AimsLittle is known about the frequency with which suspected adverse drug reactions are seen by general practitioners after the prescription of newly marketed drugs. We investigated age and sex specific incidence rates of suspected adverse drug reactions recorded by general practitioners in England after the prescription of selected newly marketed drugs. Methods Information was collected from 48 national cohort studies of newly marketed drugs studied by prescription-event monitoring. Questionnaires were sent to prescribers asking for details of events and suspected adverse drug reactions recorded in the patients' notes occurring after the drugs were prescribed. Results During the 48 cohort studies, a total of 513 608 patients were investigated, of which 221 781 (43.2%) were males and 285 862 (55.7%) were females. The overall incidence of suspected adverse drug reactions in males was 12.9 per 10 000 patientmonths of exposure (95% confidence limits 12.3 to 13.5), and in females was 20.6 per 10 000 patient-months of exposure (95% confidence limits 19.9 to 21.3). The overall age-standardised relative risk of an adverse drug reaction in females compared with males was 1.6 (1.5-1.7). This sex difference was significant in all age groups above 19 years of age, and was relatively consistent across all age groups (x 2 test for heterogeneity= 9.2, P=0.3). The highest rate of recording in males was in the 50-59 year age group, and in females was in the 30-39 year age group. Conclusions In general practice in England, suspected adverse drug reactions to newly marketed drugs are recorded more often in adults aged between 30 and 59 years of age and are 60% more common in women than in men. The sex difference occurs in all age groups over 19 years of age.

Summary:Purpose: To examine the safety of lamotrigine (LTG) used in general practice to treat epilepsy.Methods: Information was collected on 11,316 patients who were included in a noninterventional observational cohort study conducted by means of Prescription-Event Monitoring (PEM). A follow-up study provided information on the first 3,994 patients who had taken LTG for 3 6 months. Incidence density (ID) measurements were used to rank the frequency of the reported events.Results: Rash was the most frequently reported nonepileptiform event (ID, 19.7/1,000 patient-months) in the first month of treatment and resulted in LTG being stopped in 2% of the 11,316 patients. Rash was reported more frequently among children aged 2-12 years (ID, 29.4/1,000 patient-months) than adults. Other events associated with the use of LTG included headache, drowsiness, nausea, vomiting, malaise, and lassitude.Rare serious events possibly associated with LTG included 12 cases reported as Stevens-Johnson syndrome, four cases of neutropenia, three cases of thrombocytopenia, and two cases of disseminated intravascular coagulation. There were also individual cases of leucopenia, a meningitic reaction, acute renal failure, hepatotoxicity, and a "lupus-like'' reaction possibly associated with the drug. No foetal abnormalities were specifically associated with the use of the drug in pregnancy. No death was attributed to LTG.Conclusions: Patients had severe epilepsy, inadequately controlled by other antiepileptic agents. The results of these two studies suggest that LTG is acceptably safe when used for the treatment of refractory epilepsy. Key Words: LamotrigineEpilepsy-Drug safety-Prescription-Event MonitoringRash.Lamotrigine (LTG) is a relatively new antiepileptic agent (AED) initially licensed as add-on therapy for seizures inadequately controlled by other drugs. LTG is therefore usually prescribed for patients with chronic, severe epilepsy, already being treated by other agents. The safety of LTG in these patients is of importance to both neurologists and general practitioners (GPs).A study was conducted by Prescription-Event Monitoring (PEM) to establish the safety of LTG. PEM identified events over an observation period of -6 months. As LTG is routinely intended for long-term use, a follow-up study was carried out to identify long-latency events in those patients who took the drug for >6 months.We report the results of the PEM study and the follow-up study.

Aims To estimate the rates of common adverse events in patients treated with the proton pump inhibitors omeprazole, lansoprazole and pantoprazole in general practice in England. Methods In prescription‐event monitoring cohort studies, data on dispensed prescriptions prescribed by general practitioners in England soon after each drug was launched were linked to subsequent clinical events recorded by the prescriber. 16 205 patients prescribed omeprazole between June 1989 and June 1990, 17 329 patients prescribed lansoprazole between May and November 1994, and 11 541 patients prescribed pantoprazole between December 1996 and June 1997 were studied. Results The commonest adverse events in the omeprazole, lansoprazole and pantoprazole cohorts were diarrhoea (incidence: 0.18, 0.39 and 0.23 per 1000 days of exposure, respectively); nausea/vomiting (incidence: 0.16, 0.22 and 0.18 per 1000 days of exposure, respectively); abdominal pain (incidence: 0.17, 0.21 and 0.17 per 1000 days of exposure, respectively); and headache (incidence rates: 0.10, 0.17 and 0.15 per 1000 days of exposure, respectively). The remaining adverse events occurred at rates of less than 0.11 per 1000 days of exposure. There were little absolute differences in the rates of most events between the three proton pump inhibitors. However, diarrhoea was more commonly associated with lansoprazole compared with omeprazole (rate difference: 0.21 per 1000 days of exposure; 95% CI 0.17, 0.25; rate ratio: 2.11; 1.78, 2.51), and there was a clear age‐response relationship. Conclusions Adverse events occurred relatively infrequently in all three cohorts. There were only small absolute differences in event rates between the three drugs, although these data suggest the hypothesis that lansoprazole is associated with more frequent occurrence of diarrhoea, particularly in the elderly.

Olanzapine is an 'atypical' antipsychotic indicated for the treatment of schizophrenia. We analysed adverse events (AEs) reported in primary practice in England. Dispensed prescriptions issued between December 1996 and May 1998 provided exposure data. Questionnaires sent to general practitioners provided outcomes. Frequently reported AEs were: drowsiness/sedation (n = 19), extrapyramidal disorder (n = 13) and unspecified side-effects (n = 33). Events with highest incidence density in first month and reason for stopping were: drowsiness/sedation [n = 153, incidence density (ID)1 18.9], weight gain (n = 117, ID1 8.9) and malaise/lassitude (n = 65, ID1 5.2). Extrapyramidal disorders were more common in elderly population (> 70 years, ID1 3.6, risk 26.0 per 1,000 patients) compared to < 70 years (ID1 1.1, risk 8.4 per 1,000 patients). Serious suspected adverse reactions were neuroleptic malignant syndrome (n = 1) and angioneurotic ooedema (n = 2). There were eight reports of diabetes mellitus assessed as possibly due to olanzapine. Diabetes mellitus was an unlabelled AE and possible signal generated by prescription-event monitoring.

Background-The long term safety of agonists, particularly in patients with heart disease, has not been fully established. Rates and relative risks of non-fatal cardiac failure and ischaemic heart disease were calculated, comparing bambuterol and salmeterol with the reference drug nedocromil. Results-The age and sex adjusted relative risk of non-fatal cardiac failure associated with bambuterol was 3.41 (95% confidence limits (CL) 1.99 to 5.86) when compared with nedocromil. When salmeterol was compared with nedocromil the adjusted relative risk of non-fatal cardiac failure was 1.10 (95% CL 0.63 to 1.91). The adjusted relative risk of non-fatal ischaemic heart disease was 1.23 (95% CL 0.73 to 2.08) and 1.07 (95% CL 0.69 to 1.66) for bambuterol and salmeterol, compared with nedocromil, respectively. However, in the first month of exposure the adjusted relative risk of non-fatal ischaemic heart disease was 3.95 (95% CL 1.38 to 11.31) when bambuterol was compared with nedocromil. Conclusions-Caution should be exercised when prescribing long acting oral agonists to patients at risk of cardiac failure. More definitive evidence would come from prospective randomised trials. (Thorax 1998;53:558-562) Methods-This

Objective To examine the safety of finasteride as used in general medical practice to treat benign prostatic hypertrophy (BPH). Patients and methods Information was collected on 14 772 patients who were included in an observational cohort study conducted using Prescription‐Event Monitoring. Results Finasteride was reported to have been effective in 60% of the patients in whom an opinion on efficacy was recorded. Impotence or ejaculatory failure was reported in 2.1% of the patients, decreased libido in 1% and gynaecomastia and related conditions in 0.4%. Impotence was the most frequent reason for stopping treatment with finasteride and was the most commonly reported adverse reaction to the drug. Of the patients included in the elderly cohort involved in this study, 819 (5.5%) died; none of these deaths was attributed to finasteride. Conclusion Impotence or ejaculatory failure, decreased libido and gynaecomastia in a small proportion of patients were associated with the use of finasteride. The results of this study strongly suggest that this drug is acceptably safe when used in accordance with the current prescribing information.

SUMMARYObjective Ð To compare the safety and side-eect pro®les of the four selective serotonin reuptake inhibitor antidepressants (SSRIs),¯uvoxamine,¯uoxetine, sertraline and paroxetine.Methods Ð The results from four observational cohort studies of the four SSRIs were compared. Each of these studies was conducted by Prescription-Event Monitoring (PEM). The exposure data were derived from general practitioner (GP) prescriptions con®dentially supplied by the Prescription Pricing Authority (PPA) in England. Outcome data were obtained from questionnaires (green forms) on which the prescribing doctor recorded event data. The main ®ndings comprised demographic information, including patients' date of birth and sex; the indication for prescribing the monitored drug; the eectiveness of the drug as perceived by the GP; the reasons for stopping treatment and all events recorded during and after treatment.Results Ð The ®nal cohort for each of the four SSRIs exceeded 10,000 patients. The sex, age distributions and indications for prescribing the four SSRIs were very similar. Only 36% of the GPs expressing an opinion reported¯uvoxamine as eective, compared with approximately 60% for uoxetine, sertraline and paroxetine. Fluvoxamine was associated with a higher incidence of adverse events than the other three SSRIs. Nausea/vomiting was both the most frequent clinical reason for stopping all four SSRIs and the most frequently reported clinical event. Adverse events reported in patients aged 70 years and over were comparable with the events reported for the total cohorts. Dierences were identi®ed between the four SSRIs for less frequently reported adverse events. Withdrawal symptoms were signi®cantly more frequent with paroxetine than the other three SSRIs.Conclusions Ð The data from the four studies were comparable in terms of age distribution, sex of patients and indication for prescribing the drugs. Fluvoxamine had a considerably higher incidence of side-eects associated with its use than the other three SSRIs. The side-eect pro®les of the four SSRIs were comparable for frequently reported events. Important dierences were identi®ed between the four SSRIs in respect of less frequently reported events. This study suggests that¯uvoxamine compares unfavourably with¯uoxetine, sertraline and paroxetine, both in terms of reported eectiveness and the incidence of adverse events. Biases possibly aecting the comparisons involved in this study are unlikely to account for the observed dierences between¯uvoxamine and the other three SSRIs. #

Risperidone is a relatively new antipsychotic agent licensed for the treatment of schizophrenia and other psychotic conditions in patients aged 15 years or older. This study examines the safety of risperidone used in general practice. Information was collected for 7684 patients included in a non-interventional observational cohort study conducted by means of Prescription-Event Monitoring. Incidence rates were calculated to rank the frequency of reported events. Drowsiness/sedation was the most frequent reason for stopping risperidone and the most frequently reported event. Extrapyramidal symptoms were reported rarely, but were more frequent in the elderly. 98 (1 . 3 per cent) patients were aged less than 15 years. Eight overdoses of risperidone alone were reported with no serious clinical sequelae. Risperidone appears to be well tolerated. #