Pharmacology

Colin L Crawford Retired physician, 23 Grafton Road, London, W3 6PB, UK clcraw13AThotmail.com To the Editor: The Australian Drug Evaluation Committee (ADEC) has recommended that thalidomide be approved for the management of erythema nodosum leprosum. This recommendation has now been accepted by the Therapeutic Goods Administration. Was ADEC unaware that the World Health Organization no longer recommends thalidomide in the management of this complication of lepromatous leprosy?1,2

Colin L Crawford

Martin H N Tattersall Chairman, Australian Drug Evaluation Committee; and Professor of Cancer Medicine, Blackburn Building D06, University of Sydney, Sydney, NSW 2006 mtattATmed.usyd.edu.au In reply: When it considered thalidomide for registration for management of erythema nodosum leprosum (ENL) and another indication (myeloma), the Australian Drug Evaluation Committee (ADEC) was not aware that the World Health Organization (WHO) does not recommend the drug for this indication. ADEC bases its recommendations on review of the scientific and clinical evidence submitted concerning the efficacy and safety of products submitted for registration. In the case of thalidomide in the management of ENL, ADEC reviewed the results of several randomised studies, together with additional published reports. Data from the US Public Health Service analysing the entire experience of thalidomide use in ENL in the United States from 1978 to 1994 were also reviewed. The committee concluded that the efficacy of thalidomide in acute ENL is beyond dispute. Moreover, thalidomide was also shown to be useful in patients with ENL already treated with corticosteroids and dapsone. ADEC discussed the side-effect profile of thalidomide in the ENL studies and concluded that skin rashes, sometimes with eosinophilia, were somewhat more common than in the myeloma studies that were also reviewed. In regard to safety concerns relating to thalidomide’s teratogenicity, the committee was informed of the sponsor’s proposed risk management program, which is based on mandatory registration of prescribing doctors, patients and dispensing pharmacists. This program is based on an effective program in the US, where the Food and Drug Administration has registered thalidomide for treatment of ENL. ADEC felt that the risk–benefit ratio favoured registration for ENL (and myeloma). However, the committee resolved that a boxed warning should be included stating: Thalidomide has caused severe birth defects when taken during pregnancy. Thalidomide should never be used by women who are pregnant or who could become pregnant whilst taking the drug, or could become pregnant within four weeks after stopping the drug. Even a single dose can cause severe birth defects. I have reviewed the WHO documents referred to by Crawford,1,2 and consulted Medline. I have also had access to a review article in press in the Lancet.3 I believe the evidence indicates that thalidomide is superior to steroids in controlling ENL. Britton and Lockwood state that thalidomide is the drug of choice for men with ENL;3 however, they comment that using thalidomide in women with ENL is a difficult decision for a woman and her doctor. The WHO documents emphasise that any benefit from thalidomide must be balanced against its known toxicity, and conclude that experience has shown that it is virtually impossible to develop and implement a foolproof surveillance mechanism to combat thalidomide toxicity. ADEC concludes that thalidomide is an effective and useful drug in the management of ENL, and that the risk management program which is to be established in Australia, together with the inclusion of a boxed warning, will ensure that the risk–benefit profile of thalidomide use in ENL is favourable.

Martin H N Tattersall

Mark R Nelson NHMRC Research Fellow, Department of Epidemiology and Preventive Medicine, Monash University, Commercial Road, Prahran, VIC 3181. mark.nelsonATmed.monash.edu.au To the Editor: The lessons from the introduction of COX-2-selective non-steroidal anti-inflammatory drugs (NSAIDs), related by Kerr et al,1 have a corollary in the introduction of angiotensin-II-receptor antagonists 2 years previously. Both cases involved common conditions (osteoarthritis and hypertension), with extensive prescribing of newly developed and marketed agents, which blocked an enzyme further down the cascade of reactions to avoid adverse outcomes — the gastrointestinal upset and bleeding associated with non-selective NSAIDs, and the cough and angioedema caused by angiotensin-converting enzyme inhibitors. In both conditions, off-patent, low-cost alternative drug therapies were available — paracetamol and acetylsalicylic acid, and thiazide diuretics and β-blockers, respectively. My quantitative investigation of general practitioners’ perceptions of newer versus older antihypertensive agents suggested that they thought newer agents were more efficacious, and were safer in the short term and long term, but were more expensive.2 These beliefs were held despite the lack of long-term safety data. Younger doctors were more likely to hold these beliefs. It is possible that the experience of using older medications permitted older doctors to maintain a healthy scepticism towards the marketing claims of medical representatives. It may be interesting for Kerr and colleagues to look at the demographics of GPs in the General Practice Research Network to see if these findings hold true for this cohort.

Mark R Nelson

Ian D Coombes,* Danielle A Stowasser,† Charles A Mitchell,‡ Paul Varghese§ * Leader, Adverse Drug Event Prevention Project, Queensland Health Medication Management Services, ‡ Associate Professor of Medicine, § Director of Geriatric Medicine, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, QLD 4102; †Manager, Queensland Health Medication Management Services, Royal Brisbane Hospital, Brisbane, QLD. Ian_coombesAThealth.qld.gov.au To the Editor: We would like to add our perspective to the discussion on computerised prescribing.1 Electronic prescribing with appropriate decision support is recognised by the Medication Safety Taskforce of the Australian Council for Safety and Quality in Health Care as a key initiative to prevent patient harm.2 Such systems reduce the opportunity for prescribing errors and improve patient safety.3 The widely espoused benefit of the clarity and legibility associated with electronic prescribing appears to have led many to assume that electronic prescribing is an essential component of medication safety systems whether or not it includes a decision support system. In fact, electronic prescribing without decision support has been associated with an increase in the incidence of error4 and inappropriate use of medications.1 A computer-generated discharge summary was developed at a tertiary referral teaching hospital in Brisbane. With this system, a discharge prescription was generated using information entered from the database by the medical officer. As part of standard practice, a pharmacist reviews all discharge prescriptions and compares them with the inpatient medication chart, discussing any apparent errors with the medical officer. We conducted an audit of 200 consecutive medical discharge prescriptions (100 generated by computer and 100 handwritten) in mid-2001. The errors detected are summarised in the Box. The same medical staff were responsible for both types of prescriptions. Significantly more errors in prescribing were noted for the computer-generated prescriptions than for the handwritten scripts (P < 0.001). The proportion of errors with potential for harm was similar in both groups. Three specific types of error occurred more frequently with electronic prescribing. We can speculate that dosing errors occurred when previous discharges were copied and the previous dose was continued, duration errors occurred as a result of a computer default to 10 days’ therapy, and the continuation of drugs not required for discharge resulted from copying previous medication records and not reviewing the current drugs prescribed. This uncontrolled observational audit demonstrated that electronic prescribing without decision support in busy medical wards can significantly increase the risk of patient harm when compared with the handwritten system. The discharge prescription component of this system was withdrawn on the basis of this audit, and the paper-based system reinstituted until a safer alternative becomes available. 1: Comparison of error rates with electronic and handwritten discharge prescribing systems Examples of prescribing errors Computer Handwritten Number of prescriptions 100 100 Number of drugs 700 605 Omissions Warfarin and irbesartan omitted 12 16 Duplications Spironolactone and atorvastatin duplicated 2 0 Dosing errors Prednisolone 50 mg in the morning for 10 days ordered: should have been reducing by 10 mg every second day 25 5 Drug errors Diltiazem oral 60 mg three times a day ordered: should have been diltiazem slow release 180 mg in the morning 4 4 Drug name unclear Fluticasone inhaler: no strength 6 0 Duration error Antibiotics intended for 3 or 5 days: ordered for 10 days (default quantity) 13 1 Drug not required on discharge Frusemide 80 mg twice daily was continued: the drug had been stopped during admission 15 4 Route error Glyceryl trinitrate 5 mg oral ordered: patch was the intended form of drug 3 0 Frequency error Carvedilol ordered for mornings: had been twice daily in hospital 1 0 Total number of errors 81 30 Error rate per item 11.6% 5.0%

Ian D Coombes · Danielle A Stowasser · Charles A Mitchell · Paul Varghese

Attention to known contraindications and intercurrent illness can avoid life-threatening acidosis Metformin, a biguanide derivative, has been used in the treatment of type 2 diabetes for nearly 50 years. It acts as an insulin-sensitising agent, lowering fasting plasma insulin concentrations by inducing greater peripheral uptake of glucose, as well as decreasing hepatic glucose output. In 1998, the United Kingdom Prospective Diabetes Study reported that, in overweight patients with type 2 diabetes, treatment with metformin compared with diet alone resulted in statistically significant absolute risk reductions (ARRs) in all-cause mortality (ARR, 7%), diabetes-related deaths (ARR, 5%), any diabetes-related endpoint (ARR, 10%), and macrovascular disease (myocardial infarction, sudden death, angina, stroke, peripheral vascular disease).1 This was achieved without hypoglycaemia or weight gain. As a result, metformin is now regarded as the oral hypoglycaemic agent of choice in the treatment of overweight people with type 2 diabetes. More recently, the use of metformin has broadened, with evidence for its benefit in other insulin-resistant states. In polycystic ovary syndrome, metformin decreases insulin resistance, restores ovulatory menses, facilitates conception, and reduces the rate of first-trimester spontaneous abortion.2 Metformin also delays progression to type 2 diabetes in people with impaired glucose tolerance.3 It is currently being evaluated in the treatment of gestational diabetes mellitus, and has shown promising results in selected individuals with type 1 diabetes.4 But this increase in the use of metformin is not without risk. The manufacturer’s product information on metformin reminds prescribers that life-threatening lactic acidosis can occur, caused by accumulation of metformin, and that risk factors for this include renal impairment, old age and doses over 2 g per day. The estimated prevalence of life-threatening lactic acidosis is one to five cases per 100 000,5 with mortality in reported cases up to 50%.6 Traditionally, this complication has been thought of as secondary to an accumulation of the drug. Metformin is excreted unchanged in the urine, with the half-life prolonged and renal clearance decreased in proportion to any decrease in creatinine clearance.6 This may occur chronically in chronic renal impairment, or acutely with dehydration, shock, and intravascular administration of iodinated contrast agents, all of which have the potential to alter renal function. Tissue hypoxia also has a significant role, and acute or chronic conditions that may predispose to this condition, such as sepsis, acute myocardial infarction, pulmonary embolism, cardiac failure and chronic liver disease, may act as triggers. Between 1985 and 2001, 48 cases of lactic acidosis with metformin were reported to the Australian Adverse Drug Reactions Advisory Committee (ADRAC). In 15 of these cases, the complication was fatal. In 35 of the 48 cases, known risk factors were identified. Over the past 4 years, the average number of cases reported to ADRAC has been six per annum. In Australia in 2002–2003, about 200 000 patients were prescribed metformin, giving a reported frequency of lactic acidosis of one in 30 000. However the actual rate of occurrence is likely to be higher, given that under-reporting is an inherent problem with voluntary pharmacovigilance programs. At the Princess Alexandra Hospital in Brisbane, since January 2000, we have identified 13 patients with lactic acidosis thought to be related to use of metformin. Of these 13 patients, two died, while three require ongoing dialysis for renal failure; another was left with severe neurological disability requiring nursing-home care. The average age of the affected patients was 67 years (range, 47–79 years), and the baseline serum creatinine concentration (known in 10 patients) ranged from 0.12 mmol/L to 0.48 mmol/L, with a mean of 0.21 mmol/L (reference range, 0.05–0.11 mmol/L in women, and 0.06–0.12 mmol/L in men). Seven of the 13 patients were taking a metformin dose of 3 g per day, three were taking 2 g, while the remaining patients were taking between 500 mg and 1.7 g. How well do we currently comply with recommendations on prescribing metformin? A study at the University of Pittsburgh Medical Center in the United States reported on 263 hospital admissions involving 204 patients who were taking metformin. Patients had at least one absolute contraindication to metformin in 27% (71) of admissions. In 41% (29) of these, treatment with metformin continued despite the contraindication.7 A Scottish study of 1847 patients taking metformin found that 24.5% (452) had a contraindication.8 It follows that metformin must be prescribed appropriately to avoid potential adverse effects, while offering patients the best treatment possible. In well, ambulatory patients, renal function should be monitored regularly. A cut-off serum creatinine concentration above which metformin should be discontinued has been arbitrarily set at 0.15 mmol/L.9 Obviously, this needs to be individualised, and age, muscle mass, and protein turnover need to be considered. This can be achieved using the Cockcroft–Gault equation, which estimates creatinine clearance from age, weight and serum creatinine concentration. For example, with this equation, a 75-year-old woman, weighing 65 kg, with a serum creatinine concentration of 0.11 mmol/L, has an estimated creatinine clearance of 40 mL/min, which is significantly reduced. We propose: setting an absolute cut-off point (a creatinine clearance of 30 mL/min), below which metformin should be discontinued; and using metformin with extreme caution in patients with a creatinine clearance in the range 30–50 mL/min. No clear guidelines exist on reducing the dose of metformin as renal function declines, but reports of lactic acidosis have occurred with doses as low as 500 mg per day. Alternative strategies for managing diabetes in this situation include the use of insulin, thiazolidinediones and sulfonylureas. The second adverse situation to be considered is the previously well patient with a significant intercurrent illness. This includes illnesses with the potential to alter renal function, such as dehydration, shock, and sepsis. Metformin should be ceased completely while the patient is unwell, and recommenced when the illness has resolved, and renal function is shown to be normal. In addition, illnesses that increase the risk of tissue hypoxia and acidosis, such as acute myocardial infarction, pulmonary embolism, and cardiac failure, can trigger lactic acidosis, and the dose of metformin should be significantly reduced (or the drug discontinued altogether) under these circumstances. Patients need to be educated about these risks. Finally, a special situation is the use of iodinated contrast agents. The current recommendation is that metformin be withheld for 24–48 hours before the procedure and be recommenced 48 hours afterwards and only when renal function is shown to be normal.10 Without doubt, metformin remains the drug of choice for most patients with type 2 diabetes. Careful and thoughtful use of this drug has the potential to avoid life-threatening adverse events.

Janelle C Nisbet MB BS · Joanna M Sturtevant BPharm, BSc · Johannes B Prins PhD, FRACP

Clinical records Case 1: An 89-year-old woman was admitted to hospital from a nursing home with a 12-hour history of drowsiness, progressing to an unrousable state and inability to eat or drink. A low dose of long-acting morphine had been commenced 2 days earlier for painful arthritis. A capillary blood glucose (glucometer) reading taken in the nursing home on the morning of hospitalisation was 4.1 mmol/L. Past history included well controlled type 2 diabetes mellitus associated with corticosteroid use, for which she had been prescribed glimepiride 0.5 mg daily 2 months previously. The last dose was given on the morning of hospital admission. She was taking multiple other medications for comorbid conditions. The ambulance officers transporting her to hospital had recorded a “Lo” glucometer reading and administered 25 mL of 50% glucose. Within 5 minutes, a repeat glucometer reading was 14.7 mmol/L. On arrival at hospital the woman was opening her eyes and responding appropriately to pain, but not verbalising. Her Glasgow Coma Score was 9/15. In emergency triage, a glucometer reading showed 4.8 mmol/L, but shortly afterwards her venous serum glucose concentration was 1.3 mmol/L and serum creatinine level was 0.19 mmol/L (normal range, 0.05–0.09 mmol/L). Results of a cerebral computed tomography scan were unremarkable. Over the next 15 hours, there were six more glucometer readings with levels < 3.5 mmol/L, including readings of 0.6 mmol/L and 1.8 mmol/L (18 and 27 hours after the last dose of glimepiride, respectively). Despite a total of 250 mL of 50% glucose in eight bolus doses and a 5% glucose infusion commenced at admission and continued throughout hospitalisation, her level of consciousness deteriorated. She died 18 hours after presentation. Case 2: A 79-year-old woman living in a nursing home had been discharged from hospital several days earlier after internal fixation of a fracture of the femoral neck. She was readmitted after a sudden deterioration, characterised by drowsiness, decreased response to questions and dyspnoea. Her past history included type 2 diabetes mellitus for 4 years, for which she was taking glibenclamide 2.5 mg twice daily, a dose which had not been changed for 3 years. Glucometer readings had ranged between 7 mmol/L and 9 mmol/L during her recent hospitalisation. Other major comorbidities included a dominant middle cerebral artery stroke resulting in persisting hemiplegia and dysphasia, atrial fibrillation, hypertension and congestive cardiac failure. Because of her multiple comorbidities she was taking numerous medications. A glucometer reading was not performed before transfer to hospital. In the emergency department, the woman was initially treated for pulmonary oedema and pneumonia, which were evident clinically and radiologically. Her venous serum glucose concentration was 0.6 mmol/L and her serum creatinine level was 0.04 mmol/L (normal range, 0.05–0.09 mmol/L). Over the ensuing 27 hours, five more glucometer readings were < 3.5 mmol/L, including one of 0.7 mmol/L, and another of 2.3 mmol/L (24 and 36 hours after the last dose of glibenclamide, respectively). In total, she required 300 mL of 50% glucose in six bolus doses and a 5% glucose infusion for 48 hours. Over the ensuing days, her condition improved and she was able to take a purée and thickened fluid diet. One week after presentation, she appeared to vomit and aspirate while eating, and suffered an asystolic cardiac arrest from which she could not be resuscitated. Sulfonylureas act by stimulating insulin secretion from the pancreas and augmenting glucose-stimulated insulin secretion. Some, such as glibenclamide and glimepiride, are long acting and have metabolites that are excreted renally. Others, such as gliclazide and glipizide, are shorter acting and do not have active metabolites.1 Hypoglycaemia is the major risk associated with the use of sulfonylureas, particularly in elderly people. Serious hypoglycaemia is usually defined as that causing death, or requiring hospitalisation or emergency department admission. The rate is probably between 1% and 2% per year.2 Previous reports suggest, and the cases described here demonstrate, that this may occur even with very low doses of a sulfonylurea. The resultant hypoglycaemia can be prolonged and recur for a period of more than 24 hours despite treatment. Case fatality rates of 4%–10% are reported and 5% of survivors may have permanent neurological impairment.3 In elderly people, the classical autonomic adrenergic symptoms and signs of hypoglycaemia may not be present (or evident), and neuroglycopenic features, such as drowsiness or confusion, may dominate the picture (as in the cases described), so the diagnosis can be easily missed.4 Elderly patients with these symptoms who are taking medication for hypoglycaemia need immediate (and repeat) measurement of blood sugar level (BSL). If the BSL is low and the patient is alert and able to swallow, oral carbohydrate loading is the preferred management regimen — otherwise an ambulance should be called and the patient transported to hospital as a matter of urgency. While 10–25 g of carbohydrate delivered in 50% glucose is essential to restore the patient to euglycaemia in the short term, in the presence of sulfonylurea it stimulates more insulin secretion by the pancreas, and therefore can contribute to recurrent hypoglycaemia. The 50% glucose bolus should be followed immediately by an infusion of 5% or 10% glucose, usually at a rate of 100–200 g of carbohydrate daily, and BSL should be monitored for at least 24 hours. Subcutaneous synthetic somatostatin analogues may be used to reduce the likelihood of rebound hypoglycaemia and reduce glucose requirements, but there is no role for glucagon in the management of sulfonylurea-induced hypoglycaemia.5 Numerous studies show that longer-acting sulfonylureas are associated with a higher risk of hypoglycaemia, including serious hypoglycaemia. Gliclazide and glipizide have been shown to cause less hypoglycaemia than glibenclamide, and one study also suggested that glimepiride was safer than glibenclamide.6-9 There are no published reports comparing glimepiride directly with gliclazide or glipizide for hypoglycaemia. Other risk factors for hypoglycaemia, evident in the cases described here, include advanced age, recent hospitalisation, multiple medications, and drug accumulation caused by renal or hepatic impairment (keeping in mind that renal function usually declines linearly with age). Medication changes, including an increase in hypoglycaemics while a patient is unwell in hospital, may not be adequately communicated to the patient’s general practitioner, and recent hospitalisation is perhaps the major risk factor for sulfonylurea-induced hypoglycaemia. The presence of any of these risk factors should affect the choice and dose of medication and increase vigilance in monitoring BSL and renal function. In conclusion, the above cases serve to remind us of the dangers of long-acting sulfonylureas, which should perhaps be avoided in elderly people. Shorter-acting sulfonylureas such as gliclazide and glipizide are safer options. Elderly patients with altered mentation taking sulfonylureas require an urgent BSL measurement and, if they are unable to take food or fluids orally, they should be referred to hospital promptly. Lessons from practice Long-acting sulfonylureas, such as glibenclamide (and perhaps glimepiride) should be used with extreme caution in frail elderly people. Recent hospitalisation is a major risk factor for sulfonylurea-induced hypoglycaemia and necessitates increased vigilance in monitoring the patient’s condition and blood sugar levels. The classical adrenergic features of hypoglycaemia may be absent (or not evident) in frail elderly people. Drowsy or confused elderly patients taking sulfonylureas should have their blood sugar level measured urgently. Once sulfonylurea-induced hypoglycaemia is confirmed, oral carbohydrate loading is the preferred management regimen in alert patients, but those unable to take oral food or fluids should be transferred to hospital as a matter of urgency. Even with low-dose sulfonylurea therapy, hypoglycaemia can be severe, prolonged and recurrent over at least 24 hours.

Peter C Veitch MB BS, FRACP · Rory J Clifton-Bligh MB BS, PhD

Johan H A Janssen,* David Henshaw† * Cardiologist, † General Physician, Kalgoorlie Regional Hospital, PO Box 8035, Hannans, Kalgoorlie, WA 6433. Johan. JanssenAThealth.wa.gov.au To the Editor: We read with interest the article by Hung on aspirin for cardiovascular disease prevention,1 and would like to alert readers to the fact that, from the same studies Hung discussed, it is clear aspirin fails to prevent 80% of recurrent serious vascular events, and that one in eight high-risk patients will suffer from another “event” in the next 2 years while taking aspirin.2 Recent studies have triggered discussion about the concept of aspirin resistance and competitive binding issues as possible causes for the observed failure of aspirin, or indeed the increased risk of all-cause mortality when aspirin is used in combination with ibuprofen.3,4 Although it may still be premature to recommend routine testing for aspirin resistance, the possibility that testing might lead to improved strategies for reducing the risk of thrombotic complications means that it should be considered. Another point for consideration is whether primary prophylaxis with aspirin might induce aspirin resistance, thereby nullifying the effect of taking it in the first place. We agree with Hung that the current main alternative to aspirin is clopidogrel, and that this agent could be used in cases in which there is any doubt about the efficacy of aspirin.

Johan H A Janssen · David Henshaw

Joseph Hung Associate Professor, School of Medicine and Pharmacology, University of Western Australia, and Head of Department, Cardiovascular Medicine, Sir Charles Gairdner Hospital, Verdun Street, Nedlands, WA 6009. jhungATcyllene.uwa.edu.au In reply: Janssen and Henshaw are correct to point out that aspirin fails to prevent 80% of recurrent serious vascular events among high-risk patients. However, to put this into perspective, simple treatment with aspirin produces about the same relative risk reduction as treatment with a statin or the angiotensin-converting enzyme inhibitor, ramipril, among patients at high risk of vascular events.1-3 Janssen and Henshaw raise the concept of aspirin resistance and the role of a screening test. However, aspirin resistance is a poorly defined term, and could mean the clinical inability of aspirin to protect individuals from arterial thrombotic events, or laboratory measures indicating the failure of aspirin to inhibit platelet activity. There is currently no specific, accurate, and reproducible measure of the antiplatelet effects of aspirin, nor are there methods that can reliably predict the clinical efficacy of aspirin.4 For now, with high-risk patients, doctors should: ensure that patients comply with aspirin therapy along with other proven preventive treatments; avoid regular concomitant use of non-steroidal anti-inflammatory drugs with aspirin because of the potential for competitive inhibition;5 and consider the addition of clopidogrel to therapy with aspirin, so as to block other pathways of platelet activation not blocked by aspirin, particularly in patients who experience thrombotic complications during aspirin therapy.1

Joseph Hung

The current “Pharmaceutical Benefits Scheme (PBS) community awareness campaign” explicitly links the difficulties facing the PBS to patient behaviour and “waste”. The campaign suggests that patients are taking advantage of affordable access to prescription medicines, and emphasises that patient responsibility is “the prescription for a healthy PBS”. By neglecting to inform the public that the pressures facing the PBS also include doctors’ prescribing habits and intensive pharmaceutical industry marketing, the campaign has missed an opportunity to initiate a balanced and constructive debate about the future viability of the PBS. It has become something of an axiom that increasing cost is endangering the Pharmaceutical Benefits Scheme (PBS), and that something must be done about it. Typically, policy responses have been to target the prescription end-user — the patient. Successive governments have increased patients’ out-of-pocket charges as a means of containing drug costs. The present federal Government, thwarted thus far by the Senate in its attempt to increase the patient co-payment, is trying an alternative — appealing to patients’ moral sensibilities rather than their hip-pocket nerve. The current “PBS community awareness campaign”,1 an initiative of the National Strategy for Quality Use of Medicines (QUM)2 has been launched at a reputed cost of $27 million through a nationwide advertising strategy.3 The objective of informing the Australian public about the operation, strengths and costs of the PBS is laudable. However, the tone of the campaign is morally charged, with the suggestion that many Australian patients are not acting responsibly in their use of prescription medicines. The two main mediums of the campaign — a series of television advertisements and an information booklet — emphasise an association between patient behaviour, “waste”, and the increasing financial pressure on the PBS, a pressure which imperils the future viability of the scheme. It appears that patient responsibility is “the prescription for a healthy PBS”. As part of the National Medicines Policy, the strategy for QUM is underpinned by a set of principles, the first of which is “the primacy of consumers”. The strategy claims to recognise “the wisdom of consumers” and states “consumer involvement in all aspects of the Strategy is critical”.2 Far from incorporating the wisdom of patients, the present campaign appears to selectively choose more extreme examples of misuse of medicines to establish a moral position and place the responsibility for increasing prescription demand on patients. The campaign booklet states “some people like to get a prescription every time they visit a doctor”. This statement implies that patients drive the demand for prescriptions and that the low cost of prescription medicines promotes wasteful behaviour. The campaign repeatedly advises patients to take note of the full cost of the prescription that is borne by the Scheme (this is now highlighted on prescription labels). With such information, patients can “use the PBS responsibly” and minimise “waste”. Patients are also exhorted to consider their need for repeat prescriptions, but are not advised of the dangers of stopping treatment for some serious disorders (eg, diabetes and heart failure). The National Medicines Policy document raises the concern that “easy access can work against the quality use of medicines”, offering the common anecdote of patients’ stocking up unnecessarily on prescription medicines “. . . because they are available free or at low cost”. While patients probably do initiate a certain amount of unnecessary prescription demand, the relationship of this to the cost of a prescription is not clear in the available evidence.4 Further, there is no substantial evidence to show that such behaviour is common enough to be a major contributor to rising drug expenditure. The emphasis on patient responsibility reveals a conviction that prescription subsidy through the PBS results in significant “moral hazard”. In other words, low out-of-pocket cost generates unnecessary prescription demand or “waste”. Arguments for the operation of a “moral hazard” rest not on direct observations of patient behaviour, but on studies of aggregate prescribing data.5 Rather than drawing on the wisdom of patients, fluctuations in use of prescription medicines after changes to out-of-pocket costs are used to make inferences about patients’ motivations. Differences in rates of use of “essential” therapies compared with “discretionary” therapies are taken as proxies for “necessary” and “unnecessary” patient behaviours.6 However, prescribing data cannot show whether the changes in pharmaceutical use reflect appropriate or inappropriate patient responses to increased cost; nor can they reveal the motives of patients who have received prescriptions. Increased demand when drugs are affordable does not itself mean that patients are using medicines unnecessarily.7 The increasing cost of the PBS does, however, mean that Australians are being given more prescriptions, often for newer or novel therapies. Australians, like the citizens of other developed nations, live in a society where prescription medicines are central to the provision of healthcare and increasingly prominent in how we prevent and manage illness. The pharmaceutical industry devotes considerable expense and effort to promoting drugs directly to doctors and less directly to patients.8 Australian doctors’ preferences for prescribing newly released medicines, often neglecting older cheaper alternatives, have long been noted.9-13 Patients may sometimes ask their doctor to prescribe the latest available drug for their condition; however, there is no evidence to indicate that low cost is a prime motivator in this demand. The diminishing numbers of general practitioners willing to “bulk-bill” their patients means that seeing a doctor requires an increasing out-of-pocket expense for many patients.14 Most Australian patients do not undertake the cost and inconvenience of consulting a doctor lightly. It is unlikely that many visit their doctor to unnecessarily access affordable medicines. Even with affordable access, the underuse of prescription medicines is a commonly acknowledged problem. While some patients may “like to get a medicine every time they visit the doctor” (quote from the Strategy), other patients don’t seek a medicine when it is necessary, do not always accept a necessary prescription, nor do they always adhere to their prescribed therapy. Despite the PBS providing affordable access, medicine costs can still present a barrier for some Australian medicine users, particularly the chronically ill and those on lower incomes but not eligible for government concessions.15 While the strategy has parallel initiatives aimed at enhancing QUM among health professionals and the pharmaceutical industry, the notion of pharmaceutical “waste” is not a prominent feature of these. In contrast to the message about “waste” that is communicated to consumers, health professionals and industry staff who visit the PBS Web home-page receive a brief outline of the PBS drug-listing process. The strategy and its current awareness campaign give the impression that whatever waste exists is largely driven by consumers taking advantage of affordable access. Related phenomena such as prescription “drift” (the tendency to prescribe newer more expensive medicines for common conditions) and “leakage” (prescribing to a broader population than was intended in the subsidy decision) and aggressive industry marketing are left out of the public gaze.13,16 This restricts the community’s awareness about the PBS, the pressures it faces and its future viability. An opportunity has been missed to provide the public with a comprehensive and balanced view of the problems facing the PBS. The Strategy, as presented to the public, has selectively focused on the role of affordable access in creating “waste” and in contributing to the pressure on the PBS. Because of the complexities of prescription drug use in the community, this will have little impact on quality use of medicines overall. Further, this focus potentially alienates patients from information on the other important factors contributing to increasing PBS expenditure, such as intensive promotion by pharmaceutical companies and doctors neglecting to prescribe older, cheaper therapies. Accepting that most prescription use is necessary begs the question of what proportion of medicine use is unnecessary and what factors combine to generate such use. These questions are still to be coherently answered, and what current knowledge exists is insufficient to justify elevating “moral hazard” to a primary cause of difficulties facing the PBS. A more balanced approach to informing the community about these problems would be to acknowledge the role of patients, health professionals and the pharmaceutical industry in creating demand, and to initiate an informed debate on how to sustain the PBS.

Evan Doran PhD · David A Henry FRCP

Amanda J Caswell Managing Editor, MIMS Australia, Locked Bag 3000, St Leonards, NSW 1590. amanda.caswellATmims.com.au To the Editor: Tan et al outline deficiencies in product information documents (PIs) as published in MIMS.1 It needs to be clarified that MIMS Australia is not responsible for the content of PIs — this is specified and approved by the Therapeutic Goods Administration in consultation with the sponsoring company. The conclusion by the authors that the “PIs for many prescription products listed . . . do not adequately detail paediatric doses” should not be specifically attributed to MIMS, as all published medicines information that relies on approved PIs will suffer from the same deficiencies.

Amanda J Caswell

Manufacturers’ claims in well funded marketing campaigns cannot replace the test of time Declaring war and prescribing drugs are decisions dependent on information, and the consequences can be calamitous if that information is incomplete or inaccurate. The calamity which threatened the sustainability of the Pharmaceutical Benefits Scheme (PBS) in 2000 and 2001 was the volume of prescriptions for cyclooxygenase (COX)-2 inhibitors. Celecoxib was listed on the PBS on 1 August 2000, and by the end of December 2000 over 1.5 million prescriptions had been written, costing the government more than $76 million.1 By the end of June 2001, the cost had exceeded $160 million.2 In this issue of the Journal (page 403), Kerr and colleagues confirm the rapid rise in prescriptions for celecoxib and rofecoxib.3 However, their research cannot explain why the general practitioners in their study were so enthusiastic about the new drugs. The doctors’ decisions to prescribe would have been based on the available information. At the time the drugs were launched in Australia, most of that information would have been supplied directly or indirectly by the manufacturers. There was little independent information, and the major randomised trials of celecoxib (CLASS4) and rofecoxib (VIGOR5) were only published in late 2000. The information from the manufacturers emphasised the relative safety of the new drugs. Compared with non-selective non-steroidal anti-inflammatory drugs (NSAIDs), the new drugs caused fewer peptic ulcers. This was an important message, as doctors are often warned about the serious gastrointestinal complications of NSAIDs. There is evidence that some patients were prescribed the new drugs because they had suffered adverse effects from NSAIDs.6 However, this did not result in a fall in the prescribing of NSAIDs. The availability of celecoxib and rofecoxib increased the number of people being treated for musculoskeletal disorders,3 suggesting the new drugs were being prescribed for conditions beyond the restrictions of the PBS. Such conditions include non-specific back pain, sprains and sports injuries.3,6 Some general practitioners believe that COX-2 inhibitors are more effective than NSAIDs.6 This belief is not confirmed by the clinical trials, and now even the evidence of their improved safety is being questioned.7 The published results of VIGOR5 and CLASS4 did not include all the data submitted to the United States Food and Drug Administration (FDA).7,8 The favourable results of CLASS were based on only the first 6 months of the trial. Analysis of the 12 months’ data that was available to the FDA suggests that celecoxib was associated with a similar number of ulcer complications as were diclofenac and ibuprofen.7,9 Similarly, analysis of the complete data for rofecoxib suggests it may be associated with an increased risk of cardiovascular events10 and that serious adverse effects may be more frequent than with naproxen.8 The Therapeutic Goods Administration (TGA) probably had access to the complete data when it evaluated the drugs for use in Australia. However, unlike the FDA data, which are published on its website,8,10 the TGA’s evaluations are kept secret. Would publication of the TGA’s evaluations have alerted Australians to the possible problems with COX-2 inhibitors? Concerns about the drugs only arose months after they were marketed. Even if they had been aired earlier, they are likely to have been lost in the excitement surrounding the launch of the drugs. Even the Minister for Health and Aged Care put out a press release listing some of the benefits of celecoxib and describing it as a “major breakthrough in arthritis therapy”.11 Enthusiasm for the COX-2 inhibitors waned slightly with experience. In Kerr and colleagues’ study, rofecoxib was not embraced to the same extent as celecoxib. Nearly a third of the patients prescribed rofecoxib had previously been prescribed celecoxib, suggesting they had been disappointed by the response.3 Initial enthusiasm followed by a slower increase or plateau in prescribing is a common pattern with new drugs. If the new drugs are not as good as they were thought to be, can they justify being twice the price of other NSAIDs? What coaxes doctors to expose their patients to new products when so little information is available? I believe that manufacturers’ marketing strategies play on doctors’ desire to give their patients the best possible care. Much of the variation in the prescribing of new drugs depends on the personality of the doctors, and probably on their susceptibility to these marketing techniques.12 The prospect of reduced adverse effects is likely to have a strong influence on prescribing practice. If adopting new drugs quickly actually puts patients at risk, prescribers must be presented with information to balance the claims of the drug companies. Achieving this balance is difficult, partly because independent information (such as Therapeutic guidelines and the Australian medicines handbook) sometimes comes at a cost, while drug company information — supported by massive advertising budgets — is free. In 2000, the amount spent on promoting rofecoxib to Americans (US$160 million) exceeded the advertising budgets for Pepsi and Budweiser beer.13 In view of the popularity of the new drugs in the United States, perhaps Australia should have been prepared for the demand. If the TGA had been able to provide its evaluations to publishers of independent information, they could have prepared prescribing guidelines before the drugs were marketed. The National Prescribing Service has recently received funding to provide doctors with independent information about new additions to the PBS. To ensure advertising does not swamp these messages, perhaps there should be limits on promotional activities around the date of PBS listing. While governments are unlikely to ban advertising, they could at least mandate that it provides quantitative information about the outcomes for patients.14 Another approach to new drugs is not to use them. This will spare patients from the serious adverse effects which sometimes only emerge after marketing. The Health Research Group in the US now recommends waiting 7 years before using a new drug that provides no clear advantage over current therapies.15 While this may be an extreme position, there is no need to feel pressured into immediately prescribing the latest drug. New is not always better.

John S Dowden MRCGP, FRACGP

Objective: To assess trends in the first two years of prescribing of COX-2-selective non-steroidal anti-inflammatory drugs (C2SNs) by Australian general practitioners.Design: Retrospective analysis of deidentified electronic patient records from GPs enrolled in the General Practice Research Network (GPRN).Setting and participants: Overall prescription rates for C2SNs and NSAIDs were assessed for all GPRN participants (437 GPs) between 1 September 1999 and 30 September 2002. Also, three cohorts of patients, with at least 12 months of prescription data, who received their first prescription for celecoxib between August and October 2000 (Cohort 1, 2366 patients), celecoxib between February and April 2001 (Cohort 2, 640 patients), and rofecoxib between February and April 2001 (Cohort 3, 608 patients) were selected for further analysis.Main outcome measures: Age and sex of patients; reason for prescription; previously prescribed pain medications and concomitant use of medications that could predispose to an adverse renal or bleeding event.Results: Prescriptions for C2SNs increased dramatically after they were listed on the Pharmaceutical Benefits Scheme (PBS). C2SN prescriptions for patients aged less than 65 years accounted for 52.6%, 59.5% and 50.7% of those in Cohorts 1, 2 and 3, respectively; large numbers of patients in the study cohort had reasons recorded for prescription that did not comply with PBS restrictions, and between 36.7% and 61.3% of patients in the three cohorts had not received a prescription for any pain medication in the year before being prescribed a C2SN. Between 4.7% and 7.9% were coprescribed drugs that could cause renal complications.Conclusions: Rapid, early adoption of C2SNs by Australian GPs has resulted in prescribing and drug use patterns that were not in accord with quality use of medicine (QUM) principles.

Stephen J Kerr BPharm, PhD · Andrea Mant MD, MA · Fiona E Horn BSc, MPH · Kevin McGeechan BSc · Geoffrey P Sayer BSc(Psychol), MCH

Milton G Roxanas Psychiatrist, The Epping Clinic, PO Box 288, Eastwood, NSW 2122. mroxanasATbigpond.net.au To the Editor: I wish to report hyponatraemia in a patient commencing therapy with mirtazapine — this is the first such report from Australia. An 86-year-old widow with depression had had a previous episode of hyponatraemia while taking venlafaxine. Anticipating the possibility of further hyponatraemia, I prescribed mirtazapine 15 mg nightly — half the recommended starting dose. At this time, she was also taking amiodarone, gliclazide, l-thyroxine, irbesartan with hydrochlorothiazide, alendronate, omeprazole, atorvastatin and zolpidem. Her baseline serum sodium level was 135 mmol/L (normal range [NR], 135–149 mmol/L), but 4 days later it had fallen to 130 mmol/L, with serum osmolality of 294 mosmol/kg (NR, 280–295 mosmol/kg), urine osmolality of 398 mosmol/kg (NR, 50–1200 mosmol/kg), spot urine sodium concentration of 42 mmol/L, and plasma antidiuretic hormone (ADH) level of 0.7 pmol/L (NR, 0.1–7.0 pmol/L). Mirtazapine therapy was stopped after a further 2 days, and 10 days later her serum sodium level was 134 mmol/L, serum osmolality 296 mosmol/kg, urine osmolality 419 mosmol/kg and spot urine sodium concentration 27 mmol/L. Her plasma glucose level varied from 7.4 mmol/L to 9.2 mmol/L (NR, 3.4–5.4 mmol/L). Her condition was subsequently stabilised on mianserin (20 mg nightly) without electrolyte abnormalities. There are 12 reports worldwide of hyponatraemia due to mirtazapine (manufacturer’s data “on file”). This antidepressant inhibits α2 auto- and heteroreceptors, blocks 5-HT2 and 5-HT3 receptors, and acts via noradrenergic and 5-HT1A receptors. The mechanism of hyponatraemia is thought to be via α1 or serotonergic stimulation of ADH, but other possible causes include increased osmoreceptor sensitivity, reduced renal ability to conserve salt and water in the elderly, enhanced renal action of ADH1 and reduced metabolism of the antidepressant. There is no known interaction between mirtazapine and amiodarone or irbesartan or thiazides to account for hyponatraemia. This patient had risk factors — she was elderly, female, was taking diuretics and had had hyponatraemia with another antidepressant medication. As in previously reported cases the ADH level was not elevated, although the syndrome of inappropriate ADH secretion (SIADH) is not always accompanied by raised ADH levels.2 Hyponatraemia is seen more often these days because of greater awareness, the increasing proportion of elderly people in the population and the trend towards polypharmacy in the elderly. Many drugs have the potential to produce SIADH; one report has indicated that almost all antidepressants are implicated.3 Amitriptyline-induced hyponatraemia was first described in 1974, and a recent retrospective study of elderly patients found an incidence of 32% with selective serotonin reuptake inhibitors and an unusually high 71% with venlafaxine.4 In the face of an increasingly common phenomenon, I recommend that patients aged over 65 years should have baseline measurements of electrolyte levels before starting therapy with an antidepressant, and that these should be repeated 2–7 days later to detect possible hyponatraemia and initiate treatment.

Milton G Roxanas

Objectives: To review the approved product information (PI) of prescription medicines to determine the extent and nature of information available on paediatric dosing and the availability of paediatric dosage formulations in Australia.Methods: The PIs for all prescription medicines listed in the Australian Monthly Index of Medical Specialties (MIMS) were reviewed. Dosing information for each PI was categorised according to age groupings. PIs claiming suitability for use in paediatric patients were reviewed for information on the availability of paediatric dosage forms.Main outcome measures: Proportion of PIs providing paediatric dosing information; availability of dosage forms suitable for children.Results: A total of 1497 PIs were reviewed. The proportions, for each age group, of PIs with inadequate paediatric dosing information were: < 1 month (80.5%), 1–3 months (79.1%), 3 months–2 years (77.5%), 2–6 years (73.2%), and 6–12 years (71.6%). The proportions, for each age group, of PIs that gave specific paediatric dosing information but did not provide a paediatric dosage form were: < 1 month (26.5%), 1–3 months (25.1%), 3 months–2 years (23.3%), 2–6 years (21.9%), and 6–12 years (24.0%).Conclusions: The PIs for many prescription products listed in MIMS do not adequately detail paediatric doses. Many medicines for which specific paediatric dosing information is given are not available in dosage forms appropriate for children.

Elaine Tan BPharm, BPharmSc(Hons) · Craig R Rayner BPharm, BPharmSc(Hons), PharmD · Colin B Chapman BPharm, PhD, FPS · Noel E Cranswick MB BS, FRACP

Corrine R Balit,* Geoffrey K Isbister,† Andrew H Dawson,‡ Frank F Daly,§ Ian M Whyte‡ * Research Pharmacist, NSW Poisons Information Centre, The Children's Hospital, Locked Bag 4001, Westmead, NSW 2145; † Lecturer and Clinical Toxicologist, ‡ Associate Professor, Newcastle Mater Misericordiae Hospital and the University of Newcastle, Newcastle, NSW; § Clinical Toxicologist, Royal Perth Hospital and University of Western Australia, Perth, WA. corrinebalitATaol.com To the Editor: Paracetamol availability is an important public health issue. Kisely et al have further investigated the impact of two paracetamol recall periods on analgesic poisoning using a dataset derived from hospital admissions.1 We are concerned about the robustness of data that uses ICD codes, because of significant coding problems that occur with poisoning admissions. The aim of their study was as a follow-up to our own,2 to look at the impact of removing paracetamol tablets from the shelf during a recall period. Availability is reported to be the most common reason for patients choosing to take paracetamol in overdose3 and, as such, has the potential to affect acute deliberate self-poisoning. However, Kisely et al recognised that it was difficult for them to distinguish between intentional and unintentional ingestions because of the limitations of their dataset1 and hence they considered both of these together. This is inappropriate if the aim is to assess the effect of availability on paracetamol deliberate self-poisoning. For example, there is no evidence that presentations with therapeutic errors in dosing are related to availability and these should be excluded. This is not possible by using ICD codes and was therefore not done by Kisely et al.1 In addition, it is only relevant to include accidental ingestions of tablet formulations of paracetamol, because only these were affected by the recall. There are significant numbers of presentations of children, who accidentally ingest liquid formulations of paracetamol (hence not related to the recall period), that are coded as paracetamol admissions. This introduces a further significant potential bias in the Kisely study. A more concerning problem is the reliability of ICD coding in separating out different analgesics. Poisoning with prescription products such as paracetamol-codeine combination analgesics, which were not affected by the recall period, are also likely to be included in the study being coded as T39.1 (paracetamol overdoses).1 There are significant limitations in using ICD codes, resulting in the dataset analysed not being a true reflection of the impact of the recall of paracetamol tablets. Our study took into account only tablet formulations of the paracetamol alone compounds.2 Paracetamol ingestions following therapeutic error were excluded and accidental ingestions of only tablet formulations were included. While the numbers in the study were small for the hospital presentations, the data set for the NSW Poisons Information Centre was much larger and showed significant increases in intentional and accidental ingestions of ibuprofen, the next most available analgesic.2 In an environment where paracetamol restriction is a hotly debated topic, particularly in light of recent coroners’ cases, it is vital to consider the impact of paracetamol restriction on all types of deliberate self-poisoning by using an appropriate dataset that reflects the measures taken to reduce availability. The challenge for state and federal health departments is to fund appropriate postmarketing toxicovigilance for accidental and intentional self-poisoning in order to clarify these important public health issues.

Corrine R Balit · Geoffrey K Isbister · Andrew H Dawson · Frank F Daly · Ian M Whyte

Elizabeth A Hender,* Jeremy Raftos† * Scientific Officer, Hazardous Substances Section, Department of Human Services, PO Box 6, Rundle Mall, Adelaide, SA 5000; † Director, Paediatric Emergency Department, Women’s and Children’s Hospital, Adelaide, SA. Elizabeth. HenderATdhs.sa.gov.au To the Editor: We read with interest the study of Kisely et al,1 which showed a decrease in admissions for poisoning with paracetamol, but no coincident increase in use of other agents, as a result of the paracetamol recalls. We had noticed there was an unusually high number of presentations (18) to the Paediatric Emergency Department at the Women’s and Children’s Hospital, Adelaide (WCH), for poisoning with aspirin in 2000, compared with one presentation in 2001 and one in 2002. We wondered if the presentations in 2000 were temporally associated with the paracetamol recalls. We extracted all WCH presentations with a primary diagnosis of paracetamol poisoning (ICD-9 code 965.4), aspirin poisoning (965.1), nonsteroidal anti-inflammatory drugs (965.6) and poisoning with all other drugs (960–979.9) for the two recall periods (16 March 2000 to 21 May 2000; 6 June 2000 to 23 August 2000)2 and the same periods in 2001 and 2002. It could not be determined whether an over-the-counter preparation of a nonsteroidal anti-inflammatory drug had been taken. The results are shown in the Box. Presentations (P) and admissions (A) for poisoning with paracetamol, aspirin, NSAIDs and other drugs at the Women’s and Children’s Hospital, Adelaide 2000 restricted 2001 available 2002 available P A P A P A Aspirin 15 13 1 0 0 0 Paracetamol 23 6 34 13 34 14 NSAID 3 1 0 0 1 0 Other drugs 86 43 89 35 60 23 NSAID = non-steroidal anti-inflammatory drug. These data show that the number of paracetamol poisoning presentations and admissions was lower during the recalls than in the same period in subsequent years, but there was a higher number of presentations and admissions for poisoning with aspirin. All the aspirin poisoning presentations and admissions during the period when paracetamol was recalled were during the second recall (affecting SmithKline Beecham products). The other three aspirin poisoning presentations in 2000 occurred within 10 days of the end of the second recall. All but one of the 18 patients with aspirin poisoning who presented during 2000 were adolescents (17 females). Most of these exposures were likely to be due to intentional self-poisoning. Although it is not possible to reach any definite conclusion from these observations, we share the concerns of Balit et al2 that limiting the availability of paracetamol could result in an increase in poisonings with potentially more acutely dangerous agents such as aspirin, particularly for adolescents. There needs to be further consideration of the motivation of patients in choosing paracetamol and the source of the drug when taken for intentional self-poisoning before measures are taken to restrict access to paracetamol.

Elizabeth A Hender · Jeremy Raftos

Stephen R Kisely,* David Lawrence,† Neil J Preston‡ * Professor of Health Outcomes, Department of Psychiatry, Dalhousie University, Canada; † Post-doctoral Fellow, Institute for Child Health Research, Perth, WA; ‡ Research Psychologist, Fremantle Hospital and Health Service, Fremantle, WA. stephen.kiselyATcdha.nshealth.ca In reply: Balit et al raise the problem of distinguishing between intentional and unintentional ingestions. As stated in our article, we did look at deliberate and accidental poisonings separately, but space restrictions, not limitations of our dataset, prevented us from presenting the results.1 Of 2266 paracetamol poisonings, 1731 (76%) were coded as deliberate, 433 (19%) were accidental and in 103 (4.5%) the intention could not be determined. Restricting the analysis to the deliberate cases yields almost identical results. Our dataset may have contained poisonings with liquid or combination formulations of paracetamol that were not recalled. This factor would have operated before, during and after the recall and would only serve to reduce the magnitude of any effect, rather than accentuating it. We considered 2663 admissions for over-the-counter analgesic poisoning,1 as opposed to 143 in the NSW study.2 We did not look at telephone calls, as reliance on data from calls to a poisons information centre raises far more concerns about data quality than hospital statistics do. How reliable was the informant? How serious was the poisoning? Do telephone data contain less serious cases that do not require admission? Hender et al report the findings of an observational study restricted to a single paediatric emergency department attached to the Women’s and Children’s Hospital, Adelaide. Unfortunately, data for only three years are presented, with no information for the years before the recall. Neither do we know how many were intentional or unintentional. By definition, their data exclude adults. As they state themselves, it is not possible to reach any definite conclusions from their observations. We should not prematurely dismiss the possible benefits of restrictions on the availability of paracetamol. If there are concerns that restricting the availability of paracetamol might increase the use of other over-the-counter analgesics in poisonings, we should be investigating the effectiveness of restrictions on the availability of these as well. Who precisely benefits from continued sales of over-the-counter analgesics in catering pack sizes?

Stephen R Kisely · David Lawrence · Neil J Preston

Secondary prevention Aspirin provides benefit in nearly all groups of patients with clinical manifestations of coronary heart disease. This includes patients with evolving acute myocardial infarction or after recovery from myocardial infarction, with unstable or stable angina, and those who undergo coronary artery bypass grafting or coronary angioplasty. Aspirin provides benefit in patients with peripheral arterial disease. This includes patients with acute or previous history of ischaemic stroke or transient ischaemic attack, those with lower limb arterial insufficiency, and those who undergo grafting or angioplasty of peripheral arterial vessels. Primary prevention People without symptoms but at increased risk of a coronary heart disease event (> 1% annual risk) may reduce this risk by taking low-dose aspirin. However, the decision to take aspirin requires detailed consideration of individual cardiovascular risk and the potential benefit versus harm of treatment, particularly bleeding. Aspirin should only be used to prevent a cardiovascular event in association with an overall program of lifestyle measures including healthy eating, cessation of smoking, control of blood pressure and regular physical activity. Aspirin for prevention Prevention benefits of aspirin in heart disease can be achieved with doses as low as 75–150 mg daily. Unwanted effects of aspirin include stomach upsets, activation of peptic ulcers, an increased tendency to bruising, allergic reactions and increased risk of major gastrointestinal and other bleeding, including intracranial haemorrhage. In general, the risk of bleeding increases with increasing dose of aspirin and when it is used in combination with non-steroidal anti-inflammatory drugs or oral anticoagulants.

for the Medical Issues Committee of the National Heart Foundation of Australia

Sam L S Yuen,* Bruce McGarity† * Medical Registrar, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050; † Physician, Bathurst Base Hospital, Bathurst, NSW. lsyuen_98ATyahoo.com To the Editor: A 71-year-old man was admitted to hospital in 2002 with nausea, abdominal discomfort and myalgia. He was dehydrated and had mild right upper quadrant tenderness. No muscle tenderness was noted. Five weeks previously, an infected right femoropopliteal gortex graft had been surgically removed. Methicillin-resistant Staphylococcus aureus was present on culture. Therapy with fusidic acid (250 mg three times daily) and rifampicin (600 mg daily) had been commenced, and the patient’s condition improved. Fusidic acid therapy was continued because of unsatisfactory wound healing. On presentation he had been taking fusidic acid for 4 weeks. He had been taking simvastatin (40 mg nightly) for 8 years. The patient had a history of generalised vascular disease and multiple bypass procedures. He had a background of paroxysmal atrial fibrillation, myocardial infarction, left ventricular failure, hypertension, hypercholesterolaemia and chronic airways limitation. His other medications were metoprolol, irbesartan, frusemide, warfarin, paracetamol and narcotic analgesics. Test results showed the following biochemical concentrations: aspartate transaminase, 1618 U/L (normal range, < 40 U/L); alanine transaminase 657 U/L (normal range [NR], < 35 U/L); alkaline phosphatase 133 U/L (NR, 25–100 U/L); total bilirubin, 29 μmol/L (NR, < 20 μmol/L); γ-glutamyltransferase, 37 U/L (NR, < 50 U/L); urea, 24.7 mmol/L (NR, 3.0–8.0 mmol/L); creatinine, 0.35 mmol/L (compared with previous creatinine concentration of 0.11 mmol/L [NR, 0.06–0.12 mmol/L]). Drug hepatitis, secondary to fusidic acid was suspected, and therapy with this drug was ceased. The following day, the patient’s clinical status declined, with generalised muscle pains and weakness, significantly impairing his mobility. The serum creatine kinase concentration was elevated at 66 710 U/L (normal range, 60–220 U/L), with a normal troponin I concentration. Myoglobinuria (567 200 ng/mL) was detected. Simvastatin therapy was ceased, and there was prompt clinical improvement, with recovery of renal function and a gradual fall in the concentration of serum creatine kinase. On discharge 14 days after admission, his serum creatine kinase concentration was 1153 U/L and creatinine concentration was 0.12 mmol/L. Transaminase concentration readings fell rapidly in line with the creatine kinase concentration, suggesting they were of muscular rather than hepatic origin. Three other cases of rhabdomyolysis have been reported as a result of interaction between an HMG CoA-reductase inhibitor and fusidic acid,1-3 but there have been no previous reports from Australia. Fusidic acid, like simvastatin, undergoes extensive first-pass metabolism in the liver (over 98%). Simvastatin is metabolised via the cytochrome P3A4 enzyme system. It is known that, if given concomitantly with inhibitors of this system (eg, macrolides and azole derivatives), statin concentrations can become elevated and lead to an increased likelihood of adverse effects.4 Fusidic acid is not known to be an inhibitor of this system (Peter Hobbs, Manager of Medical Affairs, CSL Limited [manufacturers of fucidin], personal communication), although our case is suggestive of such an interaction. This case demonstrates the interaction of fusidic acid with simvastatin resulting in rhabdomyolysis. The extensive use of statin therapy in patients with vascular disease makes it important for doctors to be aware of this interaction when prescribing fusidic acid.

Sam L S Yuen · Bruce McGarity

Jill S Butty Quality Facilitator, Werribee Mercy Hospital, 300 Princes Highway, Werribee, VIC 3030 jbuttyATmercy.com.au To the Editor: It was refreshing to see the report by South et al, describing a simple, inexpensive intervention which resulted in a positive effect on the appropriate prescribing of antibiotics and a cost saving for the organisation.1 In the current climate, it has been much more fashionable to suggest computerised prescribing as the cure-all for medication and prescribing errors. As demonstrated by Newby et al,2 computerised prescribing has inherent problems, including an increase in repeat ordering of antibiotics. The Australian Council for Safety and Quality in Healthcare suggests computerised prescribing as one of several strategies to reduce medication critical incidents.3 However, the costs of establishing such a system in smaller hospitals and community health centres can prove prohibitive. This can lead to an attitude of “too expensive” so do nothing. Other strategies and interventions can be introduced at minimal cost to the organisation and yet prove effective in reducing both inappropriate prescribing and the number of critical incidents or errors. The provision of easily accessible standardised protocols and guidelines, the review of medication charts and their ease of use, changing the times of daily medication administration to maximise access to clinicians, and empowering patients to be more aware and responsible for their medications are just a few. In summary, other strategies need to be developed and their success or failure reported. There should also be awareness that familiarity with procedures can lead to errors and reinforcement is required for all interventions. Computerised prescribing should not be viewed as the solution to all medication adverse events, but one of several strategies that healthcare organisations can use in their battle with medication errors.

Jill S Butty · Saji S Damodaran

Saji S Damodaran Associate Professor, Department of Psychological Medicine, Monash University, and Clinical Director, Monash Medical Centre, 246 Clayton Road, Clayton, VIC 3168 saji.damodaranATmed.monash.edu.au To the Editor: Australia has a high rate of antibiotic use. Increasing antibiotic resistance, spiralling pharmaceutical cost, need for evidence-based practice, public awareness, and widespread variation in prescribing practice, which may lead to quality and safety issues, are reported as the drivers for improving antibiotic use and prescribing. South et al are to be commended for the introduction of a laminated card for doctors as a simple intervention to improve prescribing practices.1 Despite the passive nature of the intervention, they found significant improvement in the appropriateness of prescribing. The authors acknowledge that they are not claiming that their intervention “is the cause or only cause” for change in practice. Areas like antibiotic prescribing and physician behaviour are highly complex and require a series of systematic approaches. Doctors are only one of the multiple stakeholders involved in this process. The level of experience, training background, and awareness of the public health and clinical implications of such interventions vary widely among doctors. Improvement of South et al’s methodology from a passive mailout to gathering systematic baseline information about the medical staff involved, clarifying the purpose of the initiative and finding the proportions of uptake among junior and senior staff would have made the intervention more robust. One of the fundamentals of any change process is to instil a sense of urgency and develop a coalition to drive and lead it. Development and evaluation of quality initiatives need more than just passive information provision. It has been suggested that any such quality and safety initiative should have set priorities, and these priorities should be developed using a systematic evaluation process with explicit criteria.2 Various systemic strategies that involved systematic methodology and evaluation processes, such as antibiotic decision support systems (both computer and manual) and drug utilisation reviews, reported sustainable changes in prescribing practices.3 The intervention by South et al is a welcome initiative, but it is important to realise that simplifying a complex problem like drug prescribing may lead to setting up wrong priorities for action and trivialise the problem and solution. Such initiatives will suffer the fate of the many quality programs that we hear about in hospital corridors but which fail to make a sustainable change.

The recently released PREVENT trial provides some answers Venous thromboembolism (VTE) affects 1–2 people per 1000 in the general population each year.1 It most commonly manifests as deep vein thrombosis of the leg, or as pulmonary embolism. There are many acute provoking factors or triggers (eg, major trauma, recent surgery), and many chronic predisposing factors, both genetic (eg, factor V Leiden) and acquired (eg, cancer). Most patients with provoked VTE have a low risk of recurrence (0–4% per year without anticoagulation), presumably because most have no major predisposing factors for VTE.2 Treatment for provoked VTE is short term and consists of giving intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin (LMWH) for at least 5 days, followed by warfarin (target international normalised ratio [INR], 2.0–3.0) for 3 months.3 Further antithrombotic therapy is usually not required unless patients are re-exposed to known triggers for VTE. Standard-intensity therapy with warfarin remains the treatment of choice for the long-term prevention of recurrent VTE in patients who are at highest risk of recurrence Most patients with unprovoked VTE, however, have a higher risk of recurrence (≥ 5% per year without anticoagulation) over many years.4,5 This is because they are chronically exposed to one or more underlying genetic or acquired predisposing factors for VTE, which may be identifiable from the clinical history or through laboratory testing. Furthermore, the absence of a provoking factor or trigger for VTE is the most important predictor of recurrence in these patients. They require longer-term or indefinite treatment, which consists of giving intravenous unfractionated heparin or subcutaneous LMWH for at least 5 days, followed by warfarin (target INR 2.0–3.0).3 This is standard-intensity anticoagulation therapy, and is highly effective in preventing recurrent episodes of VTE for as long as it is continued. In trials in which patients were treated for a median of 4–6 months, it reduced the absolute risk by 7.6%, which is equivalent to preventing one event for every 13 patients treated (odds ratio [OR], 0.15; 95% CI, 0.10–0.23).6 In patients considered at highest risk of recurrent unprovoked VTE (eg, > 10% per year; see Box), warfarin therapy is continued indefinitely, whereas in most patients, it is discontinued after 6–12 months.3 This is because long-term anticoagulation is associated with a cumulative risk of bleeding, which is perceived to outweigh its benefits in preventing recurrent VTE. Standard-intensity therapy with warfarin causes minor "nuisance" bleeding in 5%–15%, major bleeding in 2%–3%, and fatal bleeding in 0.2%–0.6% of patients each year.7 A hitherto burning question for patients with unprovoked VTE is whether there are other anticoagulant treatment regimens with a more acceptable benefit-to-harm ratio, such as lower-intensity oral anticoagulation therapy. The recently reported Prevention of Recurrent Venous Thromboembolism (PREVENT) trial was initiated in July 1998 to test the hypothesis that long-term, low-intensity warfarin therapy (target INR, 1.5–2.0) might provide a safe and effective method of reducing the risk of recurrent VTE among patients who had a previous idiopathic (unprovoked) venous thrombosis.8 After completing at least 3 months of standard-intensity warfarin therapy (target INR, 2.0–3.0), 508 patients were randomly allocated to receive low-intensity warfarin therapy or placebo in a double-blinded fashion. The trial was terminated after a mean follow-up duration of 2.1 years because there was strong evidence of efficacy of warfarin. Of 253 patients assigned to placebo, 37 had recurrent venous thromboembolism (7.2 per 100 person-years), compared with 14 of 255 patients assigned to low-intensity warfarin therapy (2.6 per 100 person-years). This represents a relative risk reduction of 64% (hazard ratio [HR], 0.36; 95% CI, 0.19–0.67; P < 0.001), and an absolute risk reduction of 4.6%, equivalent to one event prevented for every 22 patients treated for 1 year. Bleeding episodes necessitating hospitalisation occurred in two patients in the placebo group (0.4 per 100 person-years), and five patients in the warfarin group (0.9 per 100 person-years); this difference was non-significant (P = 0.25).8 Although the PREVENT trial showed no significant excess of major bleeding with low-intensity warfarin therapy compared with placebo, event rates were low (5 v 2), and the 95% confidence intervals do not reliably exclude even a 13-fold increase in risk of major bleeding (HR, 2.53; 95% CI, 0.49–13.03). Yet, there is no doubt that low-intensity warfarin causes bleeding. In the PREVENT trial, "minor" bleeding was significantly increased in the warfarin group compared with the placebo group (12.8% v 6.7%; HR, 1.92; 95% CI, 1.26–2.93), with an increase in absolute risk of 6.1%, equivalent to one minor bleed caused for every 16 patients treated for 1 year. The results of the PREVENT trial indicate that low-intensity warfarin therapy is effective for long-term prevention of recurrent VTE. However, it was not shown to be sufficiently superior to placebo for low-intensity warfarin to be adopted for this indication. Standard-intensity warfarin is also superior to placebo when continued for up to 4 years after an initial thrombotic event.6,9-11 Indeed, it almost eliminates the risk of recurrent VTE in patients who continue the therapy, but is not routinely used because of the bleeding risks. Mini-dose warfarin therapy (fixed-dose, 1–2 mg daily) has never been shown to be effective for this indication, while low-intensity warfarin therapy is unlikely to offer any advantages over standard-intensity therapy in terms of convenience, and would only be a viable alternative if it were significantly safer. Indirect comparisons of the relative effectiveness and safety of low-intensity and standard-intensity therapy with warfarin, compared with placebo, are unreliable.8-11 For example, the apparently lower rates of bleeding in the PREVENT trial when indirectly compared with previous trials of warfarin might simply be explained by differences in patient selection. The PREVENT trial randomly allocated patients to treatment or placebo after they had completed a median of 6.5 months of warfarin treatment, and also included a 28-day run-in phase. It is thus likely that patients at increased risk of bleeding were excluded from the long-term phase of the study. By contrast, in most previous trials of long-term standard-intensity therapy with warfarin, patients were randomly allocated after no more than 3 months of treatment. This is as unreliable as comparing two sporting teams by their respective performances against another team rather than having them oppose each other directly. Indeed, the results of a recent direct head-to-head randomised comparison showed that low-intensity warfarin therapy was not only less effective than standard-intensity therapy for preventing recurrent VTE (absolute risk increase of 1.3% per patient year, equivalent to one event caused for every 77 patients treated for 1 year), but provided no advantage in terms of major bleeding (1.0% v 0.9% per patient-year; HR, 1.0; 95% CI, 0.4–2.7) or minor bleeding (4.9% v 3.6% per patient-year; HR, 1.3; 95% CI, 0.8–2.1).12 Taken together, these results indicate that standard-intensity therapy with warfarin is more effective for preventing recurrent VTE than low-intensity warfarin therapy, which, in turn, is more effective than placebo. However, because low-intensity warfarin therapy does not appear to be any safer in terms of bleeding and still requires close laboratory monitoring, it is difficult to justify this approach as an alternative to standard-intensity therapy for the long-term prevention of VTE, irrespective of a patient's baseline risk of recurrence or bleeding. The implications of these results for clinicians are that standard-intensity therapy with warfarin (target INR, 2.0–3.0) remains the treatment of choice for the long-term prevention of recurrent VTE in patients who are at highest risk of recurrence (eg, history of recurrent unprovoked VTE, major predisposing factor such as cancer; see Box) or with an initial life-threatening event (eg, major pulmonary embolism), and low risk of haemorrhagic complications. For patients with a first episode of unprovoked VTE or at increased risk of haemorrhagic complications, to decide about long-term treatment, doctors need to weigh the absolute risks of recurrent VTE and bleeding complications with and without warfarin treatment in each patient. In most cases, this is likely to result in the discontinuation of treatment after 6–12 months. The implications of these results for researchers are that more data are required to improve the reliability of clinical and laboratory predictors of recurrent VTE and haemorrhagic complications in individual patients, and that randomised controlled trials are required to evaluate the effectiveness and safety of alternative long-term antithrombotic therapies (eg, ximelagatran,13 antiplatelet agents) that are likely to be more convenient or have a more favourable benefit-to-risk profile than either standard-intensity or low-intensity warfarin therapy. Major determinants of the risk of recurrent venous thromboembolism Low risk (0–4% per year) Provoked event* Isolated distal deep vein thrombosis Intermediate risk (5%–10% per year) First unprovoked event Major predisposing factor(s)† Highest risk (> 10% per year) More than one unprovoked event First unprovoked event plus major predisposing factor(s)† Active cancer * Provoking factors include, in the last 3 months: hospitalisation, major surgery, trauma, leg fracture, plaster cast, puerperium. †Major predisposing factors include: prolonged immobility, neurological disease with paresis, homozygosity for factor V Leiden, combined (multiple) thrombophilic abnormalities, antiphospholipid antibody syndrome, inferior vena caval filter. Cancer is also a major predisposing factor but is mentioned separately because it is such a strong predisposing factor in its own right.

John W Eikelboom FRACP, FRCPA · Graeme J Hankey MD, FRACP

QuestionDoes indomethacin given prophylactically after birth improve long-term outcome for babies with extremely low birth weight? Trial details Design: Randomised, double-blind, controlled trial. Setting: 32 intensive care nurseries in Australia, Canada, Hong Kong, New Zealand and the United States. Participants: 1202 babies of 500–999 g birthweight; groups were similar in demographic and perinatal characteristics. Exclusions included major anomalies and inability to give indomethacin before 6 hours of life. Interventions: Indomethacin (0.1 mg/kg, intravenously) once daily for 3 days, or equivalent volume of saline placebo. Main outcome measures: Composite outcome of mortality, cerebral palsy, developmental delay, deafness or blindness at 18 months of age, corrected for prematurity. Main results: There was no substantial difference in the primary composite outcome between the indomethacin (47% [261/574]) and placebo (46% [261/569]) groups (odds ratio [OR], 1.1; 95% CI, 0.8–1.4; P = 0.61). However, the indomethacin group had a lower rate of patent ductus arteriosus (PDA), including cases requiring medical or surgical treatment, and severe (grade 3 or 4) cerebroventricular haemorrhage (CVH). Conclusion: In infants with extremely low birthweight, prophylaxis with indomethacin does not improve the rate of survival without neurosensory impairment at 18 months, despite reducing the frequency of PDA and severe CVH. CommentaryRationale for the trialPersistent patent ductus arteriosus (PDA) is a problem after birth for very tiny or preterm infants, many of whom require either medical or surgical intervention to close the ductus in the newborn period. Indomethacin is often successful in closing the ductus when used therapeutically, but is associated with many short-term side effects. Before this trial, prophylactic use of indomethacin was known to reduce the frequency of symptomatic PDA and severe cerebroventricular haemorrhage (CVH) in these babies.1 Reducing severe CVH might be expected to improve long-term neurological outcome. However, the mechanism for reducing severe CVH may be diminishing cerebral blood flow, which in turn may cause long-term neurological problems. Therefore, whether prophylaxis with indomethacin confers any long-term benefits that outweigh the risks of drug-induced reductions in cerebral blood flow, as well as reduced blood flow to other organs, is not certain. Trial methodsInfants were stratified by birthweight (< 750 g or ≥ 750 g) and individual study centre. This stratification was sensible, as the rate of the major adverse outcomes in the study was much higher in those of < 750 g birthweight (62% [298/481]) than in those of birthweight ≥ 750 g (35% [234/662]), and was bound to differ between individual centres (although individual centre data were not reported). Most infants (86%) received their allocated treatment within 6 hours of birth, and most (81%) received all three doses; there were no differences in drug administration (compliance) between the treatment groups. Other aspects of care followed an individual unit's protocol. Blinding was achieved by having a placebo that looked identical to the indomethacin. Although unblinding was theoretically possible through observing urine output, only 7% in the indomethacin group and 4% in the placebo group had treatment withdrawn because of oliguria. Significantly more babies in the placebo group (46%) subsequently received open-label indomethacin to treat a PDA than did babies in the treated group (17%). The follow-up rates to 18 months corrected age were very high (95%) in each group, which is important methodologically, as babies who are difficult to follow-up have more adverse outcomes than those who are followed up more easily.2 All analyses were by intention to treat. New informationIn infants of extremely low birthweight, prophylaxis with indomethacin did not improve the rate of survival without neurosensory impairment at 18 months, despite the fact that it reduces the frequency of PDA and severe CVH. Before this study, it would have been assumed that because prophylactic indomethacin reduces severe CVH, it should improve long-term outcome. This study highlights the problem of relying on changes in surrogate (or intermediate) endpoints, or in risk factors, to determine the effectiveness of therapies. For any therapy to be introduced into clinical practice, the endpoints in trials must be clinically meaningful. Implications for clinical practiceThe types of babies included in this study are typically found in intensive care nurseries in the developed world, and hence the results of the study are widely applicable to infants of birthweight < 1000 g, including those cared for in Australian intensive care nurseries. The study has been incorporated into an update of the Cochrane review of prophylactic indomethacin.3 There are now 19 trials with a total of 2872 babies enrolled. The study by Schmidt et al4 is the largest in the review, with 42% of the total babies enrolled. Its results dominate the review, especially those for long-term neurosensory outcomes, where the study contributes more than two-thirds of all babies in the review. The Cochrane review confirms that prophylactic indomethacin confers no important long-term benefit (or harm) on survival free of neurosensory impairment, despite significantly reducing the rate of severe CVH (relative risk [RR], 0.66; 95% CI, 0.53–0.82). However, the duration of follow-up in most studies is short, and important long-term neurological effects may not be manifest until school-age or later. Hence, it is still not certain that indomethacin imparts no long-term harm. Prophylactic indomethacin reduces the incidence of symptomatic PDA (RR, 0.44; 95% CI, 0.38–0.50), and the need for ductal ligation (RR, 0.51; 95% CI, 0.37–0.71). The absolute reduction in the rate of surgical ligation is 5%, which means that prophylaxis would need to be given to 20 babies to prevent one surgical ligation. For neonatal units where surgical ligation is not an option and where the need for surgical ligation is relatively frequent, giving 20 babies indomethacin to prevent one operation might be a reasonable option. However, this should be undertaken in the full knowledge that indomethacin prophylaxis does not impart any other important short-term benefits, such as a reduction in oxygen requirements, and that there remains the unknown issue of potential longer-term harm. There is no evidence of substantial differences in rates of necrotising enterocolitis, gut perforation, excessive clinical bleeding, or sepsis.

Lex W Doyle MD, FRACP

F Frank Pyefinch Director of MD Development, Health Communication Network, 2 Santa Fe Drive, Bundaberg, QLD 4670 frank.pyefinchAThcn.com.au To the Editor: I would like to comment on the recent article by Newby et al.1 They conclude that the default settings in computerised prescription packages result in a significant increase in the use of antibiotics. I do not believe this is a valid conclusion. As the authors state that 85% of general practitioners generating computerised prescriptions are using Medical Director (MD), it is reasonable to assume that the default settings in MD would contribute significantly to this effect if their conclusion is correct. I have installed and tested MD v.2.3 from February 2000, MDW v.1.85 from February 2000 and MD v.2.4 from May 2000. These were the versions that would have been in use at the time of this study. All versions default to printing "once-only" prescriptions without repeats. In fact, when a "once-only" prescription has been selected, MD's default behaviour is to display a prompt for the quantity and repeats with the default repeats field set to "0". This is very easy to verify simply by installing a copy of MD onto a "clean" computer and printing some scripts. As this was evidently not done, it casts doubt on the quality of the whole study. How can the authors reach a conclusion about the effect of the default settings in computerised prescription packages without first ascertaining what those default settings are? They appear to have assumed that the default behaviour of all computer prescription packages is to print the maximum number of repeats allowed by the Pharmaceutical Benefits Scheme. No attempt appears to have been made to verify whether this is the case. Whatever the reason for the observed increase in repeat antibiotic prescriptions, it is incorrect to conclude that it is due to the default settings in computerised prescribing packages. No discussion of other possible explanations for the observed increase is presented and it appears as though the data have been used to support a conclusion that had been decided before the study was commenced.

F Frank Pyefinch

David A Newby,* Jayne L Fryer,† David A Henry‡ * Lecturer, † Statistical Analyst, ‡ Professor, Department of Clinical Pharmacology, University of Newcastle, Newcastle Mater Misericordiae Hospital, Newcastle, NSW 2298 mddanATalinga.newcastle.edu.au In reply: As Pyefinch notes, if the "once only" option in Medical Director (MD) is chosen during prescribing, the doctor must enter the quantity and number of repeats that he or she wishes to order. However, if the doctor chooses the "regular" medicine option (both options are offered during prescribing), then the maximum Pharmaceutical Benefits Schedule quantities and repeats are inserted. There are various reasons why doctors may be using the "regular" option rather than the "once only" option when prescribing antibiotics using MD. Some of these have been discussed on the General Practice Computing Group Listserv,1 and include factors such as confusion regarding the terms "regular" and "once only" and difficulties recalling patient medication histories if the "once only" option is used. Another explanation is that doctors commonly prescribe chronic medications, and therefore use of the "regular" option may become a habit. Whatever the cause, there is no obvious explanation for the differences observed, except for the use of prescribing software. Our recommendation that prescribing software be altered to avoid these shortcuts was made because it represents the most immediate way of resolving the problem.

David A Newby · Jayne L Fryer · David A Henry