Drug Utilisation Patterns in Children Admitted to a Paediatric General Medical Ward in Five Countries.

OBJECTIVE: To investigate and compare drug prescription patterns in children admitted to a paediatric general medical ward in five countries. METHODS: A prospective cohort study conducted on paediatric medical wards in the UK, Germany, Australia, Hong Kong (HK) and Malaysia. Data were collected over 3 months in each country except in Australia (1 month). All medications prescribed were classified according to the WHO Anatomical Therapeutic Chemical (ATC) classification. For each drug, frequency of prescriptions and patient exposures were calculated for ATC anatomical and therapeutic levels overall and by country. RESULTS: One thousand two hundred and seventy-eight patients were included (Australia 146, Germany 376, UK 313, HK 143 and Malaysia 300); 89.2 % of patients (1140) received medications, median 3 (interquartile range 2-5) drugs per patient. 5367 drugs were prescribed. The most frequently prescribed therapeutic groups in all countries were: systemic antibacterials (1355; 25.2 %), analgesics/non-steroidal anti-inflammatory drugs (NSAIDs) (1173; 21.8 %) and drugs for obstructive airway diseases (472; 8.8 %). Overall, 65.1 % (742) of patients received at least one systemic antibacterial, 63.7 % (726) received one or more analgesic/NSAIDs, and 23.6 % (269) received 'drugs for obstructive airway diseases'. The number of patients exposed to these groups differed significantly between countries (p < 0.05). Paracetamol was the most frequently prescribed in all countries, but metamizole was only used in Germany. Morphine was mainly prescribed in the UK. CONCLUSION: This study provides an overview of drug use patterns in five culturally and ethnically diverse countries. The most frequently used therapeutic groups were similar, but the proportion of patients treated differed between countries. Also within a therapeutic group the specific drug used varied between countries.

Trends and patterns of hormonal contraceptive prescribing for adolescents in primary care in the U.K.

BACKGROUND: Hormonal contraceptives are the most common method used worldwide by teenagers to prevent unwanted pregnancies. To date there are limited data about such use by teenagers in the UK. This study investigated trends and patterns of hormonal contraceptive prescribing to adolescents aged 12-18 years in UK primary care between 2002 and 2011. METHODS: A retrospective cohort study using the IMS Disease Analyzer database was conducted. All females aged 12-18 years with ≥1 prescription for a contraceptive drug between 1 January 2002 and 31 December 2011 were included. Annual prevalence of contraceptive drug prescribing was calculated, and indications for prescribing, and types of contraceptive drug prescribed, were examined. RESULTS: In 2002, 13.7% (6135/44 532) of female adolescents received prescriptions for hormonal contraceptives, compared to 19.0% (6597/34 676) in 2011. The majority of female adolescents [2002: 76.2% (4676/6135); 2011: 65.7% (4334/6597)] received a contraceptive drug for 'contraceptive management'. The combined oral contraceptive (COC), 'progestogen+estrogen', was the most commonly prescribed. Although use of progestogen-only contraceptives was lower than COCs, the number of patients who received desogestrel pills and etonogestrel implants increased during the study period; levonorgestrel pill use declined. Only one injectable progestogen, long-acting depot medroxyprogesterone acetate, was prescribed. CONCLUSIONS: Use of hormonal contraceptives among adolescents increased between 2002 and 2011, and COC usage was dominant. The increasing use of hormonal contraceptives in adolescents, especially in younger adolescents, warrants further investigation, including research into the long-term safety of these medicines in this age group.

Epidemiology and potential risk factors of drug-related problems in Hong Kong paediatric wards.

AIMS: A drug-related problem (DRP) is 'an event or circumstance involving drug therapy that actually or potentially interferes with the desired health outcome'. The extent and characteristics of DRPs in children in Hong Kong are unknown. The aim of this study was to determine the epidemiology of and identify riskf actors for DRPs in hospitalized children in Hong Kong. METHODS: This was a prospective cohort study in children aged 0­18 years who were admitted to a medical ward, paediatric intensive care unit or neonatal intensive care unit of seven Hong Kong hospitals, during a 3 month period. Patients' charts, medical records and laboratory data were reviewed daily to identify DRPs; their preventability and severity were assessed. Logistic regression was used to analyse potential risk factors associated with the incidence of DRPs. RESULTS: Three hundred and twenty-nine children (median age, 2 years; interquartile range, 0 months to 9 years) were included. In total, 82 DRPs were experienced by 69 patients. The overall incidence of DRPs was 21.0% (95% confidence interval, 16.7­25.8%). The incidence was higher in neonatal and paediatric intensive care units than medical wards. Dosing problems were the most frequently reported DRPs (n = 35; 42.7%), followed by drug choice problems (n = 19; 23.2%) and adverse drug reactions (n = 11; 13.4%). Sixty-seven (81.7%) DRP cases were assessed as preventable, 42 (51.2%) as minor and 40 (48.8%) as moderate. The number of prescribed drugs and 'certain infectious and parasitic diseases' were potential risk factors for occurrence of DRPs. CONCLUSIONS: Drug-related problems were common in hospitalized children in this study in Hong Kong; the most frequent were dosing and drug choice problems, and the majority of them were preventable. Polypharmacy and 'certain infectious and parasitic diseases' were potential risk factors.

Drug-related problems found in children attending an emergency department in Saudi Arabia and in the United Kingdom.

BACKGROUND: No published studies investigating drug-related problems (DRPs) in children visiting emergency department (ED) in either the Kingdom of Saudi Arabia (KSA) or the United Kingdom (UK) were identified. OBJECTIVE: To determine the frequency and characteristics of DRPs in paediatric patients attending ED in the KSA and the UK. METHOD: An observational study. DRPs were identified by a researcher, reviewing the medical records of children attending the ED during a three-month period in KSA and a 1 month period in UK; severity and preventability of the DRPs were assessed. Incidence of DRPs overall and in each country was calculated. RESULTS: A total of 253 patients (KSA n = 143, UK n = 110) were included. Fifty-five patients (22%; 55/253), experienced 69 DRPs. 2% (5/253) of the patients attended the ED due to DRPs. Overall incidence was 21.7% (95% CI, 16.8-27.3). 78% (54/69) of the DRPs were assessed as preventable; 33% (23/69) as of moderate severity. CONCLUSION: DRPs were common in paediatric patients attending EDs; the majority were preventable. Further study is needed to investigate the impact of mild and moderate DRPs on paediatric patients' health and also to improve the care provided to minimise the occurrence of preventable DRPs.

Safety profile of modafinil across a range of prescribing indications, including off-label use, in a primary care setting in England: results of a modified prescription-event monitoring study.

BACKGROUND: Modafinil (Provigil) was marketed in the UK in 1998 to promote wakefulness in the treatment of narcolepsy. In April 2004, the licence was extended to include chronic pathological conditions; 2 years later, the prescription of modafinil was restricted to patients with shift work sleep disorder, narcolepsy and obstructive sleep apnoea/hypopnoea syndrome. Following a recent review of the safety data, the licence has been further restricted to only treat patients with narcolepsy. The review highlighted the degree of off-label usage of modafinil, including patients with multiple sclerosis. OBJECTIVE: The aim of this study was to examine the safety profile of modafinil in real-world clinical usage and across a range of prescribing indications, including multiple sclerosis. METHODS: The study was conducted using the observational cohort technique of Modified Prescription-Event Monitoring. Patients were identified from dispensed prescriptions issued by primary care physicians from July 2004 to August 2005. Patient demographics and information on prescribing behaviour were included in the questionnaire sent to the prescribing general practitioner (GP) 6 months after the initial prescription for each patient. The questionnaire sought data on any events that patient may have experienced during that time, reasons for stopping treatment with modafinil, adverse drug reactions (ADRs), potential interaction with contraceptives, and pregnancies. Incidence densities (IDs) were calculated for all events, and stratified according to indication and dose. Specific events were evaluated by requesting further information. RESULTS: Of the 4,023 questionnaires sent to GPs, 2,416 were returned (response rate 60.1 %). Of these, only those patients issued modafinil after April 2004 (with the associated broadening of the indications for treatment) were included in the study, resulting in a final cohort of 1,096 patients: 497 (45.3 %) male, median age of 52 years (interquartile range [IQR] 41-63), and 599 (54.7 %) female, median age of 47 years (IQR 38-57). Nine patients were aged 16 years or younger; no serious skin reactions were reported in this group. Thirty-four percent of the cohort had an indication of multiple sclerosis. In this study, the majority of the clinical events that were most frequently reported as ADRs or reasons for stopping or that occurred in month 1 have been previously documented with modafinil. The results of the study show that less than half of the women of child-bearing potential were established on a recommended contraceptive programme; three women became pregnant whilst taking modafinil and the oral contraceptive pill. Stratification of IDs by dose revealed certain additional events occurred during month 1 of treatment at the higher dose only. Assessment of individual cases of cardiac, psychiatric and skin events indicated causal associations with modafinil. CONCLUSIONS: This study provides important additional safety data on the use of modafinil in patients in 'real-world' use, including those for whom the prescribing indication is outside the terms of licence, as per recent changes to the licensed indications for treatment. In addition to safety data, our study provides useful utilization data. Results from this study indicate that a significant number of women of child-bearing potential had not been commenced on appropriate contraceptive programmes prior to starting modafinil. There were three pregnancies that occurred whilst taking contraception, highlighting the necessity of ensuring effective contraceptive cover for women during and after stopping treatment with modafinil. Analysis of the data showed that the majority of events reported as ADRs or reasons for stopping and ranked events during the first month of treatment had been previously documented with the use of modafinil. Stratification of events according to dose revealed a number of events that occurred at the higher dose only, including serious events such as psychosis. The targeted events for which causality assessments were undertaken confirmed the potential of modafinil to induce certain types of events in individual patients, including cardiac and psychiatric events.

Management of adult attention deficit hyperactivity disorder in UK primary care: a survey of general practitioners.

BACKGROUND: Compared to existing literature on childhood attention deficit hyperactivity disorder (ADHD), little published adult data are available, particularly outside of the United States. Using General Practitioner (GP) questionnaires from the United Kingdom, this study aimed to examine a number of issues related to ADHD in adults, across three cohorts of patients, adults who received ADHD drug treatment in childhood/adolescence but stopped prior to adulthood; adults who received ADHD drug treatment in childhood/adolescence and continued treatment into adulthood and adults who started ADHD drug treatment in adulthood. METHODS: Patients with a diagnosis of ADHD and prescribed methylphenidate, dexamfetamine or atomoxetine were identified using data from The Health Improvement Network (THIN). Dates when these drugs started and stopped were used to classify patients into the three cohorts. From each cohort, 50 patients were randomly selected and questionnaires were sent via THIN to their GPs.GPs returned completed questionnaires to THIN who forwarded anonymised copies to the researchers. Datasets were analysed using descriptive statistics. RESULTS: Overall response rate was 89% (133/150). GPs stated that in 19 cases, the patient did not meet the criteria of that group; the number of valid questionnaires returned was 114 (76%). The following broad trends were observed: 1) GPs were not aware of the reason for treatment cessation in 43% of cases, 2) patient choice was the most common reason for discontinuation (56%), 3) 7% of patients who stopped pharmacological treatment subsequently reported experiencing ADHD symptoms, 4) 58% of patients who started pharmacological treatment for ADHD in adulthood received pharmacological treatment for other mental health conditions prior to the ADHD being diagnosed. CONCLUSION: This study presents some key findings relating to ADHD; GPs were often not aware of the reason for patients stopping ADHD treatment in childhood or adolescence. Patient choice was identified as the most common reason for treatment cessation. For patients who started pharmacological treatment in adulthood, many patients received pharmacological treatment for comorbidities before a diagnosis of ADHD was made.

Rhabdomyolysis reported for children and adolescents treated with antipsychotic medicines: a case series analysis.

OBJECTIVE: Rhabdomyolysis is a rare and potentially serious adverse drug reaction (ADR) to antipsychotic medicines. The aim of this study was to investigate the clinical circumstances surrounding the diagnosis of rhabdomyolysis in children and adolescents treated with antipsychotic medicines. We also critically reviewed individual case safety reports (ICSRs) of suspected ADRs to evaluate how clinically useful they can be in a case series analysis. METHODS: This was a descriptive and an exploratory study. Published case reports and ICSRs from the World Health Organization (WHO) Global ICSR database, VigiBase, reported with rhabdomyolysis and antipsychotic medicines for patients ≤17 years years of age were described. Reporting patterns of ICSRs with rhabdomyolysis and antipsychotic medicines were explored in VigiBase for children and adolescents and for adults. The VigiBase ICSRs were also systematically evaluated regarding the report content. RESULTS: Of the 26 evaluated reports, 6 co-reported neuroleptic malignant syndrome (NMS) and 20 reports concerned rhabdomyolysis in the absence of NMS. The reported suspected antipsychotic medicines for these 20 reports were olanzapine, risperidone, haloperidol, paliperidone, quetiapine, clozapine, cyamemazine, and aripiprazole. In VigiBase, rhabdomyolysis (in the absence of NMS) was reported more frequently with olanzapine relative to all reports for children and adolescents with antipsychotic medicines. In the range of events that preceded rhabdomyolysis, muscle pains and abdominal pain were commonly recorded to have started during the week prior to the diagnosis. Other preceding symptoms were general weakness and dark urine. Onset of rhabdomyolysis for most patients occurred at any time within 2 months of starting antipsychotic treatment, in several cases triggered by changes to the patient's drug therapy or known risk factors of rhabdomyolysis. It was found that ICSRs can contribute with additional information, but that access to free text and narratives were crucial in order to capture clinically useful features of rhabdomyolysis. CONCLUSION: Monitoring of children and adolescents needs to be intensified during dose increases, or when a new, added, or switched antipsychotic medicine is introduced to their drug regimen, and during exposure to known risk factors for rhabdomyolysis. The development of seemingly nonserious events, such as abdominal pain, muscle pain, weakness, and dark urine, should be followed up during antipsychotic use, as they might be precursory events to rhabdomyolysis that eventually could develop into acute renal failure.

Persistence of pharmacological treatment into adulthood, in UK primary care, for ADHD patients who started treatment in childhood or adolescence.

BACKGROUND: ADHD guidelines in the UK suggest that children and adults who respond to pharmacological treatment should continue for as long as remains clinically effective, subject to regular review. To what extent patients persist with treatment from childhood and adolescence into adulthood is not clear. This study aims to describe, in UK primary care, the persistence of pharmacological treatment for patients with ADHD who started treatment aged 6-17 years and to estimate the percentage of patients who continued treatment from childhood and adolescence into adulthood. METHODS: The Health Improvement Network (THIN) database was used to identify patients with ADHD who received their first prescription for methylphenidate/ dexamfetamine/atomoxetine, aged 6-17 years. Patients were monitored until their 'censored date' (the earliest of the following dates: date the last prescription coded in the database ended, end of the study period (31st December 2008), date at which they transferred out of their practice, date of death, the last date the practice contributed data to the database). Persistence of treatment into adulthood was estimated using Kaplan Meier analysis. RESULTS: 610 patients had follow-up data into adulthood. 213 patients (93.4% male) started treatment between 6-12 years; median treatment duration 5.9 years. 131 (61.5%) stopped before 18 years, 82 (38.5%) were still on treatment age ≥18 years. 397 patients (86.4% male) started treatment between 13-17 years; median treatment duration was 1.6 years. 227 (57.2%) stopped before 18 years, 170 (42.8%) were still on treatment age ≥18 years. The number of females in both age categories was too small to formally test for differences between genders in persistence of treatment. CONCLUSION: Persistence of treatment into adulthood is lower (~40%) compared with published rates of persistence of the condition (~65% when symptomatic definition of remission used). Due to the limited number of patients with data past 18 years, it is important that ongoing monitoring of prescribing into later adulthood is undertaken, particularly to observe the effects of recommendations in new guidelines.

The epidemiology of pharmacologically treated attention deficit hyperactivity disorder (ADHD) in children, adolescents and adults in UK primary care.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder characterised by the symptoms of inattention, impulsivity and hyperactivity. ADHD was once perceived as a condition of childhood only; however increasing evidence has highlighted the existence of ADHD in older adolescents and adults. Estimates for the prevalence of ADHD in adults range from 2.5-4%. Few data exist on the prescribing trends of the stimulants methylphenidate and dexamfetamine, and the non-stimulant atomoxetine in the UK. The aim of this study was to investigate the annual prevalence and incidence of pharmacologically treated ADHD in children, adolescents and adults in UK primary care. METHODS: The Health Improvement Network (THIN) database was used to identify all patients aged over 6 years with a diagnosis of ADHD/hyperkinetic disorder and a prescription for methylphenidate, dexamfetamine or atomoxetine from 2003-2008. Annual prevalence and incidence of pharmacologically treated ADHD were calculated by age category and sex. RESULTS: The source population comprised 3,529,615 patients (48.9% male). A total of 118,929 prescriptions were recorded for the 4,530 patients in the pharmacologically treated ADHD cohort during the 6-year study. Prevalence (per 1000 persons in the mid-year THIN population) increased within each age category from 2003 to 2008 [6-12 years: from 4.8 (95% CI: 4.5-5.1) to 9.2 (95% CI: 8.8-9.6); 13-17 years: from 3.6 (95% CI: 3.3-3.9) to 7.4 (95% CI: 7.0-7.8); 18-24 years: from 0.3 (95% CI: 0.2-0.3) to 1.1 (95% CI: 1.0-1.3); 25-45 years: from 0.02 (95% CI: 0.01-0.03) to 0.08 (95% CI: 0.06-0.10); >45 years: from 0.01 (95% CI: 0.00-0.01) to 0.02 (95% CI: 0.01-0.03). Whilst male patients aged 6-12 years had the highest prevalence; the relative increase in prescribing was higher amongst female patients of the same age - the increase in prevalence in females aged 6-12 years was 2.1 fold compared to an increase of 1.9 fold for their male counterparts. Prevalence of treated ADHD decreased with increasing age. Incidence (per 1000 persons at risk in the mid-year THIN population) was highest for children aged 6-12 years. CONCLUSIONS: A trend of increasing prescribing prevalence of ADHD drug treatment was observed over the period 2003-2008. Prevalence of prescribing to adult patients increased; however the numbers treated are much lower than published estimates of the prevalence of ADHD. This study has added to the limited knowledge on ADHD prescribing in primary care, particularly in the area of drug treatment in adulthood.

Epidemiology and potential associated risk factors of drug-related problems in hospitalised children in the United Kingdom and Saudi Arabia.

AIM: Drug-related problems (DRP) are "an event or circumstance involving drug therapy that actually or potentially interferes with the desired health outcome". The extent and characteristics of DRPs in children in the UK and the Kingdom of Saudi Arabia (KSA) are unknown. Our aim was to determine the epidemiology of and identify risk factors for DRPs in hospitalised children. METHODS: A prospective cohort study was carried out in children aged 0-18 years, admitted to the medical ward, paediatric intensive care unit (PICU) and neonatal intensive care unit (NICU) during a 3-month period in two hospitals. Patients' charts, medical records and laboratory data were reviewed daily to identify DRPs; their preventability and severity were assessed. Logistic regression was used to analyse the potential risk factors associated with DRP incidence. RESULTS: Seven hundred and thirty-seven children (median age 2.3 years, interquartile range 6 months to 8 years, 58.1% male) were included. Three hundred and thirty-three patients suffered from 478 DRPs. Overall DRP incidence was 45.2% (95% CI, 41.5-48.8); KSA (51.1%; 95% CI, 45.8-56.3), UK (39.4%; 95% CI, 34.4-44.6). Incidence was highest in the PICU (59.7%; 95% CI, 47.0-71.5). Dosing problems were the most frequently reported DRPs (n = 258, 54%). 80.3% of DRP (n = 384) cases were preventable; 72.2% (n = 345) of DRPs were assessed as minor; 27% (n = 129) as moderate. Number of prescriptions and type of admission (transferred) were potential risk factors for DRP occurrence in children. CONCLUSIONS: Drug-related problems were common in the hospitalised children in this study; the most frequent were dosing problems and drug choice problems; the majority of them were preventable. Polypharmacy and transferred admission (another hospital or ward) were potential risk factors. To improve prescribing practices and minimise the risk of DRPs in hospitalised children, paediatric pharmacology and pharmacotherapy are important in medical education.

The use of medications with anticholinergic properties and risk factors for their use in hospitalised elderly patients.

PURPOSE: The aims of the present study were to evaluate the use of drugs with anticholinergic properties in elderly patients and to identify risk factors that increase the patient's chance of being given such medications. METHODS: The study was performed on a sample of 1636 patients aged ≥65 years hospitalised during the period between 1 January 2008 and 31 December 2009 in three municipal hospitals. To evaluate the factors influencing the use of anticholinergic medications, we compared two groups-users and non-users of such drugs-in terms of sociodemographic and clinical characteristics as well as comorbid conditions. The most important risk factors were identified using the binary logistic regression model. RESULTS: Hospitalisation led to a significant increase in the prevalence of anticholinergic medication users, when comparing their occurrence at the time of hospital admission and discharge (10.5% and 14.2%, respectively; p < 0.001). A significantly higher total number of prescribed drugs were found in the group of users compared with non-users, at both hospital admission (7.2 ± 3.5 vs 5.7 ± 3.1; p < 0.001) and discharge (8.7 ± 3.1 vs 7.5 ± 2.9; p < 0.001). Immobilisation, urinary incontinence and retention, constipation, gastroduodenal ulcer disease as well as neurologic and psychiatric comorbidities (depression, Parkinson's disease, epilepsy) appeared as the most important risk factors of using anticholinergic medications. CONCLUSIONS: Physicians should be aware of the greater risk of adverse anticholinergic effects of drugs in certain therapeutic classes in the elderly. In patients with risk factors mentioned previously, special attention should be paid to active identification of anticholinergic effects of medications.

Risk of depressive episodes with rimonabant: a before and after modified prescription event monitoring study conducted in England.

BACKGROUND: Marketing authorization for rimonabant was withdrawn in October 2008, mainly because the psychiatric adverse effects could not be addressed by further risk minimization. OBJECTIVE: The aim of the study was to compare the risk of major and minor depressive episodes in the 6 months prior to and the 6 months after starting treatment with rimonabant. METHODS: We conducted a before and after study using the observational cohort technique of Modified Prescription Event Monitoring to compare the risk of major and minor depressive episodes in new users of rimonabant reported in the 6 months before to the 6 months after starting treatment with rimonabant. Patients were identified from dispensed prescriptions issued by primary care physicians from June 2006 to October 2008. Patient demographics and information on depressive episodes were requested 6 months after the date of the first prescription for each patient. Risk ratios (RR) were calculated by comparing before and after events using a matched analysis. RESULTS: The cohort comprised 10,011 patients. The number of patients who had major depressive episodes before and after starting treatment were 147 and 168, respectively (RR 1.14; 95% CI 0.94, 1.39) and the number of patients who had minor depressive episodes were 825 and 829, respectively (RR 1.00; 95% CI 0.93, 1.10). For patients who had a previous history of psychiatric illness (n = 1132), 91 and 73, respectively, experienced major depressive episodes (RR 0.80; 95% CI 0.62, 1.03), and 367 and 220, respectively, experienced minor depressive episodes (RR 0.59; 95% CI 0.53, 0.68). For patients without a previous history of psychiatric illness (n = 8879), 56 and 95, respectively, experienced major depressive episodes (RR 1.7; 95% CI 1.2, 2.3), and 458 and 609, respectively, experienced minor depressive episodes (RR 1.33; 95% CI 1.20, 1.48). CONCLUSIONS: When comparing all patients in the cohort, there was no increased risk of developing a depressive episode whilst taking rimonabant. However, when considering subsets of patients with and without a previous history of psychiatric illness, the risk profiles were different. In patients without a previous history of psychiatric illness, there were more depressive episodes in the 6 months after starting treatment compared with the 6 months before starting treatment with rimonabant.

Paediatric post-marketing pharmacovigilance: comparison of the adverse event profile of vigabatrin prescribed to children and adults.

PURPOSE: Post-marketing pharmacovigilance is a cornerstone of monitoring and evaluating the safety of medicines in children and adults. However the methods may require modification to detect paediatric signals. The aim of this study was to compare the adverse event (AE) profile of children and adults taking vigabatrin, using modified signal detection methods (SDMs). METHODS: Data from the vigabatrin prescription-event monitoring study an observational cohort study (cohort 10,177 patients), stratified into one paediatric (0-17 years) and one adult (≥ 18 years) age group were examined using summary statistics for adverse drug reactions (ADRs), reasons for stopping and deaths. Incidence densities of AEs in children and adults in the first month of treatment were compared to months two to six to examine whether the AE rate was different in these two periods. AE rates in children were compared to those in adults (proportional reporting rates; PRRs and incidence rate ratios), to compare the AE profile between these age groups. RESULTS: Abnormal behaviour (PRR 5.3) and hyperactivity (PRR 4.5) were more frequently reported in children; confusion (PRR 25.0) and psychosis (PRR 12.5) more frequently in adults. In children 11.8% of ADRs were reported to the regulatory authority compared to 27.3% in adults. A higher proportion of children stopped treatment due to lack of effectiveness (57.7% vs. 47.5%). No deaths were attributed to vigabatrin. CONCLUSION: This study demonstrated that modified SDMs can be used to detect differences in the AE profiles between children and adults taking a medicinal product, and also to identify drug safety signals.

Hypoglycaemia with pioglitazone: analysis of data from the Prescription-Event Monitoring study.

AIMS AND OBJECTIVES: To investigate the relationship between patients' characteristics, use of concomitant anti-diabetic therapies and the incidence of hypoglycaemia, an acute complication of the treatment of diabetes mellitus reported by general practitioners (GPs) during the first 9 months of the treatment with pioglitazone. METHODS: We used data collected for the Prescription-Event Monitoring (PEM) study conducted by the Drug Safety Research Unit for patients prescribed pioglitazone between November 2000 and June 2001 by their GP in England. A Cox proportional-hazards regression model was used to assess this relationship. RESULTS: The original pioglitazone PEM cohort included 12,772 patients (mean age 60.9 years); 53% (6777) were male. A total of 77 patients experienced at least one hypoglycaemic episode (9.64 per 1000 patient-years). Women were estimated to have twice the hazard of having a hypoglycaemic event compared with men [hazard ratio (HR) 2.05; confidence interval (CI) 1.24, 3.41]. Patients taking combination therapy with sulfonylurea or insulin were estimated to have approximately three and four times the hazard of having an event compared with those who were not taking these adjunctive therapies [HR=3.11 (CI 1.64, 5.88); HR=4.15 (CI 1.74, 9.91), respectively]. Patients treated with adjunctive metformin were 25% less likely to experience hypoglycaemia than those who did not take concomitant metformin (HR=0.75; CI 0.44, 1.27). CONCLUSIONS: This study has shown that the treatment with pioglitazone was associated with a low incidence of hypoglycaemia. The factors possibly increasing the risk of hypoglycaemia were concomitant therapy with sulfonylurea or insulin and female gender.

Paediatric postmarketing pharmacovigilance using prescription-event monitoring: comparison of the adverse event profiles of lamotrigine prescribed to children and adults in England.

BACKGROUND: Using postmarketing pharmacovigilance data collected shortly after market authorization of lamotrigine in the UK, a study was conducted to compare the adverse event (AE) profiles of children and adults taking lamotrigine, using modified signal detection methods. METHODS: Data from the lamotrigine Prescription Event Monitoring (PEM) study, an observational cohort study, were stratified by age and examined using summary statistics for adverse drug reactions (ADRs), reasons for stopping treatment, deaths and follow-up information. Incidence densities of AEs in children (0-17 years) and adults (> or =18 years) in the first month of treatment were compared with months 2-6 to examine whether the AE rates were different in these two periods. AE rates in children were compared with those in adults (proportional reporting ratio [PRR] and incidence rate ratios), to compare the AE profiles between these age groups. RESULTS: The cohort included 2457 children and 7379 adults. Differences in the AE profiles between children and adults were observed. Rash (PRR 1.2) and Stevens-Johnson syndrome (PRR 4.5) were more commonly reported in children, and confusion more frequently in adults (PRR 6.3). In children, 33% of ADRs were reported to the Regulatory Authority compared with 44% in adults. A higher proportion of children stopped treatment due to lack of effectiveness (45% vs 38%). No deaths were attributed to lamotrigine. CONCLUSIONS: This study demonstrated that signal detection methods can be used to detect quantitative and qualitative differences in the AE profiles between the first children and adults taking a newly licensed drug.

Incidence of venous thromboembolism in users of strontium ranelate: an analysis of data from a prescription-event monitoring study in England.

BACKGROUND: Strontium ranelate is indicated for the treatment of postmenopausal osteoporosis. An association between strontium ranelate and venous thromboembolism (VTE) was identified in an analysis of phase III clinical trials. OBJECTIVE: To estimate the incidence of VTE in patients within the strontium ranelate (Protelos(R)) Prescription-Event Monitoring (PEM) study cohort during the first 12 months after starting treatment. METHODS: Patients in this analysis were identified from dispensed prescriptions that had been issued by general practitioners (GPs) in England for strontium ranelate between October 2004 and January 2008. For each individual patient, a Green Form questionnaire was sent to their GP 12 months after the date of the first prescription issued for strontium ranelate, requesting information about the patient including start and stop dates of treatment (if stopped), age, sex, indication, any history of VTE events, reasons for stopping and whether the patient had any events since starting the drug. VTE was defined as reports of deep vein thrombosis (DVT) or pulmonary embolism (PE). The crude incidence of VTE was calculated for events that occurred during the first 12 months after starting treatment (plus 30 days after stopping), with 95% Poisson exact CIs for the whole cohort, and subsets defined by age and past history of VTE. RESULTS: The final analysis cohort consisted of 10 782 patients. Where specified, mean age was 73.3 years (SD 11.45) [n = 10 696]; 9833 (91.3%) were female and 934 (8.7%) were male. Where the history of VTE was specified, 233 patients (2.6%) had a history of VTE prior to starting. In the first 12-month period, there were 48 incident reports of VTE (DVT or PE) during treatment (or within 30 days of stopping) in the cohort, with 7696.89 years of exposure, giving a crude incidence rate of VTE of 6.24 cases (95% CI 4.60, 8.27) per 1000 patient-years exposed. CONCLUSIONS: This analysis has provided an estimate of the incidence of VTE in patients treated with strontium ranelate in the general practice setting. The rate is similar to estimates in populations of similar age and corresponds to the incidence found in patients from phase III clinical studies and observational cohort studies of strontium ranelate on this topic. The crude annual incidence rate of VTE in the PEM cohort is higher than the background annual incidence rate found in the UK population, but is similar to estimates in populations of similar age and populations receiving treatment for postmenopausal osteoporosis. Also, we acknowledge the potential for underestimating the incidence in this population. Nevertheless, this analysis contributes to the ongoing postmarketing safety assessment of this product.

Hypoglycaemia with oral antidiabetic drugs: results from prescription-event monitoring cohorts of rosiglitazone, pioglitazone, nateglinide and repaglinide.

BACKGROUND: Hypoglycaemia is an acute complication associated with intensive treatment of patients with diabetes mellitus. This complication poses a major challenge in diabetes management. Furthermore, severe hypoglycaemia may be life threatening. Although hypoglycaemia is more often associated with insulin treatment, oral hypoglycaemic agents have the potential to trigger hypoglycaemia. AIM: The aim of this study was to quantify the incidence of hypoglycaemic events and to describe the pattern of these incident events during the first 9 months of treatment with four oral antidiabetic drugs, rosiglitazone, pioglitazone, nateglinide and repaglinide, prescribed in general practice in England. METHODS: We used data collected for prescription-event monitoring (PEM) studies of rosiglitazone, pioglitazone, nateglinide and repaglinide. PEM is an observational, non-interventional, incept cohort study. Observation time for each patient and incidence rate (IR) per 1000 patient-years of treatment for hypoglycaemia was calculated for each drug cohort. Smoothed hazard estimates were plotted over time. Case/non-case analysis was performed to describe and compare patients who had at least one hypoglycaemic event in the first 9 months of treatment with those who did not. RESULTS: The total number of patients included in the analysis was 14,373, 12,768, 4,549 and 5,727 in rosiglitazone, pioglitazone, nateglinide and repaglinide cohorts, respectively. From these, 276 patients experienced at least one episode of hypoglycaemia. The IR was between 50% and 100% higher in patients receiving treatment with meglitinides compared with those treated with the thiazolidinediones (TZDs) [IR = 9.94, 9.64, 15.71 and 20.32 per 1,000 patient-years for rosiglitazone, pioglitazone, nateglinide and repaglinide, respectively]. The plot of the hazard function and the estimated shape parameter from the Weibull regression model showed that pioglitazone, nateglinide and repaglinide had non-constant (decreasing) hazards over time, whereas the hazard for rosiglitazone-treated patients was approximately constant over time. Nateglinide and repaglinide had similar shape hazard function, indicating a significantly higher number of hypoglycaemic episodes shortly after starting treatment. For women treated with TZDs, hypoglycaemia was reported more frequently than for men. CONCLUSION: This analysis shows that the frequency of reported hypoglycaemia within the study cohorts was relatively low. The rates of hypoglycaemia were not equal between drug classes. Treatment with nateglinide or repaglinide was characterized by a higher incidence of hypoglycaemia at the beginning of treatment. Further investigation is necessary to assess whether women treated with TZDs are more prone to hypoglycaemia than men. Findings from this study should be taken into account with other clinical and pharmacoepidemiological studies.

Safety and drug utilization profile of varenicline as used in general practice in England: interim results from a prescription-event monitoring study.

BACKGROUND: Varenicline tartrate (Champix), a new smoking cessation medicine, was launched in the UK in December 2006. Varenicline is a highly selective partial agonist of the alpha(4)beta(2) nicotinic acetylcholine receptor (alpha(4)beta(2) receptor). The partial agonistic binding leads to alleviation of symptoms of craving and withdrawal, and simultaneously prevents nicotine from binding to the alpha(4)beta(2) receptor thereby causing reduction in the rewarding and reinforcing effects of smoking. Regulatory concerns have arisen about psychiatric events associated with varenicline, including depression, suicidal ideation and changes in behaviour/emotion. AIM: To present the interim results of an ongoing study by the Drug Safety Research Unit (DSRU) monitoring the safety of varenicline. METHODS: The observational cohort study is being conducted to study the postmarketing safety of varenicline, using modified prescription-event monitoring (PEM) methodology. Patients are identified from dispensed prescriptions issued by general practitioners (GPs) from December 2006. Demographic, clinical event (during the course and 1 month after stopping varenicline, reasons for discontinuing and suspected adverse drug reactions [ADRs] to varenicline) and drug utilization data are collected from detailed study-specific questionnaires posted to GPs at least 4 months after the date of first prescription for each patient. Event incidence densities (IDs; number of first reports of an event/1000 patient-months of exposure) are calculated. RESULTS: The interim cohort comprises 2,682 patients: median age 47 years (interquartile range [IQR] 38-56), 60.7% females (n = 1627). Nausea/vomiting was the most frequent clinical reason for stopping varenicline (n = 91; 35.3% of clinical reasons) and the most frequently reported suspected ADR to varenicline (n = 60, 50.9% of patients for whom an ADR was reported). The most frequently reported psychiatric events (causality not implied) during treatment included (n; % of cohort): sleep disorder (43; 1.6%), anxiety (33; 1.2%), depression (29; 1.1%), abnormal dreams (26; 1.0%) and mood change (17; 0.6%). Two cases of attempted suicide were reported during treatment with varenicline (one patient took an overdose of a benzodiazepine with alcohol, the other slashed their wrist). Both these patients had previous history of psychiatric illness and precipitating factors for the event. CONCLUSION: This study reflects 'real life' use of varenicline. Nausea/vomiting - the event most frequently reported as an ADR and as reason for stopping treatment - is listed in the UK Summary of Product Characteristics (SPC). The most frequently reported psychiatric events are listed in the UK SPC. All patients with suicidal events either had a past medical history of psychiatric illness prior to starting varenicline and/or a precipitating factor for the event. Clinicians should closely monitor patients with pre-existing psychiatric illness who are taking varenicline. Further evaluation of events of interest including psychiatric events is ongoing. Results presented are expected to change as the cohort size increases. Results of this study should be taken into account together with other clinical and pharmacoepidemiological studies.

Examining the tolerability of the non-sedating antihistamine desloratadine: a prescription-event monitoring study in England.

BACKGROUND: Desloratadine is a non-sedating, long-acting histamine H(1) receptor antagonist indicated for the symptomatic relief of allergic rhinitis (AR) and chronic idiopathic urticaria in patients aged>12 years. OBJECTIVE: To monitor the safety of desloratadine as prescribed in England, using the observational cohort technique of prescription event monitoring (PEM). METHODS: Exposure data were derived from dispensed prescriptions written by primary care physicians (general practitioners [GPs]) for desloratadine (March-May 2001); patient demographics, indication, pattern of use and outcome (event) data were obtained via simple questionnaires returned by GPs. Incidence density observation rates (IDobs) were calculated to compare the difference in event rates between months 1 and 2 (m1/m2) and were compared for the whole cohort and by groups defined by indication and pattern of use. RESULTS: The cohort comprised 11 828 patients (median age 37 years [interquartile range 22, 54]; 59.9% were female). The most frequent indication was AR (n=8001; 67.6%). After 2 months, 36.8% (n=2464) of patients were still taking desloratadine. 'Condition improved' was the most common event and reason for stopping. Headache/migraine was uncommon but associated with starting treatment (IDobs(m1/m2) ratio 3.99 [95% CI 1.70, 10.83]). Cardiovascular events occurred rarely or very rarely, as did central and peripheral nervous system events. No serious adverse drug reactions (ADRs) were reported. Events related to effectiveness were more frequent in month 1 than month 2 for all patient subgroups. CONCLUSIONS: This postmarketing surveillance study shows that desloratadine is well tolerated when used in general practice in England. No previously unrecognized ADRs were detected. This study highlights how modifications to PEM are contributing to the evaluation of drug utilization factors in relation to risks.

Use and risk management of carvedilol for the treatment of heart failure in the community in England: results from a modified prescription-event monitoring study.

BACKGROUND: In the UK, the licence for carvedilol was extended in 1998 to include symptomatic heart failure (New York Heart Association [NYHA] class II and III heart failure) with the recommendation that initiation and up-titration should be under the supervision of a hospital physician. A post-marketing surveillance study was conducted to address the UK regulatory authority's request for monitoring the use and safety of carvedilol prescribed for heart failure in clinical practice. AIM: To investigate adherence to risk management recommendations for the use of carvedilol for heart failure, monitor how patients' subsequent care was managed and collect event data to evaluate the safety profile of carvedilol used for the treatment of heart failure. METHODS: An observational cohort study using a modified prescription-event monitoring technique identified patients from dispensed primary care prescriptions in England (August 1999 to June 2001). An eligibility questionnaire was used to identify patients who had been prescribed carvedilol for heart failure for the first time after 31 July 1999. Up to three follow-up questionnaires were sent to the prescribers of eligible patients, requesting demographic information, dosage, supervision of treatment, status of cardiac failure and event information. RESULTS: 2311 patients met the eligibility criteria. For 1666 patients, one or more valid follow-up questionnaires were returned: 68.5% were male; male median age 66 years; female median age 72 years; the observation period was up to 3 years. Hospital physicians supervised initiation of treatment and first up-titration in 85.6% and 61.4% of patients, respectively. 49.2% of patients were prescribed the recommended starting dosage of carvedilol (6.25 mg/day). Approximately 25% of patients started on a lower dose than recommended, and the same proportion were prescribed a higher dose. NYHA status of cardiac failure between starting treatment and the third questionnaire improved for 39.5% of patients, deteriorated for 10.9%, and 11.7% of those for whom NYHA status was given died. Adverse drug reactions (ADRs) were reported for 2.4% of patients; the most commonly reported ADR was malaise/lassitude. Overall, 27.1% of patients stopped taking carvedilol. None of the 163 deaths were attributed to carvedilol. CONCLUSIONS: Regulatory guidelines for the use and risk management of carvedilol in heart failure were mostly followed, and most patients appeared to benefit from treatment with carvedilol for heart failure. Malaise/lassitude was the main reason for discontinuing treatment. Further investigations may be warranted to examine the prescribing of carvedilol at lower than recommended doses.