Implications for Drug Development and Use

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Chapter: Pharmacovigilance: Drugs and the Elderly

The need for research in elderly persons has been addressed by Williams and Denham (1998).


The need for research in elderly persons has been addressed by Williams and Denham (1998). It should be clear from the studies referred to in this chapter that the effects of drugs can alter significantly with age as a consequence of changes in body composi-tion and physiology and the effectiveness of various detoxifying mechanisms. Additional factors include the presence of disease, polypharmacy and possi-ble differences in patient behaviour. Consequently, doses of drugs required to achieve desired results in elderly people may be substantially different from those used in younger persons. Furthermore, the risk of ADRs and interactions is enhanced by the pres-ence of concomitant diseases and remedies for them. The use of quality indicators for drug use in older persons to decrease the incidence of preventable drug-related morbidity has been reviewed recently (Hanlon et al., 2003). Suggested indicators included drugs to avoid, drug–disease interactions, drug–drug interac-tions, drug duplication and required monitoring.

The optimisation of drug prescribing in the elderly has recently been highlighted in the United King-dom by the introduction of the National Service Framework in Older People (Department of Health, 2001). This highlights several important areas where drug prescribing to older patients can be improved including the linking of prescribing and clinical data to identify and thereby reduce ADRs. Electronic prescribing will increase the potential to link prescrib-ing and clinical outcomes enabling feedback and an opportunity to direct prescriber’s thinking by issuing ‘alerts’ in real time – the so-called decision support (Jackson et al., 2004). Electronic prescribing has been seen as a promising tool in solving many of the problems of prescribing in the elderly by providing realtime information for drug selection, prescription checks, and clinical drug information from databases (Venot, 1999).

The benefits and harms of many drug treatments in older patients are often not provided by standard clin-ical evidence. The need for clinical trials to involve elderly people is obvious, therefore, if treatments are to be used safely and effectively in this age group. Yet, the major part of the so-called therapeutic explosion which occurred during the twentieth century relied on research carried out in younger patients, and there were casualties. These included the development of a hepato-renal syndrome associated with the use of benoxaprofen (Hamdy, Murnane and Perera, 1982) and problems with other NSAIDs (Castleden and Pickles, 1988). The need for dose modification for agents such as triazolam (Greenblatt et al., 1991) was identified, as was the need for attention to labelling and modification of package inserts. However, by the time that a new medicine has been marketed, experi-ence with its use remains confined to a relatively small number of people, of whom only a proportion will be elderly and fewer will be frail elderly. There is, there-fore, a need for careful pharmacovigilance to identify unexpected adverse effects such as those produced by terodiline. This agent, which was introduced for use in urinary incontinence due to detrusor muscle insta-bility, was subject to prescription event monitoring by the Drug Safety Research Unit in Southampton (Freemantle et al., 1997). The latter system relies on reporting of significant events such as ‘a broken leg’ which may be due to hypotension, ataxia or metabolic bone disease. In the case of terodiline, an excess of fractures was identified, many of which were the result of falls. Further investigations revealed that the cause was syncope due to torsade des pointes which can be identified by means of Holter Monitoring (Committee on Safety of Medicines, 1991).

Although prescription event monitoring is likely to identify important adverse reactions occurring at a low frequency, we rely on other systems to iden-tify those which occur more rarely. Most of these are the so-called type B adverse effects. Examples include agranulocytosis caused by co-trimoxazole and by oxyphenbutazone, eventually shown by voluntary reporting systems, for example the yellow card system operated by the Committee on Safety of Medicines, to occur predominantly in old people (Inman, 1977). This led to the advice to avoid using co-trimoxazole in the elderly and the revocation of the licence for oxyphenbutazone. Fortunately, the need for clinical studies and trials in the elderly is now recognised by all major drug regulatory bodies. Thus, in Europe, official recognition by the European Commission occurred in the 1970s, and a regulatory requirement (Directive 78 of the 318 of the EC) and similar regulations were introduced by the Food and Drugs Administration in the United States (Food and Drug Administration Center, 1989; International Confer-ence on Harmonisation, 1993.

In an era of evidence-based medicine, good qual-ity evidence of the benefits and harms of medicines is scarce for elderly patients and neglects certain diseases altogether. Valuable contributions can be made by studying drug utilisation over time, investi-gating variations in pharmacokinetics and pharmaco-dynamics with age and applying pharmacovigilance principles, in addition to extending the age range of clinical trials. Challenges exist in translating research into meaningful endpoints that older patients will understand to allow them to make valid decisions about whether to take medications or not. Clinicians will have to be ready to meet this challenge in our ageing population.

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