Emergency use authorization for intravenous peramivir: evaluation of safety in the treatment of hospitalized patients infected with 2009 H1N1 influenza A virus.

BACKGROUND: On 23 October 2009, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for intravenous peramivir, an unapproved antiviral, to treat suspected or confirmed 2009 H1N1 influenza A virus infection. Eligible hospitalized patients were unresponsive to or unable to tolerate available antivirals or lacked dependable oral or inhaled drug delivery routes. The EUA required healthcare providers to report medication errors, selected adverse events (AEs), serious AEs, and deaths to the FDA. METHODS: An FDA safety team analyzed reports submitted to the Adverse Event Reporting System (AERS) and sought follow-up in selected cases. RESULTS: The FDA received AERS reports for 344 patients (including 28 children and 3 pregnant women). Many patients were critically ill on mechanical ventilation (41%) and renal replacement therapies (19%); 38% had received oseltamivir. The most frequently reported serious AEs by MedDRA preferred term were death (15%), H1N1 influenza (8%), respiratory failure (8%), acute renal failure (7%), and acute respiratory distress syndrome (7%). Six medication errors were reported. Most deaths occurred among patients who were obese, immunosuppressed, aged >65 years, or received oseltamivir. Rash was the only treatment-emergent AE attributable to peramivir. Influenza severity, comorbidities, and concomitant medications confounded additional peramivir AE assessments. Missing clinical and laboratory data precluded evaluation of some reports. CONCLUSIONS: Many peramivir recipients under the EUA were critically ill and at risk for influenza-related complications. The safety data were insufficient to assess whether peramivir affected outcome or caused adverse reactions other than rash. Clinical trials in hospitalized patients with serious influenza infections should provide additional information.

Spectrum of central anticholinergic adverse effects associated with oxybutynin: comparison of pediatric and adult cases.

We reviewed Food and Drug Administration postmarketing reports of central nervous system (CNS) anticholinergic effects in association with oxybutynin. Taking domestic usage by age group into account, there is a disproportionately higher number of CNS adverse event cases reported in pediatric patients as compared with adult patients. CNS stimulation was prominent in the pediatric cases.

An Alternative to Disproportionality: A Frequency-Based Method for Pharmacovigilance Data Mining.

BACKGROUND: Safety surveillance relies on mining of large pharmacovigilance (PV) databases to generate insights regarding the safe use of pharmaceutical products. The predominant approach to PV data mining involves computation of disproportionality scores for drug-adverse event (drug-AE) pairs. However, this approach requires a database to be sufficiently large, sufficiently diverse for the analysis to be reliably sensitive and specific, and fails to consider the particular safety profile of a product. OBJECTIVE: The present study proposes and tests a novel, frequency-based approach to PV data mining that (1) leverages product knowledge and historical drug-AE trends and (2) imposes no requirement for the size and diversity of the database to which it is applied. METHOD: A focus group of physicians and scientists was convened to identify quantitative characteristics of data trends that they consider informative when reviewing counts of adverse events for products under surveillance. Feedback was transferred into a series of decision rules that, when applied to adverse event counts, identifies adverse event trends that are classified as Continuing Trend, Emerging Trend, or No Trend. Regression analyses are completed to verify the presence of a linear trend; and categorical measures of association completed to compare this frequency-based approach to disproportionality scores in a simulated database. RESULTS: A significant, positive linear trend is present for the Continuing Trend and Emerging Trend categories ( P < .0001). There is a significant association between trend categorizations and disproportionality scores ( P < .0001). CONCLUSION: The proposed alternative frequency-based method for PV data mining would be useful where disproportionalities scores are not appropriate. Additionally, this method may be useful in conjunction with disproportionality scores, where appropriate, highlighting adverse events that are both reported disproportionately and have increasing trends.

Atazanavir-associated nephrolithiasis: cases from the US Food and Drug Administration's Adverse Event Reporting System.

The risk of nephrolithiasis associated with atazanavir is not well characterized. The US Food and Drug Administration's Adverse Event Reporting System was searched for reports of nephrolithiasis in HIV-infected patients taking an atazanavir-based regimen. Thirty cases were identified. Many patients required hospitalization for management, including lithotripsy, ureteral stent insertion, or endoscopic stone removal. Some cases of nephrolithiasis resulted in atazanavir discontinuation. Healthcare professionals and patients should be informed that nephrolithiasis is a possible adverse event with atazanavir.

Current advances in pharmacovigilance in the USA and Europe: meeting the challenges of safety monitoring in HIV.

PURPOSE OF REVIEW: The success of antiretroviral therapy in HIV disease comes currently with the realization that patients are committed to life-long treatment, which raises the possibility of long-term toxicity. Such long-term side effects may not be identified in initial clinical trials requiring, therefore, a different approach to monitoring patients over time - a pharmacovigilance approach. RECENT FINDINGS: Several key issues in long-term management of HIV infection have been addressed by a pharmacovigilance approach - including unusual and rare side effects and elucidation of emerging toxicities such as cardiovascular, bone and renal disease. Recent changes in legislation in the USA and Europe are aimed to strengthen pharmacovigilance in developed countries. SUMMARY: HIV infection and its treatment provide an important example of the role of pharmacovigilance. As clinical trials can rarely address the question of long-term tolerability, effective pharmacovigilance programs are and will remain essential.