Synthetic cannabis: adverse events reported to the New Zealand Pharmacovigilance Centre.

INTRODUCTION: Synthetic Cannabinoid Receptor Agonists (SCRA) were legally available in New Zealand (NZ) prior to May 2014. During the period November 2012-November 2019, reports of adverse events associated with SCRA use from across the country were submitted to the New Zealand Pharmacovigilance Centre (NZPhvC). The purpose of this study was to investigate adverse reactions associated with SCRA reported to the NZPhvC. METHODS: The NZPhvC database was searched for adverse events involving SCRA. Cases were extracted and analysed for demographic information of users, reactions reported and SCRA involved. Summary statistics were performed using SAS 9.3. RESULTS: One hundred and thirteen cases were identified from 1 November 2012 to 31 November 2019, comprising 81 males (71.7%) and 32 females (28.3%), with a mean age of 28.4 ± 10.1 years. Ethnicity included European (51.3%, n = 58), Maori (39.8%, n = 45), Indian (1.8%, n = 2), and Polynesian (0.9%, n = 1). There were a total of 327 reactions recorded in these cases, and the majority were psychiatric (52%, n = 170), followed by nervous system (11%, n = 35), alimentary (7%, n = 24), and cardiovascular (7%, n = 23). Where the compounds could be identified, the majority of events involved AB-FUBINACA (n = 18), 5 F-PB-22 (n = 17), and PB-22 (n = 6). CONCLUSIONS: This study found that young, male and European populations frequently were involved in SCRA adverse events. A disproportionate number of Maori were present in this group. Psychiatric reactions were of clinical significance, and possibly correlated to the high potency and efficacy of SCRA compared to cannabis. Pharmacovigilance is a useful tool to measure and monitor illicit drug use, and with appropriate infrastructure and capacity has the potential to contribute to drug policy at a national level.

Cardiovascular events in patients taking varenicline: a case series from intensive postmarketing surveillance in New Zealand.

BACKGROUND: 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.

Psychiatric adverse events associated with varenicline: an intensive postmarketing prospective cohort study in New Zealand.

BACKGROUND: 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.

Utilization of the smoking cessation medicine varenicline: an intensive post-marketing study in New Zealand.

PURPOSE: To examine the utilization of varenicline during the first year of marketing in New Zealand (NZ) and to examine how this compares with the dosing instructions recommended in the Champix product information. METHODS: Dispensing records for all NZ patients prescribed varenicline were collected by the Intensive Medicines Monitoring Programme (IMMP) during the first year this medicine was available in this country. Analyses of these data included patient characteristics and patterns of usage-in particular the duration of treatment dispensed as the first course. An assessment of the effectiveness of varenicline in post-marketing use was also performed on a sub-group of the cohort for whom follow-up information was available. RESULTS: Of 3415 patients in the first year IMMP cohort, only 125 patients (4%) were dispensed the recommended 12 weeks varenicline treatment. 1299 (38%) were dispensed 14 days treatment (most often as a Starter Pack), 766 (22%) were dispensed 6 weeks, 411 (12%) were dispensed 4 weeks and 332 (8%) patients were dispensed more than 12 weeks treatment as a continuous course. The most common reasons for stopping varenicline prematurely were adverse reactions and cost of treatment. In a subgroup of 1299 patients, varenicline was reported to have been effective for 359 (28%) patients. CONCLUSIONS: In 'real-life' post-marketing use, most patients did not receive 12 weeks varenicline treatment as recommended in the Champix product information. This observation may have implications for the effectiveness of this smoking cessation medicine.

Fatal and non-fatal cardiovascular events in a general population prescribed sibutramine in New Zealand: a prospective cohort study.

BACKGROUND: 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.

A nationwide cohort study of the use of the levonorgestrel intrauterine device in New Zealand adolescents.

BACKGROUND: While the use of the levonorgestrel intrauterine device (LNG-IUD) is well established in the adult population, there have been no research studies specifically on the use of the LNG-IUD in adolescents. STUDY DESIGN: A nationwide cohort study of 179 adolescents in New Zealand using the LNG-IUD, by means of a follow-up questionnaire to their practitioner, was conducted to determine the indications for insertion of the LNG-IUD and to establish patterns of use, including duration of use and reasons for removal. RESULTS: The study, with a 94% response rate, demonstrated that the most common indication for use was menorrhagia (17%); 29% of adolescents had an "off-label" primary indication. There was a 1-year continuation rate of 85%. The cumulative incidence of expulsion was 8%. CONCLUSION: The results of this study should be reassuring for practitioners and adolescents considering use of the LNG-IUD. However, further research is required into the safety and efficacy of the LNG-IUD in adolescents especially in the management of off-label indications.

The Intensive Vaccines Monitoring Programme (IVMP): an electronic system to monitor vaccine safety in New Zealand.

New Zealand introduced a tailor-made vaccine (MeNZB) for epidemic control of Group B meningococcal disease. The Intensives Vaccine Monitoring Programme (IVMP), which prospectively collected data electronically on a cohort of children receiving vaccinations in sentinel practices across NZ, was developed as part of a national multi-faceted safety strategy. The main aim of the IVMP was to identify the presence of unexpected adverse events occurring with MeNZB vaccination. We describe the methodology and success factors plus consider the limitations encountered in this system which shows potential as a means for post-marketing vaccine and medicine surveillance in the future.

Hair loss with use of the levonorgestrel intrauterine device.

BACKGROUND: The levonorgestrel intrauterine device (IUD) has associated systemic side effects. However, there is little published information about the risk of alopecia. STUDY DESIGN: Review of both the New Zealand Intensive Medicines Monitoring Programme (IMMP) data on alopecia associated with levonorgestrel IUD and the international evidence. METHODS: The IMMP uses Prescription Event Monitoring to study the safety of medicines during the postmarketing period. All reported cases of alopecia with levonorgestrel IUD use were identified in the IMMP databases and assessed for causality. World Health Organization (WHO) spontaneous reporting data were also obtained. RESULTS: Five reports of alopecia associated with the levonorgestrel IUD were identified in the IMMP database. From the cohort of insertions during 2000-2001, the estimated cumulative incidence of alopecia was 0.33% (95% CI 0.07-0.95) in the responder population. The WHO database contained a further 68 reports. CONCLUSIONS: Counselling prior to insertion of the levonorgestrel IUD should include information on systemic effects, including the possibility of alopecia.

Sibutramine usage in New Zealand: an analysis of prescription data by the Intensive Medicines Monitoring Programme.

PURPOSE: To describe patterns of sibutramine usage in New Zealand during the first 3 years of marketing using data acquired during post-marketing safety surveillance. METHODS: Demographic and prescription data were examined from a nationwide cohort of 17 298 patients prescribed sibutramine between 1 February 2001 and 31 March 2004. Outcome measures were age and sex distribution of the cohort; period prevalence of sibutramine usage for each ethnic group; duration of treatment and reasons for cessation of therapy. Limited BMI data were also examined. RESULTS: About 0.5% of the NZ population were prescribed sibutramine in the period studied. Overwhelmingly, the highest users of sibutramine were NZ European women aged 30-59 years. Maori and Pacific Peoples were under-represented in the cohort, despite the higher prevalence of obesity among these populations. Sibutramine usage was predominantly short-term: 59% of the cohort used sibutramine for 90 days or less, half of whom used it for only 1 month. CONCLUSIONS: There has been extensive use of sibutramine in New Zealand. Sibutramine has been relatively under-utilised by Maori and Pacific ethnic groups, compared to New Zealand Europeans, despite their higher prevalence of obesity. A number of factors may have contributed to the predominantly short-term use of this medicine, including the cost of the medicine to the consumer, weight loss not meeting expectations and adverse effects of the medicine.

Safety and usage of atypical antipsychotic medicines in children: a nationwide prospective cohort study.

OBJECTIVE: 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 < or =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.

Incidence of thrombotic cardiovascular events in patients taking celecoxib compared with those taking rofecoxib: interim results from the New Zealand Intensive Medicines Monitoring Programme.

BACKGROUND: Rofecoxib was withdrawn from the market worldwide because of concerns relating to cardiovascular safety. There is conflicting evidence as to whether celecoxib, the most popular alternative to rofecoxib, carries the same cardiovascular risks. This study's aim was to compare the incidence of thrombotic cardiovascular events in patients taking celecoxib with patients taking rofecoxib. METHODS: Prescription event monitoring methodology was used in this prospective, longitudinal, observational cohort study, in which cohorts of patients were established from prescription data and thrombotic cardiovascular events were identified from follow-up questionnaires to patients' doctors and other sources. SUBJECTS: New Zealand patients with at least one prescription for either rofecoxib or celecoxib between 1 December 2000 and 30 November 2001. ANALYSIS: For this interim analysis the total cohorts were separated into three groups at different stages of follow-up: complete, incomplete and no follow-up. Cox's proportional hazards models were applied to calculate hazard ratios for celecoxib compared with rofecoxib. RESULTS: The total cohorts included 26,403 patients receiving rofecoxib and 32,446 patients receiving celecoxib. 4882 (18%) rofecoxib and 6267 (19%) celecoxib patients had been completely followed up. In this group the unadjusted hazard ratio for celecoxib compared with rofecoxib was 1.07 (95% CI 0.59, 1.93). After adjustment for age this hazard ratio was 0.94 (95% CI 0.51, 1.70). Further adjustment for sex, 'as required' use, indication for use, concomitant NSAID use and pre-existing cardiovascular disease resulted in only minor changes to the hazard ratio. CONCLUSION: This interim analysis of the Intensive Medicines Monitoring Programme data suggests that in 'real-life' postmarketing use in New Zealand there is no significant difference in the risk of cardiovascular thrombotic events in patients taking celecoxib compared with those taking rofecoxib.

Uterine perforation on intrauterine device insertion: is the incidence higher than previously reported?

The objective of the study was to determine the rate of uterine perforation associated with insertion of Multiload Cu375 in 'real-life' clinical use. It was a prospective observational cohort study using Prescription Event Monitoring methodology. There were 17,469 Multiload Cu375 insertions in 16,159 women between 1991 and 2001. The insertions were performed by 1,699 different doctors (mostly general practitioners) in surgeries, clinics, and hospitals throughout New Zealand. The results found 28 reports suggesting complete or partial uterine perforation, giving an incidence of 1.6 per 1000 insertions. Most perforations (86%) were not diagnosed at the time of insertion, with some remaining undiagnosed for several years. Doctors who reported inserting fewer than 10 Multiload Cu375 devices in the study period reported significantly more perforations than doctors who reported inserting between 10 and 100 devices did. In conclusion, we found the perforation rate in this study is higher than in clinical trials of Multiload Cu375. This might be because of inclusion of partial perforations in this study, a longer follow-up period, the large number of insertions studied, or because the majority of inserting doctors were less experienced than inserters in other studies.

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.