Rare Variation in Drug Metabolism and Long QT Genes and the Genetic Susceptibility to Acquired Long QT Syndrome.

BACKGROUND: Acquired long QT syndrome (aLQTS) is a serious unpredictable adverse drug reaction. Pharmacogenomic markers may predict risk. METHODS: Among 153 aLQTS patients (mean age 58 years [range, 14-88], 98.7% White, 85.6% symptomatic), computational methods identified proteins interacting most significantly with 216 QT-prolonging drugs. All cases underwent sequencing of 31 candidate genes arising from this analysis or associating with congenital LQTS. Variants were filtered using a minor allele frequency <1% and classified for susceptibility for aLQTS. Gene-burden analyses were then performed comparing the primary cohort to control exomes (n=452) and an independent replication aLQTS exome sequencing cohort. RESULTS: In 25.5% of cases, at least one rare variant was identified: 22.2% of cases carried a rare variant in a gene associated with congenital LQTS, and in 4% of cases that variant was known to be pathogenic or likely pathogenic for congenital LQTS; 7.8% cases carried a cytochrome-P450 (CYP) gene variant. Of 12 identified CYP variants, 11 (92%) were in an enzyme known to metabolize at least one culprit drug to which the subject had been exposed. Drug-drug interactions that affected culprit drug metabolism were found in 19% of cases. More than one congenital LQTS variant, CYP gene variant, or drug interaction was present in 7.8% of cases. Gene-burden analyses of the primary cohort compared to control exomes (n=452), and an independent replication aLQTS exome sequencing cohort (n=67) and drug-tolerant controls (n=148) demonstrated an increased burden of rare (minor allele frequency<0.01) variants in CYP genes but not LQTS genes. CONCLUSIONS: Rare susceptibility variants in CYP genes are emerging as potentially important pharmacogenomic risk markers for aLQTS and could form part of personalized medicine approaches in the future.

The Role of the Contextual Cohort to Resolve Some Challenges and Limitations of Comparisons in Pharmacoepidemiology.

In pharmacoepidemiology, comparison studies can provide a useful estimate of the level of increased or decreased risk of specific events with a medication (through a measure of effect). A key focus of pharmacoepidemiological studies is the safety and effectiveness of medicines in their real-world use, and adequate comparisons of effect estimates are critical. However, consideration of guidelines, pharmacoeconomic assessments, and policies for reimbursement have made comparisons in pharmacoepidemiological studies far more difficult to conduct in recent years. Where certain subject characteristics influence the probability of being exposed to a treatment, this can introduce issues of selection bias and confounding. Methodologies are available to minimise selection bias (through case-only and randomised study designs) and deal with confounding (such as regression modelling or propensity score matching methods), however these each have their own limitations. Where prescribing guidelines are present, conducting comparisons in pharmacoepidemiology produces many challenges and not all of these can be easily overcome. Patient channelling can be more frequent with adherence to clinical guidelines compared with when prescribing decisions by doctors are based predominantly on their clinical judgement. Use of a contextual cohort could be considered as an option to characterise the adoption of new medications into clinical practice and describe the prevalence of clinical characteristics and risk factors in the two cohorts, rather than compare event rates and produce an estimate of effect.

Safety profile of oxcarbazepine: results from a prescription-event monitoring study.

PURPOSE: To monitor safety of oxcarbazepine, prescribed in primary care in England, using prescription-event monitoring (PEM). METHODS: Postmarketing surveillance using observational cohort technique of PEM. Exposure data were obtained from dispensed British National Health Service prescriptions issued by general practitioners (GPs) March 2000-July 2003. Demographic, drug utilization, and clinical event data were collected from questionnaires posted to GPs at least 6 months after first prescription date for each patient. Incidence densities (IDs) (number of first reports per 1,000 patient-months of treatment) were calculated and differences for events reported in month 1 (ID(1)) and months 2-6 (ID(2-6)) (99% confidence intervals) were examined for changes in event rates. Follow-up and causality assessment of medically significant events were undertaken. RESULTS: The cohort comprised 2,243 patients [mean age 40.4 years; range 2-99 years; standard deviation (SD) 18.8; 46.3% (n = 1,038) male]. Most frequently reported primary indications were epilepsy, convulsion (n = 1,111; 49.5%, n = 209; 9.3%, respectively). GPs recorded 932 reasons for stopping medication in 698 (31.1%) patients; most frequent clinical reason "drowsiness/sedation" (n = 57; 2.5% of cohort). Clinical events (excluding indication) associated with starting treatment (lower 99% CI > 0) included: "drowsiness/sedation" (ID(1)-ID(2-6) = 14.2), "nausea/vomiting" (ID(1)-ID(2-6) = 13.0), and dizziness (ID(1)-ID(2-6) = 11.6). Events followed up and assessed as probably related to oxcarbazepine use included rash (7 of 11) and hyponatremia (15 of 38). DISCUSSION: There were no serious adverse drug reactions reported during this study. Results of the study should be taken in context with other epidemiologic studies.

Observational assessment of safety in seroquel (OASIS): a specialist cohort event monitoring (SCEM) study in England.

BACKGROUND: This study was designed to monitor the short-term (up to 12 weeks) use and safety of quetiapine (Seroquel) extended release (XL) and quetiapine immediate release (IR) prescribed to patients with a clinical diagnosis of schizophrenia, and/or manic episodes associated with bipolar disorder by psychiatrists under normal conditions of use. METHODS: A Specialist Cohort Event Monitoring (SCEM) study was conducted in England February 2010-April 2013. This observational cohort study recruited patients prescribed quetiapine XL within the secondary care setting by psychiatrists. A reference cohort of quetiapine IR users was also recruited. Baseline and 12 week observational data were collected from psychiatrists who abstracted information from medical records onto bespoke questionnaires. Data were collected on demographics, indication, past medical history, prescribing information and events of interest. Summary descriptive statistics were calculated. RESULTS: The final cohort consisted of 869 eligible patients; 646 XL users and 223 IR users. The majority of XL and IR users were female (56.2% and 55.6%, respectively), with a median age of 40 (interquartile range [IQR]: 29, 49) and 39 (IQR: 28, 50) years, respectively. The most frequent indication for treatment was Manic episodes associated with Bipolar Affective disorder (53.4% XL and 49.8% IR). Median index dose was 200 mg/day (IQR: 100, 300) for XL users and 50 mg/day (IQR: 50, 100) for IR users, while median final maintenance dose was 400mg/day (IQR: 250, 600) and 300 mg/day (IQR: 100, 400), respectively. The most frequently reported event of interest in both cohorts was sedation (n = 151, 23.9% XL cohort and n = 49, 23.0% IR cohort). CONCLUSION: Utilisation of quetiapine XL appeared to be in line with prescribing guidelines in terms of dose, and commonly reported events of interest were in concordance with the known safety profile. Overall, this SCEM study provided important information on the safety and utilisation of quetiapine XL in the secondary care setting in England.

Systematic benefit-risk assessment for buprenorphine implant: a semiquantitative method to support risk management.

BACKGROUND: Prior to approval in the European Union, a systematic benefit-risk assessment was required to compare buprenorphine implant to sublingual buprenorphine as part of the license application to the European Medicines Agency. OBJECTIVE: The Benefit-Risk Action Team framework was used to describe the overall benefit-risk of buprenorphine implant in comparison to sublingual buprenorphine. STUDY SELECTION/METHODS: A value tree of key benefits and risks related to the implant formulation of buprenorphine was constructed. Risk differences (RD) or reporting ORs (ROR) and corresponding 95% CIs were calculated for each outcome, along with the number needed to treat and number needed to harm. Swing weighting was assigned to outcomes and the weighted net clinical benefit (wNCB) was calculated. FINDINGS: Key benefits assessed: reduced risk of illicit opioid use (RD=0.09, 95% CI 0.01 to 0.17), reduced risk of misuse and diversion (ROR=0.13, 95% CI 0.02 to 0.94), improved compliance and convenience (RD=0.20) and quality of life measures (RD=0.03). Key risks assessed: clinically significant implant breakage (RD=0.01, 95% CI 0.00 to 0.01), migration/missing implant (RD=0.01, 95% CI 0.00 to 0.02), infection at insertion/removal site (RD=0.08, 95% CI 0.03 to 0.12) and implant-related allergic reaction (RD=0.07, 95% CI 0.03 to 0.11). The wNCB for buprenorphine implant was 4.96, which suggests a favourable benefit-risk profile. CONCLUSIONS: The benefit-risk profile of buprenorphine implant is considered favourable in comparison to sublingual buprenorphine, based on this semiquantitative analysis using available data. Further data from real-world use on benefits and risks should be used for ongoing monitoring of the benefit-risk profile of buprenorphine implants in the postmarketing setting.

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.

Risk management and outcomes of adverse events to pioglitazone in primary care in the UK: an observational study.

BACKGROUND: Pioglitazone is an antidiabetic drug that belongs to the thiazolidinedione (TZD) class of insulin-sensitizing agents. Adverse events to pioglitazone of potential severity are listed in the 'special warnings and special precautions for use' section of the pioglitazone summary of product characteristics (SPC), with recommendations for monitoring and management. OBJECTIVE: To describe the risk management and outcomes of recognized TZD class effects in patients prescribed pioglitazone. METHODS: An observational study of risk management and event outcomes for the adverse events of cardiac failure, fluid retention/oedema, weight gain, anaemia and abnormal liver function tests (LFTs) was performed. Patients were identified from within a prescription-event monitoring (PEM) postmarketing cohort of first-users of pioglitazone. Patients with pre-existing events or alternative causes, or with no possibility of collecting further information, were excluded. Outcomes included (i) the method of detection of the adverse event, i.e. whether the patient or the prescriber identified the problem; (ii) whether responsibility for risk management was taken at a primary- or secondary-care level; (iii) interventions taken to manage the event, including discontinuation of treatment; (iv) resolution and/or other outcomes of the event; and (v) general practitioner (GP) opinion of relatedness of the event to pioglitazone. RESULTS: Acute events such as cardiac failure and oedema were more likely to be detected by the patient presenting with the event rather than at regular follow-up. GPs were more likely to take responsibility for management of abnormal LFTs, anaemia and oedema events, whereas hospital admissions occurred mainly in patients with cardiac failure (45.3%). Pioglitazone was stopped in more than 50% of each type of event, apart from anaemia. Oedema events were the most likely to resolve (87.6%) and anaemia the least likely (42.9%). Oedema events were the most likely to be attributed to the drug by GPs, whereas cardiac failure was the event least attributed to pioglitazone. CONCLUSIONS: Timely drug withdrawal and/or interventions such as corrective treatment or referral to a specialist can lead to successful resolution of class-effect adverse events of pioglitazone. Regular follow-up of patients on antidiabetic agents is essential to detect certain events, but more acute events are more likely to be reported spontaneously. Treatment options for patients with diabetes mellitus and cardiovascular risk factors are limited, requiring careful benefit-risk assessment of pioglitazone use in these patients and careful monitoring for signs of worsening cardiac function.

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.

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.

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.

The safety profile of tadalafil as prescribed in general practice in England: results from a prescription-event monitoring study involving 16 129 patients.

OBJECTIVES: To examine the safety of tadalafil as used in general practice in England, and to compare the mortality rate due to ischaemic heart disease (IHD) in tadalafil users with that in the male population in England. PATIENTS AND METHODS: Patients in this observational cohort study were identified from dispensed prescriptions for tadalafil issued by general practitioners (GPs) from February 2003 to November 2004. Demographic and outcome data (clinical events) were requested from patients' GPs using a postal questionnaire. A standardized mortality ratio (SMR) was calculated using indirect standardization for deaths from IHD in the cohort (where age was known) over a 1-year observation period compared to that in the English male population (2003). A sensitivity analysis was carried out to investigate the effects of missing data for age and cause of death. RESULTS: Clinical information was obtained for 16 129 patients (median age 60 years, interquartile range 52-67); the age was not specified for 3212 (19.9%) patients. At least a third of the patients had diabetes mellitus and 29% had hypertension. Comparison of the mortality rate due to IHD for the patients of known age with that in the English male population provided an SMR of 0.57 (95% confidence interval 0.38-0.83) indicating fewer observed deaths in the cohort than expected. The results of the sensitivity analyses investigating the effect of missing data for age and cause of death produced similar SMR estimates. One confirmed case of non-arteritic anterior ischaemic optic neuropathy (NAION) was reported during tadalafil therapy in a patient with other risk factors for this condition. CONCLUSION: The results from this prescription-event monitoring study suggest that tadalafil is generally well tolerated when used in general practice in England. The most frequently reported adverse clinical events were in keeping with clinical trial data and include headache, dyspepsia and back pain. There was no evidence of a greater mortality rate due to IHD in the tadalafil cohort than in the general male population. However, these results are limited by the use of an external comparator group and might be explained by a 'healthy cohort effect'. One event of NAION was reported, and although a causal relationship was not established it indicates that NAION occurs rarely in patients prescribed tadalafil.

Safety profile of esomeprazole: results of a prescription-event monitoring study of 11 595 patients in England.

OBJECTIVE: Esomeprazole, the S-isomer of omeprazole, was launched in the UK in September 2000. The first proton pump inhibitor, omeprazole, has been marketed in the UK for over 10 years. However, the adverse event database of newly marketed drugs is limited, and it is only after widespread clinical use that the adverse effect profile of a drug is ascertained more comprehensively. This study aims to monitor the safety of esomeprazole prescribed in the primary care setting in England using prescription-event monitoring (PEM). METHODS: A postmarketing surveillance study using the observational cohort technique of PEM. Patients were identified from dispensed prescriptions for esomeprazole issued by general practitioners between September 2000 and April 2001. Questionnaires ('green forms') requesting clinical event data on these patients were sent to prescribers approximately 6 months after the date of the first dispensed prescription for each individual patient. Incidence densities (IDs), expressed as the number of first reports of an event/1000 patient-months of exposure (PME), were calculated. Significant differences between IDs for events reported in the first month (ID1) and the following 5 months (ID2-6) of exposure were regarded as potential signals. Other methods for signal detection such as medical evaluation of selected events and evaluation of reasons for stopping were also applied. RESULTS: Green forms containing clinically useful information for 11 595 patients (median age 56 years; 53.2% female) were received. Diarrhoea was the event with the highest ID1 in month 1 (8.0 per 1000 patient months of exposure). Adverse events that occurred significantly more often in the first month of treatment with esomeprazole compared with months 2-6 included diarrhoea, nausea/vomiting, abdominal pain, dyspepsia, headache/migraine, intolerance, malaise/lassitude, pruritus, unspecified adverse effects and abnormal sensation. CONCLUSIONS: The safety profile of esomeprazole was consistent with the prescribing information and experience reported in the literature.

Monitoring the safety of pioglitazone : results of a prescription-event monitoring study of 12,772 patients in England.

BACKGROUND: Pioglitazone is an antidiabetic drug that targets insulin resistance in patients with type 2 diabetes mellitus by stimulating the peroxisome proliferator-activated receptor (PPAR)-gamma. Pioglitazone belongs to a class of drugs called thiazolidinediones (TZDs) and was launched in the UK in November 2000. OBJECTIVE: To monitor, using prescription-event monitoring, the post-marketing safety of pioglitazone, which is prescribed in primary care in England. METHODS: An observational cohort study in which patients were identified from dispensed prescriptions issued by primary-care physicians/general practitioners (GPs) between November 2000 and June 2001. Information on demographics, the use of pioglitazone, clinical event data, events suspected as adverse drug reactions, reasons for stopping the drug and cause of death (if appropriate) were collected using questionnaires posted to GPs at least 8 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] were calculated. RESULTS: The cohort comprised 12 772 patients (median age 62 years); 53.1% were males. The most frequent starting daily dose of pioglitazone was either 15 mg or 30 mg (n = 10 298). Pioglitazone/metformin was the most frequently used combination reported (n = 4029). Of the 3690 patients who stopped treatment, 1143 stopped due to reasons related to poor glycaemic control. 'Oedema/fluid retention' (n = 121) and 'weight gain' (n = 118) also appeared high on the list of reasons for discontinuing. 'Malaise/lassitude' and 'nausea/vomiting' were the most frequently reported suspected adverse drug reactions (ADRs) associated with pioglitazone. Specific clinical events considered as early onset events with pioglitazone were: 'malaise/lassitude', 'nausea/vomiting', 'dizziness', 'headache/migraine', 'diarrhoea', 'weight gain' and 'abnormal liver function test'. CONCLUSION: Pioglitazone was considered to be a reasonably well tolerated drug, with the main reasons for discontinuing being related to the drug not being effective. The frequency of individual ADRs reported in this study did not exceed the frequency in the summary of product characteristics (SPC) for pioglitazone. However, amongst the frequently reported suspected ADRs, 'nausea/vomiting' and 'diarrhoea' are not listed in the SPC. Further research is required to assess whether the risk of myocardial infarction and deaths due to cardiovascular causes is a class effect of the thiazolidinediones. Results from this study should be taken into account with other clinical and pharmacoepidemiological studies.

Evaluation of risk profiles for gastrointestinal and cardiovascular adverse effects in nonselective NSAID and COX-2 inhibitor users: a cohort study using pharmacy dispensing data in The Netherlands.

BACKGROUND: Newly approved drugs, in comparison with older drugs, are more often prescribed to patients who have not responded satisfactorily to established related drugs or as first-line therapy to patients with a high baseline risk for adverse outcomes (i.e. channelling). However, these patients are less likely to benefit from the prescribed drug and/or are more prone to adverse drug reactions. Therefore, it is difficult to unravel whether observed risks or increases in risk of new drugs are real, i.e. related to the pharmacology, or whether these are related to selective prescribing to patients who are more susceptible to adverse events because of some underlying risk factor(s). The channelling paradox may exist for cyclo-oxygenase (COX)-2 selective inhibitors ('coxibs') instead of traditional nonselective NSAIDs in relation to both gastrointestinal (GI) and cardiovascular (CV) safety. OBJECTIVE: To evaluate the risk profiles for GI and CV adverse effects in nonselective NSAID and coxib new-user populations over time, in terms of a quantitative measure since the introduction of coxibs. METHODS: This was a population-based cohort study using the Dutch pharmaceutical claims database (Foundation for Pharmaceutical Statistics). Eligible patients (>/=18 years) were those where the date of their first prescription (index date) of an NSAID (first-line [e.g. ibuprofen] or second-line [e.g. piroxicam] nonselective NSAID, COX-2 preferential NSAID or coxib) was between January 1999 and December 2003. For each patient, GI and CV risk profiles at index date were defined by a cumulative score derived from dispensing data (patient age, sex and history of medication use within 6 months of index date). Risk scores were categorized as low (score = 0), medium (1) or high (2+). Patients were recorded as switchers based on other NSAID use prior to the index date. Other information collected included the Chronic Disease Score (CDS). Crude odds ratios (ORs) were calculated for risk factors for each NSAID group versus first-line nonselective NSAID users as the reference cohort. The effect of calendar time was examined by plotting mean CV or GI risk score by quarter-year. Correlation between GI and CV scores was examined using the Pearson correlation coefficient (R). Data were stratified by patients' history of switching. RESULTS: The four cohorts comprised patients using: first-line nonselective NSAIDs (n = 42 750); second-line nonselective NSAIDs (n = 1771); COX-2 preferential NSAIDs (n = 3661) and coxibs (n = 4861) patients. New coxib users were most likely to have high GI and CV risk scores (OR 5.3 [95% CI 5.0, 5.6] and OR 2.2 [95% CI 2.1, 2.4], respectively). At the individual patient level, GI and CV risk profiles were moderately well correlated for all NSAID cohorts (R range 0.48 to 0.62). There was no remarkable change in mean GI or CV risk profile of patients over calendar time since the market introduction of coxibs. DISCUSSION: Of the four NSAID cohorts, new coxib users tended to have the highest numbers of GI and CV risk factors, with no obvious change over calendar time. There was also evidence of correlation between GI and CV risk scores. Thus, selective prescribing of coxibs applies to people with co-existing CV as well as GI risk factors. This is important when comparing the safety and/or efficacy of new therapies to existing therapies, and emphasizes the difficulties encountered by prescribers in assessing levels of risk when initiating coxib treatment.

Prescriber adoption of newly approved selective COX-2 inhibitors.

INTRODUCTION: There is no consistent definition of prescribers who adopt new drug treatments early. This study examines if COX-2 inhibitors (coxibs) were prescribed by subsets of practitioners and describes GP adoption patterns of coxibs and existing NSAIDs over time. METHODS: A population-based drug utilisation study using a Dutch medication claims database. Prescribers of patients (18+yrs) prescribed an NSAID January 1999-December 2003 were identified. Four NSAID categories were chosen reflecting selectivity (coxibs, preferential COX-2 inhibitors and non-selective (ns) NSAIDs (sub-categorised as first or second line treatment)). The characteristics of prescribers issuing>10 prescriptions examined were: Type (GP, Specialist, Other); GP NSAID prescribing preference ratio (nsNSAIDs/coxib first prescription); coxib (ratio<3); prescriber proportion responsible for 100%, 80% and 50% of initiations. Odds Ratios (95%CI) were calculated (first-line nsNSAIDs as reference). Plots of prescribing proportions by quarter year were examined. RESULTS: NSAID cohorts comprised: first-line ns (N=38783); second-line ns (N=1459); COX-2 preferential (N=3107); coxib (N=4202) patients. For all four cohorts, GPs were the most common prescriber type (>67%); the most frequent prescribing preference was for first-line nsNSAIDs; 50% percentile prescribing proportions were low (<9%). GPs were equally as likely to prescribe coxibs as first-line nsNSAIDs [OR 1.0 (0.9, 1.1)]. Plots of 100% prescriber proportion for first-line nsNSAIDs and coxibs showed convergence; 50th percentile prescriber proportions plots were constant. CONCLUSIONS: Small subsets of prescribers accounted for the majority of initiations regardless of NSAID type. Further studies are needed on such prescribers to inform healthcare policies and encourage participation in post-marketing safety studies.

Utilisation and Safety of Deferasirox: Results from an Observational Cohort Study in England.

INTRODUCTION: Deferasirox (EXJADE®, Novartis, UK) is an oral iron-chelating agent primarily used to reduce chronic iron overload in patients receiving blood transfusions for various chronic anaemias and some non-transfusion dependant anaemias. OBJECTIVE: The aim of this study was to examine the utilisation and safety of deferasirox used in general practice in England. METHOD: A single exposure observational cohort study design was used. Patients were identified from dispensed prescriptions for deferasirox between September 2006 and September 2014. Outcome data were collected via postal questionnaires sent to prescribers ≥ 6 months after first dispensed prescription for an individual patient. Summary descriptive statistics were calculated. RESULTS: The evaluable cohort consisted of 122 patients, of which 41.8% were aged 2-17 years. Frequent reasons for prescribing were sickle cell anaemia (27/103 where specified, 26.2%) and beta thalassaemia (26, 25.2%). The majority of patients (43/51, 84.3%) were prescribed the licensed doses of 10 or 20 mg/kg/day at start. Prior measurements of serum creatinine were only reported for a small proportion this study (18/122, 14.8%). In total, 91 incident events were reported, including two of raised serum creatinine. CONCLUSION: These results show that deferasirox is largely being prescribed for its licensed indications in general practice in England and events reported were consistent with the known safety profile.

Safety of Atrovent® CFC-free inhaler: respiratory events reported from an observational cohort study in England.

OBJECTIVES: The aim of the study was to identify any unexpected clinical events associated with starting the new CFC-free formulation of Atrovent® MDI in general practice in England. METHODS: An active surveillance cohort study was conducted with a focus on selected clinical events, including respiratory symptoms, in past users of Atrovent® CFC MDI ('switchers') and Atrovent® naïve users. Incidence density rate ratios (with 99% confidence intervals) for events occurring in the first 3 months of exposure (risk period-ID1-3 ) compared to 3 months prior to starting treatment (reference period-IDR ) were calculated. RESULTS: The cohort consisted of 13 211 patients (median age 70 years, 50.1% female; 63.5% prior users of Atrovent® CFC MDI ('switchers')). Common respiratory events occurred at higher rates after starting treatment than before for switchers, for example lower respiratory tract infection (LRTI) [ID1 /IDR = 1.45 (99% CI: 1.17, 1.81)] and worsening asthma [ID1 /IDR = 1.58 (99% CI: 1.00, 2.51)]. Of these events only LRTI was significant for Atrovent® naïve patients [ID1 /IDR = 1.42 (99% CI: 1.04, 1.95)]. CONCLUSIONS: The results of this study suggest effect modification of risk as a result of prior Atrovent® CFC MDI use. Overall, Atrovent® CFC-free MDI appeared to be reasonably well tolerated in the immediate postmarketing period and the safety profile appeared similar to that of the CFC formulation.

Application of the bradford hill criteria to assess the causality of cisapride-induced arrhythmia: a model for assessing causal association in pharmacovigilance.

INTRODUCTION: The Bradford Hill criteria are a widely used, useful tool for the assessment of biomedical causation. We have examined their application to pharmacovigilance using the example of cisapride-induced QTc interval prolongation/arrhythmia. METHODS: A literature search was conducted using MEDLINE, EMBASE, Reactions Weekly and regulatory websites to identify evidence for the association between cisapride and QTc interval prolongation/arrhythmia that had been published in the English language. Two hundred and five publications were identified as being potentially suitable for the study. After excluding irrelevant articles, studies on high-risk populations and review articles, 70 publications were assessed using the Bradford Hill criteria. These included 24 case reports, case series or spontaneous report summaries; eight epidemiological studies; 22 clinical studies; and 16 experimental (in vivo and in vitro) publications. RESULTS: The most compelling evidence for an association between cisapride use and QTc interval prolongation/arrhythmia came from case/spontaneous reports and biological plausibility. Considering the rare incidence of serious cardiac events, these criteria formed the basis for the strength of the association. The number of reports from different populations showed consistency. Specificity was supported by clinical and cardiographic characterisation of the events. There were temporal relationships between the events and the initiation of cisapride treatment, increases in the dosage and the receipt of interacting medications. The relationships between the adverse events and the latter two factors exhibited biological gradients. Experimental evidence could be found from biological models, as well as reports of positive dechallenge and/or rechallenge found in individual patients. Cisapride was found to bind the human ether-a-go-go-related gene (HERG) potassium channel, which provides a plausible mechanism for QTc interval prolongation/arrhythmia. Other QTc interval-prolonging/arrhythmic drugs that also bind to HERG provided an analogy for cisapride causing QTc interval prolongation/arrhythmia via this mechanism. The evidence provided by clinical studies was inconsistent, and epidemiological studies failed to demonstrate an association. Nevertheless, this did not prevent the assessment of causation. DISCUSSION: This study showed how different types of evidence found in pharmacovigilance can be evaluated using the Bradford Hill criteria. Further work is required to examine how the criteria can be applied to different types of adverse events and how they may be applied to pharmacovigilance.

A modified prescription-event monitoring study to assess the introduction of Seretide Evohaler in England: an example of studying risk monitoring in pharmacovigilance.

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

Safety of zafirlukast: results of a postmarketing surveillance study on 7976 patients in England.

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