Intensive Medicines Monitoring Programme Research Articles

Epistaxis and other haemorrhagic events associated with the smoking cessation medicine varenicline: a case series from two national pharmacovigilance centres

To present a case series of haemorrhagic events associated with varenicline identified from the New Zealand (NZ) and Netherlands national pharmacovigilance centres and propose a possible mechanism for these adverse events. Reports of epistaxis and other haemorrhagic events (in all system organ classes excluding gynaecological) associated with varenicline were identified and assessed in both the NZ Intensive Medicines Monitoring Programme (IMMP) and the Netherlands Pharmacovigilance Centre Lareb (Lareb). Additional reports were identified from the World Health Organisation Uppsala Monitoring Centre (WHO-UMC) datasets, and these also underwent causality assessment. A total of 30 reports of haemorrhagic events were identified by the NZ IMMP (16 reports) and Lareb (14 reports). Six cases of epistaxis were identified, and four patients had a positive dechallenge on withdrawal of varenicline, suggesting a causal association. Another five reports of gingival bleeding were identified, with three patients having a positive dechallenge. Another patient who experienced haemoptysis while taking varenicline had a positive dechallenge and a positive rechallenge. In the WHO datasets, a further 49 reports of epistaxis, 39 reports of haemoptysis and 21 reports of thrombocytopenia were identified. A plausible mechanism for haemorrhagic events associated with varenicline may be a result of interaction with the serotonin (5-HT) receptor system and transporter. This is the first specific investigation of haemorrhagic events associated with varenicline. The results of our assessment of reports identified by two national pharmacovigilance centres suggest that there may be causal relationship between varenicline and these adverse events.

Cardiovascular Events in Patients taking Varenicline

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. 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. 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. 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. 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.

Electronic capture of dispensing data by the New Zealand Intensive Medicines Monitoring Programme: a consultation study of community and hospital pharmacists

To obtain pharmacists' views on proposals for electronic transmission of dispensing data to the New Zealand Intensive Medicines Monitoring Programme (IMMP). Consultation with a randomly selected group of 100 community pharmacists and all 28 hospital pharmacies in New Zealand was conducted by postal survey. A specific questionnaire was designed to obtain pharmacists' views on several aspects of electronic data transmission including willingness to co-operate with a new system, awareness of other electronic systems and views on security. Survey response rates were 95% for community pharmacists and 73% for hospital pharmacists. Ninety (95%) of the community pharmacists and 18 (95%) of the hospital pharmacists who responded stated they would use the IMMP proposed method of electronic data transmission. Some 91% of community pharmacists and 100% of hospital pharmacists considered the proposed new method would be equally or more secure than the present hard-copy system of posting dispensing records. There is a high level of support from New Zealand pharmacists for electronic capture of prescription dispensing data for medicines monitored by the IMMP. This electronic method will now be implemented. Development of such systems is important for enhancing patient safety and pharmacovigilance programmes worldwide.

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

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. 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. 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. 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.

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.

Alopecia associated with quetiapine

Alopecia has previously been reported with the atypical antipsychotic medicines olanzapine and risperidone, but has not been described with quetiapine. Case reports of alopecia associated with quetiapine reported to the New Zealand Intensive Medicines Monitoring Programme were reviewed. The World Health Organization international spontaneous reporting database was also searched for additional case reports. Literature searches were conducted for previous reports of alopecia associated with quetiapine. The Intensive Medicines Monitoring Programme database included two case reports of alopecia associated with quetiapine. Assessment of these cases suggested a causal relationship with the medicine. The World Health Organization international database included a further 15 case reports, providing evidence supporting this association. No previously published reports of alopecia associated with quetiapine were identified. In conclusion, these are the first published case reports of alopecia associated with quetiapine.

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.

Myopathy including polymyositis: a likely class adverse effect of proton pump inhibitors?

Polymyositis occurring in patients treated with omeprazole has been signalled as a possible adverse drug reaction (ADR) by the New Zealand Intensive Medicines Monitoring Programme (IMMP) and the WHO Collaborating Centre for International Drug Monitoring: the Uppsala Monitoring Centre (UMC). Polymyositis and other myopathies have also been reported in post-marketing data and in the medical literature in association with proton pump inhibitor (PPI) use. We wished to follow-up these signals and investigate the evidence of causality for the association of polymyositis and other myopathy with PPI use. Spontaneously reported ADRs from national monitoring centres are sent to the WHO ADR database (VigiBase). VigiBase was searched for case reports of the PPIs, omeprazole, pantoprazole, lansoprazole, esomeprazole and rabeprazole, with terms indicative of myopathy, and further information was elicited from the national centres to help establish causality. Literature sources were reviewed for the occurrence of the above terms in combination with PPIs. In total, there were 292 reports of various myopathies with PPIs, excluding 868 cases of 'myalgia'. In this analysis, 69 patients recovered when the drug was withdrawn and, in 15 patients, the reaction re-occurred when the drug was reinstated. In one-third of the 292 cases, the PPI was the single administered drug, and the PPI was the single suspected drug by the reporter in 57% of reports where concomitant medication was used. In this analysis, three index cases are documented. One involves the same patient taking three different PPIs (lansoprazole, esomeprazole and rabeprazole) at different time periods, with myalgia and muscle weakness occurring with all three drugs. In the two other index cases, myopathies with esomeprazole and omeprazole were reported with positive rechallenge, and causality was assessed as 'possible' and 'certain' by the reporting centres. In 27 cases myositis or polymyositis was reported. Other myopathies were reported, including 35 cases with rhabdomyolysis. In 9 of these cases, the PPI was withdrawn and the reaction abated. The PPI was reinstated in one patient, but the reaction did not re-occur. Time to onset was given in 17 of the rhabdomyolysis cases, rhabdomyolysis occurred with the first week in 9 cases, and in 3 cases the reaction occurred between 14 days to 3 months of treatment. In 12 of these patients, an HMG-CoA reductase inhibitor (statin) was taken concomitantly. Case reports from the WHO ADR database, including index cases involving four out of five PPIs, along with evidence of a possible mechanism, provide compelling evidence that there is a causal association between members of the PPI drug class and myopathy including polymyositis. Evidence was also obtained to support the view that PPI use may be associated with occurrence of other myopathies, including the serious reaction rhabdomyolysis.

Bruising associated with sibutramine: results from postmarketing surveillance in New Zealand

To determine whether postmarketing data provide evidence of an association of sibutramine with bruising. During a postmarketing surveillance study of sibutramine in New Zealand by the Intensive Medicines Monitoring Programme (IMMP), a series of reports of bruising was identified. Further case reports were also obtained from the World Health Organisation (WHO) adverse drug reactions database. All platelet, bleeding and clotting events associated with sibutramine were identified and causality assessments were performed. From the IMMP and WHO databases a total of 16 cases of bruising that improved on withdrawal of sibutramine were identified. Of these, two had a recurrence of bruising on reintroduction of sibutramine. Evidence from postmarketing surveillance suggests that there is a causal association between sibutramine and bruising/ecchymosis. This represents a newly recognized adverse reaction for this medicine.

QT interval prolongation associated with sibutramine treatment

To investigate a possible association of sibutramine with QT interval prolongation. Post-marketing surveillance using prescription event monitoring in the New Zealand Intensive Medicines Monitoring Programme (IMMP) identified a case of QT prolongation and associated cardiac arrest in a patient taking sibutramine for 25 days. This patient was further investigated, including genotyping for long QT syndrome. Other IMMP case reports suggesting arrhythmias associated with sibutramine were assessed and further reports were obtained from the World Health Organisation (WHO) adverse drug reactions database. The index case displayed a novel mutation in a cardiac potassium channel subunit gene, KCNQ1, which is likely to prolong cardiac membrane depolarization and increase susceptibility to long QT intervals. Assessment of further IMMP reports identified five additional patients who experienced palpitations associated with syncope or presyncopal symptoms, one of whom had a QT(c) at the upper limit of normal. Assessment of reports from the WHO database identified three reports of QT prolongation and one fatal case of torsade de pointes in a patient also taking cisapride. This case series suggests that sibutramine may be associated with QT prolongation and related dysrhythmias. Further studies are required, but in the meantime we would recommend that sibutramine should be avoided in patients with long QT syndrome and in patients taking other medicines that may prolong the QT interval.

Cyclo-Oxygenase-2 Inhibitors

Chronic pain in the elderly is frequently a result of arthritic disorders, particularly osteoarthritis. The cyclo-oxygenase (COX)-2 inhibitors are as effective as standard NSAIDs for the relief of pain and for improving function in elderly patients with osteoarthritis and rheumatoid arthritis. COX-2 inhibitors increase the risk of serious gastroduodenal adverse reactions but there is evidence that they carry a lower risk for these adverse effects than standard NSAIDs, except when there is concurrent aspirin use. Since gastroduodenal disorders are the most frequently reported serious adverse effects of NSAIDs and these disorders occur more frequently in the elderly, COX-2 inhibitors offer an alternative to standard NSAIDs in this age group. However, they are not appropriate for many patients with cardiovascular and renal disease. The adverse reaction profile of the COX-2 inhibitors has confirmed the role of the COX-2 enzyme in renal function, salt and water homeostasis and the vascular endothelium. Thus, like standard NSAIDs, COX-2 inhibitors can cause renal failure, hypertension and exacerbation of cardiac failure. Of note is that these disorders are dose related. Thus, there are good reasons to avoid high doses of COX-2 inhibitors in the elderly. Clinical trials indicate that daily doses of rofecoxib 12.5 mg, celecoxib 100-200 mg, valdecoxib 10mg and etoricoxib 60 mg are the minimum effective doses of these agents. Data from the New Zealand Intensive Medicines Monitoring Programme indicate that celecoxib 200 mg/day and rofecoxib 25 mg/day are/were the most commonly prescribed doses and that 6% of patients had taken rofecoxib 50 mg/day for longer than recommended. Recent research indicates that COX-2 inhibitors have a thrombotic potential, especially in high doses and when use is prolonged, and this further limits the extent to which they can be used in the elderly. Important interactions with COX-2 inhibitors in the elderly include those with warfarin, which can result in loss of control of anticoagulation, and those with ACE inhibitors, angiotensin II type 1 receptor antagonists and diuretics, which can result in loss of control of blood pressure and cardiac failure and, in hypovolaemic conditions, renal failure. The clinical significance of an interaction between celecoxib and aspirin to reduce the antiplatelet effect of the latter drug is unknown. Preliminary information from spontaneous reporting systems indicates that there may be differences in the risk of cardiac failure and hypertension between standard NSAIDs and COX-2 inhibitors and between rofecoxib and celecoxib. More formal studies using equivalent doses are needed to test this observation. Use of COX-2 inhibitors may be considered in the elderly to reduce the risk of gastroduodenal complications associated with standard NSAIDs but only when consideration has first been given to use of less toxic medicines as alternatives or supplements, the appropriate dose of the COX-2 inhibitor or standard NSAID, the presence and possible impact of co-morbidities, and the implications of taking COX-2 inhibitors with any concomitant medications. Equally important is regular monitoring of the patient taking a COX-2 inhibitor for efficacy and adverse effects, and ensuring that the patient has a continuing need to keep taking the drug. Close attention also needs to be paid to intercurrent illnesses and new prescriptions that may reduce the safety of the COX-2 inhibitor. A standard NSAID plus a proton pump inhibitor may be equally effective as a COX-2 inhibitor in reducing the risk of gastroduodenal toxicity and if used the same prescribing advice applies. Current knowledge concerning the thrombotic potential of COX-2 inhibitors suggests that this combination, if tolerated, may be preferable to a COX-2 inhibitor, particularly where prolonged use is required. This knowledge also indicates that for patients with or at high risk of ischaemic heart disease or stroke, COX-2 inhibitors are contraindicated.

Nose bleeds associated with use of risperidone

The New Zealand Intensive Medicines Monitoring Programme has received two reports of nose bleeds associated with risperidone. A 57 year old woman began having profuse nose bleeds associated with headaches...

Linking Pharmacovigilance with Pharmacogenetics

The ability to identify individuals who are susceptible to adverse drug reactions (ADRs) has the potential to reduce the personal and population costs of drug-related morbidity. Some individuals may show an increased susceptibility to certain ADRs through genetic polymorphisms that alter their responses to various drugs. We wished to establish a methodology that would be acceptable to members of the general population and that would enable estimation of the risks that specific genetic factors confer on susceptibility to specific ADRs. Buccal swabs were selected as a minimally invasive method to obtain cells for DNA extraction. We wished to determine whether DNA of sufficient quantity and quality could be obtained to enable genotyping for two different polymorphic genes that code for enzymes that are widely involved in drug disposition. This article describes a small pilot study of methodology developed in the New Zealand Intensive Medicines Monitoring Programme (IMMP) to link prescription event monitoring (PEM) studies with pharmacogenetics. The methodology involves a nested case-control study design to investigate whether patients with genetic variants in P-glycoprotein (P-gp) and cytochrome P450 (CYP) 2C9 are more susceptible to psychiatric or visual disturbances following cyclo- oxygenase-2 inhibitor use (ADR signals identified in the IMMP database) than matched control patients taking the medication without experiencing any ADRs. It was concluded that the use of buccal swabs is acceptable to patients and provides DNA of sufficient quantity and quality for genotyping. Although no differences in the distribution of genotypes in the case and control populations were found in this small study, case-control studies investigating genetic risks for ADRs using drug cohorts from PEM studies are possible, and there are several areas where population-based studies of genetic risk factors for ADRs are needed. Examples are discussed where research in large populations is required urgently. These are: (i) genetic variations affecting P-gp function; (ii) variations affecting drugs metabolised by CYP2C9 and other polymorphic CYP enzymes; (iii) genetic variation in beta-adrenergic receptors and adverse outcomes from beta-adrenoceptor agonist therapy; and (iv) genetic variation in cardiac cell membrane potassium channels and their association with long QT syndromes and serious cardiac dysrhythmias. Such studies will help to identify factors that increase the risk of unwanted outcomes from drug therapy. They will also help to establish in what circumstances genotyping should be performed prior to commencing drug treatment and in tailoring drug treatment for individual patients.

Use of the New Zealand Intensive Medicines Monitoring Programme to study the levonorgestrel-releasing intrauterine device (Mirena).

To demonstrate how the Intensive Medicines Monitoring Programme (IMMP) can be used to monitor adverse events associated with an intrauterine device, using the levonorgestrel-releasing intrauterine device (Mirena) as an example. A long-term prospective observational cohort study using Prescription Event Monitoring (PEM) is currently being undertaken in women using Mirena in New Zealand. This report describes the method used and reports the early results for those women who used the device between March 1998 and March 2001. Adverse events were recorded by inserting doctors and general practitioners on registration forms and systematic follow-up questionnaires. Between March 1998 and March 2001, the IMMP received 3519 registration forms for insertions in 3452 women. 'Difficult insertion' was the most frequently reported event (3.6% of all insertions). Approximately, 2% of the Mirena insertions were carried out under GA and there were three uterine perforations (0.9 per 1000 insertions) in the total cohort. To date, follow-up questionnaires have been processed for 495 patients. The response rate for these was 83%. As adapted in the IMMP, PEM is an effective tool for the early post-marketing surveillance of an intrauterine device in real life clinical practice.

Signal generation in the New Zealand Intensive Medicines Monitoring Programme: a combined clinical and statistical approach.

The New Zealand Intensive Medicines Monitoring Programme (IMMP) undertakes prospective observational cohort studies on selected new drugs in the early postmarketing period using prescription-event monitoring (PEM) methodology with the purpose of identifying signals of previously unrecognised ADRs and establishing risk profiles for each drug. Events are reviewed by a physician and a relationship is established between each event and the drug. The events are then sorted into reactions and incidents. The latter are used to assist signal detection and control for bias. Rates for reports, reactions and incidents are used to assess the adequacy of reporting, signal detection and identification of confounders. Most signals are identified by clinical evaluation of the reports at a stage when statistical analyses are unlikely to have the power to detect them with confidence. The incident group is used for signal detection and controlling for bias. A low reporting rate indicates that certain types of event are unlikely to be reported. A systematic review of the original case reports at the site of collection provides the best opportunity for early signal detection. More resources need to be invested in the training and support of clinical evaluators. Categorising events into reactions and incidents gives added value to the data. Rates of reporting should be quoted with the results of cohort studies to facilitate assessment of their power to detect new signals.

Privacy issues and the monitoring of sumatriptan in the New Zealand Intensive Medicines Monitoring Programme.

The purpose of this paper is to describe how the New Zealand (NZ) Intensive Medicines Monitoring Programme (IMMP) functions in relation to NZ privacy laws and to describe the attitudes of patients to drug safety monitoring and the privacy of their personal and health information. The IMMP undertakes prospective observational event monitoring cohort studies on new drugs. The cohorts are established from prescription data and the events are obtained using prescription event monitoring and spontaneous reporting. Personal details, prescribing history of the monitored drugs and adverse events data are stored in databases long term. The NZ Health Information Privacy Code is outlined and the monitoring of sumatriptan is used to illustrate how the IMMP functions in relation to the Code. Patient responses to the programme are described. Sumatriptan was monitored in 14,964 patients and 107,646 prescriptions were recorded. There were 2344 reports received describing 3987 adverse events. A majority of the patients were involved in the recording of events data either personally or by telephone interview. There were no objections to the monitoring process on privacy grounds. Given the fact that all reasonable precautions are taken to ensure privacy, patients perceive drug safety to have greater priority than any slight risk of breach of confidentiality concerning their personal details and health information.

Drug metabolism genotypes and their association with adverse drug reactions in selected populations: a pilot study of methodology

Aims-(1) To undertake a pilot population study of the investigation of pharmacogenetic factors that may lead to adverse drug reactions (ADRs). (2) To investigate whether a population of patients taking fluoxetine, moclobemide or omeprazole reported to the New Zealand (NZ) Intensive Medicines Monitoring Programme (IMMP) with ADRs, have a higher frequency of CYP2D6 and CYP2C19 poor metabolizer (PM) genotypes than a reference population. (3) To determine the frequency of CYP2C19 alleles in the NZ Caucasian population.Methods-150 patients who had been notified to the NZ IMMP as experiencing an adverse event after being prescribed fluoxetine, moclobemide or omeprazole (50 on each) were approached by letter and asked if they would consent to take part. Of these, 31 patients and 56 subjects from a population of blood donors were genotyped for common CYP2D6 and CYP2C19 alleles.Results and conclusions-At either loci the distributions of genotypes were not significantly different in the IMMP patients compared with the reference population or with other reported studies. In this small study CYP2D6 or CYP2C19 PM genotypes are not overrepresented in selected patients with adverse reactions. Population studies involving sampling of blood for genotyping are feasible in the general population. Copyright (c) 2000 John Wiley & Sons, Ltd.

The New Zealand intensive medicines monitoring programme in pro-active safety surveillance

Purpose-The purpose of this paper is to demonstrate the pro-active nature of the New Zealand Intensive Medicines Monitoring Programme (IMMP) and make an assessment of its effectiveness in postmarketing drug safety evaluation.Methods-The IMMP undertakes prospective observational cohort studies of selected new drugs. Patient cohorts are established from prescription data received from dispensing pharmacists nationwide. Adverse events are reported by doctors on prescription follow-up questionnaires or as spontaneous reports. The method of signal generation is reviewed with particular emphasis on the review of individual event reports and their relationship to the medicine. Signals reported over the last 10 years are assessed for timeliness in advising the regulatory authority.Results-Mean cohort size is 10,964 patients and the mean study period for each drug was 58 months. A total of 153 signals were recorded from 11 drugs with 132 (86%) being notified to the regulatory authority prior to any publication in the literature. The use of 'incidents' in controlling for reporting bias is illustrated and examples are given of data on safety in pregnancy and lactation, the assessment of deaths, reassurance with drug scares, risk comparison and signal validation studies.Conclusion-PEM type methodology is effective and cost-efficient in pro-active safety surveillance even with limited resources. Copyright (c) 2000 John Wiley & Sons, Ltd.

The New Zealand Intensive Medicines Monitoring Programme.

The New Zealand Intensive Medicines Monitoring Programme which has been in operation for 20 years is described. The methodology is reviewed in detail and illustrated in the results. Some of the principles of early postmarketing surveillance and advantages and problems associated with the IMMP are discussed. The methodology is based on establishing cohorts of patients and the aggregation of adverse events from a combination of prescription follow-up (PFU) and intensified spontaneous reporting. In signal detection particular emphasis is placed on provisional 'causality' assessment and a study of the events thought not to be reactions (incidents) and in addition, their use in controlling for reporting bias particularly in respect of reaction rates and the identification of risk factors. With the small population base, cohorts are built up more slowly, but the longer duration of observation has advantages. Monitoring has been completed for 20 drugs with an average cohort size of 10,511 patients and a mean monitoring period of 55 months. The use of duplicate prescriptions with PFU achieved much higher reporting rates than IMMP spontaneous reporting. Information on deaths was best obtained from questionnaires on reasons for cessation of therapy which also provided data on efficacy.

Angiooedema and urticaria with angiotensin converting enzyme inhibitors.

To review reports of angiooedema and urticaria associated with angiotensin converting enzyme inhibitors (ACEI) in the New Zealand Centre for Adverse Reactions Monitoring and Intensive Medicines Monitoring Programme (IMMP) database. Adverse reaction reports describing angiooedema and/or urticaria between April 1981 and December 1994 were examined. Captopril, enalapril and lisinopril were intensively monitored on the IMMP during this period. Of a total of 116 reports there were 68 reports of angiooedema and 37 of urticaria alone and 11 where angiooedema and urticaria occurred in the same patient. The total number of patients is unknown, but cohorts of patients on captopril, enalapril and lisinopril in the IMMP were 16342, 25686 and 11235, totalling 53263 patients. There were 63 reports of angiooedema/urticaria in patients monitored on the IMMP, giving a reported rate of 1.2/1000 (0.9-1.5). Forty seven reactions occurred between 3 weeks and 4 years after commencement of therapy. Severe angiooedema occurred in 9 patients with early-onset angiooedema and 6 with late-onset angiooedema. There were no deaths. Seventeen patients had up to 12 episodes before diagnosis. Angiooedema/ urticaria occurred without gender preference. Although a dose relationship was not apparent, 3 patients developed angiooedema or urticaria after an increase in dose. Although reactions are more common shortly after initiation of ACEI therapy, late onset reactions may be less well recognised. Clinicians should be reminded, and ACEI data sheets should emphasise, that onset may be delayed for weeks or months, that patients may have multiple episodes with long symptom free intervals, and that angiooedema may occur with or without urticaria.