Lynda Wilton

Comparison of the risk of drowsiness and sedation between Levocetirizine and Desloratadine: a prescription-event monitoring study in England

AbstractBackground and objectives: Desloratadine and levocetirizine are histamine H1 receptor antagonists (antihistamines) that were launched in the UK in 2001. Our objective was to compare the frequency with which drowsiness and sedation were reported for desloratadine and levocetirizine within the first 30 days of observation, as monitored using the observational cohort technique of prescription-event monitoring (PEM). Methods: Exposure data were derived from dispensed prescriptions written by primary care physicians and outcome data were derived from questionnaires that were posted to prescribers at least 6 months after the date of the first prescription for each patient. The odds ratio (OR) was calculated using unconditional logistic regression modelling. The effect of age, sex, reported prescribing indication (allergic rhinitis with asthma/wheezing, allergic rhinitis without asthma/wheezing, ‘other’), pattern of use and reported previous antihistamine use on the OR was examined. A time-to-event analysis was performed. Results: The cohorts comprised >24 000 patients in total. Cohort demographics were similar (both cohorts: median age 37 years; 60% women); the most frequently reported prescribing indication for both drugs was allergic rhinitis without asthma/wheezing (54%). The incidence of first reports of drowsiness/sedation for levocetirizine or desloratadine was low (46 [0.37%] and 9 [0.08%], respectively) and statistically different (p < 0.0001). These events tended to occur earlier for desloratadine than levocetirizine (50% at 7 or 14 days of observation, respectively; p = 0.6487), but the cumulative time to event differed, with more events observed for levocetirizine than expected (p < 0.0001; 46 vs 28.09). The final estimates of risk were the sex-adjusted ORs for each prescribing indication category: allergic rhinitis with asthma/wheezing (3.51; 95% CI 0.71, 17.43; n = 3357), allergic rhinitis without asthma/wheezing (6.75; 95% CI 2.37, 19.22; n = 12 627) and ‘other’ (3.11; 95% CI 0.86, 11.31; n = 6725). Discussion: Although the reporting rates of drowsiness and sedation are low for both drugs, patients prescribed levocetirizine are more likely to experience drowsiness and sedation in the first month of observation (after starting treatment) than patients prescribed desloratadine. For patients with allergic rhinitis without asthma/wheezing, the sex-adjusted odds of drowsiness/sedation were over six times greater in patients using levocetirizine than desloratadine in the first month of observation, with the OR being statistically significant. For the other two indication categories, allergic rhinitis with asthma/wheezing and ‘other’, the OR was not statistically significant. Conclusions: Although the risk of drowsiness/sedation is low, conditions such as allergic rhinitis are common, which makes any impact on patient cognitive function important. Doctors should be aware of this when prescribing these products to patients where daytime sedation is undesirable. However, essential components of the comparative benefit-risk evaluation of these two products include assessment of efficacy and patient preference (neither of which forms part of this study).

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

AbstractBackground: 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 14373, 12768, 4549 and 5727 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 1000 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.

A Comparison of Reported Gastrointestinal and Thromboembolic Events Between Rofecoxib and Celecoxib Using Observational Data

Background and objectives: Rofecoxib, a selective cyclo-oxygenase (COX)-2 inhibitor, was a widely marketed drug that was used for relief of pain and inflammation in arthritic conditions. It was withdrawn from the market worldwide in September 2004 because of an increased risk of cardiovascular events. Celecoxib, which belongs to the same class of drugs, is now under scrutiny for the risk of similar events. The objective of our study was to compare the incidence of gastrointestinal (GI) [symptomatic and complicated upper GI] events and thromboembolic (cardiovascular, cerebrovascular and peripheral venous) events reported for patients prescribed rofecoxib or celecoxib in primary care.Methods: A retrospective analysis of selected events was conducted using data collected from previously conducted prescription-event monitoring (PEM) studies for rofecoxib and celecoxib. PEM is an observational cohort technique. Exposure data were derived from dispensed prescriptions for rofecoxib (July–November 1999) and celecoxib (May–December 2000) that were written by primary care general practitioners in England. Outcome data were clinical events and information on potential risk factors reported on simple questionnaires (posted to prescribers approximately 9 months after the date of the first prescription). Incidence rates of the first event during treatment within each thromboembolic and GI group were calculated during the 270 days after the patient started receiving either of the drugs; crude and adjusted rate ratios (RR) were calculated for rofecoxib compared with celecoxib using Poisson regression modelling.Results: The rofecoxib and celecoxib PEM cohorts contained 15 268 and 17 458 patients, respectively. For the GI event groups, the adjusted RRs for rofecoxib compared with celecoxib were: 1.21 (95% CI 1.09, 1.36) for symptomatic upper GI events and 1.60 (95% CI 0.95, 2.70) for complicated upper GI conditions. For the thromboembolic event groups, the adjusted RRs were: 1.04 (95% CI 0.50, 2.17) for cardiovascular thromboembolic events; 1.43 (95% CI 0.86, 2.38) for cerebrovascular thromboembolic events; and 0.36 (95% CI 0.01, 1.34) for peripheral venous thromboembolic events.Conclusions: This study was a retrospective comparison of PEM studies conducted for rofecoxib and celecoxib. For symptomatic upper GI events, a 21% increase in the relative rate was found for rofecoxib users compared with celecoxib users after adjusting for identified risk factors. For complicated upper GI events, no statistically significant difference in the incidence was observed between rofecoxib and celecoxib users after adjusting for identified risk factors. For the three thromboembolic event groups, no evidence of a statistically significant difference between rofecoxib and celecoxib users was found after adjusting for identified risk factors.This study contributes to the understanding of the association between COX-2 inhibitors and thromboembolic events. However, it should be borne in mind that we had information on only a limited number of confounding variables for thromboembolic events. Further research is required to fully understand the risks and benefits of using celecoxib and other COX-2 inhibitors. Meanwhile, doctors should be cautious when prescribing these products, particularly to patients with risk factors for developing thromboembolic events.

Risk of Depressive Episodes with Rimonabant

AbstractBackground: Marketing authorization for rimonabant was withdrawn in October 2008, mainly because the psychiatric adverse effects could not be addressed by further risk minimization. Objective: The aim of the study was to compare the risk of major and minor depressive episodes in the 6 months prior to and the 6 months after starting treatment with rimonabant. Methods: We conducted a before and after study using the observational cohort technique of Modified Prescription Event Monitoring to compare the risk of major and minor depressive episodes in new users of rimonabant reported in the 6 months before to the 6 months after starting treatment with rimonabant. Patients were identified from dispensed prescriptions issued by primary care physicians from June 2006 to October 2008. Patient demographics and information on depressive episodes were requested 6 months after the date of the first prescription for each patient. Risk ratios (RR) were calculated by comparing before and after events using a matched analysis. Results: The cohort comprised 10011 patients. The number of patients who had major depressive episodes before and after starting treatment were 147 and 168, respectively (RR 1.14; 95% CI 0.94, 1.39) and the number of patients who had minor depressive episodes were 825 and 829, respectively (RR 1.00; 95% CI 0.93, 1.10). For patients who had a previous history of psychiatric illness (n= 1132), 91 and 73, respectively, experienced major depressive episodes (RR 0.80; 95% CI 0.62,1.03), and 367 and 220, respectively, experienced minor depressive episodes (RR 0.59; 95% CI 0.53, 0.68). For patients without a previous history of psychiatric illness (n = 8879), 56 and 95, respectively, experienced major depressive episodes (RR 1.7; 95% CI 1.2,2.3), and 458 and 609, respectively, experienced minor depressive episodes (RR 1.33; 95% CI 1.20, 1.48). Conclusions: When comparing all patients in the cohort, there was no increased risk of developing a depressive episode whilst taking rimonabant. However, when considering subsets of patients with and without a previous history of psychiatric illness, the risk profiles were different. In patients without a previous history of psychiatric illness, there were more depressive episodes in the 6 months after starting treatment compared with the 6 months before starting treatment with rimonabant.

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

AbstractBackground: Strontium ranelate is indicated for the treatment of postmeno-pausal 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®) 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 post-menopausal 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.

The Safety and Effectiveness of Newer Antiepileptics: A Comparative Postmarketing Cohort Study

Clinical trials for the newer antiepileptic drugs (AEDs) have provided inconclusive information to evaluate comparative risk benefit. The authors use data from postmarketing observational cohort studies to compare the failure of treatment with lamotrigine, vigabatrin, and gabapentin in patients with refractory epilepsy. The Drug Safety Research Unit has conducted prescription event monitoring (PEM) studies for lamotrigine, vigabatrin, and gabapentin to monitor their safety when used in primary care. The primary outcome of this study was time to treatment failure in patients who had been prescribed the drug after the start of the PEM study. Patients on gabapentin had reduced time to treatment failure compared to those on the other 2 drugs. The age‐ and sex‐adjusted hazard ratio of failure was 1.53 (95% confidence interval [CI] = 1.38–1.70) for gabapentin compared to lamotrigine and 1.19 (95% CI = 1.10–1.30) for vigabatrin compared to lamotrigine. The observed differences between the 3 study drugs might be confounded by a higher proportion of patients treated with gabapentin having refractory epilepsy, a shorter duration of the gabapentin PEM study, and a lower relative dose of gabapentin (approved at the time of the PEM study). The current study provides information about the routine usage of newer AEDs, which complements evidence from clinical trials regarding the efficacy and safety of these AEDs. Although this study showed differences on times to treatment failure between lamotrigine, vigabatrin, and gabapentin, the results are only useful when considered together with results from other studies seeking to answer the same questions.

Ophthalmological Events in Patients Receiving Risedronate Summary of Information Gained Through Follow-Up in a Prescription-Event Monitoring Study in England

AbstractBackground: 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.

Paediatric Postmarketing Pharmacovigilance Using Prescription-Event Monitoring Comparison of the Adverse Event Profiles of Lamotrigine Prescribed to Children and Adults in England

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

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

AbstractBackground: Desloratadine is a non-sedating, long-acting histamine H1 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.

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

Post‐marketing pharmacovigilance is a cornerstone of monitoring and evaluating the safety of medicines in children and adults. However the methods may require modification to detect paediatric signals. The aim of this study was to compare the adverse event (AE) profile of children and adults taking vigabatrin, using modified signal detection methods (SDMs).