Deborah Layton

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.

Cardiovascular events in users of sildenafil: results from first phase of prescription event monitoring in England

Sildenafil is used to treat erectile dysfunction, and prescription on the NHS is restricted. We are conducting a study of prescription event monitoring for sildenafil in England, the first phase of which investigates possible short term effects in a cohort of about 5000 users. In view of the interest in myocardial infarction as a possible short term side effect1 we report on an analysis of selected cardiovascular events reported in the first phase. Prescription event monitoring has been described elsewhere.2 Patients were identified from NHS prescriptions in England. Simple questionnaires were posted to the prescribing general practitioners about five months after the first prescription. These forms requested reporting of events after the drug had been prescribed. An “event” was any new diagnosis, any reason for referral to a consultant or admission to hospital, unexpected deterioration (or improvement) in a …

Causal association in pharmacovigilance and pharmacoepidemiology: thoughts on the application of the Austin Bradford-Hill criteria.

The methods used for the evaluation of drug safety signals (including major signals leading to withdrawal of products from the market) are inconsistent and sometimes of poor quality. While the assessment of the safety of medicines needs to consider specific issues such as drug interactions and variation in compliance, the general principles, which are used to study environmental hazards, can be applied for this purpose. The criteria proposed by Sir Austin Bradford-Hill more than 35 years ago for attributing disease causation to environmental factors have been used widely in epidemiology, are applicable to pharmacovigilance and pharmacoepidemiology.The Austin Bradford-Hill criteria include strength, consistency, specificity, temporality, biological gradient, plausibility, coherence, experimental evidence and analogy. The paper reviews each of these criteria with emphasis on pharmacovigilance and pharmacoepidemiology and with some examples. The application of the Austin Bradford-Hill criteria to the evaluation of causal association in pharmacovigilance and pharmacoepidemiology is very useful. However, it requires understanding of the limitations of the data, such as, under-reporting, poor quality of information from third parties and misclassification. Further work is required to develop strategies to handle these limitations.

Do some inhibitors of COX-2 increase the risk of thromboembolic events? Linking pharmacology with pharmacoepidemiology

Inhibitors of the cyclo-oxygenase (COX)-2 isoenzyme were developed with the expectation that their use would be accompanied by a reduction in adverse reactions thought to be mediated through COX-1 compared with conventional nonselective NSAIDs. However, the results of some clinical studies and other evidence have led to the hypothesis that use of COX-2 inhibitors may contribute to an increased risk of adverse thromboembolic (TE) events. In this review, we have evaluated the evidence from small-scale in vitro and in vivo pharmacological studies, clinical trials and large-scale pharmacoepidemiological studies and commented on the relationship between the pharmacological characteristics related to thromboembolic events and the clinical effects in large-scale clinical trials and pharmacoepidemiological studies.Overall, the pharmacological evidence suggests that a prothrombotic effect of COX-2 selective inhibitors is plausible. To date, despite the results from the Vioxx Gastrointestinal Outcome Research (VIGOR) study from which the clinical concern regarding cardiovascular TE risk arose, the published data from other randomised controlled trials (RCTs), retrospective observational studies and spontaneous reporting schemes provide a conflicting body of evidence on the TE risk with COX-2 inhibitors.Concerns that COX-2 inhibitors may be associated with prothrombotic effects remain and these need to be addressed in large scale, RCTs designed specifically to investigate the possibility of an excess of adverse cardiovascular outcomes in users of some or all selective COX-2 inhibitors, both with and without concomitant low-dose aspirin (acetylsalicylic acid). Consideration must also be given to other pathophysiological mechanisms for potential cardiovascular risk linked with inhibition of COX-2.In view of the evidence reviewed, it is recommended that selective COX-2 inhibitors should be prescribed with caution, only in patients with conditions for which these drugs have proven efficacy and with careful monitoring of outcomes and adverse events. This is particularly important in the elderly, in patients with cardiovascular/renal disease and in patients with other risk factors that might predispose them to adverse events.

Comparison of incidence rates of cerebrovascular accidents and transient ischaemic attacks in observational cohort studies of patients prescribed risperidone, quetiapine or olanzapine in general practice in England including patients with dementia

Following changes in the safety information on the use of risperidone and olanzapine in elderly patients with dementia, data from prescription-event monitoring (PEM) studies of risperidone, quetiapine and olanzapine were examined. The aim was to compare incidence rates for events reported as cerebrovascular accident (CVA) and transient ischaemic attack (TIA) during the first 180 days of treatment in patients prescribed atypical antipsychotics for dementia or other indications, because of the possible association between dementia and stroke in users of atypical antipsychotics. A retrospective analysis of data from the three observational studies was conducted using Poisson regression modelling and survival analysis. Within the risperidone, quetiapine and olanzapine cohorts, 23 (0.30%), 6 (0.35%) and 10 (0.11%) patients respectively, were reported to have had a CVA/TIA event. Age, sex and indication (dementia or other) were identified as important confounding variables; age being the most important. The crude rate ratios (RRs) for CVA/TIA for risperidone or quetiapine vs. olanzapine indicated an approximate threefold relative difference in rate during the first six months but after adjustment for age, sex and indication, the RRs were non-significant (1.2 (95% CI 0.5,3.0) and 2.1 (95% CI 0.6,7.7), respectively). For risperidone vs. quetiapine, crude and adjusted RRs were not significantly different. Of the three drugs, the time to event was shortest for risperidone and also shortest for risperidone or quetiapine users where the indication was dementia. The age and sex adjusted RR of CVA/TIA in patients prescribed risperidone for dementia vs. other indications was 6.7 (95% CI 2.4,18.9). The adjusted RRs for quetiapine, according to indication, could not be calculated due to missing information on age and sex. There were no cases of CVA/TIA with dementia for olanzapine, thus the RRs and time to event curves according to indication could not be examined. This study revealed no significant difference in the adjusted RR of CVA/TIA events in the first 180 days of treatment in patients prescribed risperidone or quetiapine when compared with olanzapine. However, dementia appears to be an important risk factor. These results should be considered alongside other pharmacoepidemiological studies on this topic.

Serious skin reactions and selective COX-2 inhibitors: a case series from prescription-event monitoring in England.

AbstractBackground: The erythema multiforme (EM) spectrum of bullous eruptions (toxic epidermal necrolysis [TEN] and Stevens-Johnson syndrome [SJS]) are rare and serious skin reactions that have been reported for cyclo-oxygenase (COX)-2 selective inhibitors. Our objectives were to identify and describe cases of serious skin reactions reported during postmarketing studies of COX-2 selective inhibitors. Methods: A retrospective review of information from reports of serious skin reactions reported during prescription-event monitoring (PEM) studies of rofecoxib, celecoxib, etoricoxib and valdecoxib conducted in England since 1999. Exposure data were derived from dispensed prescriptions written by primary care physicians for each study drug. Outcome data were derived from questionnaires posted to prescribers at least 9 months after the date of the first prescription for each patient (valdecoxib data collection ongoing at the time of this study). Reports of EM, exfoliative dermatitis, SJS, TEN and symptoms associated with EM (EM syndrome) were identified from the PEM database. Additional data on diagnosis, relevant risk factors and management were requested for each case from the prescriber. A causality assessment was undertaken by a Drug Safety Research Unit research fellow and referred for expert review to a consultant dermatologist. Results: Nine cases of serious skin reactions and two cases of symptoms associated with EM (EM syndrome) were identified. No reports of TEN were recorded. Six skin reaction questionnaires were returned. Of the nine cases of serious skin reactions, four cases (all SJS; one for each COX-2 selective inhibitor studied) were assessed as possibly related to use of the study drug (for combined cohorts: incidence risk 0.008%, 4 of 52 644 patients; rate 0.019 per 1000 patient-months of treatment). These four cases (two male, two female; age range 54–64 years) occurred within 2 weeks of starting treatment; the patient prescribed rofecoxib had reported risk factors (history of allergy, adverse reaction [asthma] to ibuprofen). The two cases from the EM syndrome search (one female, 35 years; one male, 80 years) occurred within 2 weeks of starting treatment; both were assessed as possibly related to use of celecoxib but considered suggestive of angio-oedema/urticaria and hypersensitivity reactions. Conclusions: This case series provides useful and complementary information to other published studies about serious skin reactions reported during treatment with COX-2 selective inhibitors. The crude incidence of cases of SJS possibly related to the use of a COX-2 selective inhibitor in this case series is very low (0.008% for all four cohorts combined). Prescribers and patients should be aware of the severe and life-threatening risk of EM potentially associated with NSAIDs, including COX-2 selective inhibitors.

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.

Safety profile of tolterodine as used in general practice in England: Results of prescription-event monitoring

AbstractBackground: Unstable bladder symptoms are a common problem in general practice. Drug therapy with anticholinergic drugs is frequently used in the management of this condition. However such drugs are associated with a high incidence of anticholinergic adverse effects. Tolterodine is a competitive anticholinergic agent, selective for the bladder as opposed to the salivary glands. Objective: To monitor the safety of tolterodine as used in general practice patients in England for the treatment of urinary frequency, urgency and incontinence. Design: Prospective observational cohort study. Patients and participants: 14 526 patients [mean age 62.7 (SD 16.4) years; 68.6% female]. Methods: Patients prescribed tolterodine in general practice, soon after the release of the drug in the UK, were followed up for a minimum of 6 months using the technique of prescription-event monitoring (PEM). Results: The most common adverse events reported were dry mouth, headache, malaise, constipation, dyspepsia, nausea and vomiting and pain in abdomen. We identified some uncommon events as possible adverse drug reactions — notably hallucinations, tachycardia and palpitations. The prevalence of these events was compared with that in patient cohorts for other drugs on the PEM database. The age- and sex-adjusted relative risk of hallucinations on tolterodine compared with 10 drugs of other therapeutic classes, and with terodiline, another drug indicated for bladder instability, was 4.85 [95% confidence interval (CI) 2.72 to 8.66] and 1.25 (95% CI 0.62 to 2.53), respectively. There was no significant difference for tachycardia/palpitation in this comparison. Conclusions: Tolterodine is well tolerated in general practice at the recommended daily dose. Hallucinations, tachycardia and palpitations are infrequently associated with the drug.

Influenza H1N1 (swine flu) vaccination: a safety surveillance feasibility study using self-reporting of serious adverse events and pregnancy outcomes

AIMS During the global H1N1 influenza A (swine flu) pandemic 2009–2010, swine flu vaccines were expeditiously licensed and a mass vaccination programme for high risk groups, including pregnant women, was introduced in the UK. This pilot active safety surveillance study was performed to establish the feasibility of rapidly monitoring the new swine flu vaccines in large patient numbers receiving or offered the vaccination under normal conditions of use within a short time frame. METHODS A cohort design with safety data capture through modern technologies was carried out in Scotland, UK during the winter swine flu vaccination programme 2009–2010 in individuals receiving or offered the swine flu vaccination. The main outcome measures were self-reported serious adverse events (SAEs) and pregnancy outcomes. RESULTS The cohort comprised 4066 people; 3754 vaccinated and 312 offered the vaccination but not vaccinated. There were 939 self-reported events (838 different events), 53 judged to fit SAE criteria by the investigators, with nine judged as possibly, probably or definitely vaccine related. None of the seven deaths (six in vaccinees) were judged as vaccine related. One hundred and twenty-eight women reported 130 pregnancies during the study with 117 pregnant at study start. There were reports of four miscarriages in three women and six possible congenital abnormalities in live births. CONCLUSIONS Overall, no significant safety issues were identified. The methodology and use of modern technologies to collect safety data from large numbers of patients was successful and could be used again in similar safety studies.

Evaluation of risk profiles for gastrointestinal and cardiovascular adverse effects in nonselective NSAID and COX-2 inhibitor users: a cohort study using pharmacy dispensing data in The Netherlands.

AbstractBackground: Newly approved drugs, in comparison with older drugs, are more often prescribed to patients who have not responded satisfactorily to established related drugs or as first-line therapy to patients with a high baseline risk for adverse outcomes (i.e. channelling). However, these patients are less likely to benefit from the prescribed drug and/or are more prone to adverse drug reactions. Therefore, it is difficult to unravel whether observed risks or increases in risk of new drugs are real, i.e. related to the pharmacology, or whether these are related to selective prescribing to patients who are more susceptible to adverse events because of some underlying risk factor(s). The channelling paradox may exist for cyclo-oxygenase (COX)-2 selective inhibitors (‘coxibs’) instead of traditional nonselective NSAIDs in relation to both gastrointestinal (GI) and cardiovascular (CV) safety. Objective: To evaluate the risk profiles for GI and CV adverse effects in nonselective NSAID and coxib new-user populations over time, in terms of a quantitative measure since the introduction of coxibs. Methods: This was a population-based cohort study using the Dutch pharmaceutical claims database (Foundation for Pharmaceutical Statistics). Eligible patients (≥18 years) were those where the date of their first prescription (index date) of an NSAID (first-line [e.g. ibuprofen] or second-line [e.g. piroxicam] nonselective NSAID, COX-2 preferential NSAID or coxib) was between January 1999 and December 2003. For each patient, GI and CV risk profiles at index date were defined by a cumulative score derived from dispensing data (patient age, sex and history of medication use within 6 months of index date). Risk scores were categorized as low (score = 0), medium (1) or high (2+). Patients were recorded as switchers based on other NSAID use prior to the index date. Other information collected included the Chronic Disease Score (CDS). Crude odds ratios (ORs) were calculated for risk factors for each NSAID group versus first-line nonselective NSAID users as the reference cohort. The effect of calendar time was examined by plotting mean CV or GI risk score by quarter-year. Correlation between GI and CV scores was examined using the Pearson correlation coefficient (R). Data were stratified by patients’ history of switching. Results: The four cohorts comprised patients using: first-line nonselective NSAIDs (n = 42 750); second-line nonselective NSAIDs (n = 1771); COX-2 preferential NSAIDs (n = 3661) and coxibs (n = 4861) patients. New coxib users were most likely to have high GI and CV risk scores (OR 5.3 [95% CI 5.0, 5.6] and OR 2.2 [95% CI 2.1, 2.4], respectively). At the individual patient level, GI and CV risk profiles were moderately well correlated for all NSAID cohorts (R range 0.48 to 0.62). There was no remarkable change in mean GI or CV risk profile of patients over calendar time since the market introduction of coxibs. Discussion: Of the four NSAID cohorts, new coxib users tended to have the highest numbers of GI and CV risk factors, with no obvious change over calendar time. There was also evidence of correlation between GI and CV risk scores. Thus, selective prescribing of coxibs applies to people with co-existing CV as well as GI risk factors. This is important when comparing the safety and/or efficacy of new therapies to existing therapies, and emphasizes the difficulties encountered by prescribers in assessing levels of risk when initiating coxib treatment.