Use of atomoxetine and suicidal ideation in children and adolescents: Results of an observational cohort study within general practice in England.

AIM: To investigate the association between atomoxetine, a drug used in the treatment of Attention Deficit Hyperactivity Disorder (ADHD), and suicidal ideation, within a cohort of 2-18-year-old patients in England. METHODS: The study was conducted using the observational cohort technique of Modified prescription event monitoring (M-PEM). Patients prescribed atomoxetine were identified from dispensed prescriptions issued by primary care physicians. A customised postal GP questionnaire was used to capture outcome data for suicidal ideation. A matched pair cohort analysis was performed within patients to compare the risk of suicidal ideation in the period after starting atomoxetine with the risk prior to starting atomoxetine; this was stratified by age and concomitant use of methylphenidate. Additional information on patient characteristics, and events of interest was also collected; individual cases of suicidal ideation were qualitatively assessed for drug relatedness. RESULTS: Of the final cohort (n=4509); 85.5% male (n=3857), median age 11 years (IQR: 9,14). Primary prescribing indication for atomoxetine was ADHD (n=4261, 94.6%). Almost a quarter of the cohort had been co-prescribed methylphenidate. Results of the matched pair cohort analysis indicated that the period after starting atomoxetine was not associated with an increase in the incidence of suicidal ideation compared to the period prior to starting treatment (RR: 0.71; CI: 0.48-1.07; P-value: 0.104). Individual case assessment of suicidal ideation suggested a causal association within a number of cases. CONCLUSIONS: This study found no evidence of an increased risk of suicidal ideation during treatment with atomoxetine, compared to the period prior to starting treatment. Amongst age specific subgroups, this risk may change. Nonetheless, individual case assessment suggested a causal relationship in some patients, hence physicians need to be aware of the possibility of developing this event, and furthermore consider how best to detect it in this paediatric population. This study demonstrates the importance of combining quantitative statistical analyses with a qualitative case series assessment.

Utilisation of extended release quetiapine (Seroquel XL™): Results from an observational cohort study in England.

BACKGROUND: A post-authorisation safety study was carried out as part of the EU Risk Management Plan to examine the long-term (up to 12 months) use of quetiapine XL as prescribed in general practice in England. AIM: To present a description of the drug utilisation characteristics of quetiapine XL. METHODS: An observational, population-based cohort design using the technique of Modified Prescription-Event Monitoring (M-PEM). Patients were identified from dispensed prescriptions issued by general practitioners (GPs) for quetiapine XL between September 2008 and February 2013. Questionnaires were sent to GPs 12 months following the 1st prescription for each individual patient, requesting drug utilisation information. Cohort accrual was extended to recruit additional elderly patients (special population of interest). Summary descriptive statistics were calculated. RESULTS: The final M-PEM cohort consisted of 13,276 patients; median age 43 years (IQR: 33, 55) and 59.0% females. Indications for prescribing included bipolar disorder (n=3820), MDD (n=2844), schizophrenia (n=2373) and other (non-licensed) indications (n=3750). Where specified, 59.3% (7869/13,276) were reported to have used quetiapine IR (immediate release formulation) previously at any time. The median start dose was highest for patients with schizophrenia (300 mg/day [IQR 150, 450]). The final elderly cohort consisted of 3127 patients and 28.5% had indications associated with dementia. The median start dose for elderly patients was highest for patients with schizophrenia or BD (both 100mg/day [IQR 50, 300]). CONCLUSIONS: The prevalence of off-label prescribing in terms of indication and high doses was common, as was use in special populations such as the very elderly. Whilst off-label use may be unavoidable in certain situations, GPs may need to re-evaluate prescribing in circumstances where there may be safety concerns. This study demonstrates the ongoing importance of observational studies such as M-PEM to gather real-world clinical data to support the post-marketing benefit:risk management of new medications, or existing medications for which license extensions have been approved.

Utilization of fentanyl buccal tablets in England: exploring off-label use reported in a cohort study.

BACKGROUND: Fentanyl citrate buccal tablets are indicated for the treatment of breakthrough pain (BTP) in cancer, in adults who are receiving maintenance opioid therapy for chronic cancer pain. OBJECTIVE: One of the objectives of this study was to describe the utilization characteristics of patients prescribed fentanyl buccal and to assess how the product is being used in relation to the terms of license of marketing approval. METHODS: An observational post-marketing cohort study was conducted. For the analysis of this study, exposure data were collected from dispensed prescriptions issued by general practitioners (GPs) between March 2009 and June 2011. Outcome data (indication, event, patient demographic and selected clinical characteristics) were collected by sending questionnaires to GPs at least 6 months after the drug was first prescribed. Summary descriptive statistics were calculated. RESULTS: The cohort consisted of 551 patients, of which 54.8% (n = 302 patients) were female. The median age for the cohort was 62 years (interquartile range: 50-72 years), with one patient (0.2%) aged less than 18 years. A primary indication of BTP in cancer was reported for 61.9% (n = 341) patients. Regular opioid therapy was reported upon starting the treatment for 383 patients (69.5% of cohort). In total, 69 patients (12.5%) had one or more contraindications for use. The most frequent initial titration dose was 100 µg/day (n = 247). CONCLUSIONS: The final study results show that fentanyl buccal is largely being prescribed according to the terms of the license in general practice in England, but off-licence use and use in the presence of contraindications and warnings have been reported.

Systematic reviews of adverse effects of drug interventions: a survey of their conduct and reporting quality.

PURPOSE: There is a need for high quality evidence on the adverse effects of medical interventions to inform policy, practice and research. Methods to systematically review adverse effects have not been fully developed. We aimed to assess the current methods and reporting used by such reviews. METHODS: Survey of general medical, drug safety and pharmacology journals published in 2006. Methods including: searching, inclusion criteria, quality assessment and meta-analysis were assessed. RESULTS: Forty three systematic reviews from 2704 abstracts in 16 journals were included. The search strategy was not reported by 10 (23%) of reviews. The collection and reporting of the adverse effects from primary studies was described by 4/37 (12%) reviews and the quality of included studies was assessed by 15 (35%) of reviews. Meta-analysis on rare outcomes and handling of zero event data were inconsistent. A polarity in the standard of reporting between reviews was observed. The reporting standard we found was similar to another survey of systematic reviews. CONCLUSION: Reporting was poor with respect to searching and definition/collection of adverse effects and guidelines such as QUOROM and MOOSE could be employed by authors. Comprehensive and clear reporting should be enforced by journals. The low proportion of reviews assessing quality, and the inconsistencies observed when modelling rare event data reflect the need for empirical research to underpin methods in these areas.

Safety of nateglinide as used in general practice in England: results of a prescription-event monitoring study.

Nateglinide (Starlix((R))) is licensed for the treatment of Type 2 diabetes in patients inadequately controlled with metformin. The study objective was to monitor the safety and use of nateglinide prescribed by primary care physicians (GPs) in England, using the observational cohort technique, Prescription-Event Monitoring. Exposure data were derived from dispensed nateglinide prescriptions issued October 2001-June 2004; demographic and outcome data, from questionnaires sent to patients' GPs at least 6 months after patients' first prescription. Incidence densities (IDs; number of first reports of an event/1,000 patient-months exposure) were calculated for month 1 (ID(1)), months 2-6 (ID(2-6)); rate differences [ID(1)-ID(2-6) (+99% CI)] were examined. Cohort comprised 4,557 patients, median age 60 (IQR 51, 68 years); 2,439 (53.5%) male; 3,463 (76.0%) received nateglinide in combination with metformin. GPs reported 1,625 reasons for stopping in 1,474 (32.3%) patients and 80 events as adverse drug reactions in 66 (1.5%) patients. Events associated with starting treatment included nausea/vomiting [ID(1)-ID(2-6) 9.6 (99% CI 5.3, 13.9)], malaise/lassitude [ID(1)-ID(2-6) 6.03 (99% CI 2.2, 9.9)]. No serious hypersensitivity reactions were reported. Two pregnancies (< 0.1%) and 73 deaths (1.6%) were reported. Nateglinide appeared to be generally well tolerated when used in combination with metformin for the treatment of Type 2 diabetes.

Safety profile of orlistat: results of a prescription-event monitoring study.

INTRODUCTION: Orlistat, the first of a new class of drugs for the treatment of obesity, was launched in the UK in December 1998. The prescribing information recommends that treatment with orlistat should be discontinued after 12 weeks if the patient has not achieved a specified loss of weight. OBJECTIVE: To monitor the safety of orlistat prescribed in the primary care setting in England using prescription-event monitoring (PEM). METHODS: A postmarketing surveillance study using the observational cohort technique of PEM. Patients were identified from dispensed prescriptions issued by primary care physicians for orlistat between December 1998 and November 1999. The outcome data were event reports obtained by sending questionnaires (green forms) to the prescribing doctor at least 6 months after the first prescription for an individual patient. Incidence densities, expressed as number of first reports of an event/1000 patient-months of exposure, were calculated. Significant differences between incidence densities (IDs) for events reported in the 1st month (ID(1)) and months 2 and 3 (ID(2-3)) of exposure were regarded as potential signals. Reasons for stopping orlistat were analysed. Follow-up information was requested for selected events and used to assess the causal association with orlistat. RESULTS: Green forms containing clinically useful information on 16 021 patients (median age 45 years (interquartile range 35-54); 80.1% females) were received. The events reported most frequently during the 1st month of treatment were 'not effective' (639; 4.0% of cohort), diarrhoea (371; 2.3%) and weight loss (230; 1.4%). Twelve clinical adverse events were identified for which ID(1) was significantly greater than ID(2-3). These included non-specific events (e.g. intolerance, malaise/lassitude, unspecified side effects), weight loss and vaginitis/vulvitis. The remaining events were gastrointestinal in nature and included diarrhoea, pain abdomen, flatulence, nausea/vomiting, rectal discharge, faecal incontinence and 'gastrointestinal unspecified' events. A similar pattern of predominately gastrointestinal events was seen for reasons for stopping and suspected adverse drug reactions. Review of selected events for causality revealed 45 events which were assessed as possibly or probably related to orlistat. CONCLUSIONS: This study shows that orlistat is fairly well tolerated. The safety profile of orlistat was similar to the prescribing information and experience reported in the literature.

The negative effect of red tape on research.

PURPOSES: To describe the kind of the difficulties encountered when seeking research governance approval for a nationwide public health and genetic study-the Drug-Induced Arrhythmia Risk Evaluation study-in England. METHODS: Description of the processes followed when seeking research governance approval for the Drug-Induced Arrhythmia Risk Evaluation study-a case control study with annual follow-up of cases and controls over 5 years, set in the English National Health Service (NHS). RESULTS: The authors describe wide variations in NHS research governance approval procedures in England. CONCLUSION: NHS research governance procedures in England are impeding the process of epidemiological studies; there is the need for a centralised NHS R&D approval of studies, which is analogous to MREC for ethical approval.

Observational cohort study to monitor the use and safety of carvedilol in the treatment of heart failure in clinical practice in England--1st interim report.

AIMS: This is an interim report of a prospective observational cohort study to monitor the safety and tolerability of carvedilol in clinical practice when prescribed for heart failure in England. The utilization of carvedilol, management of adverse events in the community and the symptomatic progression of heart failure were examined. It is a non-interventional, observational cohort surveillance study using questionnaires sent to the patients' general practitioners. METHODS: The general practitioners (GPs) of the patients identified by the Prescription Pricing Authority were sent an eligibility questionnaire if the patient had been newly prescribed carvedilol between September 1999 and July 2001. Further questionnaires requesting baseline clinical information about eligible patients (carvedilol indicated for cardiac failure) and subsequent event data were sent to consenting GPs at 12 months. The questionnaires also requested specific information about initiation and supervision of treatment, including severity of heart failure and treatment withdrawal. The data were analyzed by using descriptive statistics. In addition, the incidence densities (ID) of each event (per 1000 person-months of treatment) were calculated, ranked and the difference between the ID of each event in the first (ID1) and subsequent 5 months of exposure (ID2) was tested by constructing 99% confidence intervals (CI). Selected events of clinical interest would be followed-up for further information to enable causal association with carvedilol to be assessed. RESULTS: In this interim report we have data on a cohort of 847 eligible patients for whom we have received information from the first follow-up questionnaire. The treatment of carvedilol was initiated in a majority of cases by hospital specialists (87%, n = 735), however, for most of them, further supervision of treatment was done under shared care between GPs and hospitals (70%, n = 595). More than 90% of the patients were started on carvedilol in the recommended dose range for the management of cardiac failure. Amongst the patients where NYHA grade of cardiac failure was expressed, the majority of patients treated with carvedilol had NYHA II (37%, n = 281) and III (40%, n = 297) symptoms at the start of carvedilol treatment. On treatment with carvedilol, improvement in NYHA status was reported for 43% (n = 364) of this cohort, whilst less than 2.5% (n = 20) of the patients deteriorated. The events reported with the highest ID1 were malaise/lassitude (14.6), dizziness (12.2), cardiac failure (9.7), dyspnea (9.7) and hypotension (8.5). The most common events reported as reasons for stopping carvedilol were "drug not effective", "dyspnea", "dizziness" and "lassitude". No events were identified as new signals (according to the ID1-ID2 statistic) of adverse events associated with carvedilol. There have been no events identified in this cohort that have required specific follow-up at the time of writing this paper. CONCLUSIONS: In summary, the interim results show that there is effective cooperation between hospital specialists and GPs in the use of carvedilol in the management of patients with heart failure. It also shows that carvedilol was well-tolerated and that patients with mild and moderate heart failure benefit symptomatically when treated with carvedilol in routine clinical practice.

Identification and evaluation of a possible signal of exacerbation of colitis during rofecoxib treatment, using Prescription-Event Monitoring data.

BACKGROUND: Identifying previously unrecognized adverse drug reactions (signals) is an important part of post-marketing surveillance. Automated signal generation now forms part of routine surveillance of spontaneous adverse drug reactions reported to the UK Yellow Card system. The Drug Safety Research Unit (DRSU) provides an additional post-marketing drug surveillance scheme in the UK, using the non-interventional observational cohort technique of Prescription-Event Monitoring (PEM), and systematically collects data on patients who were prescribed selected newly licensed drugs in primary care clinical practice. The introduction of a new computer system in January 2000 enabled the development of an automated signal generation system to compliment the process of identification of possible safety signals in drug data collected using PEM. AIMS: To use incidence rate ratios (IRRs) as a form of signal generation in the DSRU database, with particular interest in rofecoxib, plus further evaluation of any signal(s) of interest by requesting additional information from the general practioner (GP) of each relevant case. METHODS: Crude IRRs were calculated for each event term of interest by comparing the incidence rate for each lower term event reported in rofecoxib users with the comparable incidence rate for the whole PEM database (77 drugs of various therapeutic classes) from the total person-exposure time up to 180 days after starting the drug. To investigate a possible class effect, IRRs were also calculated using a second comparator cohort including only those PEM study drugs within the same therapeutic class (non-steroidal anti-inflammatory drugs, NSAIDs) and used for similar indications. Cases arising out of potential signals were followed up for additional information. RESULTS: A potential signal of 'colitis' was identified when rofecoxib was compared with the rest of the database, IRR 5.8 (95% CI 2.7,11.3; z statistic 5.6), and when the comparator group was changed to include only the other four NSAIDs, IRR 4.3 (95% CI 1.4,14.5; z statistic 2.8). Other possible signals, compared with the rest of the database, included events deemed to be related to the underlying condition, labelled adverse events and events describing effectiveness of treatment. Further evaluation of this signal revealed that there were 11 reports of colitis (two reports for one patient) that occurred while taking rofecoxib and within 180 days of exposure. A causality assessment for these 10 patients did not confirm an association with newly developing colitis, but showed that the events were 'possible' exacerbations of pre-existing colitis during treatment with rofecoxib. CONCLUSIONS: The use of IRRs for signal generation using PEM data is worthwhile and enables time to be taken into account. Previously unrecognized adverse events require further evaluation to confirm that a possible safety signal exists. In this study, the number of patients reported to have colitis was small but compared with other drugs on the database, the incidence rate was relatively high. Follow-up revealed a possible relationship between exacerbation of pre-existing colitis and treatment with rofecoxib. Hypotheses arising from signal generation require evaluation and cannot be taken as a conclusive evidence for clinical differences in the safety profiles of drugs.

Evaluation of the safety of sildenafil for male erectile dysfunction: experience gained in general practice use in England in 1999.

OBJECTIVE: To examine the safety of sildenafil, the first of the phosphodiesterase type 5 inhibitors licensed for the treatment of male erectile dysfunction (ED), as used in general medical practice in England, quantifying the incidence of a range of events in patients treated with sildenafil, and identifying any previously unrecognized adverse drug reactions. METHODS: In a postmarketing observational cohort study using prescription-event monitoring (PEM), exposure data were derived from dispensed prescription details for patients who started treatment between April and August 1999. Outcome data were derived from "green form" questionnaires (GFs) returned by general practitioners (GPs). RESULTS In all, 24 835 (54.7%) of GFs posted to GPs were returned, of which 22 473 contained useful data for 22 471 male and two female patients. The major primary indications/clinical context of prescribing were impotence (16 583, 73.8%) and diabetes mellitus (183, 0.8%); 145 events were reported as adverse drug reactions to sildenafil. GPs recorded 3951 reasons for stopping sildenafil, and ischaemic heart disease (IHD) in 135 patients was the commonest clinical reason reported. The clinical condition reported most frequently in the first month of observation was diabetes mellitus and/or hyperglycaemia (in 99 events). A standardized mortality ratio (SMR) for deaths caused by IHD in the first 8893 of 22 473 patients was 31.41 (95% confidence interval 18.29-50.29), using the comparator population of males in England in 1998. CONCLUSION: This study identified the safety profile of sildenafil as used in the community, showing no unexpected events. The SMR analysis of deaths from IHD provided no evidence to suggest a higher incidence of deaths in the study cohort than in the male population in England.

Comparison of the incidence rates of thromboembolic events reported for patients prescribed rofecoxib and meloxicam in general practice in England using prescription-event monitoring (PEM) data.

BACKGROUND: Rofecoxib and meloxicam are classified as cyclo-oxygenase (COX)-2 selective inhibitors. The Drug Safety Research Unit (DSRU) monitored the post-marketing safety of these drugs in England using the non-interventional observational cohort technique of prescription-event monitoring (PEM). OBJECTIVES: To compare the incidence rates of selected thromboembolic (TE)(cardiovascular, cerebrovascular and peripheral venous thrombotic) events reported for patients prescribed rofecoxib and meloxicam in general practice. METHODS: Patients were identified from dispensed prescriptions written by general practitioners (GPs) for meloxicam (December 1996 to March 1997) and rofecoxib (July to November 1999). Simple questionnaires requesting details of events recorded during/after treatment, indication and potential risk factors (including age, sex and NSAIDs prescribed within 3 months of treatment) were posted to prescribing GPs approximately 9 months after the first prescription for each patient. Incidence rates of the first event within each TE group were calculated; crude and age- and sex-adjusted rate ratios (RR) obtained using regression modelling. RESULTS: During the 9 months after starting treatment, 21 (0.14%) and 19 (0.10%) patients were reported to have cardiovascular TE events, and 74 (0.48%) and 52 (0.27%) cerebrovascular TE events, and 6 (0.05%) and 20 (0.10%) were reported to have peripheral venous thrombotic events for rofecoxib and meloxicam, respectively. Regarding time to first event, there was a persistent divergence between the two drugs from the start of treatment for both the cerebrovascular TE event group (log rank test P = 0.0063) and the peripheral venous thrombotic event group (log rank test P = 0.0264). Indication and use of a NSAID within 3 months prior to starting treatment had no statistically significant effect on the relative risk estimates of the event groups and was excluded from subsequent analyses. Adjusting for the two identified risk factors of age (age2) and sex, for rofecoxib the adjusted cerebrovascular TE event group rate was higher than for meloxicam [RR 1.68 (95% CI 1.15, 2.46)]; lower than meloxicam for the peripheral venous thrombotic event group [RR 0.29 (95% CI 0.11, 0.78)], and not different for the cardiovascular TE event group [RR 1.38 (95% CI 0.71, 2.67)]. CONCLUSIONS: This study reports a relative increase in the rate of cerebrovascular TE events and a relative reduction in peripheral venous thrombotic events in users of rofecoxib compared with meloxicam. There was no difference in the rate of cardiovascular thromboembolic events. The incidence of these three groups of events reported in each of these two drug cohorts was low (less than 0.5%), therefore the relevance of our findings needs to be taken into consideration with other clinical and pharmacoepidemiological studies.

Comparison of the incidence rates of selected gastrointestinal events reported for patients prescribed celecoxib and meloxicam in general practice in England using prescription-event monitoring (PEM) data.

BACKGROUND: Celecoxib and meloxicam are classified as cyclo-oxygenase (COX)-2 selective inhibitors, and were developed to minimize the risk of gastrointestinal (GI) toxicity commonly associated with non-steroidal anti-inflammatory drugs (NSAIDs). The Drug Safety Research Unit (DSRU) monitored the safety of these drugs immediately after launch in England using the non-interventional observational cohort technique of prescription-event monitoring (PEM). Our objective was to investigate whether there is a clinically relevant difference in incidence of reported symptomatic (acid/peptic) and complicated upper GI conditions (perforations/bleeding) between celecoxib and meloxicam during use in general practice. METHODS: Patients were identified from dispensed prescriptions written by general practitioners (GPs) for meloxicam (December 1996 to March 1997) and celecoxib (May to December 2000). Simple questionnaires requesting details of events occurring during/after treatment and potential risk factors (including age, sex, history of upper GI problems, and NSAIDS prescribed within 3 months of treatment) were posted to prescribing GPs at least 6 months after the first prescription for each patient. Incidence rates of the first event were calculated; crude and adjusted rate ratios (RR) obtained using regression modelling. RESULTS: For celecoxib and meloxicam, respectively, 1054 (6.0%) and 1376 (7.2%) patients had symptomatic (acid/peptic) upper GI events whereas 42 (0.2%) and 67 (0.4%) had complicated upper GI conditions (perforations/bleeding). A higher proportion of the celecoxib cohort had an indication for osteoarthritis (28.1 vs 23.2%), were female (68.3 vs 67.1%), were aged 60 yr or more (59.5 vs 55.0%), were prescribed NSAIDs within 3 months of starting treatment (49.4 vs 47.9%), and had a past medical history of upper GI conditions (54.7 vs 29.2%) than those prescribed meloxicam. This suggests differential channelling of groups at higher risk of such events on to celecoxib compared with meloxicam. There was no difference between the two drugs in the time to occurrence of either group of event. The RR over the 270-day study period for celecoxib compared with meloxicam were 0.77 (95% CI 0.69, 0.85) and 0.56 (95% CI 0.32, 0.96) for symptomatic (acid/peptic) upper GI events and complicated upper GI conditions (perforations/bleeding), respectively, adjusted for age, age2, sex, indication, medical history of upper GI problems and whether NSAIDs were prescribed within 3 months prior to starting treatment. CONCLUSIONS: This study reports a relative reduction (23%) in the incidence of symptomatic (acid/peptic) GI events, and a relative reduction (44%) in the incidence rate of complicated upper GI conditions (perforations/bleeding) for celecoxib compared with meloxicam.

Comparison of the incidence rates of selected gastrointestinal events reported for patients prescribed rofecoxib and meloxicam in general practice in England using prescription-event monitoring data.

BACKGROUND: and objectives. Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with gastrointestinal (GI) toxicity. Rofecoxib and meloxicam are classified as cyclooxygenase (COX)-2 selective inhibitors. The Drug Safety Research Unit monitored the safety of these drugs immediately after their launch in England using the non-interventional observational cohort technique of prescription-event monitoring (PEM). Our objective was to investigate whether there is a clinically relevant difference in the incidence of reported symptomatic (acid/peptic) and complicated upper GI conditions (perforations/bleeding) between rofecoxib and meloxicam during use in general practice. METHODS: Patients were identified from dispensed prescriptions written by general practitioners (GPs) for meloxicam (between December 1996 and March 1997) and rofecoxib (between July and November 1999). Simple questionnaires requesting details of events occurring during/after treatment and potential risk factors (including age, sex, history of upper GI problems, and NSAIDS prescribed within 3 months of treatment) were posted to prescribing GPs approximately 9 months after the first prescription for each patient. Incidence rates of the first event were calculated, and crude and adjusted rate ratios were obtained using regression modelling. RESULTS: For rofecoxib and meloxicam respectively, 1127 (7.4%) and 1376 (7.2%) patients had symptomatic (acid/peptic) upper GI events, whereas 57 (0.4%) and 67 (0.4%) had complicated upper GI conditions (perforations/bleeding). A past medical history of upper GI problems was an important risk factor only for symptomatic (acid/peptic) upper GI events for both drugs, despite a two-fold difference in the proportion reporting previous GI problems (48.4 and 25.1% for rofecoxib and meloxicam respectively). The adjusted rate ratio of symptomatic (acid/peptic) upper GI events or complicated upper GI conditions (perforations/bleeding) for rofecoxib compared with meloxicam was 0.71 (95% confidence interval 0.65, 0.79) and 0.91 (95% confidence interval 0.59, 1.42) respectively. CONCLUSIONS: This study reports a relative reduction (29%) in the incidence rate of symptomatic (acid/peptic) GI events, and no difference in the incidence rate of complicated upper GI conditions (perforations/bleeding) for rofecoxib compared with meloxicam.

Prospective observational cohort safety study to monitor the introduction of a non-CFC formulation of salbutamol with HFA134a in England.

OBJECTIVE: To monitor the safety of a salbutamol MDI with a hydrofluoroalkane propellant (Ventolin Evohaler) during its introduction into primary care use in England. METHODS: Prospective observational cohort study. 1,365 GPs in England submitted data on 10,472 regular users of Ventolin MDI, over five 3-month periods of observation between October 1, 1998 and December 31, 1999. The primary aim was to compare event rates occurring before and after the introduction of Ventolin Evohaler. The secondary aim was a comparison of event rates between users of Ventolin Evohaler and Ventolin MDI. The main outcome measures were: indication for use of Ventolin MDI, assessment of disease severity, event rates during each period of observation; deaths, pregnancies, reported adverse drug reactions and reasons for discontinuation of MDI. Event rates were adjusted using a ratio for under-reporting derived from a validation study on 4.6% of the study population and stratified by severity of indication. RESULTS: The primary indication was asthma in 94%, distributed by severity as 47% mild, 44% moderate and 9% severe; 13% were children. By October 1999, 52.7% of the 8,973 remaining patients had transitioned to Ventolin Evohaler. There was no increase in major or minor events observed following the introduction of Ventolin Evohaler. No serious adverse events, abnormal pregnancy outcomes or deaths have been related to Ventolin MDI or Ventolin Evohaler. The validation study showed a degree of under-reporting. CONCLUSION: These results on a large cohort of community patients in England indicate that Ventolin Evohaler is well tolerated among asthmatics.

Pharmacovigilance of over-the-counter products based in community pharmacy: methodological issues from pilot work conducted in Hampshire and Grampian, UK.

PURPOSE: The incidence of serious adverse events from non-prescription medicines remains to be established. The aim of this initial pilot work, using an observational cohort design, was to determine the feasibility of conducting a pharmacovigilance study of a non-prescription medicine, based in community pharmacies. METHOD: Community pharmacists from Grampian, Scotland, and Hampshire, England, recruited user-purchasers of ibuprofen. Exposure data were collected from a series of self-completed questionnaires. Outcome data were any new symptoms, use of concomitant medication and subsequent health-care utilization. RESULTS: A total of 1021 eligible customers were recruited, 6.4% (466/7320) and 48.2% (555/1152) by the Hampshire and Grampian networks respectively. The cohorts differed with regard to age, smoking and socio-economic status, reason for purchase and recommendation, and duration of use. The two cohorts reported different use of concomitant medication (46.0 and 65.5%), asthma (7.2 and 10.5%), stomach/peptic ulcer (3.5 and 2.1%), a higher prevalence of gastrointestinal symptoms post-compared to pre-purchase (12.9 vs. 7.2%, p = 0.0006 and 8.8 vs. 5.8%, p = 0.034), ingestion of doses in excess of the licensed non-prescription dose by 5.1 and 3.9%, and discontinuation of treatment because the medicine upset them by 4.5 and 3.1%, respectively. Most participants did not seek medical advice for their symptoms. CONCLUSION: Greater vigilance is required for adverse events that may be attributable to non-prescription product use. Development of pharmacovigilance models using community pharmacies is one means of systematically collecting information regarding drug safety. Further work is needed to identify a method which maximizes patient recruitment whilst maintaining acceptable follow-up rates.

A case of nonarteritic ischemic optic neuropathy (NAION) in a male patient taking sildenafil.

Sildenafil is a phosphodiesterase-type-5 inhibitor indicated for the treatment of erectile dysfunction in men. We report a case of NAION identified from a cohort of 8,893 patients (from a Prescription-Event Monitoring study) prescribed sildenafil by their primary care physician in England between April and June 1999. This 61-year-old patient had risk factors for NAION independent of drug therapy. It was not possible to be confident about a causal association between sildenafil and NAION, though the possibility could not be ruled out. Epidemiological data suggest that one case of NAION might be expected in a cohort of 8,893 subjects. Thus it remains important for clinicians to consider the range of risk factors for NAION; while equally, the processes of pharmacovigilance need to continue as for any recently launched drug preparation.

A post-marketing observational study to assess the safety of mibefradil in the community in England.

OBJECTIVES: To conduct a post-marketing observational cohort study to assess the safety of mibefradil in the community, using Prescription-Event Monitoring (PEM). METHOD: Data were collected and analyzed on patients prescribed mibefradil by 1,996 General Practitioners (GPs) throughout England. Incidence densities were calculated for all reported events and selected events were followed-up by means of further questionnaires. RESULTS: The study was terminated early due to the voluntary withdrawal of mibefradil from the market because of potential drug interactions. A cohort of 3,085 patients was recruited, with a mean age of 64.5 years. The major indication for use was hypertension (55% of the cohort), the indication was not specified in 33% of patients. 80% of GPs expressing an opinion rated mibefradil as effective. The major reason for stopping was withdrawal from the market (2,342 patients). The commonest reported adverse events and reasons for stopping were malaise/lassitude, dizziness, edema and headache. Seven clinically serious reports of bradycardia/collapse were considered to be possible adverse drug reactions (ADRs) to mibefradil. All were in the elderly (> 65 years), 6 were considered to be a result of possible drug interactions. In total, 11 possible drug interactions occurred. Nine (8 reports of bradycardia and 1 of syncope) involved beta-blockers. Another, a report of collapse and severe bradycardia, occurred in a patient who had started a dihydropyridine calcium channel blocker within 24 hours of stopping mibefradil and the other was a report of palpitations and dyspnea in a patient on concomitant digoxin and sotalol. None of the 53 deaths occurring during the study was attributed to mibefradil. CONCLUSION: Mibefradil was only available on the UK market for 6 months before it was withdrawn from the market because of potential drug interactions. With respect to the reasons leading to its withdrawal, in this cohort of 3,085 patients, 11 possible drug interactions were detected (6 clinically significant) involving beta-blockers, a dihydropyridine calcium channel blocker and digoxin and/or sotalol. PEM can contribute to the understanding of ADRs caused by drug interactions occurring in real-life settings.

Prescription-event monitoring and reporting of adverse drug reactions.

Newly marketed drugs in the UK are marked with a black triangle, indicating that doctors should report all adverse drug reactions associated with them to the Committee on Safety of Medicines (CSM). However, under-reporting of adverse reactions is frequent. Our aim was to establish what types of adverse reactions are under-reported to the CSM by family doctors who work in England. We used prescription-event monitoring data obtained for 15 newly marketed drugs. Only 9% (376) of 4211 events found on prescription-event monitoring were reported to the CSM. However, 53% (27) of 51 events classified as serious adverse drug reactions were reported. Overall, serious events were five times more likely to be reported to the CSM than non-serious events. Our results should not be extrapolated to calculate incidence rates of adverse drug reactions in the community from spontaneous reports.

Evaluation of the safety of fexofenadine from experience gained in general practice use in England in 1997.

BACKGROUND: Fexofenadine is the active metabolite of the non-sedating anti-histamine terfenadine. Pre-licensing clinical trials in over 6000 patients suggested it was effective and well tolerated. OBJECTIVE: To assess the tolerability and safety of fexofenadine immediately after its availability on the UK market in March 1997. METHODS: Post-marketing non-interventional observational cohort study using the methodology of prescription-event monitoring. Exposure data derived from dispensed prescription details supplied in confidence by the Prescription Pricing Authority. Outcome data derived from questionnaires returned by general practitioners (GPs) in England between March and August 1997. RESULTS: Of the 35,817 questionnaires sent, 18,238 (50.9%) were returned, of which 16,638 contained useful data. These included 40% male (mean age 36+/-19 years) and 59% female (mean age 39+/-19 years). Most common indications were allergic rhinitis (55%), not specified (28%), urticaria, pruritus or rash (10%) and other indications (7%). There were 40 reports of adverse drug reactions in 27 patients. Less than 2% of patients stopped the drug because of side effects. Events reported after exposure to fexofenadine were uncommon and already reported in clinical trials. There were eight reports of possible cardiac side effects (palpitations, three; chest pain, three; arrhythmia, one; and chest tightness, one). None was felt to be serious. There were no drug interactions reported. None of the 30 deaths was related to fexofenadine. None of the three adverse outcomes from the 47 pregnancies reported was related to fexofenadine. CONCLUSION: Within the limitations for an observational cohort study, fexofenadine was found to be well tolerated and safe in 16,638 users in general practice in England.