this association further along with the risk of melanoma with TNFαI therapy.

1 South Carolina Center of Economic Excellence for Medication Safety and Efficacy and the Southern Network on Adverse Reactions (SONAR), South Carolina College of Pharmacy, University of South Carolina, Columbia, SC; 2 Pharmacoeconomics, Epidemiology, Public Policy and Outcomes Research (PEPPOR), College of Pharmacy, University of New Mexico, and Veterans Affairs Cooperative Studies Program Clinical Research Pharmacy, Albuquerque, NM; 3 Tulane Cancer Center, Tulane University, New Orleans, LA; 4 eHealthMe, Madison, WI; and 5 Hollings Cancer Center, Medical University of South Carolina, Charleston, SC

In April 2009, the FDA retracted a warning asserting that ceftriaxone and intravenous calcium products should not be coadministered to any patient to prevent precipitation events leading to end-organ damage. Following that announcement, we sought to evaluate if the retraction was justified. A search of the FDA Adverse Event Reporting System was conducted to identify any ceftriaxone-calcium interactions that resulted in serious adverse drug events. Ceftazidime-calcium was used as a comparator agent. One hundred four events with ceftriaxone-calcium and 99 events with ceftazidime-calcium were identified. Adverse drug events were recorded according to the listed description of drug involvement (primary or secondary suspect) and were interpreted as probable, possible, unlikely, or unrelated. For ceftriaxone-calcium-related adverse events, 7.7% and 20.2% of the events were classified as probable and possible for embolism, respectively. Ceftazidime-calcium resulted in fewer probable embolic events (4%) but more possible embolic events (30.3%). Among cases that considered ceftriaxone or ceftazidime and calcium as the primary or secondary drug, one case was classified as a probable embolic event. That patient received ceftriaxone-calcium and died, although an attribution of causality was not possible. Our analysis suggests a lack of support for the occurrence of ceftriaxone-calcium precipitation events in adults. The results of the current analysis reinforce the revised FDA recommendations suggesting that patients >28 days old may receive ceftriaxone and calcium sequentially and provide a transparent and reproducible methodology for such evaluations.

Decision-makers utilize the results of economic analysis in a wide range of settings that include governmental agencies, managed care, and other health-care payers [1,2]. A cornerstone of such analysis is the quality-adjusted life-year (QALY), which is formed by the arithmetic product of quantity and quality of life. The expansion in use of economic evaluation by health agencies has mirrored the growing recognition of the usefulness of healthrelated quality of life (HrQoL) as an important indicator of outcome of disease treatment among clinicians and patients [3–7]. This information has a dual use in that it informs both clinicians and health economists in the evaluation of treatment options. The use of the QALY as a health outcome measure for groups of patients is fairly clear for payers, managed care, and governmental organizations who seek to make decisions that maximize the value of health-care spending in terms of health outcomes achieved through the most efficient use of limited resources. Nevertheless, the importance and need to bring QALYs into the wider decision-making process of clinicians and patients is more controversial. For the purposes of this article, it is assumed that economic evaluation of health-care interventions by national reimbursement or other health-care decision-making bodies is largely a given, although there clearly are health-care jurisdictions in which this is not the case. Nevertheless, in a global marketplace, the requirements of dominant health-care jurisdictions are likely to influence the behaviors of other stakeholders across the world community. Hence, the influential role of cost-utility analysis (CUA) as part of an information toolkit for high-level decisionmaking is unlikely to be radically altered in the next 5 to 10 years. Central to CUA is the need for an outcome measure that combines the effects of health interventions on mortality and morbidity into a single index—the QALY. Critical to the computation of QALYs is the assessment of the impact of morbidity, represented through the measurement of HrQoL from data gathered in clinical trials and observational studies. Although these same data are applied in the economic evaluation of new health technologies, they may also be used in other non-economic applications, for example, in monitoring health status in individual patients, or in measuring population health or the impact of therapies in clinical studies. Different health jurisdictions permit or require different forms of HrQoL measurement in the economic evaluation of health technologies. Some stipulate that the weights used to value HrQoL states are social preferences that reflect the views of the general population. Others are open to the use of values derived from patients or others directly affected by the health technology. The question as to whose values do (or should) count is a matter for local arbitration within the decision-making framework of specific societies and their individual health-care systems. Ultimately, it is a political choice. It is not (and should not be) determined by health economists or other single stakeholder groups. For the purposes of this article, it is sufficient to note that the quality-adjustment factor used in computing QALYs can emanate from several sources and may or may not represent the views of the patient or those who care for them. It is worth briefly reflecting on both “decision-maker” as an attribute of an individual or set of individuals and “decisionmaking” as an activity undertaken by members of that set. Highlevel policy that shapes the development of health-care programs is clearly distinct from the day-to-day delivery of care to patients. Decision-making activity in support of the former is more likely to make use of economic evaluation than is the case in the latter. Policy formation is informed to some extent by aggregated measures of costs and benefits. Individual clinicians may contribute to those data but more often are faced with decisions that are made in relative ignorance of the wider societal-level picture. A decision by a clinician to admit a patient to hospital for treatment, or to provide innovative therapy or embark on diagnostic investigations is likely to be taken with minimal reference to the evidence of any economic evaluation (should it exist). Conversely, health programs are more likely to be formulated with regard for evidence of effectiveness and cost-effectiveness of such interventions when applied to population subgroups, occasionally to whole populations. This article addresses a number of related issues that stem from a more widely drawn interpretation of the QALY in which its status as a composite measure of health benefit is recognized, but where its role is not wholly contained within or limited to a cost-effectiveness framework. Under what circumstances is QALY-based information of value to decision-makers such as clinicians and other staff with direct responsibility for patient care? Is the QALY in its present format useful for the comparison of health outcomes within a given therapeutic area? How might the value to clinicians and patients of QALY-based information and its application in low-level decision-making be enhanced? And finally, what obstacles need to be overcome in extending the uses and usefulness of the QALY to noneconomist health-care decision-makers?

Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP. Data were abstracted from a systematic review of English-language literature for thienopyridine-associated TTP identified in MEDLINE, EMBASE, the public website of the Food and Drug Administration, and abstracts from national scientific conferences from 1991 to April 2008. Ticlopidine and clopidogrel are the two most common drugs associated with TTP in FDA safety databases. Epidemiological studies identify recent initiation of anti-platelet agents as the most common risk factor associated with risks of developing TTP. Laboratory studies indicate that most cases of thienopyridine-associated TTP involve an antibody to ADAMTS13 metalloprotease, present with severe thrombocytopenia, and respond to therapeutic plasma exchange (TPE); a minority of thienopyridine-associated TTP presents with severe renal insufficiency, involves direct endothelial cell damage, and is less responsive to TPE. The evaluation of this potentially fatal drug toxicity can serve as a template for future efforts to comprehensively characterize other severe adverse drug reactions.

Objectives We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP). Background The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA). Methods Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals. Results Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p 15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p 2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p Conclusions Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival.

Background: Prevention of cardiovascular disease (CVD) events by initiating an angiotensin-converting enzyme (ACE) inhibitor on diagnosis of type 2 diabetes may increase survival and decrease costs. Objective: To determine the incremental cost-effectiveness ratios of ACE inhibitor initiation in normoaIbuminuric, microalbuminuruc, and macroaIbuminuric patients with newly diagnosed type 2 diabetes. Methods: A cohort of patients with newly diagnosed type 2 diabetes was followed for 8 years in a Markov model. Clinical outcomes included CVD events, dialysis, all-cause mortality, and the composite endpoints of the 3 events. Probabilities and costs were obtained from the literature. One-way and two-way sensitivity analyses were conducted to test the robustness of the model. Results: Implementation of ACE inhibitor therapy on diagnosis of type 2 diabetes in normoalbuminuric and microalbuminuric patients is a dominant strategy (ie, more effective and less costly) across all outcomes. In macro-albuminuric patients, an additional $4,10 and $4.58 saves one life and avoids one composite endpoint, respectively; however, in these patients, not giving an ACE inhibitor is dominant for prevention of CVD events and dialysis. This is due to a 28.62% higher mortality rate in patients not receiving an ACE inhibitor. Thus, analysts of the composite endpoint shows that not giving an ACE inhibitor does not remain dominant. A limitation of our study is the inability to determine causality. Conclusions: If every newly diagnosed patient with type 2 diabetes in the US was prescribed an ACE inhibitor, our model shows that 68 314 CVD events would be averted, 46410 lives would be saved, and 48 people would be prevented from needing dialysis over 8 years. These findings suggest that ACE inhibitors prevent numerous events in patients with type 2 diabetes who are normoalbuminuric at diagnosis, in addition to those already identified as being at risk for CVD events.

Gemtuzumab ozogamicin (GO) was approved for marketing in 2000 by the United States Food and Drug Administration (FDA) for older patients with relapsed acute myeloid leukemia (AML). Four months later, 14 phase II clinical trial participants who received novel GO-containing combination chemotherapy regimens developed an unexpected hepatic toxicity termed sinusoidal obstructive syndrome (SOS) or hepatic veno-occlusive disease (VOD). Investigators associated with the Research on Adverse Drug Events and Reports (RADAR) project reviewed safety reports for GO included in reports of clinical trials and observational studies, interim reports from an FDA mandated Prospective Observational Registry, and the Food and Drug Administration's Adverse Event Reporting System. Medline searches provided incidence estimates of GO-associated SOS and comparative rates of SOS without GO. SOS is characterized by hyperbilirubinemia, painful hepatomegaly, ascites, and sudden weight gain developing at a median of 10 days following GO administration for patients who did not undergo an allogeneic SCT procedure and 13 days following an allogeneic SCT for patients who had previously received GO. Among adult AML patients who received GO in clinical trials, SOS incidence was 3% at doses < or =6 mg/m(2) if administered as monotherapy or in combination with non-hepatotoxic agents versus 28% if administered with thioguanine and 15% when administered as monotherapy at a dose of 9 mg/m(2). Observational studies identified SOS rates between 15% and 40% if an SCT is performed within 3 months of GO administration. The FDA mandated Prospective Observational Registry of patients who receive care at 60 medical centers has identified GO-associated SOS rates of 14% if an SCT is performed and 9% otherwise. Caution is advised when administering GO in routine clinical practice, particularly if administered with other hepatotoxic agents, at doses and schedules more intensive than those approved by the FDA, or within 3 months of a SCT procedure.

Knowledge of distinct motivations and reasons toward or against future trial participation is invaluable to any organization conducting trial research. Study delays often occur due to lack of recruitment. This study's primary objective was to compare veteran and nonveteran motivations and reasons.People in two outpatient waiting rooms were approached. The questionnaire assessed motivation toward trial involvement through use of five-point Likert-type scales and hypothetical trial scenarios; it also analyzed reasons for participation through subject ranking of reasons.Veterans were more likely to participate in a trial in which all participants received the active treatment (p = 0.025). Veterans had different reasons for participation than nonveterans. Specifically, veterans felt altruism and "paying back" people who treated them were more important (p = 0.024 and p = 0.003) while financial compensation for volunteering was less important (p0.001).Knowledge of the varying reasons for participation could potentially aid recruitment efforts.

Background: Patient characteristics increase the risk of gastrointestinal (GI) complications associated with nonsteroidal antiinflammatory drugs (NSAIDs). Patients at risk may not be prescribed protective therapies that might mitigate their risk of NSAID-associated GI complications. Objective: To assess GI risk among Veterans Affairs (VA) patients on NSAID therapy, determine whether therapy conformed to VA guidelines for lessening the risk of GI complications, and identify patient risk factors associated with conformance. Methods: Using databases from 3 VA medical centers, we retrospectively identified patients receiving NSAIDs and obtained data regarding age, history of GI bleed over 8 years, GI adverse effects associated with NSAIDs, diagnoses, and medication history over one year. We inferred health status from age-adjusted Charlson comorbidity index values. Each patient's risk of developing GI complications over one year was calculated using these data. Among patients at significant or substantial risk, we assessed conformance to VA guidelines. We used logistic regression to identify risk factors associated with conformance and determine adjusted ORs (AORs) with 95% CIs for each risk factor. Results: There were 19122 patients receiving NSAIDs. Of 4589 patients at significant risk and 1246 at substantial risk, 1161 (25.3%) and 356 (28.6%), respectively, were prescribed guideline-conformant therapy. Risk factors associated with conformance (p s 0.001) among patients at significant risk were rheumatoid arthritis (AOR 1.34; 95% CI 1.13 to 1.58) and GI adverse effects (AOR 1.53; 95% CI 1.42 to 1.64). For substantial risk patients, risk factors associated with conformance (p s 0.031) were rheumatoid arthritis (AOR 1.65; 95% CI 1.37 to 1.98), concomitant corticosteroids (AOR 1.21; 95% CI 1.02 to 1.43), GI hospitalization (AOR 2.01; 95% CI 1.57 to 2.59), and GI adverse effects (AOR 1.79; 95% CI 1.47 to 2.18). Conclusions: Many patients at risk for GI adverse events do not receive guideline-conformant therapy. Educational interventions to improve conformance could focus on specific risk factors for GI complications.

OBJECTIVES The purpose of this study was to determine quality of life (QOL) and exercise performance (EP) in patients with persistent atrial fibrillation (AF) converted to sinus rhythm (SR) compared with those remaining in or reverting to AF. BACKGROUND Restoration of SR in patients with AF improving QOL and EP remains controversial. METHODS Patients with persistent AF were randomized double-blind to amiodarone, sotalol, or placebo. Those not achieving SR at day 28 were cardioverted and classified into SR or AF groups at 8 weeks (n = 624) and 1 year (n = 556). The QOL (SF-36), symptom checklist (SCL), specific activity scale (SAS), AF severity scale (AFSS), and EP were assessed. RESULTS Favorable changes were seen in SR patients at 8 weeks in physical functioning (p < 0.001), physical role limitations (p = 0.03), general health (p = 0.002), and vitality (p < 0.001), and at 1 year in general health (p = 0.007) and social functioning (p = 0.02). Changes in the scores for SCL severity (p = 0.01), functional capacity (p = 0.003), and AFSS symptom burden (p < 0.001) at 8 weeks and in SCL severity (p < 0.01) and AF symptom burden (p < 0.001) at 1 year showed significant improvements in SR versus AF. Symptomatic patients were more likely to have improvement. The EP in SR versus AF was greater from baseline to 8 weeks (p = 0.01) and to 1 year (p = 0.02). The EP correlated with physical functioning and functional capacity except in the AF group at 1 year. CONCLUSIONS In patients with persistent AF, restoration and maintenance of SR was associated with improvements in QOL measures and EP. There was a strong correlation between QOL measures and EP.

Little is known about the underlying intentions to use herbal medicines among Hispanic older adults. Understanding these intentions is critical to the provision of effective counseling.The objectives were to (1) identify predictors of the intention to use herbal medicines for health problems in the next 6 months among Hispanic and non-Hispanic older adults using the Theory of Planned Behavior (TPB); and (2) compare their beliefs underlying significant predictors of intention with use herbal medicines for health problems in the next 6 months.Using a cross-sectional research design, data were collected via self-administered questionnaires from convenience samples at a Senior Health Clinic and a Veterans Affairs Hospital outpatient pharmacy. Study subjects were community dwelling adults aged 65 years and older and able to complete the survey in English. Multiple regression analysis was used to identify the significant predictors of intention to use herbal medicines in the TPB within each ethnicity. Independent t tests were used to compare the beliefs underlying the significant predictors of intention with use herbal medicines across the 2 groups.For both Hispanic (N=80) and non-Hispanic (N=171) patients, attitudes toward using herbal medicines was the only significant predictor of the intention to use herbal medicines in the next 6 months (Hispanics, Adj. R(2)=0.59, beta=0.78, P.001; non-Hispanics, Adj. R(2)=0.57, beta=0.66, P.001). The magnitude of the beta coefficients did not differ significantly between the 2 ethnicities. Compared with non-Hispanics, Hispanics believed that herbal medicines are cheaper, have fewer side effects, work better, and are more convenient to use than other medicines.Understanding ethnic differences in behavioral beliefs underlying attitudes toward the use of herbal medicines can help pharmacists and other health care professionals in educating and formulating appropriate counseling strategies specific to older patients of different ethnicities.