Rachna Kasliwal

Safety and Drug Utilization Profile of Varenicline as Used in General Practice in England Interim Results from a Prescription-Event Monitoring Study

AbstractBackground: 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 α4β2 nicotinic acetylcholine receptor (α4β2 receptor). The partial agonistic binding leads to alleviation of symptoms of craving and withdrawal, and simultaneously prevents nicotine from binding to the α4β2 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 2682 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 3-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 pharmacoepidemio-logical studies.

Safety Profile of Rosuvastatin Results of a Prescription-Event Monitoring Study of 11 680 Patients

AbstractBackground 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.

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.

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

AbstractBackground: Pioglitazone is an antidiabetic drug that targets insulin resistance in patients with type 2 diabetes mellitus by stimulating the peroxisome proliferatoractivated receptor (PPAR)-#

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

. 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.

Hypoglycaemia with Pioglitazone: Analysis of data from the Prescription-Event Monitoring (PEM) Study

AbstractBackground: 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) post-marketing 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 anti-diabetic 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.

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

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