Prescription-event Monitoring Study Research Articles

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

Raloxifene, a selective estrogen receptor modulator (SERM) licensed for the prevention of non-traumatic vertebral fractures in postmenopausal women at increased risk of osteoporosis, was launched in the UK in August 1998. The aim of the study was to monitor the safety of raloxifene prescribed in the primary care setting in England using prescription-event monitoring (PEM). Patients were identified by means of prescription data supplied by the Prescription Pricing Authority between September 1998 and November 2000. Demographic and clinical event data were collected from questionnaires posted to primary care physicians (GPs) at least 6 months after the date of the first prescription for each patient. Information on medical events, suspected adverse drug reactions (ADRs), reasons for stopping treatment, pregnancies, and causes of death was requested. Event rates [Incidence Densities (IDs): no. first reports /1000 patient-months of treatment] were calculated. Differences between IDs for events reported in month one (ID(1)) and months 2-6 (ID(2-6)) of treatment were examined. The cohort comprised 13,987 patients [median age 62 years (IQR 55,69); 99.8% female]. The major indication was osteoporosis (40.9%, n=5725). Flushing was the event with the highest ID in month 1 (22.8), reported most frequently by GPs as an ADR to raloxifene (67/461 reports) and as the reason for stopping (700/4592 reports). Events associated with starting treatment included flushing, malaise/lassitude, headache/migraine, nausea/vomiting, sweating, cramp, pain abdomen, dizziness, diarrhea, mastalgia and vaginal hemorrhage. Less common events reported during treatment included deep vein thrombosis (n=13), pulmonary embolism (n=13), thrombophlebitis (n=31) and visual disturbance (n=29). In this study, there were 122 (0.9%) confirmed deaths, of which 32 causes of death were unknown. This study shows that raloxifene is generally well tolerated when used in general practice in England. Potential signals of unrecognised ADRs requiring further evaluation included gastrointestinal adverse symptoms and vaginal hemorrhage. There were also a small number of reports of events associated with venous thromboembolism and visual disorders that require further investigation.

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

A post-marketing surveillance study using the technique of Prescription Event Monitoring was undertaken to monitor the safety of celecoxib, a cyclo-oxygenase (COX)-2 inhibitor, as prescribed in primary care in England. Patients were identified from dispensed British National Health Service prescription data supplied in confidence by the Prescription Pricing Authority for celecoxib between May and December 2000. Simple questionnaires were sent to the prescribing general practitioner at least 6 months after the date of the first dispensed prescription for each individual patient. Event incidence densities (IDs) [the number of 1st reports per 1000 patient-months of exposure (pme)] were calculated. ID differences for events reported in month 1 (ID1) and months 2-6 (ID2) were examined for temporal changes in event rate. Information on suspected adverse drug reactions (ADRs), reasons for stopping treatment, outcome of pregnancies and cause of death were also requested. Data were gathered on potential gastrointestinal (GI) risk factors [recent use of other non-steroidal anti-inflammatory drugs (NSAIDs), past history of upper GI disorders and concomitant gastro-irritant agents or anti-ulcer drugs]. Crude IDs per 1000 pme and ID ratios were calculated according to potential risk factors, and age (> or = 65 years, < or = 64 years). The cohort comprised of 17,458 patients [median age 62 years (IQR 51,73); 68.3% female]. The most common specified indication was osteoarthritis (28.1%, n = 4905). Not effective was the event with the highest ID1 (139.9 per 1000 pme). The clinical events with the highest ID1 were dyspepsia (25.4 per 1000 pme) followed by abdominal pain (10.6). These were also given frequently as reasons for stopping (551 and 174 of 9126 reports). Of 436 events in 325 patients (1.9% of total cohort) that were reported as ADRs, the most frequent were events within the alimentary system (186 reports). Uncommon events reported during treatment (not necessarily as ADRs) included allergy (0.10%, n = 17), anaphylaxis (0.01%, n = 2), angioneurotic oedema (0.02%, n = 3) and bronchospasm (0.05%, n = 9). There were 103 reports of events associated with thromboembolism and 111 reports of serious GI events [90 GI bleeds (upper and lower); 21 peptic ulcers] received during treatment or within 1 month of stopping. A past history of dyspeptic/other upper GI conditions and use of concomitant gastro-protective drugs were each associated with a significantly increased risk of dyspepsia and abdominal pain. Frequently reported adverse events were those GI events commonly associated with treatment with other NSAIDS. Stratification by identified risk factors suggested that channelling of high-risk patients is likely. Serious upper and lower GI events, and thromboembolic events did occur during this study, although the incidence was low (< 1%). Doctors should continue to prescribe NSAIDs, including COX-2-specific inhibitors, with caution.

Linking Pharmacovigilance with Pharmacogenetics

The ability to identify individuals who are susceptible to adverse drug reactions (ADRs) has the potential to reduce the personal and population costs of drug-related morbidity. Some individuals may show an increased susceptibility to certain ADRs through genetic polymorphisms that alter their responses to various drugs. We wished to establish a methodology that would be acceptable to members of the general population and that would enable estimation of the risks that specific genetic factors confer on susceptibility to specific ADRs. Buccal swabs were selected as a minimally invasive method to obtain cells for DNA extraction. We wished to determine whether DNA of sufficient quantity and quality could be obtained to enable genotyping for two different polymorphic genes that code for enzymes that are widely involved in drug disposition. This article describes a small pilot study of methodology developed in the New Zealand Intensive Medicines Monitoring Programme (IMMP) to link prescription event monitoring (PEM) studies with pharmacogenetics. The methodology involves a nested case-control study design to investigate whether patients with genetic variants in P-glycoprotein (P-gp) and cytochrome P450 (CYP) 2C9 are more susceptible to psychiatric or visual disturbances following cyclo- oxygenase-2 inhibitor use (ADR signals identified in the IMMP database) than matched control patients taking the medication without experiencing any ADRs. It was concluded that the use of buccal swabs is acceptable to patients and provides DNA of sufficient quantity and quality for genotyping. Although no differences in the distribution of genotypes in the case and control populations were found in this small study, case-control studies investigating genetic risks for ADRs using drug cohorts from PEM studies are possible, and there are several areas where population-based studies of genetic risk factors for ADRs are needed. Examples are discussed where research in large populations is required urgently. These are: (i) genetic variations affecting P-gp function; (ii) variations affecting drugs metabolised by CYP2C9 and other polymorphic CYP enzymes; (iii) genetic variation in beta-adrenergic receptors and adverse outcomes from beta-adrenoceptor agonist therapy; and (iv) genetic variation in cardiac cell membrane potassium channels and their association with long QT syndromes and serious cardiac dysrhythmias. Such studies will help to identify factors that increase the risk of unwanted outcomes from drug therapy. They will also help to establish in what circumstances genotyping should be performed prior to commencing drug treatment and in tailoring drug treatment for individual patients.

Biases affecting the proportional reporting ratio (PRR) in spontaneous reports pharmacovigilance databases: the example of sertindole

Automated measures of reporting disproportionality in databases of spontaneous reports of adverse drug reactions are an emerging tool to identify drug-related alerts. Sertindole, a new atypical neuroleptic known to prolong the QT interval, was suspended in November 1998 because the proportion of reports of fatal reactions suggesting arrhythmia among all reports with sertindole was almost ten times higher than that for other atypical neuroleptics in the UK. This excess risk was not predicted in preclinical data and had not been found in premarketing trials. Reporting patterns over time were analysed. Prescription Event Monitoring (PEM) studies and a large retrospective cohort allowed for the comparison of actual death rates with atypical neuroleptics, and to assess which proportion of the deaths that occurred were reported. There were indications of possible skewing of reporting related to notoriety, surveillance and market size effects. Death rates in PEM studies were essentially similar between sertindole and other neuroleptics. Cardiac deaths had been two to three times more often reported than other causes of death. Proportional reporting ratios indicate differential reporting of possible reactions, not necessarily differential occurrence. There was no indication of an actual increase of risk of all causes or cardiac deaths during sertindole treatment, but only an increased risk of its being reported. The suspension of sertindole was rescinded by Committee on Proprietary Medicinal Products (CPMP) in October 2001.

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

A postmarketing Prescription-Event Monitoring study was undertaken to monitor the safety of rofecoxib, a cyclo-oxygenase (COX)-2 selective inhibitor prescribed in primary care in England. Questionnaires requesting clinical event data were sent to prescribing physicians between February and November 2000, and the data analysed for all events. There were 15,268 patients identified, mean age 62 years, 67% female. The commonest specified indication was osteoarthritis (24%). Dyspepsia and nausea were the most frequently reported adverse events. A history of dyspeptic or upper gastrointestinal (GI) conditions, recent use of other nonsteroidal anti-inflammatory drugs (NSAIDs), use of selected concomitant gastroirritant drugs (NSAIDs, aspirin, anticoagulants, antiplatelet drugs), or gastroprotective drugs (misoprostol, antacids, proton-pump inhibitors, histamine-2 antagonists), and age (>/= 65 years) modified the risk of having minor GI events. During treatment or within 1 month of stopping, 110 serious GI events were reported (including 76 upper GI bleeds/peptic ulcers, one perforated colon), 101 thromboembolic events, three reports of acute renal failure, one each of Stevens-Johnson syndrome, severe anaphylaxis and angio-oedema. Doctors should continue to prescribe NSAIDs including COX-2 selective inhibitors with caution.

The pharmacovigilance of pantoprazole: the results of postmarketing surveillance on 11 541 patients in England.

To conduct a postmarketing surveillance study involving patients treated with pantoprazole in general practice in the 6-month period following the launch of this drug in November 1996. Prescription-event monitoring (PEM) provides data on a large cohort of patients in 'real life' settings. The aim was to monitor the safety of pantoprazole as used in general practice. It was the third proton pump inhibitor launched in the UK. Patients were identified by data from dispensed prescriptions (FP10s) written by general practitioners (GPs) in England for pantoprazole. Green forms were posted to GPs approximately 6 months following the first prescription identified. GPs were asked to list events that occurred during and after treatment. The incidence density of each event was calculated, ranked and the difference between the incidence of each event in the first and subsequent months of exposure was tested by constructing confidence intervals. Data were collected for 11 541 patients. The major indications for treatment were oesophageal reflux (22.7%) and dyspepsia (16.9%). Of GPs expressing an opinion, 81.9% reported pantoprazole to be effective. GPs reported 107 events as adverse drug reactions. The most frequent reason given for stopping was diarrhoea (106 patients), which corresponded with the adverse event with the highest incidence density. This PEM study has defined the reported safety profile of pantoprazole as used in general practice in England. The commonest adverse events found in this study have already been reported in the Summary of Product Characteristics.

Results of a postal survey of the reasons for non‐response by doctors in a Prescription Event Monitoring study of drug safety

A Prescription Event Monitoring (PEM) study was carried out by the Drug Safety Research Unit (DSRU) to monitor the safety of irbesartan, an angiotensin II antagonist, immediately after launch in the United Kingdom in September 1997. The DSRU 'green form' questionnaire response rate was lower than expected. The manufacturer was conducting a concurrent postmarketing surveillance study. The aim of this cross-sectional study, was to identify reasons for non-response by general practitioners in England. In PEM, questionnaires are posted to the prescribing general practitioner approximately 6 months after the date of the first prescription for each patient, requesting details of clinical events recorded in the patients' notes since starting treatment. Those that failed to respond were sent a second questionnaire, including tick box questions to elucidate reasons for non-response. A total of 21.3% (3088/14502) second send forms were returned. There were 1747 tick box responses. The most common reason specified for non-response was 'I was too busy' (31.2%) followed by 'no payment included' (13.4%). Participation in another study accounted for only 3.4%. The concurrent postmarketing surveillance study was not a significant factor. The general practitioner's workload appeared to have a far larger impact. While research remains a non-core activity and receives no payment, participation is likely to fall. Researchers need to find means of benefiting the general practitioner if participation is to continue.

Efficacy and Tolerability of Meloxicam, a COX-2 Preferential Nonsteroidal Anti-Inflammatory Drug

Meloxicam is an enolcarboxamide with preferential COX-2 inhibitory activity. In vitro studies with human tissues have confirmed the high affinity of meloxicam for COX-2, whereas COX-1 was inhibited only at the highest concentrations (ratio of 50% inhibitory concentration for COX-2: COX-1 = 0.09 in whole blood assays). Meloxicam has a bioavailability of 89% after oral administration, is strongly bound to plasma proteins, and its half-life is 20–24 hours. It readily penetrates into synovial fluid, reaching 45–57% of plasma concentrations. Meloxicam pharmacokinetics are not significantly altered in elderly patients or in those with mild renal/hepatic impairment. The efficacy and tolerability of meloxicam in the treatment of pain and inflammation associated with rheumatic and musculoskeletal disorders has been evaluated in numerous studies comparing meloxicam 7.5–15 mg/day (up to 22.5 mg/day in ankylosing spondylitis), administered for 2 weeks to 12 months, with placebo or other nonsteroidal anti-inflammatory drugs (NSAIDs). Overall, the efficacy of meloxicam was significantly superior to that of placebo and similar to that of other NSAIDs, whereas the incidence of adverse events (especially gastrointestinal) was lower than with other NSAIDs. Intramuscular meloxicam provided faster pain relief than the oral drug in patients with rheumatoid arthritis. Meloxicam also appears to be effective in the prevention of postoperative pain, as shown in patients undergoing abdominal hysterectomy or inguinal hernia repair. Meloxicam may also have a cardioprotective role: in patients with acute coronary syndrome without ST-segment elevation, a lower incidence of cardiovascular events was observed in those who received meloxicam plus aspirin and heparin versus aspirin and heparin alone, both during coronary care stay and at 90-day follow-up. Meloxicam has demonstrated a favourable tolerability profile in large-scale comparative trials, where its gastrointestinal tolerability was superior to that of nonselective NSAIDs. In particular, meloxicam 7.5 mg/day was associated with a lower incidence of gastrointestinal adverse events compared with diclofenac (13% vs 19%; p < 0.001) or piroxicam (10.3% vs 15.4%; p < 0.001). This was confirmed by a prescription-event monitoring study that found a relatively low incidence of dyspepsia, upper gastrointestinal haemorrhage and peptic ulcer (28.3, 0.4 and 0.3 per 1000 patient-months, respectively) among first-time users of meloxicam. In conclusion, meloxicam is at least as effective as nonselective NSAIDs in the treatment of rheumatic disease or postoperative pain, but has a more favourable gastrointestinal tolerability profile. Further investigations into the potential role of meloxicam as a cardioprotective agent are warranted.

Automated signal generation in prescription-event monitoring.

Signal generation is a method of highlighting potential safety issues in a drug that then need to be investigated further. Previously automated signal generation has mainly been applied to spontaneous reporting systems. The Drug Safety Research Unit (DSRU) performs observational postmarketing studies on selected newly marketed medicines in England using a method known as prescription-event monitoring (PEM). The DSRU has investigated automated procedures for the generation of signals using the event data from PEM studies. Proportional reporting ratios (PRRs) and incidence rate ratios (IRRs) were studied as possible tools for signal generation in PEM data. The PEM database contains 78 completed studies of drugs prescribed in primary care from a variety of therapeutic classes. Retrospective studies were carried out to identify the implications of changing the comparator group of drugs, along with analysing the results at different levels in the DSRU's hierarchical dictionary and performing signal generation after 30 and 180 days of observation since starting the drug. Automated signal generation is a useful hypothesis generating method that is likely to prove to be useful both in clinical trials and postmarketing studies. PRRs are simple to apply and do not require a denominator. IRRs take into account the time subjects were exposed to the drug prior to the event of interest, and offers a useful, and more in depth look into the data. However, with both methods it is important to perform signal generation at multiple levels in the dictionary and with careful selection of the comparator group.

Montelukast and improvement of eczema: observations from a prescription event monitoring study in England

Montelukast is an orally administered cysteinyl receptor antagonist, approved for the treatment of asthma. There is pharmacological plausibility of its effectiveness in the treatment of other immunologically mediated conditions such as eczema and urticaria. The objective of this study was to determine whether there are any beneficial effects of montelukast on eczema and urticaria. A non-interventional observational cohort study was conducted between February 1998 and December 1998 using Prescription-Event Monitoring (PEM). During PEM studies, patients are systematically identified from dispensed prescription data and questionnaires are sent to the prescribing general practitioner (GP) asking them to report events occurring during and after treatment. In this study, events reported as eczema or urticaria improved were identified. A simple questionnaire was sent to the GPs for additional information. The cohort comprised 15,612 patients, in which 16 reports of eczema or urticaria improved were identified. Questionnaires were sent to the GPs for additional information. Fifteen of the 16 questionnaires were returned. In 5 cases the GPs thought that there was an improvement of eczema or urticaria with montelukast treatment in patients who had history of longstanding eczema or urticaria. Of the remaining 11 cases there was an alternative explanation for the improvement of eczema or urticaria in 10 cases and one was unassessable. PEM is conducted to monitor the safety of medicines, and doctors report events including improvement in pre-existing conditions. Although the number of cases of improvement of eczema or urticaria in this cohort is small, there is a possibility that leukotriene inhibitors may be helpful in the treatment of these diseases. Further studies are needed to provide evidence as to whether montelukast will have a role in the treatment of these conditions.

Sildenafil prescription-event monitoring study. No evidence of an increase in cardiovascular outcomes among 5,000 men prescribed sildenafil in general practice in England Saad A. W. Shakir, Lynda V. Wilton, Emma Heeley, Deborah Layton. Drug Safety Research Unit, Southampton, United Kingdom

Sildenafil prescription-event monitoring study. No evidence of an increase in cardiovascular outcomes among 5,000 men prescribed sildenafil in general practice in England Saad A. W. Shakir, Lynda V. Wilton, Emma Heeley, Deborah Layton. Drug Safety Research Unit, Southampton, United Kingdom

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...

How Sedating Are Non-Sedating Antihistamines?

These investigators analyzed the outcomes of 4 prescription-event monitoring studies from the UK to determine the sedating effects of the second-generation antihistamines loratadine, cetirazine, fexofenadine, and acrivastine. In this type study design, a pharmacist sends a copy of each antihistamine prescription to a central government …

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

A PEM study of nicorandil (Ikorel) was undertaken to assess the drug's overall safety in everyday clinical practice. 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. 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). 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.

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. Copyright © 1999 John Wiley & Sons, Ltd.

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

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. 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. 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). 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.

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.

Prescription-event monitoring--recent progress and future horizons.

Post-marketing surveillance (PMS) is essential because the safety database on newly licensed drugs is limited by both the number and characteristics of the patients involved. In the UK, for example, successful applications for product licences for medicines containing new active substances include, as a safety database, information on a median number of 1480 (range 129–9400) patients [1]. Most of these patients will have been carefully chosen to have only one disease being treated with one drug. Few, if any of them, will be typical of the patients likely to receive the drug once it has been marketed. The identification of uncommon, even if serious or lethal, adverse reactions from such a small number of highly selected patients is unlikely. This led the Committee on Safety of Drugs (the forerunner of today's Committee on Safety of Medicines) to conclude that ‘It is well recognised that no drug which is pharmacologically effective is without hazard. Furthermore not all hazards can be known before a drug is marketed: neither tests in animals nor clinical trials in patients will always reveal all the possible side effects of a drug. These may only be known when the drug has been administered to large numbers of patients over considerable periods of time’. The Committee on Safety of Drugs Annual Report [2] which contained these remarkable conclusions was for 1969/1970. Thus, for almost 30 years it has been recognised that drug safety in clinical practice cannot depend solely upon pre-marketing data. The backbone of the post-marketing techniques that have been developed to survey the use of newly marketed drugs in large populations is provided by the hypothesis-generating methods, including spontaneous adverse drug reaction (ADR) reporting and prescription-event monitoring (PEM). The findings of such studies can be confirmed or refuted by hypothesis-testing techniques, such as case-control or cohort studies or randomised controlled clinical trials. Computerised clinical data are currently available from completed PEM studies of 58 newly marketed medicines and, as shown in Table 1, these studies have an average cohort size of 10 624 (median 11 081; range 1371–17 329) patients. Thus, PEM frequently enlarges the available safety database on newly marketed medicines. It also provides information on the ‘real-world’ use of these medicines: the data show the age, sex and geographical distribution that typifies the everyday clinical use of these drugs in general medical practice. Table 1 Details of 58 complete PEM studies. This paper briefly reviews the methodology of PEM and the current and planned activities that relate to this technique.

Is the incidence of upper respiratory tract infection independent of drug treatment in large cohort studies of longer term use drugs?

In observational cohort studies which monitor drug safety, the patterns of reported events are likely to be influenced by a number of factors. We hypothesized that the distribution of events which are unlikely to be adverse events associated with drug use, differ from that for events which may be adverse drug reactions. In 39 individual Prescription-Event Monitoring (PEM) studies, the incidence rates for upper respiratory tract infections (URTI) and back pain, in the first month of treatment and in the subsequent 5 months, were compared to those for nausea/vomiting and malaise/lassitude. For URTI and back pain there was no statistically significant difference in the event rates between these time periods. This pattern may be characteristic of events which are independent of the disease being treated and are unlikely to be adverse events associated with drug use. However, for nausea/vomiting and malaise/lassitude, which can be adverse events associated with drug treatments, the event rates in the first month of treatment were significantly greater than in subsequent months. These observations confirm that doctors are reporting events irrespective of whether or not they suspect the event to be an adverse event associated with the drug. This provides a simple validation of the PEM methodology.