Mira Harrison-Woolrych

Safety and Usage of Atypical Antipsychotic Medicines in Children A Nationwide Prospective Cohort Study

AbstractObjective: To study the safety and usage of atypical antipsychotic medicines in post-marketing use in a nationwide paediatric population. Design: Prospective observational cohort study using prescription event monitoring and record linkage. Population: New Zealand children aged ≤15 years, who were prescribed atypical antipsychotic medicines between April and July 2003. Outcomes: Usage measures included prescription data for each medication, the diagnosis for which the patient was being treated and main target symptom. Safety outcome measures were all new clinical adverse events between the start of treatment (which could be before April 2003) and 30 November 2004. Results: The cohort included 420 children aged 2–15 years. Total exposure to atypical antipsychotic medicines was 641.2 patient-years of treatment with most (94%) of the exposure being to risperidone. The most common diagnoses were disruptive disorders. The symptoms most frequently targeted by the atypical antipsychotic were aggression and difficult behaviour. The treatment of sleep disorders as a target symptom was reported in 3% of children. A total of 131 (31 %) children experienced an adverse event. The most frequent adverse events reported were weight gain, severe dental caries and somnolence. The incidence of diabetes mellitus was 4 (95% CI 0.5,15) cases per 1000 patient-years of treatment in this study. Four children prescribed risperidone developed symptoms of depression, giving an incidence of 8 (95% CI 2.0, 21) cases per 1000 patient-years of treatment. Conclusions: This study provides a picture of ‘real-life’ use of atypical antipsychotics in a nationwide cohort of children. Most prescriptions were for risperidone and the most common diagnoses were disruptive disorders. Investigation of the symptoms targeted by these medicines identified unexpected use for the treatment of sleep disorders. Regarding safety, symptoms of depression were identified as a potential new signal for risperidone in the paediatric population. Further research is now required to investigate this.

Psychiatric Adverse Events Associated with Varenicline

AbstractBackground: Psychiatric adverse events, including depression, suicidal ideation and psychotic reactions have been reported in patients taking the smoking cessation medicine varenicline. However, data regarding the frequency of psychiatric adverse reactions in ‘real-life’ postmarketing use are limited to date. Objective: The aim of the study was to calculate the occurrence rates of psychiatric adverse reactions in a nationwide general population prescribed varenicline in New Zealand. Methods: Observational prospective cohort study using Prescription Event Monitoring methods. All New Zealand patients dispensed a prescription for varenicline from 1 April 2007 to 31 March 2008 were included in this study. Patients were followed up by multiple methods, including linkage to national morbidity and mortality datasets, questionnaires to patients’ doctors and assessment of spontaneous reports sent to the Intensive Medicines Monitoring Programme. Main outcome measures were occurrence rates of psychiatric adverse events in the total patient cohort and in the subgroup for whom a follow-up questionnaire was returned (the ‘responder population’). Results: The cohort for this study included 3415 patients prescribed varenicline during the first year of monitoring in New Zealand. Follow-up by record linkage was performed for 3353 (98%) patients, and questionnaires were returned for 1394 (42%) of these patients. Of 1394 questionnaires returned, 1310 were valid and defined as the ‘responder’ population. Sleep disorders, including insomnia, sleep disturbance, dreams and nightmares, were the most frequently reported psychiatric events and were experienced by 56 (4.3%) patients in the responder population. Symptoms of depression were reported by 39 (2.98%) patients in the responder population (24 new-onset depression, 14 worsening of pre-existing depression and 1 report of impaired motivation). Withdrawal reactions after stopping varenicline were reported by 6 (0.46%) patients in the responder population. Serious psychiatric reactions including suicide (one case), suicidal ideation (two cases) and psychotic reactions (three cases) were also identified. Six self-harm events (one fatal, five non-fatal) were identified in the total cohort, giving an occurrence rate of 0.18% (95% CI 0.06, 0.38) in this population. Conclusions: This intensive postmarketing study of 3415 New Zealand patients demonstrates that psychiatric adverse events are commonly reported in patients taking varenicline. Approximately 3% of patients experienced symptoms of depression and the majority of these cases appeared to have a causal association with varenicline. Serious psychiatric reactions including suicide, suicidal ideation and psychotic reactions were also identified, but these were less frequently reported.

Nocturnal enuresis in patients taking clozapine, risperidone, olanzapine and quetiapine: comparative cohort study

BACKGROUND Nocturnal enuresis has been reported in patients taking clozapine, but the incidence has not been accurately established. The incidence of enuresis in patients taking risperidone, olanzapine or quetiapine is unknown. Aims To compare nocturnal enuresis in patients taking clozapine with that in patients taking risperidone, olanzapine or quetiapine. METHOD Observational cohort study using prescription event monitoring methods. Patients prescribed atypical antipsychotic medicines were followed up by questionnaires that were sent to their medical practitioner. Practitioners were asked to directly ask their patients about bed-wetting. RESULTS Nocturnal enuresis was reported by 17 of 82 (20.7%) patients taking clozapine, 11 of 115 (9.6%) taking olanzapine, 7 of 105 (6.7%) taking quetiapine and 12 of 195 (6.2%) taking risperidone. Compared with clozapine, the risk of nocturnal enuresis was significantly lower in patients taking olanzapine (odds ratio, OR = 0.43, 95% CI 0.19-0.96), quetiapine (OR = 0.33, 95% CI 0.13-0.59) or risperidone (OR = 0.27, 0.12-0.59), with odds ratios adjusted for age, gender and duration of treatment. CONCLUSIONS Approximately one in five patients prescribed clozapine experienced bed-wetting. This was significantly higher than the rate of nocturnal enuresis in patients taking olanzapine, quetiapine or risperidone.

Cardiovascular Events in Patients taking Varenicline

AbstractBackground: The smoking cessation medicine varenicline has been associated with an increased risk of cardiovascular adverse events compared with placebo in clinical trials. Cases of cardiovascular events, including myocardial infarction (MI) and cardiac dysrhythmias, have been noted from spontaneous reporting systems. Objective: The aim of this study was to summarize and describe cardiovascular adverse reactions identified in a general population during intensive postmarketing surveillance of varenicline in New Zealand. Methods: Observational prospective cohort study using prescription event monitoring methods. The patient cohort was established from pharmacy dispensing data sent directly to the Intensive Medicines Monitoring Programme (IMMP) for all New Zealand patients prescribed varenicline. Adverse cardiovascular events were identified from follow-up questionnaires completed by doctors, spontaneous reports and by record linkage to national datasets. Cardiovascular events were organized into clinical groupings for further clinical assessment, and key cases were identified. Results: All New Zealand patients dispensed a prescription for varenicline from 1 April 2007 to 30 November 2010 were included in this study. At 31 January 2011, the IMMP varenicline events dataset included a total of 172 adverse events in the IMMP circulatory System Organ Class. There were 48 reports of myocardial ischaemia, including 12 reports of MI and 8 reports of angina. Two key cases of myocardial ischaemia suggested that this may have been induced by coronary artery spasm secondary to varenicline treatment. There were 50 reports of hypotensive events, with two key cases having documented hypotension associated with chest pain/tightness, and a further 27 reports of dysrhythmia events, including two unexplained sudden deaths. Conclusions: This paper presents a series of cases of cardiovascular events in patients taking varenicline. Whilst there were multiple confounding factors in some patients, key cases were identified that suggested a possible mechanism of dysregulation of blood pressure leading to vasospasm or hypotension.

Uterine Perforation with the Levonorgestrel-Releasing Intrauterine Device Analysis of Reports from Four National Pharmacovigilance Centres

AbstractBackground: Levonorgestrel-releasing intrauterine devices (LNG-IUD) are commonly used for contraception and other indications in many countries. National pharmacovigilance centres have been receiving reports from healthcare professionals and patients of uterine perforation associated with the use of these LNG-IUDs. Methods: National pharmacovigilance centres in the Netherlands, New Zealand, Switzerland and Germany did a search on their adverse drug reaction databases for reports of cases of uterine perforation after insertion of a LNG-IUD received between the introduction of the LNG-IUD onto the market in the late 1990s and 15 July 2007.The number of women affected and patient characteristics such as age, parity and breastfeeding status were examined. In addition, the method of detection of the perforation and the time until discovery of the perforation were analysed. Results: Between the introduction of the LNG-IUD onto the market in each country and 15 July 2007, 701 cases of uterine perforation with a LNG-IUD were reported; 8.5% of the perforations were detected at the time of insertion. Abdominal pain and control/check-up visits were the most common events that lead to the detection of a perforation. Of 462 women known to be parous, 192 (42%) were breastfeeding at the time the perforation was discovered. Conclusions: Uterine perforations can be asymptomatic and may remain undetected for a long time after IUD insertion. Abdominal pain, control/ check-up visits or changes in bleeding patterns are triggers for detection of perforation and should therefore be taken seriously.

Fatal and Non-Fatal Cardiovascular Events in a General Population Prescribed Sibutramine in New Zealand A Prospective Cohort Study

AbstractBackground: The cardiovascular safety of sibutramine is currently under review by medicines regulatory authorities worldwide after the SCOUT (Sibutramine Cardiovascular Outcome Trial) showed an increased risk of cardiovascular events in patients taking sibutramine. Further data regarding the cardiovascular safety of sibutramine in a general population are now required. Objective: To quantify the risk of fatal and non-fatal cardiovascular adverse events in a general population prescribed sibutramine in postmarketing use. Study Design: Observational prospective cohort study of patients dispensed sibutramine during a 3-year period (2001–4) and followed up for at least 1 year after their last prescription. The study included record-linkage to national mortality datasets to identify fatal events. Setting: Postmarketing ‘real-life’ use of sibutramine in a general population in New Zealand. Patients: All New Zealand patients dispensed a prescription for sibutramine in a 3-year period (for whom a National Health Identification number could be validated). 15 686 patients were included in the record linkage study for fatal events. A subgroup of 9471 patients was followed up by intensive methods for non-fatal events. Main Outcome Measures: (i) Rate of death from all causes and from cardiovascular events; and (ii) rates of non-fatal cardiovascular adverse events. Results: Total exposure to sibutramine for 15 686 patients in the validated cohort was 5431 treatment-years. The rate of death from all causes in this cohort was 0.13 (95% CI 0.05, 0.27) per 100 treatment-years exposure. The rate of death from a cardiovascular event was 0.07 (95% CI 0.02,0.19) per 100 treatment-years exposure. The most frequent non-fatal cardiovascular events in the intensively followed up cohort were hypertension, palpitations, hypotensive events and tachycardia. Conclusions: Risk of death from a cardiovascular event in this general population of patients prescribed sibutramine was lower than has been reported in other overweight/obese populations. The results of this study suggest that further evaluation of the benefit-risk profile of sibutramine is now required.

Insertion of the Multiload Cu375 intrauterine device; experience in over 16,000 New Zealand women

Insertion of Multiload Cu375 was studied in 16,159 women in a 10-year prospective observational cohort study in New Zealand. Of 17,468 insertions, about 9% were performed in nulliparous women. Problems fitting Multiload Cu375 (e.g., failed or difficult insertion) were experienced during approximately 2% of all insertions. The incidence of these was significantly higher in nulliparous women compared to parous women. Adverse reactions to insertion (e.g., pain, bleeding) occurred in 1.2% of all insertions, with nulliparous women experiencing significantly more adverse reactions than parous women. The insertions were performed by 1,700 different doctors in New Zealand with general practitioners performing 92% of these. Doctors who reported inserting over 100 devices in the study period experienced significantly less insertion problems than doctors who reported inserting less than 10 devices. This study suggests that insertion of Multiload Cu375 in a mixed community setting is associated with few inserting problems and adverse reactions to insertion. Risk factors identified for inserting problems included nulliparity and experience of the doctor inserting the intrauterine device.

Safety data from New Zealand

The recent letters on varenicline and suicide raise interesting issues about different approaches to identify and quantify risk in pharmacovigilance.1 2 In New Zealand the Intensive Medicines Monitoring Programme (IMMP)3 is currently performing an observational cohort study of varenicline. Our cohort is established directly from pharmacy dispensing data, which more accurately estimates varenicline exposure than prescription records …

Focusing on risk communication about medicines: why now?

Communication about the risks of medicines is not a new issue. Patients have long since sought advice about remedies, whether from family, healthcare workers or the wider community in traditional ways, or via websites and social media in today’s world. As pharmacovigilance professionals, interacting with patients, healthcare professionals, health policy makers, journalists and the general public has become part of our daily activity, in order to manage risks with medicines appropriately and reduce patient harm.

The Role of the New Zealand Intensive Medicines Monitoring Programme in Identification of Previously Unrecognised Signals of Adverse Drug Reactions

The New Zealand Intensive Medicines Monitoring Programme (IMMP) was established in 1977 to enhance monitoring for previously unrecognised adverse drug reactions associated with selected new medicines. This involved establishing cohorts from prescription data and collection of event information: thus New Zealand was a pioneer in the development of the methodology now known as Prescription Event Monitoring (PEM). In the IMMP, PEM cohorts are established using information, supplied by pharmacies, from prescriptions for medicines that have been selected for monitoring. Events are identified subsequently from follow-up questionnaires to prescribing physicians and from other sources, including spontaneous reporting of events. The objective of this review is to illustrate how the IMMP methodology enables identification of signals of previously unrecognised adverse reactions. This is enhanced by high response rates from pharmacists and prescribers in providing prescription and event data respectively. In addition, high quality event reports are obtained from multiple sources including follow-up event returns from prescribers, reports received through the national spontaneous reporting programme, prescription returns and from record linkage to other databases. Collaboration with other national centres and with the WHO Collaborating centre for international drug monitoring in Uppsala, Sweden (WHO-UMC) enables information on cases from their databases to be used in validation of IMMP signals. The NZ IMMP methodology and signals of previously unrecognised adverse drug reactions arising from the IMMP databases are reviewed. Recent signals include amnesia and QTc prolongation with sibutramine; pain activation with sumatriptan; epistaxis with risperidone; psychiatric and visual disturbances with the COX-2 inhibitors celecoxib and rofecoxib and psoriasis with rofecoxib. In addition, other types of investigation are discussed along with the importance of rapid communication to prescribers of new information concerning the risks of medications. The IMMP has features that differ from those of other centres that incorporate PEM methodology. New Zealand is a small country (approximately 4 million) and thus communication is relatively easy. This facilitates good rapport with prescribing doctors. However, mainly because of the small population, several years may be required to achieve a large cohort. Although this has drawbacks in terms of rapid results, it enables a longitudinal approach to prescription data analysis, including aspects of prescribing such as reasons for cessation of therapy and changes in prescribing practise. Although not specifically reviewed in this article, the programme has also made significant contributions in determining the incidence of certain adverse drug reactions and in carrying out in-depth epidemiological investigations relating to the safe use of medicines. Through these activities, the New Zealand IMMP provides an ongoing contribution to safety in the use of medicines.