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Abstract The safety of the atypical antipsychotic quetiapine as used in general practice in England was examined by prescription-event monitoring (PEM). Patients were identified from dispensed National Health Service (NHS) [...]

Clinical trials for the newer antiepileptic drugs (AEDs) have provided inconclusive information to evaluate comparative risk benefit. The authors use data from postmarketing observational cohort studies to compare the failure [...]

Introduction: There is a need to identify effective, safe treatments for COVID-19 (coronavirus disease) rapidly, given the current, ongoing pandemic. A systematic benefit-risk assessment was designed and conducted to examine the benefit-risk profile of remdesivir in COVID-19 patients compared with standard of care, placebo or other treatments. A key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation, which starts with inevitably limited information (to meet the urgent unmet public health need worldwide), then update the benefit-risk evaluation as more data become available.Methods: The Benefit-Risk Action Team (BRAT) framework was used to assess the overall benefit-risk of the use of remdesivir as a treatment for COVID-19 compared with standard of care, placebo or other treatments. We searched PubMed, Google Scholar and government agency websites to identify literature reporting clinical outcomes in patients taking remdesivir for COVID-19. A value tree was constructed and key benefits and risks were ranked by two clinicians in order of considered importance.Results: Using the BRAT method, several key benefits and risks for use of remdesivir in COVID-19 compared with placebo have been identified. In one trial, the benefit of time to clinical improvement was not statistically significant (21 vs 23 days, HR 1.23, 95% CI 0.87-1.75), although the study was underpowered. In another trial, a shorter time to recovery in patients treated with remdesivir was observed (11 vs 15 days), with non-significant reduced mortality risk (8% vs 12%). Risk data were only available from one trial. This trial reported fewer serious adverse events in patients taking remdesivir (18%) compared with the placebo group (26%); however, more patients in the remdesivir group discontinued treatment as a result of an adverse event compared with those patients receiving placebo (12% vs 5%).Conclusions: Preliminary clinical trial results suggest that there may be a favourable benefit-risk profile for remdesivir compared with placebo in severe COVID-19 infection and further data on benefits would strengthen this evaluation. There is limited safety data for remdesivir, which should be obtained in further studies. The current framework summarises the key anticipated benefits and risks for which further data are needed. Ongoing clinical trial data can be incorporated into the framework when available to provide an updated benefit-risk assessment. [ABSTRACT FROM AUTHOR]

Introduction: Monitoring was required for the introduction of non-chlorofluorocarbon (CFC) propellants in metered dose inhalers (MDIs) to ensure that there were no unexpected adverse events due to the new products. A postmarketing surveillance study has been conducted to evaluate the introduction of the MDI Seretide Evohaler™ (hydrofluoroalkane-134a inhaler containing salmeterol and fluticasone propionate). Objectives: To summarise the modified prescription-event monitoring (PEM) study conducted to evaluate the introduction of Seretide Evohaler™ and discuss the relevance of this type of study towards pharmacovigilance risk-management planning. Methods: Modified PEM methodology was used to examine the introduction of Seretide Evohaler™ into general practice in England. Patients were identified from the first National Health Service prescriptions dispensed in England for Seretide Evohaler™. One postal questionnaire was sent to the prescribing doctor, requesting demographic information, severity of the indication, concomitant medication for this condition, smoking history, event data 3 months prior to and 3 months after the first prescription for Seretide Evohaler™ and also reason for stopping if it had been stopped. Pregnancies, deaths and selected events were followed up. Incidence density ratios were calculated to compare event rates 3 months prior to and 3 months after the introduction of Seretide Evohaler™. A matched cohort analysis examined oral corticosteroid use and hospital admissions between the pre- and post-exposure periods. Results: The cohort comprised 13 464 patients prescribed Seretide Evohaler™, with a response rate of 62%. There was no significant difference in the length of courses of oral corticosteroid use when the pre- and post-exposure periods were compared. A matched cohort analysis showed there was no increase in the use of oral corticosteroids (relative risk [RR] 0.95; 95% CI 0.90, 0.99) or hospital admissions in the post-exposure period (RR 0.87; 95% CI 0.73, 1.04). When the number of patients with events were compared for the periods 3 months before and 3 months after exposure, fewer events were reported in the post-exposure period. There were 64 patients who experienced adverse events within an hour of using Seretide Evohaler™, including one report of paradoxical bronchospasm and one of myocardial infarction with fatal outcome that were both assessed as possibly related to treatment. Discussion: The results of the study suggest that the introduction of Seretide Evohaler™ was generally well tolerated. The modified methodology has allowed a comparison of the event rates before and after the introduction of this CFC-free inhaler into general practice. [ABSTRACT FROM AUTHOR]

Objectives: A prescription event monitoring (PEM) postmarketing surveillance study was carried out to examine the safety of zafirlukast as used in general practice in England.Methods: Exposure data were obtained from the first National Health Service (NHS) prescription dispensed for patients whose prescription details were processed by the Prescription Pricing Authority between August 1998 and December 2000. Outcome data were obtained from 'green form' questionnaires sent to general practitioners (GPs) at least 6 months following the first prescription issued. Incidence densities (IDs) were calculated for events reported per 1000 months of patient exposure and ID differences between the first month of treatment and months 2-6 combined were analysed. Events of medical interest were followed up by postal questionnaire sent to GPs.Results: 21 557 green forms were sent to 8051 doctors, of which 9124 (42.3%) were returned. Useful clinical data was obtained for 7976 patients of which 4664 (58.5%) were female and 3265 (40.9%) were male. The patient's sex was not specified in 47 (0.6%) forms. The median age of the cohort was 53 years (interquartile range 38-66 years). The most frequently reported primary indication was the licensed indication of asthma, but for a small proportion of the cohort it was prescribed 'off label'.A total of 152 events in 120 (1.5%) patients were reported as adverse drug reactions (ADRs) by GPs on the green forms. ADRs with the highest reported frequency were headache and nausea. There were 3514 reasons for stopping zafirlukast in 3148 (39.5%) patients, the most frequently reported of which was that the drug was 'ineffective' (2008 patients; 25.2%). The most frequently reported specified clinical reason for stopping was headache (82 patients; 1.0%). There were 28 pregnancies reported in this cohort, 20 of which were reported to have exposure to zafirlukast during the first trimester. Nine live births with no recorded congenital abnormalities were reported for pregnancies with exposure in the first trimester. There were 151 deaths reported during the study period (1.9%). The most frequently reported causes of death were related to the respiratory system (57; 37.7%), including chronic obstructive pulmonary disease, asthma and bronchopneumonia.Conclusion: This study showed that zafirlukast, as used in general practice in England, is a generally well tolerated drug with few associated adverse events. [ABSTRACT FROM AUTHOR]

Background and Objective: Rosuvastatin is a lipid-lowering drug, the newest of a class of drugs called HMG-CoA reductase inhibitors, or 'statins', launched in the UK in March 2003. Our objective was to monitor the post-marketing safety of this drug, prescribed in primary care in England, using prescription-event monitoring.Methods: An observational cohort study in which patients were identified from dispensed prescriptions issued by primary care physicians/general practitioners (GPs) between August and December 2003. Demographic and clinical-event data were collected from questionnaires posted to GPs at least 6 months after the date of first prescription for each patient. Stratified analysis of specific events by starting dose of rosuvastatin was conducted. Follow-up and causality assessment of medically significant events was undertaken.Results: The cohort comprised 11,680 patients (median age 64 years); 50.3% were males (5880 of 11,680). The median period of treatment was 9.8 months. Of these patients, 72.7% (n = 8494) were started on rosuvastatin 10 mg/day. A total of 17.5% (n = 2047) of the patients were reported to have stopped treatment with rosuvastatin. Myalgia was the most frequent reason for stopping rosuvastatin and the most frequently reported clinical event. A 2.5-fold increase in the rate of abnormal liver-function tests (LFTs) was observed for patients started on rosuvastatin 40 mg/day compared with those started on 10 mg/day (2.71; 95% CI 1.53, 4.53). No case of rhabdomyolysis was reported in this cohort.Conclusion: Rosuvastatin was considered to be a reasonably well tolerated drug. In the majority of patients, rosuvastatin was prescribed in line with recommendations. Abnormality of LFTs was found to be more frequent with the 40 mg/day dosage of rosuvastatin. Results from this study should be taken into account together with those of other clinical and pharmacoepidemiological studies of rosuvastatin. [ABSTRACT FROM AUTHOR]

Background: 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. [ABSTRACT FROM AUTHOR]

Background: In the UK, the nitrogen bisphosphonate risedronate is licensed for the prevention and treatment of osteoporosis and corticosteroid-induced osteoporosis in postmenopausal women. It is also licensed for the treatment of Paget’s disease. During a prescription-event monitoring (PEM) study on risedronate we noted a number of ophthalmological events. Recently, case reports of ophthalmological adverse drug reactions in patients taking bisphosphonates were published in the medical literature. The aim of this study was to further evaluate the association of ophthalmological events reported in relation to risedronate treatment during a PEM study on the drug. Methods: An observational cohort study (PEM study) was conducted in England between September 2000 and June 2002. General practitioners (GPs) were asked for follow-up information on selected events. Events followed up were classified as either ‘probably’, ‘possibly’ or ‘unlikely’ to be related to risedronate, using a modified WHO classification. If insufficient information was obtained on the follow-up questionnaire, the cases were categorised as ‘unassessable’. Results: Of the total PEM study cohort of 13 643 patients, 11 156 (82%) were females and 2398 (18%) were males. We received 359 reports of ophthalmological events in 313 patients during the entire study period. Of these we followed up 178 events in 178 patients. Nineteen events in 19 patients were assessed as possibly or probably related to risedronate. The age range for these patients was 50–92 years and the time to onset ranged from 7 days to 5 months. Dry eye (six reports), sore eye (five reports) and conjunctivitis (three reports) were the most frequently reported ophthalmological events assessed as probably or possibly related to risedronate therapy. GPs also reported several other inflammatory conditions of the eye, amongst them two events each of iritis and episcleritis as well as one of keratitis. However, the information received on follow up of these events was insufficient to make causality assessments. Conclusion: Patients receiving risedronate can present with a variety of signs and symptoms affecting the eye with different degrees of severity. Patients may present after the first month of treatment. Doctors should have an increased awareness of possible ophthalmological adverse drug reactions in patients receiving this drug, which may affect the eyesight in a population at increased risk of fracture if they fall. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to assess the publicly disseminated evidence used to support decisions to withdraw medicinal products for safety reasons, and related implications for the conduct of systematic reviews of harm.Methods: Medicinal products withdrawn from the UK and US markets for safety reasons were identified from websites of the UK Medicines Control Agency (now known as the Medicines and Healthcare products Regulatory Agency) and the US FDA. Related scientific evidence was identified from communications made to the public and healthcare professionals at the time of each product withdrawal. Evidence for each product withdrawal decision was classified according to study design and outcome.Results: Eleven products were withdrawn during 1999-2001. Randomised trial evidence was cited for two products (18%) and comparative observational studies for two products (18%). Evidence from spontaneous reports supported the withdrawal of eight products (73%), with four products (36%) apparently withdrawn on the basis of spontaneous reports alone. Only two products (18%) were withdrawn on evidence for a patient relevant outcome from comparative studies.Conclusions: It is rare that evidence other than spontaneous reports is cited in support of drug withdrawals. The serious implications of product withdrawal mandate the elevation of the level of evidence that supports such public health decisions. Once suspicions of important safety hazards have emerged, prospective studies may be unfeasible and may be seen as unethical. Prospective studies can strengthen the evidence base and should be planned to commence when every drug is first marketed. Systematic reviews are unlikely to elicit evidence of harm associated with a drug unless they include spontaneous reports and surrogate outcomes. [ABSTRACT FROM AUTHOR]

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 three-fold 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. [ABSTRACT FROM AUTHOR]

Background and Objectives: Rofecoxib, a selective cyclo-oxygenase (COX)-2 inhibitor, was a widely marketed drug that was used for relief of pain and inflammation in arthritic conditions. It was withdrawn from the market worldwide in September 2004 because of an increased risk of cardiovascular events. Celecoxib, which belongs to the same class of drugs, is now under scrutiny for the risk of similar events. The objective of our study was to compare the incidence of gastrointestinal (GI) [symptomatic and complicated upper GI] events and thromboembolic (cardiovascular, cerebrovascular and peripheral venous) events reported for patients prescribed rofecoxib or celecoxib in primary care.Methods: A retrospective analysis of selected events was conducted using data collected from previously conducted prescription-event monitoring (PEM) studies for rofecoxib and celecoxib. PEM is an observational cohort technique. Exposure data were derived from dispensed prescriptions for rofecoxib (July-November 1999) and celecoxib (May-December 2000) that were written by primary care general practitioners in England. Outcome data were clinical events and information on potential risk factors reported on simple questionnaires (posted to prescribers approximately 9 months after the date of the first prescription). Incidence rates of the first event during treatment within each thromboembolic and GI group were calculated during the 270 days after the patient started receiving either of the drugs; crude and adjusted rate ratios (RR) were calculated for rofecoxib compared with celecoxib using Poisson regression modelling.Results: The rofecoxib and celecoxib PEM cohorts contained 15 268 and 17 458 patients, respectively. For the GI event groups, the adjusted RRs for rofecoxib compared with celecoxib were: 1.21 (95% CI 1.09, 1.36) for symptomatic upper GI events and 1.60 (95% CI 0.95, 2.70) for complicated upper GI conditions. For the thromboembolic event groups, the adjusted RRs were: 1.04 (95% CI 0.50, 2.17) for cardiovascular thromboembolic events; 1.43 (95% CI 0.86, 2.38) for cerebrovascular thromboembolic events; and 0.36 (95% CI 0.01, 1.34) for peripheral venous thromboembolic events.Conclusions: This study was a retrospective comparison of PEM studies conducted for rofecoxib and celecoxib. For symptomatic upper GI events, a 21% increase in the relative rate was found for rofecoxib users compared with celecoxib users after adjusting for identified risk factors. For complicated upper GI events, no statistically significant difference in the incidence was observed between rofecoxib and celecoxib users after adjusting for identified risk factors. For the three thromboembolic event groups, no evidence of a statistically significant difference between rofecoxib and celecoxib users was found after adjusting for identified risk factors. This study contributes to the understanding of the association between COX-2 inhibitors and thromboembolic events. However, it should be borne in mind that we had information on only a limited number of confounding variables for thromboembolic events. Further research is required to fully understand the risks and benefits of using celecoxib and other COX-2 inhibitors. Meanwhile, doctors should be cautious when prescribing these products, particularly to patients with risk factors for developing thromboembolic events. [ABSTRACT FROM AUTHOR]

Objective: At the time of marketing, experience of long-term use of prescription medicines in general clinical practice is limited. Postmarketing surveillance is particularly important at this time when medicines may be prescribed to large numbers of patients of all ages, for long-term use. Following marketing of formoterol (Foradil) in the UK in 1996 we undertook a postmarketing surveillance study of formoterol use in general practice.Design: A non-interventional observational cohort study was conducted using the technique of prescription-event monitoring. Exposure data were obtained from prescription details; outcome data from questionnaires sent to general practitioners approximately 12 months after the first prescription was dispensed for individual patients. Incidence rates were calculated for reported events, reasons for stopping treatment and outcomes of pregnancy were determined.Results: Data were collected for 5777 patients aged 3 to 96 years, 65% of whom continued treatment for >12 months. Formoterol was prescribed 'off label', to 258 children, (4.5%) of the cohort. The most commonly reported events excluding those related to respiratory disease, were headache, tremor, palpitation, cramp and nausea/vomiting. These events were also among the more common reasons for stopping treatment and reported as suspected adverse drug reactions. 33 patients took formoterol during pregnancy. The cause of death was established for 186 of the 190 deaths (3% of cohort).Conclusions: Formoterol appears to have been well tolerated by the majority of patients in this study. The most frequently reported adverse events were those known to be associated with beta(2)-agonists, although the frequency of nausea/ vomiting was greater than given in Summary of Product Characteristics. [ABSTRACT FROM AUTHOR]

Sertindole (Serdolect), an atypical antipsychotic, was voluntarily suspended in the European Union in 1998 following regulatory concerns over reports of serious cardiac dysrhythmias and sudden unexpected deaths. The reported causes of death, their frequency, prolongation of the rate corrected QT interval (QTc) and cardiac dysrhythmias in patients prescribed sertindole were compared with those for patients treated with two other atypical antipsychotics. All patients in England, prescribed atypical antipsychotics by general practitioners during each drug's immediate post-marketing period, were identified using an observational cohort technique, prescription-event monitoring. Mortality rates in the sertindole cohort were compared with those in a comparator cohort using standardized mortality ratios and incidence rate ratios. Cardiovascular events were reviewed and followed up to identify cases of prolongation of QTc interval. There was no statistically significant difference in mortality rates between sertindole and the comparator cohort, although confidence intervals (CI) were wide due to small numbers in the sertindole cohort. A much smaller number of patients were prescribed sertindole than the other antipsychotics. Six cases of prolongation of QTc interval were identified in 462 patients (1.3%, 95% CI 0.5-2.8) treated with sertindole and one with unspecified electrocardiogram changes in the comparator cohort of 16,542 patients. This study contributes to the understanding of the occurrence of prolongation of QTc interval during clinical use of sertindole, the incidence of which was similar to that in clinical trials. Although no statistically significant difference was shown in mortality rates between sertindole and comparator cohort, the sertindole cohort was too small to rule out an association between the use of this drug and cardiovascular deaths. [ABSTRACT FROM AUTHOR]