Outputs of PEM in New Zealand

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Chapter: Pharmacovigilance: PEM in New Zealand

There are several key elements to successful identification of previously unrecognized adverse reactions in the IMMP.



There are several key elements to successful identi-fication of previously unrecognized adverse reactions in the IMMP. These have been reviewed recently (Clark and Harrison-Woolrych, 2006) and include (a) the intensive methodology used to obtain events from multiple sources (see above), (b) the high quality and completeness of reports received by the IMMP and (c) the evaluation of every event report by at least one clinical assessor. The IMMP does not rely on auto-mated processes for signal identification, preferring regular clinical assessment of event listings for each medicine from early in the monitoring study. In addi-tion, analyses of ‘incidents’ – as outlined above – contributes to the process at a later stage of monitoring.

Possible signals first identified by individual clin-ical assessment are further investigated by obtain-ing additional evidence from other sources. These might include the reporting doctor (or other reporter), other databases including the WHO-UMC interna-tional spontaneous reporting database, pharmaceuti-cal companies, medicine regulatory bodies and the published literature. Using these methods, the IMMP has had some success in signal identification, as outlined in this section.


Signals generated in 11 drugs between 1985 and 1995 were searched from the agenda material and minutes of the MARC meetings and from publications. For the purposes of this evaluation, a signal was recorded as such if the MARC was alerted before the date of the second non-IMMP publication. The date that the MARC was alerted to each signal was recorded, and this date was compared with the date of the first two publications (if any) found by Medline and AdisBase searches of the international literature (all languages with an English abstract). Medline was searched from 1985 and AdisBase from 1989. Case reports and clinical trials were included in the searches. Adis-Base searches included publications from regula-tory authorities internationally. Data sheets were not searched. The dates of any IMMP publications were also recorded. Any recommendations of the MARC because of considering the signals were noted. Events that are expected because of known pharmacologi-cal action (e.g. tremor with beta-agonists) were not recorded as signals.

This analysis identified 153 signals recorded in the 10-year period. Many of the early signals were published in the NZ Family Physician published by the Royal NZ College of General Practitioners or in Prescriber Update (Table 25.5). Of the 153 signals identified, 132 (86%) were notified to the MARC before any publication found in the international liter-ature. Eighty-six (56%) of the signals have since been strengthened or confirmed by at least one non-IMMP publication. In 72 (47%) instances, the IMMP publi-cation was the first report of the signal identified, and in 23 (15%) it was the second. On 39 (25%) occa-sions, the MARC recommended action after consider-ing the signals. These included articles in Prescriber Update, writing to pharmaceutical companies for further information, changes to data sheets and further investigations.


Early signals published in the wider medical literature include cough and angiotensin-converting enzyme (ACE) inhibitors (Coulter and Edwards, 1987), eye pain with nifedipine (Coulter, 1988), ACE inhibitors and anaemia (Edwards and Coulter, 1989), mianserin and agranulocytosis (Coulter and Edwards, 1990), the intestinal effects of captopril (Edwards, Coulter and Macintosh, 1992), psoriasis with ACE inhibitors (Coulter and Pillans, 1993) and fluoxetine and hyponatraemia (Pillans and Coulter, 1994).


Signals published in the international literature during the last 11 years (from 1995 to 2006) include hypertension with moclobemide (Coulter and Pillans, 1995b), fluoxetine and extrapyramidal effects (Coul-ter and Pillans, 1995a), acute psychiatric reactions with the COX II inhibitors (Coulter, 2002), acute visual impairment with rofecoxib and celecoxib (Coulter, Clark and Savage, 2003), psoriasis associ-ated with rofecoxib use (Clark and Coulter, 2003), the activation of pain by sumatriptan (Coulter et al., 2003), nose bleeds associated with risperi-done (Harrison-Woolrych and Clark, 2004), amnesia associated with sibutramine (Clark and Harrison-Woolrych, 2004), QT interval prolongation associated with sibutramine (Harrison-Woolrych et al., 2006) and cardiac dysrhythmias with COX II inhibitors (Savage, Coulter and Harrison-Woolrych, 2005).


Investigating Signals by Survey of Cohort Sample

The IMMP cohorts offer a great opportunity to further investigate signals identified early in the monitoring process. Such studies aim to estimate incidence or prevalence of specific adverse reactions and may also investigate risk factors for these reactions. Follow-ing a cluster of reports of nocturnal enuresis (bed wetting) associated with the atypical antipsychotic medicine clozapine, the IMMP is now further inves-tigating this signal. Cohorts of patients taking clozap-ine, olanzapine, quetiapine or risperidone during 2003 have been established, and follow-up questionnaires with additional specific questions about bed wetting have been sent to patients’ doctors. It was considered necessary to add specific questions for doctors/mental health nurses to ask the patients directly, as enuresis is an embarrassing problem which is unlikely to be spontaneously reported. This study will enable calcu-lation of the prevalence of enuresis in patients taking clozapine (and identify risk factors for this adverse event) and will allow comparison with three other atypical antipsychotics.

Use of Prescription History

The evaluation of 50 reports coded as ‘tolerance’ with sumatriptan was facilitated by having a longitudinal record of prescription data with the numbers of tablets or injections dispensed recorded for many patients over a period of several years. The reports described patients who claimed that over a period of months or years the drug did not work as well as it did initially and they required higher or more doses to relieve an attack of migraine, or the drug did not work at all. In the natural history of the disease, there are fluctuations in frequency and severity of attacks, and so these reports were difficult to interpret. It was felt that if there was any general trend to tolerance, then mean usage per patient over time would increase.

The prescription data were therefore analysed, and the mean number of injections or tablets (100 mg equivalent) per patient per 6-month interval was calcu-lated. The results for those patients who had used injections only are shown in Table 25.6 over a period of eight intervals, and an increase was demonstrated at each interval. The first interval was omitted because it would be a trial period of use and for many patients may not be typical of later use. The latest interval was also excluded because it may not have been complete. The slope of the changes was statistically significant for both the injections and the tablets, but the changes were more marked for the injections. There were no identifiable confounders (Coulter, DM, presentation at the 18th Annual Meeting of National Centres Partic-ipating in the WHO International Drug Monitoring Programme, Portugal, 1996).

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