Safety of sertindole versus risperidone in schizophrenia: principal results of the sertindole cohort prospective study (SCoP).

OBJECTIVE: To explore whether sertindole increases all-cause mortality or cardiac events requiring hospitalization, compared with risperidone. METHOD: Multinational randomized, open-label, parallel-group study, with blinded classification of outcomes, in 9858 patients with schizophrenia. RESULTS: After 14147 person-years, there was no effect of treatment on overall mortality (sertindole 64, risperidone 61 deaths, Hazard Ratio (HR) = 1.12 (90% CI: 0.83, 1.50)) or cardiac events requiring hospitalization [sertindole 10, risperidone 6, HR = 1.73 (95% CI: 0.63, 4.78)]: Of these, four were considered arrhythmia-related (three sertindole, one risperidone). Cardiac mortality was higher with sertindole (Independent Safety Committee (ISC): 31 vs. 12, HR=2.84 (95% CI: 1.45, 5.55), P = 0.0022; Investigators 17 vs. 8, HR=2.13 (95% CI: 0.91, 4.98), P = 0.081). There was no significant difference in completed suicide, but fewer sertindole recipients attempted suicide (ISC: 68 vs. 78, HR=0.93 (95% CI: 0.66, 1.29), P = 0.65; Investigators: 43 vs. 65, HR=0.67 (95% CI: 0.45, 0.99), P = 0.044). CONCLUSION: Sertindole did not increase all-cause mortality, but cardiac mortality was higher and suicide attempts may be lower with sertindole.

Prospective cohort study of adverse events monitored by hospital pharmacists. Hospital Adverse Event Monitoring Study (HAEMS) Group.

PURPOSE: To examine the feasibility of pharmacist-led intensive hospital monitoring of adverse events (AEs) associated with newly marketed drugs. SUBJECTS/SETTING: 303 patients admitted to Southampton Hospitals who were prescribed selected newly marketed drugs during their inpatient stay in 1998. METHODS: Prospective observational study. Patients were identified from computerized pharmacy records, clinical pharmacist ward rounds, dispensary records or via nursing staff. The pharmacist reviewed medical notes and recorded AEs, suspected adverse drug reactions (ADRs) and reasons for stopping drugs. OUTCOMES: Incidence of AEs, ADRs; proportionate agreement between the physician's and pharmacist's event recording. RESULTS: 303 patients were monitored. Of the patients taking newly marketed drugs 92% were identifiable using pharmacy computer systems and pharmacist ward visits. There were 21 (7%) suspected ADRs detected during this pilot study. The types of adverse events detected were broadly similar to those identified by general practice-based prescription event monitoring. However, biochemical changes featured more frequently than in general practice. Differences between adverse events recorded by pharmacist and physician were systematic and attributed to differences in event coding. CONCLUSION: Pharmacist-led monitoring in a typical NHS hospital setting was effective at detecting ADRs in newly marketed drugs. However, this effort might have been substantially less time-consuming and more effective were electronic patient records (EPRs) available. Pharmacy computer systems are not designed to be patient focused and are therefore unable to identify patients taking newly marketed drugs. It is argued that future EPR and computerised patient-specific prescribing systems should be designed to capture this data in the same way as some US systems are currently able to do.

Finasteride and tamsulosin used in benign prostatic hypertrophy: a review of the prescription-event monitoring data.

OBJECTIVE: To review the results of non-interventional observational cohort studies of 14 772 patients treated with finasteride and 12 484 patients treated with tamsulosin, both studies being of national proportions and undertaken in general medical practice in England. METHODS: Both studies were undertaken by prescription-event monitoring (PEM), whereby the exposure data are derived from information provided in strict confidence by the Prescription Pricing Authority of the National Health Service. The outcome data are derived from 'green form' questionnaires completed by the prescribing general practitioners (GPs). Additional data are obtained by medical follow-up with the attending practitioners. Adverse experience was measured in three ways; as reports of events which the doctors considered to represent adverse drug reactions; as reports of reasons for stopping the drug; and by studying the incidence density of each reported event. For these purposes a computerized dictionary containing 1430 higher level terms was used. The duration of exposure in the finasteride study was approximately 1 year and was approximately 6 months in the tamsulosin study. RESULTS: The outcome data on the 14 772 and 12 484 patients treated in the finasteride and tamsulosin studies were derived from the 63% and 57.4% of the green forms sent out and returned, respectively. The finasteride cohort included two women and the tamsulosin cohort 70 women. The mean (SD) age of the men in the two cohorts was, respectively, 69.0 (9.2) and 66.2 (11.7) years. Both drugs were well tolerated on long-term therapy and 69.6% (10 274 patients) of the total finasteride and 62.0% (7739 patients) of the total tamsulosin cohort were still receiving the drug at the end of 6 months. In the finasteride study, impotence or ejaculatory failure was reported in 2.0% of the patients still receiving the drug; there were reports of decreased libido in 1.0% and gynaecomastia was reported whilst the drug was still being prescribed in 39 patients (0.3% of the cohort). With tamsulosin, uncommon cases of dizziness, headache, malaise and hypotension (89 reports in 12 484 patients, i.e. 0.7% of the cohort) were common to the findings of reported adverse reactions, reasons for stopping the drug and events of highest incidence density. None of the deaths which occurred in either of these large cohorts was attributed by either the reporting GPs or the PEM medical staff to the drugs examined. Conclusion The GPs rated the drugs effective in most patients; tolerance and adverse experience was consistent with the known pharmacology of the two drugs. No serious, unexpected adverse effects were identified.

Costs of seeking ethics approval before and after the introduction of multicentre research ethics committees.

With the advent of multicentre research ethics committees in the UK, local research ethics committees (LRECs) are required to advise only on issues relating to the local acceptability of a project. We looked at the handling of two commercially sponsored studies, one initiated before the change and one after, confining the analysis to 21 LRECs approached in both. As judged by the amount of paper per application, the new system for LRECs is simpler and should be less costly. However, there was an increasing tendency for LRECs to charge for their services (30% study 1, 47% study 2) and these charges varied by more than 400%. If such fees must be levied, a common scale is desirable.

The incidence of adverse events and risk factors for upper gastrointestinal disorders associated with meloxicam use amongst 19,087 patients in general practice in England: cohort study.

AIMS: Meloxicam is a novel nonsteroidal anti-inflammatory drug (NSAID) which may be associated with fewer adverse upper gastrointestinal events than other NSAIDs because it preferentially inhibits the inducible enzyme cyclo-oxygenase-2 relative to the constitutive isoform, cyclo-oxygenase-1. The aims of the study were to: determine the rate of adverse events associated with meloxicam in general practice, stratify these rates by selected risk factors, and to identify signals of previously unsuspected adverse events associated with meloxicam. METHODS: As part of the national prescription-event monitoring pharmacovigilance system for newly launched drugs in general practice, all patients prescribed meloxicam in England between December 1996 and March 1997 were identified by the central Prescription Pricing Authority. We sent short questionnaires to all prescribers asking about adverse events experienced within 6 months of the first prescription. RESULTS: There were 19 087 patients in the study. The rate of dyspepsia during the first month of exposure was 28.3 per 1000 patient-months. There were 33 reports of upper gastrointestinal haemorrhage during treatment (rate: 0.4 per 1000 months). A history of gastrointestinal disorder in the previous year was associated with an increased rate of dyspepsia (rate ratio: 3.0; 95% confidence interval: 2.6, 3.4), abdominal pain (2.1; 1.6, 2.6), and peptic ulcer (4.0; 1.4, 13.2). Prior NSAID use was associated with a 20-30% decrease in the rate of dyspepsia and abdominal pain in patients starting meloxicam, while patients prescribed concomitant gastroprotective agents had a two to three-fold increased rate of dyspepsia, abdominal pain and peptic ulceration. Other rare events were thrombocytopenia (n = 2); interstitial nephritis (n = 1) and idiosyncratic liver abnormalities (n = 1). CONCLUSIONS: In the absence of gastro-intestinal risk factors the incidence of gastro-intestinal disturbance was low. Such risk factors should be carefully reviewed prior to prescribing meloxicam.

Regional variation in incidence and case fatality of myocardial infarction among young women in England, Scotland and Wales.

OBJECTIVES: To examine the regional variation in incidence and case fatality of myocardial infarction among young women. DESIGN: Cross sectional survey, using population based incidence data. SETTING: England, Scotland and Wales. SUBJECTS: Subjects were women aged 16-44 with a diagnosis of myocardial infarction between 1 October 1993 and 15 October 1995. OUTCOME MEASURES: Incidence of myocardial infarction per 100,000 women years, with case fatality as a percentage of total cases. RESULTS: Incidence of myocardial infarction rose steeply from age 33 upwards, (maximum = 20.2 cases per 100,000 women years at age 44). The adjusted incidence rate for myocardial infarction was 3.7 (95% CI 3.2, 4.2) times greater in Scotland than in southern England. In contrast, case fatality was significantly lower in Scotland: 18.5% (95% CI 13.1%, 25.0%), compared with 31.0% (95% CI 25.9%, 36.0%) in southern England. CONCLUSIONS: The incidence of myocardial infarction varied widely within the United Kingdom. Case fatality variation may reflect differences in ambulance response, or in diagnostic acumen, within the regions.

Sedation with "non-sedating" antihistamines: four prescription-event monitoring studies in general practice.

OBJECTIVES: To investigate the frequency with which sedation was reported in post-marketing surveillance studies of four second generation antihistamines: loratadine, cetirizine, fexofenadine, and acrivastine. DESIGN: Prescription-event monitoring studies. SETTING: Prescriptions were obtained for each cohort in the immediate post-marketing period. SUBJECTS: Event data were obtained for a total of 43 363 patients. MAIN OUTCOME MEASURES: Reporting of sedation or drowsiness. RESULTS: The odds ratios (adjusted for age and sex) for the incidence of sedation were 0.63 (95% confidence interval 0.36 to 1.11; P=0.1) for fexofenadine; 2.79 (1.69 to 4.58; P<0.0001) for acrivastine, and 3.53 (2.07 to 5.42; P<0.0001) for cetirizine compared with loratadine. No increased risk of accident or injury was evident with any of the four drugs. CONCLUSIONS: Although the risk of sedation was low with all four drugs, fexofenadine and loratadine may be more appropriate for people working in safety critical jobs.

The pharmacovigilance of tamsulosin: event data on 12484 patients.

OBJECTIVE: To determine drug effectiveness and adverse effects in a noninterventional observational cohort study of over 10 000 patients treated with tamsulosin in general medical practice. METHODS: Using prescription-event monitoring, data were collected of all prescriptions for tamsulosin issued nationally during June 1996 to January 1998. For each patient entered into the cohort a computerized longitudinal record of exposure was constructed. The outcome data, patient information and an opinion about the effectiveness of the drug were provided by the prescriber, using a standard questionnaire sent 6 months after the initial prescription for tamsulosin. The incidence of each of almost 2000 events listed in the Drug Safety Research Unit computerized dictionary was calculated and scrutinized by medical assessors for possible adverse reactions, and any difference determined between the incidence of each event in the first month and subsequent months of exposure. All deaths were followed up to detect possibly drug-related causes. RESULTS: Event data were obtained on 12484 patients, from the 52.9% of questionnaires returned and that contained valid event data. Tamsulosin was reported to have been effective in 7428 (78.3%) of the 9487 patients in whom the general practitioners expressed an opinion about effectiveness. Suspected adverse drug reactions were reported in only 171 (1.4%) of the cohort. Dizziness, headache, malaise and hypotension were common to the reported adverse reactions, reasons for stopping the drug and events of greatest incidence density. None of the 282 deaths that occurred in this elderly cohort were attributed to the drug. CONCLUSION: This study suggests that tamsulosin has a highly acceptable benefit-to-risk ratio. No untoward features not already mentioned in the prescribing guidance were identified.

Prescription-event and other forms of epidemiological monitoring of side-effects in the UK.

The post-marketing surveillance (PMS) of drugs is necessary because of the limited size of the clinical safety database at the time of marketing. The principal hypothesis-generating methods of PMS are spontaneous reporting (e.g. the yellow card) and Prescription Event Monitoring. These methods are discussed in this chapter and certain basic pharmacoepidemiological issues that are relevant are briefly reviewed.

Cohort study on calcium channel blockers, other cardiovascular agents, and the prevalence of depression.

AIMS: Some reports have suggested that calcium channel blockers may be associated with an increased incidence of depression or suicide. There is a paucity of evidence from large scale studies. The aim of this study was to assess rates of depression with calcium channel antagonists using data from prescription event monitoring studies. METHODS: Observational studies on large cohorts of patients using lisinopril, enalapril (ACE inhibitors), nicardipine (type 2 calcium channel blocker) and diltiazem (type 3 calcium channel blocker) were conducted, using prescription-event monitoring. Rates of depression in the different drugs and rate ratios (95% CI) were computed. RESULTS: The crude overall rates of depression during treatment were 1.89, 1.92 and 1.62 per 1000 patient months for the ACE inhibitors, diltiazem and nicardipine, respectively. Using the ACE inhibitors as the reference group, the rate ratios for depression were 1.07 (0. 82-1.40) and 0.86 (0.69-1.08) for diltiazem and nicardipine, respectively. CONCLUSIONS: This study does not support the hypothesis that calcium channel blockers are associated with depression, when considering patients treated in general practice in the UK.

Cough and angiotensin II receptor antagonists: cause or confounding?

AIMS: Cough is one of the most frequent side effects associated with angiotensin converting enzyme inhibitors (ACEIs) but is not thought to be associated with losartan, an angiotensin II receptor antagonist (ARA). This study compares reports of cough with losartan and three ACEIs used in general practice. METHODS: Studies have been conducted for losartan, and three ACEIs enalapril, lisinopril and perindopril, using the technique of Prescription-Event Monitoring. Patients were identified using dispensed prescription data. Questionnaires were sent to patients' general practitioners 6 months after the date of first prescription. Cases of cough within the first 60 days of treatment with losartan resulting in withdrawal of the drug were followed up with additional questionnaires. Incidence rates for reports of cough were calculated. In order to reduce the impact of carry-over effects, rate ratios were calculated for first reports of cough between days 8 and 60 using losartan as the index drug. RESULTS: The cohort for each drug exceeded 9000 patients. Age and sex distributions and indications for prescribing the four drugs were similar. Cough was the most frequent reason for discontinuation of losartan and the most frequently reported event in the first month of treatment with this drug. When reports of cough between days 1-7 were excluded, rates of cough were significantly higher for the three ACEIs when compared with losartan (rate ratios 1.5, 4.8 and 5.7, all P<0.03). 101 patients had discontinued losartan due to cough. 91% of these had previously been prescribed an ACEI and 86% had previously experienced ACEI cough. CONCLUSIONS: Carry-over accounted for the observed excess of reports of cough with losartan. Rates of cough between days 8 and 60 were significantly higher for the three ACEIs compared with losartan. Confounding factors associated with comparative observational cohort studies are discussed.

Interim report on the incidence of visual field defects in patients on long term vigabatrin therapy.

The incidence was determined of visual field defects in patients in the Prescription-Event Monitoring (PEM) study, treated for > or =6 months with the antiepileptic drug vigabatrin. Questionnaires were sent to the general practitioners of the 7228 patients in the PEM study, treated with vigabatrin for > or =6 months, to ascertain whether any serious adverse events, including changes in vision, had occurred. Ophthalmologists were asked to give the results of the perimetry tests and their opinion of the cause of the visual field defect for those patients referred to them. 6793 (94%) of the 7228 questionnaires were returned. 5090 (75%) contained clinical data. 328 patients were deceased. Seventy seven cases identified from the 4762 surviving patients, are being followed up with ophthalmologists. To date, 2 weeks after posting, 12 cases of visual field defect have been confirmed by formal perimetry tests. Ten of these 12 were considered to be probably or possibly related to vigabatrin use, giving an incidence of 2.0 per 1000 patients compared with 0.4 per 1000 patients in the original PEM cohort. These interim results show a substantial increase in the incidence of visual field defects associated with long term use of vigabatrin and demonstrate that PEM can be used to assess long latency adverse events.

The use of newly marketed drugs in children and adolescents prescribed in general practice.

This study determined the licensed and 'off label' (outside the terms of the licence) use of newly marketed medicines in children (2-11 years) and adolescents (12-17 years), by general practitioners in England. In addition, the incidence rates during the first month of therapy (ID(1)) for three adverse events, in these groups were compared with those of adults (> or =18 years). The use of these drugs was monitored in 63 individual prescription-event monitoring (PEM) studies, conducted to monitor the safety of these medicines. Patients and drug exposures were identified from dispensed prescriptions. Outcome data (events and demographic information) were obtained from questionnaires. Although only six of these 63 drugs were licensed for use in children, 44 of the 63 drugs were used to treat children. For the majority of the drugs there was no specific reference to adolescents in the data sheets therefore it has been assumed that the drugs were licensed for those aged > or =12 years unless specified otherwise; 55 have been taken as licensed for use in adolescents. Over 690,000 patients were included in the 63 PEM studies, 9081 (1.3%) of these were children and 15,256 (2.2%) were adolescents. 78% of the 9081 children and 93% of the 15,256 adolescents were treated with 'licensed' drugs. There was a significant difference in the incidence rate for rash and nausea/vomiting, two adverse events commonly reported during treatment with lamotrigine, between children and adolescents compared to adults. This survey has shown that although only a small proportion (10%) of newly marketed drugs were licensed for use in children the majority of children (78%) were treated with these licensed products but 22% of children received drugs 'off label' during the first few years that the drug was marketed and a small number of children and adolescents were given drugs contraindicated in these age ranges.

Did knowledge, opinions, background, and health authority advice influence early prescribing of the novel Alzheimer's disease drug donepezil in general practice?--national postal survey.

BACKGROUND: Donepezil was licensed in the UK in February 1997 for the treatment of Alzheimer's disease. AIMS: To determine the advice from health authorities about prescribing Alzheimer's disease drugs. To determine whether the first general practitioners who prescribed donepezil in England differed from non-prescribers in terms of knowledge, opinions, background, and the prescribing-advice issued by their health authority. METHODS: National postal survey of pharmaceutical advisors. Structured postal survey of all general practitioners in England who prescribed donepezil to two or more patients within the first 6 months of launch, compared with a random sample of non-prescribers. RESULTS: Pharmaceutical advisors' survey: 75/100 pharmaceutical advisors responded, of whom 83% indicated that general practitioners should not initiate prescribing of Alzheimer's disease drugs and 63% said that they should not prescribe, even under shared care arrangements. General practitioner survey: 311/473 (66%) prescribers and 484/947 (51%) non-prescribers responded after two mailings. Prescribers were similar to non-prescribers in terms of demographic and practice characteristics, knowledge about Alzheimer's disease, diagnostic and initial management strategies, and the prescribing advice from health authorities. Prescribers were significantly more likely than non-prescribers to strongly agree/agree that new drugs should be prescribed for mild (p=0.0008) and moderate (p=0.003) Alzheimer's disease, that they should normally be initiated (p=0.003) and monitored by a general practitioner (p<0.0001), and that financial constraints should not be a consideration (p=0.0001). CONCLUSION: Early prescribers differed from non-prescribers in their opinions about using Alzheimer's disease drugs. Future research should examine methods to promote nationally equitable and rational prescribing of new drugs.

Nefazodone in community use: the results of prescription-event monitoring.

PURPOSE: This study was a pharmacovigilance exercise which aimed to determine the post-marketing event profile of nefazodone, a newly marketed antidepressant, in community use. METHODS: Information was collected on patients included in a non-interventional observational cohort study conducted by means of Prescription-Event Monitoring in England. Incidence densities were calculated for all reported events. RESULTS: Information was obtained for 11 834 patients. Nausea and dizziness were the most frequent adverse events that led to stopping nefazodone and the most frequently reported events during the first month of treatment. Unsteadiness and falls were reported more frequently in the elderly. Hepatic events, involuntary movements, thrombocytopenia, hallucinations and withdrawal reactions were reported rarely but were possibly associated with nefazodone. Eight overdoses involving nefazodone alone were reported with no serious clinical sequelae. Two premature births, one low birth weight term baby and two babies with renal abnormalities were outcomes in 38 pregnancies exposed in the first trimester to nefazodone. One death in a woman aged 71 years followed an illness with serotonergic features. CONCLUSIONS: Event data are presented for patients dispensed nefazodone in the community. The findings are discussed.

Prevalence of Churg-Strauss syndrome, vasculitis, eosinophilia and associated conditions: retrospective analysis of 58 prescription-event monitoring cohort studies.

PURPOSE: Churg-Strauss syndrome is characterised by hypereosinophilia, systemic vasculitis and asthma. The cause is usually unknown, but there have been reports of an association with particular drugs, including anti-asthma drugs. Our aim was to estimate the prevalence of Churg-Strauss syndrome and related conditions in post-marketing safety studies of new anti-asthma drugs. METHODS: We accessed the prescription-event monitoring (PEM) database of the Drug Safety Research Unit (DSRU). This database currently has information on 622 294 patients observed during 58 completed PEM studies of individual drugs, including 35 799 patients in studies of new anti-asthma drugs. RESULTS: Overall, four cases of Churg-Strauss syndrome were identified during these studies, giving a period prevalence rate of 6.8 (95% confidence limits [CL]: 1.8-17.3) per million patient-years of observation. The period prevalence of Churg-Strauss syndrome was significantly greater in the PEM cohorts of anti-asthma drugs (64.4 million patient-years of observation; 95% CL: 13.3-188.1), than the other PEM drug cohorts (1.8 per million patient-years of observation; 95% CL: 0.05-10.2) (rate ratio: 35.1; 95% CL: 2.8-1839.9; p=0.002). CONCLUSION: Our data provide estimates of the prevalence of Churg-Strauss syndrome and related conditions in cohorts of asthmatic patients, which may be useful during the pharmacovigilance of new asthma drugs, including the new leukotriene receptor antagonists.

Safety profile of nicorandil--prescription-event monitoring (PEM) study.

PURPOSE: A PEM study of nicorandil (Ikorel) was undertaken to assess the drug's overall safety in everyday clinical practice. METHODS: The prescription data used covered the period December 1994 to October 1996. The event data, which were based on a minimum observation period of 6 months, came from questionnaires returned by the prescribing general practitioners. Incidence densities (IDs) were calculated for all events occurring during month 1, months 2-6, and the overall treatment period. Selected events were followed up. RESULTS: The study was based on a cohort of 13,260 patients and 86,760 patient-months of nicorandil treatment. Major indications for use were angina (8744) and ischaemic heart disease (846). Adverse reactions (258) were reported in 175 (1.3%) of patients--the most frequent being headache (58; 0.4%) and unspecified side effects (36; 0.3%). The most common reasons for stopping treatment (excluding those confounded by indication) were headache (477; 3.5%), dizziness (88; 0.65%) and 'not effective' (491; 3.6%). The number of patients still being prescribed nicorandil after 6 months was 74.3%. In those cases where an opinion on effectiveness was given, nicorandil was reported to be effective in 80% (8713) of patients. The event of headache/migraine had the highest ID in the first month of treatment (49.4 per 1000 patient-months) and was not confounded by indication. Follow-up of selected events was reassuring overall; rare side effects included angioneurotic oedema and photosensitivity (3 cases each). CONCLUSION: This PEM study provides information on the 'real-world' use of nicorandil and shows generally that the drug is safe when used in the recommended dosage.