Drug Safety
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After reports from Japan of neuropsychiatric adverse events (NPAEs) in children taking oseltamivir phosphate (hereafter referred to as oseltamivir [Tamiflu; F. Hoffmann-La Roche Ltd, Basel, Switzerland]) during and after the 2004--5 influenza season, Roche explored possible reasons for the increase in reporting rate and presented regular updates to the US FDA and other regulatory authorities. This review summarizes the results of a comprehensive assessment of the company's own preclinical and clinical studies, post-marketing spontaneous adverse event reporting, epidemiological investigations utilizing health claims and medical records databases and an extensive review of the literature, with the aim of answering the following questions: (i) what the types and rates of neuropsychiatric abnormalities reported in patients with influenza are, and whether these differ in patients who have received oseltamivir compared with those who have not; (ii) what levels of oseltamivir and its active metabolite, oseltamivir carboxylate are achieved in the CNS; (iii) whether oseltamivir and oseltamivir carboxylate have pharmacological activity in the CNS; and (iv) whether there are genetic differences between Japanese and Caucasian patients that result in different levels of oseltamivir and/or oseltamivir carboxylate in the CNS, differences in their metabolism or differences in their pharmacological activity in the CNS. ⋯ Oseltamivir or oseltamivir carboxylate did not interact with human neuraminidases or with 155 known molecular targets in radioligand binding and functional assays. A review of the information published to date on functional variations of genes relevant to oseltamivir pharmacokinetics and pharmacodynamics and simulated gene knock-out scenarios did not identify any plausible genetic explanations for the observed NPAEs. The available data do not suggest that the incidence of NPAEs in influenza patients receiving oseltamivir is higher than in those who do not, and no mechanism by which oseltamivir or oseltamivir carboxylate could cause or worsen such events could be identified.
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While beneficial therapeutically, almost all medications have untoward effects on various body tissues and functions, including the eye in which organ toxic reactions are readily detectable. Every part of the eye and all ocular functions could be affected adversely. In this review, we describe the most commonly recognized drug-induced ocular disorders, their specific clinical features, the medications that can cause the problem, the differential diagnosis and possible mechanisms of action, as well as guidelines for the management of the adverse reactions. ⋯ Many different kinds of medications can cause similar ocular adverse reactions. Conversely, a single medication may affect more than one ocular structure and cause multiple, clinically recognizable disorders. Clinicians should be mindful of drug-induced ocular disorders, whether or not listed in product package inserts, and, if in doubt, consult with an ophthalmologist.
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Given the high prevalence of medication use in the US, the risk of drug-drug interactions (DDIs) and potential for patient harm is of concern. Despite the rise in technologies to identify potential DDIs, the ability of physicians and other prescribers to recognize potential DDIs is essential to reduce their occurrence. The objectives of this study were to assess prescribers' ability to recognize potential clinically significant DDIs and to examine the sources of information they use to identify potential DDIs and prescribers' opinions on the usefulness of various DDI information sources. ⋯ This study suggests that prescribers' knowledge of potential clinically significant DDIs is generally poor. These findings are supported by other research and emphasize the need to develop systems that alert prescribers about potential interactions that are clinically relevant. Physicians most commonly reported learning about potential DDIs from pharmacists, suggesting further work is needed to improve the drug-prescribing process to identify potential safety issues earlier in the medication use process.
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Bupropion was the first alternative to nicotine replacement therapy in the pharmacological treatment for smoking cessation. Its safety profile has been monitored in France via spontaneous reporting. ⋯ To ensure safer use of bupropion, health professionals must respect the strict contraindications and warnings about use of this drug in patients with a history of seizures. Seizures, angioedema and serum sickness-like reactions were the most frequently reported SARs to bupropion treatment in our study. Moreover, younger people appeared to be more at risk for cutaneous SARs generally, and younger women for angioedema in particular, perhaps because of weight-related differences in pharmacokinetics. A dose-dependent effect for angioedema and the results of skin tests were suggestive of a histamine liberation mechanism. Our analysis showed that taking more notice of the contraindications to use of bupropion could have prevented half the seizures reported to the database. The sex and age characteristics of patients with ischaemic heart disease and suicide attempts in the study population were similar to those of the French population as a whole. Whether bupropion is associated with an increase in these potential adverse effects of therapy can be determined only by epidemiological studies that take into account specific risk factors in the smoking population. Finally, the median time to onset of the SARs identified in this study suggests that prescribers should monitor patients exposed to bupropion more carefully during the first 2 weeks of treatment.
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QT prolongation is an incomplete measure of drug-induced changes in repolarization. In this study, we investigated a novel, automatic ECG technique for describing ventricular repolarization morphology and we compared these results to corrected QT (QTc) prolongation for identifying ECGs of healthy individuals on moxifloxacin. ⋯ Repolarization morphology is significantly altered by moxifloxacin. The computerized ECG technique provides a novel method for quantifying morphological changes of repolarization segment. Our new parameters reflecting the morphology of the T-wave outperformed QTc measurements when identifying moxifloxacin-induced blockade of the outward rapid components of the delayed rectifier repolarizing potassium current (I(Kr)). These data indicate that the analysis of T-wave morphology could play a role in the assessment of drug toxicity.