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.

Specialist Cohort Event Monitoring studies: a new study method for risk management in pharmacovigilance.

The evolving regulatory landscape has heightened the need for innovative, proactive, efficient and more meaningful solutions for 'real-world' post-authorization safety studies (PASS) that not only align with risk management objectives to gather additional safety monitoring information or assess a pattern of drug utilization, but also satisfy key regulatory requirements for marketing authorization holder risk management planning and execution needs. There is a need for data capture across the primary care and secondary care interface, or for exploring use of new medicines in secondary care to support conducting PASS. To fulfil this need, event monitoring has evolved. The Specialist Cohort Event Monitoring (SCEM) study is a new application that enables a cohort of patients prescribed a medicine in the hospital and secondary care settings to be monitored. The method also permits the inclusion of a comparator cohort of patients receiving standard care, or another counterfactual comparator group, to be monitored concurrently, depending on the study question. The approach has been developed in parallel with the new legislative requirement for pharmaceutical companies to undertake a risk management plan as part of post-authorization safety monitoring. SCEM studies recognize that the study population comprises those patients who may have treatment initiated under the care of specialist health care professionals and who are more complex in terms of underlying disease, co-morbidities and concomitant medications than the general disease population treated in primary care. The aims of this paper are to discuss the SCEM new-user study design, rationale and features that aim to address possible bias (such as selection bias) and current applications.

Indicators of drug-seeking aberrant behaviours: the feasibility of use in observational post-marketing cohort studies for risk management.

BACKGROUND: Problematic prescription drug use is reflected by or associated with drug-seeking aberrant behaviours. Research gaps include lack of post-marketing evidence and instruments. As part of the pharmacovigilance requirements, a risk management plan was developed for fentanyl buccal tablets (FEBT) by the manufacturer, with an additional pharmacovigilance activity requested by the regulatory authority, to investigate the risks of misuse, abuse, criminal use, off-label use and accidental exposure to FEBT after the product became commercially available. A Modified Prescription-Event Monitoring (M-PEM), observational, post-authorisation safety surveillance (PASS) study was conducted, with an overall aim to examine the use of FEBT in relation to their safety as prescribed in primary care in England. One of the exploratory objectives included estimating the prevalence of aberrant behaviours during FEBT treatment. OBJECTIVE: To determine the feasibility of estimating the prevalence of risk factors associated with dependence on starting treatment and aberrant behaviours in patients during treatment with a prototypical abuse liable substance (fentanyl), as based on the application of an existing index (the Chabal criteria). METHODS: Data were collected as part of the M-PEM PASS study; exposure and outcome data (including risk factors for dependence and aberrant behaviours based on behavioural not clinical manifestations) were derived from questionnaires sent to primary care physicians in England during April 2008 to June 2011. For the exploratory objective of interest, descriptive statistics and simple (non-weighted) risk scores were constructed on aggregate counts (score ≥3 considered 'high-risk'). Supplementary analyses explored the relationship between the two indices and the characteristics of patients with aberrant behaviours and those without (crude odds ratios plus 95% confidence interval (CI) were calculated). RESULTS: In a cohort of 551 patients, the prevalence of at least one pre-existing risk factor for dependence was 26% (n = 145), whilst the frequency of aberrant behaviours observed during treatment was 8% (n = 46). Patients with aberrant behaviours had several different characteristics to patients without. The two indices were associated (χ (2) df (20) = 58.72, p < 0.001), but a high-dependence risk-factor score provided a poor indication of high aberrant behaviour risk; the area under the receiver operating characteristic curve was 0.58 (95% CI 0.41, 0.74). LIMITATIONS: Study limitations included subjectivity in relation to physicians identifying aberrant behaviours, and under-reporting thereof in PASS observational study designs. The presence of these criteria does not confirm misuse, but should be considered as a signal of problematic opioid misuse, which requires investigation. Further research is needed to develop a more robust analytical construct. CONCLUSION: In this PASS study, the prevalence of at least one pre-existing risk factor for dependence was 26%, whilst the frequency of aberrant behaviours observed during treatment was 8%. Patients with aberrant behaviours had several different characteristics to patients without. This study demonstrates the feasibility of the systematic collection of physician reports of risk factors for dependence and aberrant behaviours to facilitate the development of risk scores, using these reports to support the post-marketing risk management of products with misuse potential.

Neuropsychiatric events with varenicline: a modified prescription-event monitoring study in general practice in England.

BACKGROUND: Varenicline (Champix(®)), launched in the UK in December 2006, is indicated for the treatment of smoking cessation in adults (≥18 years of age). In 2008, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK issued a warning suggesting that varenicline was associated with disparate neuropsychiatric symptoms, including depression, suicidal thoughts and behaviour. In response to this regulatory warning, the Drug Safety Research Unit conducted a modified prescription-event monitoring (M-PEM) study to monitor the safety of varenicline. OBJECTIVE: The aim of this study was to estimate the incidence and examine the pattern of neuropsychiatric events reported to general practitioners (GPs) in England during the immediate postmarketing period for varenicline. METHODS: A postmarketing surveillance study was conducted using the observational cohort technique of M-PEM. Patients were identified from dispensed prescriptions issued by primary care physicians between December 2006 and March 2007. Data on exposure, previous history of psychiatric illness and events reported during and after treatment were collected from questionnaires. In order to determine whether hazards for neuropsychiatric events of interest (depression, anxiety, aggression, suicidal ideation, non-fatal self-harm) were non-constant over time (which could indicate a possible association with the drug), the pattern of events was examined by plotting the smoothed hazard function estimate and then fitting a Weibull model. The Weibull model shape parameter (ß) and 95 % confidence interval were used as a test for a non-constant hazard function (where a value of 1 indicates a constant hazard over time). In addition to this analysis, the difference in incidence densities (IDs) between month 1 and months 2-3 were calculated and compared. RESULTS: The cohort comprised of 12,159 patients (median age 47 years [interquartile range 19]; 56.9 % [n = 6924 female]). The number of events reported during treatment, reason for stopping, adverse drug reactions (ADRs), and the p-value for the Weibull shape parameter were as follows: depression (n = 94; 42; 19; p = 0.144); anxiety (n = 94; 49; 9; p = 0.009); aggression (n = 7; 4; 2; p = 0.465); suicidal ideation (n = 8; 4; 1; p = 0.989) and non-fatal self-harm (n = 5; 1; 0; p = 0.771). No differences in the IDs between months 1 and months 2-3 were found for any of the events. CONCLUSION: Whilst between 7 and 17 % of neuropsychiatric events were attributed to the drug by GPs and approximately 20-50 % were given as reasons for stopping, no signal was raised using the ID differences approach, and only anxiety was flagged as a potential signal for an ADR using the Weibull model. The signal for anxiety requires further evaluation to determine whether the drug plays a part in the development of anxiety or whether it is a withdrawal symptom caused by smoking cessation. Analysis methods will lack power when the numbers of events are low even when a large number of participants are included in the study.

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.

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.

Drug utilization of Intrinsa (testosterone patch) in England: interim analysis of a prescription-event monitoring study to support risk management.

BACKGROUND: Intrinsa is a transdermal testosterone patch that is indicated for use in hypoactive sexual desire disorder (HSDD) in women who have undergone bilateral oophorectomy and hysterectomy (surgically-induced menopause) receiving concomitant oestrogen therapy. OBJECTIVE: To describe the utilization characteristics of the patients prescribed testosterone patch (Intrinsa) based on an interim analysis of an ongoing Prescription-Event Monitoring study in England, and to assess, where possible, if the product is being used within the licensed therapeutic indication. METHODS: In this interim analysis, patients were identified from dispensed prescriptions that had been issued by general practitioners (GPs) for Intrinsa from March 2007. 'Green form' questionnaires were sent to GPs 6 months following the date of the first prescription for Intrinsa for each individual patient, requesting information including age, sex, start and stop dates of treatment (if stopped), prescribing indication and reasons for stopping. Additional questions were asked regarding the patient's menopausal status and use of concomitant oestrogen therapy. RESULTS: The interim cohort consisted of 756 patients. The majority of patients were reported to be female (746 [98.7%]) with a median (interquartile range) age of 50 years (44-55 years). The most commonly reported indication was the licensed indication of HSDD in 580 patients (76.7%). Just under one-half of the patients (n = 364 [48.1%]) were reported to have been hysterectomized and bilaterally oophorectomized (surgically-induced menopause) prior to starting Intrinsa; 127 patients (16.8%) were naturally menopausal. For 222 patients (29.4%) the GP specified that the patient was not using concomitant oestrogen therapy. Overall, only 219 patients (29.0%) in the cohort were being prescribed Intrinsa according to the manufacturer's recommendations. CONCLUSIONS: This study has highlighted that some clinicians are prescribing this product outside the recommended terms of the licence, with less than 30% of patients receiving Intrinsa according to prescribing guidelines. All events experienced by these patients will be analysed to detect any possible adverse events from using Intrinsa outside of the licensed therapeutic indication. The findings support the ongoing postmarketing risk management of the product.

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.

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.

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.

Safety profile of rosuvastatin: results of a prescription-event monitoring study of 11,680 patients.

BACKGROUND AND OBJECTIVE: Rosuvastatin is a lipid-lowering drug, the newest of a class of drugs called HMG-CoA reductase inhibitors, or 'statins', launched in the UK in March 2003. Our objective was to monitor the post-marketing safety of this drug, prescribed in primary care in England, using prescription-event monitoring. METHODS: An observational cohort study in which patients were identified from dispensed prescriptions issued by primary care physicians/general practitioners (GPs) between August and December 2003. Demographic and clinical-event data were collected from questionnaires posted to GPs at least 6 months after the date of first prescription for each patient. Stratified analysis of specific events by starting dose of rosuvastatin was conducted. Follow-up and causality assessment of medically significant events was undertaken. RESULTS: The cohort comprised 11,680 patients (median age 64 years); 50.3% were males (5880 of 11,680). The median period of treatment was 9.8 months. Of these patients, 72.7% (n = 8494) were started on rosuvastatin 10 mg/day. A total of 17.5% (n = 2047) of the patients were reported to have stopped treatment with rosuvastatin. Myalgia was the most frequent reason for stopping rosuvastatin and the most frequently reported clinical event. A 2.5-fold increase in the rate of abnormal liver-function tests (LFTs) was observed for patients started on rosuvastatin 40 mg/day compared with those started on 10 mg/day (2.71; 95% CI 1.53, 4.53). No case of rhabdomyolysis was reported in this cohort. CONCLUSION: Rosuvastatin was considered to be a reasonably well tolerated drug. In the majority of patients, rosuvastatin was prescribed in line with recommendations. Abnormality of LFTs was found to be more frequent with the 40 mg/day dosage of rosuvastatin. Results from this study should be taken into account together with those of other clinical and pharmacoepidemiological studies of rosuvastatin.

Serious skin reactions and selective COX-2 inhibitors: a case series from prescription-event monitoring in England.

BACKGROUND: The erythema multiforme (EM) spectrum of bullous eruptions (toxic epidermal necrolysis [TEN] and Stevens-Johnson syndrome [SJS]) are rare and serious skin reactions that have been reported for cyclo-oxygenase (COX)-2 selective inhibitors. Our objectives were to identify and describe cases of serious skin reactions reported during postmarketing studies of COX-2 selective inhibitors. METHODS: A retrospective review of information from reports of serious skin reactions reported during prescription-event monitoring (PEM) studies of rofecoxib, celecoxib, etoricoxib and valdecoxib conducted in England since 1999. Exposure data were derived from dispensed prescriptions written by primary care physicians for each study drug. Outcome data were derived from questionnaires posted to prescribers at least 9 months after the date of the first prescription for each patient (valdecoxib data collection ongoing at the time of this study). Reports of EM, exfoliative dermatitis, SJS, TEN and symptoms associated with EM (EM syndrome) were identified from the PEM database. Additional data on diagnosis, relevant risk factors and management were requested for each case from the prescriber. A causality assessment was undertaken by a Drug Safety Research Unit research fellow and referred for expert review to a consultant dermatologist. RESULTS: Nine cases of serious skin reactions and two cases of symptoms associated with EM (EM syndrome) were identified. No reports of TEN were recorded. Six skin reaction questionnaires were returned. Of the nine cases of serious skin reactions, four cases (all SJS; one for each COX-2 selective inhibitor studied) were assessed as possibly related to use of the study drug (for combined cohorts: incidence risk 0.008%, 4 of 52,644 patients; rate 0.019 per 1000 patient-months of treatment). These four cases (two male, two female; age range 54-64 years) occurred within 2 weeks of starting treatment; the patient prescribed rofecoxib had reported risk factors (history of allergy, adverse reaction [asthma] to ibuprofen). The two cases from the EM syndrome search (one female, 35 years; one male, 80 years) occurred within 2 weeks of starting treatment; both were assessed as possibly related to use of celecoxib but considered suggestive of angio-oedema/urticaria and hypersensitivity reactions. CONCLUSIONS: This case series provides useful and complementary information to other published studies about serious skin reactions reported during treatment with COX-2 selective inhibitors. The crude incidence of cases of SJS possibly related to the use of a COX-2 selective inhibitor in this case series is very low (0.008% for all four cohorts combined). Prescribers and patients should be aware of the severe and life-threatening risk of EM potentially associated with NSAIDs, including COX-2 selective inhibitors.

Ophthalmological events in patients receiving risedronate: summary of information gained through follow-up in a prescription-event monitoring study in England.

BACKGROUND: In the UK, the nitrogen bisphosphonate risedronate is licensed for the prevention and treatment of osteoporosis and corticosteroid-induced osteoporosis in postmenopausal women. It is also licensed for the treatment of Paget's disease. During a prescription-event monitoring (PEM) study on risedronate we noted a number of ophthalmological events. Recently, case reports of ophthalmological adverse drug reactions in patients taking bisphosphonates were published in the medical literature. The aim of this study was to further evaluate the association of ophthalmological events reported in relation to risedronate treatment during a PEM study on the drug. METHODS: An observational cohort study (PEM study) was conducted in England between September 2000 and June 2002. General practitioners (GPs) were asked for follow-up information on selected events. Events followed up were classified as either 'probably', 'possibly' or 'unlikely' to be related to risedronate, using a modified WHO classification. If insufficient information was obtained on the follow-up questionnaire, the cases were categorised as 'unassessable'. RESULTS: Of the total PEM study cohort of 13 643 patients, 11 156 (82%) were females and 2398 (18%) were males. We received 359 reports of ophthalmological events in 313 patients during the entire study period. Of these we followed up 178 events in 178 patients. Nineteen events in 19 patients were assessed as possibly or probably related to risedronate. The age range for these patients was 50-92 years and the time to onset ranged from 7 days to 5 months. Dry eye (six reports), sore eye (five reports) and conjunctivitis (three reports) were the most frequently reported ophthalmological events assessed as probably or possibly related to risedronate therapy. GPs also reported several other inflammatory conditions of the eye, amongst them two events each of iritis and episcleritis as well as one of keratitis. However, the information received on follow up of these events was insufficient to make causality assessments. CONCLUSION: Patients receiving risedronate can present with a variety of signs and symptoms affecting the eye with different degrees of severity. Patients may present after the first month of treatment. Doctors should have an increased awareness of possible ophthalmological adverse drug reactions in patients receiving this drug, which may affect the eyesight in a population at increased risk of fracture if they fall.

An assessment of the publicly disseminated evidence of safety used in decisions to withdraw medicinal products from the UK and US markets.

BACKGROUND: The objective of this study was to assess the publicly disseminated evidence used to support decisions to withdraw medicinal products for safety reasons, and related implications for the conduct of systematic reviews of harm. METHODS: Medicinal products withdrawn from the UK and US markets for safety reasons were identified from websites of the UK Medicines Control Agency (now known as the Medicines and Healthcare products Regulatory Agency) and the US FDA. Related scientific evidence was identified from communications made to the public and healthcare professionals at the time of each product withdrawal. Evidence for each product withdrawal decision was classified according to study design and outcome. RESULTS: Eleven products were withdrawn during 1999-2001. Randomised trial evidence was cited for two products (18%) and comparative observational studies for two products (18%). Evidence from spontaneous reports supported the withdrawal of eight products (73%), with four products (36%) apparently withdrawn on the basis of spontaneous reports alone. Only two products (18%) were withdrawn on evidence for a patient relevant outcome from comparative studies. CONCLUSIONS: It is rare that evidence other than spontaneous reports is cited in support of drug withdrawals. The serious implications of product withdrawal mandate the elevation of the level of evidence that supports such public health decisions. Once suspicions of important safety hazards have emerged, prospective studies may be unfeasible and may be seen as unethical. Prospective studies can strengthen the evidence base and should be planned to commence when every drug is first marketed. Systematic reviews are unlikely to elicit evidence of harm associated with a drug unless they include spontaneous reports and surrogate outcomes.

Deep vein thrombosis and pulmonary embolism reported in the Prescription Event Monitoring Study of Yasmin.

AIM: To evaluate cases of deep vein thrombosis (DVT) and pulmonary embolism (PE) reported in a prescription event monitoring study of Yasmin, an oral contraceptive. METHODS: Reports of DVT/PE and events suggestive of DVT/PE were followed up by questionnaire. RESULTS: Thirteen cases (DVT five; PE eight), each with possible risk factor(s), were identified in 15 645 females using Yasmin. Applying complete case analysis, the crude incidence rate was 13.7 cases per 10 000 woman-years (95% confidence interval 7.3, 23.4). CONCLUSIONS: Yasmin is associated with venous thromboembolism. An incidence rate has been calculated, but this may be subject to bias and should be interpreted with caution.

The pharmacovigilance of mirtazapine: results of a prescription event monitoring study on 13554 patients in England.

Mirtazpine is the first noradrenaline and serotonin specific antidepressant. We monitored the safety of mirtazapine as reported in primary practice in England. The exposure data were provided by monitoring the dispensed prescriptions issued between September 1997 and February 1999. Questionnaires sent to GPs provided outcome data. Drowsiness/sedation and malaise/lassitude were the most frequent ADRs (116, 71 respectively) and had the highest incidence density (per 1000 patient-months) in the first month of treatment (58.1, 27.8 respectively). Agitation (73), aggression (70), rash (20), hallucinations (13) and abnormal dreams (31 were unlabelled AES while abnormal liver function tests (12), syncope (8), abnormal behaviour (4) and visual disturbance (3) were labelled AES possibly due to mirtazapine use. Serious suspected ADRs reported were facial oedema (5), allergy (3), bone marrow toxicity (2) and myelodysplasia (1).