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.

Comparison of the risk of drowsiness and sedation between levocetirizine and desloratadine: a prescription-event monitoring study in England.

BACKGROUND AND OBJECTIVES: Desloratadine and levocetirizine are histamine H(1) 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).

An observational cohort study investigating the cardiovascular safety of tadalafil when prescribed in primary care in England: mortality due to ischaemic heart disease.

OBJECTIVE: To examine the cardiovascular safety of tadalafil, a phosphodiesterase type-5 inhibitor used for treating erectile dysfunction in patients prescribed this drug by general practitioners (GPs) in England in 2003, focusing on mortality due to ischaemic heart disease (IHD). PATIENTS AND METHODS: Patients in this observational cohort study were identified from dispensed prescriptions for tadalafil issued by GPs from February to November 2003. Demographic and outcome data were requested from patients' GPs using a postal questionnaire. A standardized mortality ratio (SMR) was calculated using indirect standardization for all deaths from IHD or myocardial infarction (MI) in male patients who were prescribed tadalafil, regardless of whether they were taking tadalafil at the time, compared to those in the English male population (2002). RESULTS: Clinical information was obtained for 6266 patients; patient sex could not be confirmed for 37 but in the remaining 6229 the median age was 61 years (interquartile range 53-68). The age was not specified for 2361 (37.7%) of the patients. Excluding patients not taking tadalafil at the time of the event, cardiovascular events included chest pain in 20, angina in 18, MI in 15 (including six fatal) and IHD in 11 (including five fatal). There were also six deaths where the cause was not ascertained; five of these patients were known to be male. Comparison of mortality due to IHD or MI for men with those in the English male population (2002) provided an SMR of 0.91 (95% confidence interval 0.50-1.48). CONCLUSIONS: The results from this study suggest a similar incidence of death due to IHD or MI in men prescribed tadalafil to that in the male English population. However, due to possible under-reporting and the limitations of using an external comparator, these results should be interpreted in context with other studies on the cardiovascular effects and safety of tadalafil.

Examination of the safety and use of apomorphine prescribed in general practice in England as a treatment for erectile dysfunction.

OBJECTIVE: To examine the safety and use of apomorphine as prescribed in general medical practice in England as a treatment for erectile dysfunction (ED). PATIENTS AND METHODS: Apomorphine hydrochloride (marketed as Uprima, Abbott Laboratories Ltd, UK) is licensed in the UK as a sublingual therapy for ED. It is the first treatment for ED with a central mode of action. This postmarketing observational cohort study was conducted using prescription-event monitoring (PEM) methods. Exposure information was obtained from dispensed prescription data for patients first prescribed apomorphine between October 2001 and December 2002. Outcome data were derived from Green-Form questionnaires posted to prescribing physicians > or = 6 months after the date of the first apomorphine prescription for each patient. The study cohort comprised 11 185 patients, 99.3% (11,111) of whom were men, with a median (interquartile range) age of 61 (54-68) years. RESULTS: The most frequently reported prescribing indication was ED and the most frequently reported reason for stopping apomorphine was that it was 'not effective'. In addition, the percentage of patients for whom apomorphine was reported to have been effective was relatively low. Headache was the most commonly reported adverse drug reaction, and the most frequently reported clinical condition occurring in the first month of observation. A small number of events (24) were reported that were not listed in the current Summary of Product Characteristics (SPC) and were considered by the prescribing general practitioner (GP) to be associated with apomorphine use. CONCLUSION: The proportion of patients for whom apomorphine was reported to be effective was low. Also, 'not effective' was the most frequently reported event and a high percentage of patients stopped apomorphine because it was 'not effective'. The most frequently reported clinical adverse events (headache and nausea) were those listed in the SPC. A small number of reports for unlabelled events were thought by prescribers to be related to apomorphine use. The confounding factors of patient age and coexisting disease should be considered when assessing data from this study.

Pregnancy outcome of women exposed to bupropion during pregnancy: a prospective comparative study.

OBJECTIVE: Bupropion was developed for the treatment of depression, but subsequently was found to be effective for smoking cessation. To date, there are no prospective comparative studies examining its safety in pregnancy. The primary objective was to determine whether bupropion increases the risks for major malformations above baseline. The secondary objective was to examine the rates of live births, stillbirths, spontaneous and therapeutic abortions, mean birth weight, and gestational age at birth. STUDY DESIGN: Women who were pregnant or planning a pregnancy and taking bupropion were enrolled in the study. Follow-up of pregnancy outcome was carried out between 4 months and 1 year after delivery. Three comparisons were carried out: 1) women exposed to bupropion vs a nonteratogen group; 2) those taking for depression vs other antidepressants, vs a nonteratogen group; 3) spontaneous abortions were compared between those taking for depression, vs another antidepressant group vs a nonteratogen group. RESULTS: We completed follow-up on 136 women exposed to bupropion during the first trimester of pregnancy. There were (105) live births, no major malformations, the mean birth weight was (3450g), the mean gestational age at delivery was (40 weeks), the number of spontaneous abortions was 20, there were 10 therapeutic abortions, there was 1 stillbirth, and 1 neonatal death. There were no statistically significant differences between any of the end points we examined between the exposed and comparison groups, with the exception of significantly more spontaneous abortions in the bupropion group (P = .009). CONCLUSION: These results suggest that bupropion does not increase the rates of major malformation above baseline. The higher rates of spontaneous abortions are similar to other studies examining the safety of antidepressants during pregnancy.

Evaluation of the safety of bupropion (Zyban) for smoking cessation from experience gained in general practice use in England in 2000.

BACKGROUND: Bupropion (Zyban) is the first new pharmacological treatment for smoking cessation to be introduced since nicotine replacement therapy. In smoking cessation trials, it has been associated with minimal side effects. A range of suspected adverse drug reactions (ADRs) were reported via the spontaneous reporting system following its use in smoking cessation. AIM: To examine the safety of bupropion used in general medical practice in England as a treatment for cessation of smoking. OBJECTIVES: To quantify the incidence of events that were reported for patients prescribed bupropion; and to identify any previously unrecognised ADRs. METHODS: A post-marketing observational cohort study was conducted using the methodology of prescription-event monitoring (PEM). Exposure data were derived from the first prescription dispensed for patients whose prescription details were processed by the Prescription Pricing Authority in August 2000. Outcome data were derived from 'green form' questionnaires (GFs) sent to general practitioners (GPs) at least 6 months following the first prescription issued. Incidence densities (IDs) were calculated for events reported per 1000 weeks of patient treatment and ID differences between time periods analysed. Events of interest were followed up by postal questionnaire sent to GPs. All-cause and condition-specific mortality up to 12 weeks after starting bupropion were compared through indirect standardisation between the PEM cohort and Cancer Prevention Study-II (USA) (CPS-II) data. RESULTS: GF response rate was 48.1%, with 11,735 GFs containing useful data - of these patients, 5695 (48.5%) were male (median age 47 years, range 16-88 years) and 6009 (51.2%) were female (median age 47 years, range 16-87 years). Age was recorded for 4092 (34.9%) of the cohort of 11,735 after follow-up. There were 566 events in 350 patients reported by GPs as ADRs to bupropion. GPs reported 10,200 reasons for stopping bupropion among 9056 patients. The highest ranked clinical events (by ID for weeks 1-6 of treatment) were; 'insomnia' ( n=308), 'nausea/vomiting' ( n=243) and 'dizziness' ( n=185). Bupropion was taken in the first trimester of 12 pregnancies and the outcome ascertained in eight cases - five live births (no congenital abnormalities reported), two therapeutic terminations and one intrauterine death (no further details). The standardised mortality ratio (SMR) for all-cause mortality up to 12 weeks after starting bupropion was 0.77 (95% CI: 0.42, 1.28). CONCLUSION: This study describes the safety profile of bupropion (Zyban) as used in the community; a small number of adverse events were reported that were not included on the SmPC. For many events, nicotine withdrawal was a confounding factor. SMR calculations did not provide evidence for a higher rate of mortality (either all-cause or condition-specific) in the PEM cohort relative to smokers from the CPS-II cohort in the USA. While reassuring, the SMR should be interpreted in context with results from other studies on bupropion when used for smoking cessation.