Assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: a comprehensive review.

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. In total, 3051 spontaneous reports of NPAEs were received by Roche, involving 2466 patients who received oseltamivir between 1999 and 15 September 2007; 2772 (90.9%) events originated from Japan, 190 (6.2%) from the US and 89 (2.9%) from other countries. During this period, oseltamivir was prescribed to around 48 million people worldwide. Crude NPAE reporting rates (per 1,000,000 prescriptions) in children (aged < or =16 years) and adults, respectively, were 99 and 28 events in Japan and 19 and 8 in the US. NPAEs were more commonly reported in children (2218 events in 1808 children aged < or =16 years vs 833 in 658 adults) and generally occurred within 48 hours of the onset of influenza illness and initiation of treatment. After categorizing the reported events according to International Classification of Diseases (9th edition) codes, abnormal behaviour (1160 events, 38.0%) and delusions/perceptual disturbances (661 events, 21.7%) were the largest categories of events, and delirium or delirium-like events (as defined by the American Psychiatric Association) were very common in most categories. No difference in NPAE reporting rates between oseltamivir and placebo was found in phase III treatment studies (0.5% vs 0.6%). Analyses of US healthcare claims databases showed the risk of NPAEs in oseltamivir-treated patients (n = 159,386) was no higher than those not receiving antivirals (n = 159,386). Analysis of medical records in the UK General Practice Research Database showed that the adjusted relative risk of NPAEs in influenza patients was significantly higher (1.75-fold) than in the general population. Based on literature reports, NPAEs in Japanese and Taiwanese children with influenza have occurred before the initiation of oseltamivir treatment; events were also similar to those occurring after the initiation of oseltamivir therapy. No clinically relevant differences in plasma pharmacokinetics of oseltamivir and its active metabolite oseltamivir carboxylate were noted between Japanese and Caucasian adults or children. Penetration into the CNS of both oseltamivir and oseltamivir carboxylate was low in Japanese and Caucasian adults (cerebrospinal fluid/plasma maximum concentration and area under the plasma concentration-time curve ratios of approximately 0.03), and the capacity for converting oseltamivir to oseltamivir carboxylate in rat and human brains was low. In animal autoradiography and pharmacokinetic studies, brain : plasma radioactivity ratios were generally 20% or lower. Animal studies showed no specific CNS/behavioural effects after administration of doses corresponding to > or =100 times the clinical dose. 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.

Perspectives on the use of data mining in pharmaco-vigilance.

In the last 5 years, regulatory agencies and drug monitoring centres have been developing computerised data-mining methods to better identify reporting relationships in spontaneous reporting databases that could signal possible adverse drug reactions. At present, there are no guidelines or standards for the use of these methods in routine pharmaco-vigilance. In 2003, a group of statisticians, pharmaco-epidemiologists and pharmaco-vigilance professionals from the pharmaceutical industry and the US FDA formed the Pharmaceutical Research and Manufacturers of America-FDA Collaborative Working Group on Safety Evaluation Tools to review best practices for the use of these methods.In this paper, we provide an overview of: (i) the statistical and operational attributes of several currently used methods and their strengths and limitations; (ii) information about the characteristics of various postmarketing safety databases with which these tools can be deployed; (iii) analytical considerations for using safety data-mining methods and interpreting the results; and (iv) points to consider in integration of safety data mining with traditional pharmaco-vigilance methods. Perspectives from both the FDA and the industry are provided. Data mining is a potentially useful adjunct to traditional pharmaco-vigilance methods. The results of data mining should be viewed as hypothesis generating and should be evaluated in the context of other relevant data. The availability of a publicly accessible global safety database, which is updated on a frequent basis, would further enhance detection and communication about safety issues.

Assessing the risk of birth defects associated with antiretroviral exposure during pregnancy.

OBJECTIVE: The purpose of this study was to examine teratogenic risk of antiretroviral (ARV) drugs. STUDY DESIGN: The Antiretroviral Pregnancy Registry (APR) monitors prenatal exposures to ARV drugs and pregnancy outcome through a prospective exposure-registration cohort. Statistical inference uses exact methods for binomial proportions. RESULTS: Through July 2003, APR has monitored 3583 live births exposed to ARV. Among 1391 first trimester exposures, there were 38 birth defects, prevalence of 2.7% (95% CI 1.9-3.7), not significantly higher than the CDC's population surveillance rate, 3.1 per 100 live births (95% CI 3.1-3.2). For lamivudine, nelfinavir, nevirapine, stavudine, and zidovudine, sufficient numbers of live births (>200) following first-trimester exposures have been monitored to allow detection of a 2-fold increase in risk of birth defects overall; no increases have been detected. CONCLUSION: APR data demonstrate no increase in prevalence of birth defects overall or among women exposed to lamivudine, nelfinavir, nevirapine, stavudine, and zidovudine.

The reporting odds ratio and its advantages over the proportional reporting ratio.

PURPOSE: The proportional reporting ratio (PRR) is the proportion of spontaneous reports for a given drug that are linked to a specific adverse outcome, divided by the corresponding proportion for all or several other drugs. The PRR is similar to the proportional mortality ratio (PMR), an old epidemiologic measure calculated from death registries and constructed in similar fashion to the PRR. The PMR has important deficiencies, however, which the PRR shares. Miettinen and Wang demonstrated that the PMR could be improved by reformulating it as an odds ratio and applying the principles of a case-control study to the measure. In this paper, we review the problem with the PRR and show how the corresponding odds ratio represents an improvement over the PRR. METHODS: The method used is discussion and illustration by way of a hypothetical example. RESULTS: The PRR does not estimate relative risk. If, however, a spontaneous report database is viewed as source data for a case-control study, the reporting odds ratio (ROR) can be used to estimate relative risk. Treating the data as source data for a case-control study allows for further reduction of bias by the judicious choice of controls. CONCLUSIONS: Calculating the ROR in spontaneous report databases offers advantages over the PRR. It allows for estimation of the relative risk, and focuses attention on which people or reports should be included or excluded from the control series, permitting more deliberate elimination of biases. It also highlights the inherent weaknesses in spontaneous report data, which become more evident in light of the usual principles of control selection in case-control studies.

Health outcomes among patients receiving oseltamivir.

PURPOSE: Oseltamivir was approved by the FDA for the treatment of influenza in 1999. The primary objective was to compare health outcomes among influenza patients who were treated with oseltamivir and those who were not. METHODS: The patient population included UnitedHealthcare members who received an influenza diagnosis during the 1999-2000 influenza season, divided into those who were dispensed oseltamivir on the same day (N = 3211) and those who were not dispensed oseltamivir (N = 19,985). Cardiovascular, neuropsychiatric and respiratory outcomes were assessed from medical claims for a 30-day period. RESULTS: The adjusted incidence rate ratio for major cardiac outcome was 0.56 (95%CI: 0.34-0.93) in those without a positive history of major cardiac disease, indicating that those in the oseltamivir group tended to be at lower risk of cardiac outcomes than those without oseltamivir. The adjusted incidence rate ratio for major neuropsychiatric outcome was 0.72 (95%CI: 0.53-0.97) in the negative history of neuropsychiatric disease stratum. The incidence rate ratios for respiratory events were more variable. CONCLUSIONS: There appears to be no increased risk of cardiac or neuropsychiatric outcomes among subjects with influenza who were treated with oseltamivir in comparison with those who were not.

Rational emotive behavior therapy: disputing irrational philosophies.

This article provides an overview of the concepts and techniques of rational emotive behavior therapy to distinguish it from cognitive-behavioral therapy. Rational emotive behavior therapy proposes that psychological disturbance is largely created and maintained through irrational philosophies consisting of internal absolutistic demands. This therapy strives to produce sustained and profound cognitive, emotive, and behavioral change through active, vigorous disputation of underlying irrational philosophies.

Skin reactions in patients with influenza treated with oseltamivir: a retrospective cohort study.

Oseltamivir phosphate is an FDA-approved treatment for influenza that has been available for prescription use in the USA since 1999. The present report describes findings from a post-marketing safety study of skin reactions associated with oseltamivir use. All patients in the claims-derived Ingenix Research Database with a physician diagnosis of influenza and/or a dispensing of oseltamivir between 1 December 1999 and 31 March 2002 were identified. Cohort eligibility criteria included minimum baseline enrolment duration of 3 months, age of at least 1 year and no influenza vaccination on the date of influenza diagnosis or oseltamivir dispensing. Patients were classified into two primary cohorts, influenza diagnosis and oseltamivir dispensing on the same day, and influenza diagnosis but no oseltamivir at any time, and a cohort included for secondary analyses comprising patients who received an oseltamivir dispensing without an influenza diagnosis on the same day. Outcomes included general skin reactions and several specific skin reactions. Events occurring during the 30 days following the date of influenza diagnosis or oseltamivir dispensing were examined using Cox proportional hazards models. Model covariates included age, use of another influenza drug, month and year of index date, and use of antitussives. Adjusted rate ratios for the general class of skin reactions among the primary cohort of oseltamivir users versus non-users were 1.05 (95% CI: 0.88-1.24) for incident cases and 0.98 (95% CI: 0.77-1.24) among patients with a history of a skin reaction. Similar results were seen for the other skin reaction categories, and secondary analyses investigating the oseltamivir users without influenza revealed no elevation in risk. It is concluded that oseltamivir use does not appear to be associated with an increased risk of skin reactions.