Pharmacology

Objectives: To assess the effect of two recalls of paracetamol products on rates of intentional and unintentional overdoses of paracetamol in all age groups, as well as any effect on poisoning by other agents.Design: A before-and-after epidemiological study using data from the Western Australian Health Services Research Linked Database, which records all admissions to public and private hospitals throughout the State.Main outcome measures: Hospital admissions in Western Australia for poisonings with all agents, including paracetamol and other over-the-counter analgesics.Results: There were 11 752 admissions for poisoning from 1996 to 2001. Paracetamol was the primary poisoning agent in 2266 (19.3%) admissions, aspirin in 120 (1%) and ibuprofen in 277 (2%). There was a significant decrease in the admission rate for paracetamol poisoning when sales were restricted in 2000 (rate ratio, 0.82; 95% CI, 0.68–0.99) compared with the same period in other years. There was no increase in poisoning with other agents at this time. However, admissions for paracetamol overdose also showed a large random variation that tended to obscure any effect.Conclusions: Our study highlights the need to control for random as well as seasonal fluctuations in admission rates, and for restrictions on paracetamol sales to last for several months across all retail outlets. Limiting access to paracetamol may reduce paracetamol poisonings without a coincident increase in the use of other agents.

Stephen R Kisely FRANZCP, FAFPHM · David Lawrence PhD · Neil J Preston MSc(Psychol)

To the Editor: The recent information that methylphenobarbitone (60 mg tablets) will be unavailable after 1 January 2003 has caused anxiety in patients with epilepsy previously treated satisfactorily with this drug. The suggested substitution of phenobarbitone, primidone or a newer antiepileptic agent seems appropriate. However, patients and perhaps practitioners may assume, as my patients have, that phenobarbitone and primidone are equivalent to methylphenobarbitone on a milligram-for-milligram or a tablet-for-tablet basis. This may not be so. The equivalence is close to 30 mg of phenobarbitone for 60 mg methylphenobarbitone, and probably around 200 mg of primidone for 60 mg of methylphenobarbitone.1 Plasma phenobarbitone concentrations should be checked before and after any changeover. In recent years, several other old, but therapeutically satisfactory, neurological drugs have also been withdrawn from the Australian market (oral neostigmine, several anticholinergic antiparkinsonian agents, ethosuximide and some phenytoin preparations, and the only ergotamine preparation not also containing caffeine). Subject to safety issues, ethics committees usually will not approve a clinical trial of a new drug unless patients who benefit from it are guaranteed supplies until the drug is marketed. Surely similar considerations should apply for patients who have had completely satisfactory long-term responses to marketed drugs. If such drugs must be withdrawn, except for safety reasons, there should be extensive prior consultation with prescribers and patient groups, prescribers should know the situation before their patients discover it from other sources, and there should be a sufficient lead time for everyone receiving the drug to return for another prescription (and for advice) before the drug becomes unavailable (a minimum lead time of six months in the case of drugs subsidised under the Pharmaceutical Benefits Scheme). The withdrawal of useful neurological drugs in Australia has reached the stage where therapeutic options are becoming limited. In the case of drugs required for long-term use, to protect the interests of new patients it has become necessary to consider whether the drug will continue to be available for the expected duration of the patient's therapy. In this regard, the prescriber's only guide may be the track record of the firm which markets the drug otherwise chosen.

Mervyn J Eadie

Objectives: To examine trends in the licit consumption of the psychostimulants dexamphetamine and methylphenidate in Australia and nine other countries from 1994 to 2000 and in each State and Territory of Australia from 1984 to 2000.Design: Annual rates of consumption of psychostimulants were compared using Poisson regression models. All drug consumption was standardised to defined daily doses per 1000 population per day.Main outcome measures: Rates of consumption of each psychostimulant in each country and in each Australian State and Territory.Results: For the 10 countries from 1994 to 2000, total psychostimulant consumption increased by an average 12% per year, with the highest increase from 1998 to 2000. Australia and New Zealand ranked third in total psychostimulant use after the United States and Canada. Australia consumed significantly more than the United Kingdom, Sweden, Spain, the Netherlands, France or Denmark. In Australia, from 1984 to 2000, the rate of consumption of licit psychostimulants increased by 26% per year, with an 8.46-fold increase from 1994 to 2000. Western Australia ranked first, with nearly twice the consumption rate of total psychostimulants as New South Wales, which ranked second. Methylphenidate is the main psychostimulant consumed in the US and Canada, and dexamphetamine in Australia.Conclusions: The consumption of psychostimulants in Australia is high internationally and varies significantly between States and Territories. The results imply varied jurisdictional prescribing determinants and supply processes throughout Australia, which may require new national prescribing standards and access to online patient data for prescribers and dispensers.

Constantine G Berbatis BSc, MSc · V Bruce Sunderland PhD, FPS · Max Bulsara BSc(Hons), MSc

To the Editor: Regarding the position statement about COX-2 inhibitors, we agree that openness about all potential conflicts of interest is the least we should expect from guideline developers, but this is not enough.1 Fifteen (65%) of the 23 members of the Australian COX-2 Specific Inhibitor Prescribing Group (including all eight of the rheumatologists involved) declared current financial links with Pfizer and Merck, Sharp and Dohme, the two drug companies marketing COX-2 inhibitors in Australia.2 The Prescribing Group can be viewed at best as a tight collaboration between some healthcare professionals and drug companies. At worst the statement published in the Journal can be seen as the "happy end" of a successful marketing campaign, which began some years ago with the enrolment of the most influential Australian rheumatologists to the advisory boards of the drug companies.3 Members of the group disregarded the "industry" bias on the basis that "some form of bias is the inevitable consequence of knowledge and involvement". However, numerous studies have shown that industry-sponsored drug information is characterised by an overemphasis on the benefits of drugs and a minimisation of the risks.4 Full trial results with celecoxib are available on the United States Food and Drug Administration website and had been consulted by the Prescribing Group.5 These data show that celecoxib is not better than diclofenac (P = 0.414) or ibuprofen (P = 0.64) in terms of ulcer complications, the prespecified primary outcome of the trials. There was also no significant difference between celecoxib and diclofenac for the combined outcome of complicated and benign ulcers (P = 0.296). It has been shown that the results previously presented in JAMA for celecoxib were flawed and had been manipulated.6,7 The wide distribution of the JAMA article by the drug company as part of intensive marketing campaigns contributed to huge sales for celecoxib. Sales of celecoxib between August 2000 and June 2002 cost Australian taxpayers more than $288 m through the Pharmaceutical Benefits Scheme (PBS), more than five times the cost for all other NSAIDs during the same time frame.8 There is some evidence to show that the PBS blow-out observed after the launch of COX-2 inhibitors is at least partly due to their use outside their approved indications (osteoarthritis and rheumatoid arthritis).9 The Prescribing Group did not give any indication for the use of COX-2 inhibitors and did not consider the cost issue, arguing that "there is little pertinent cost-effectiveness literature in the public domain". The position statement appeared to be an evidence-based review of the safety of COX-2 inhibitors involving eminent rheumatologists, active members of the PHARM committee and National Prescribing Service staff. We believe, however, that the statement promotes misinformation from the pharmaceutical industry. We invite readers to look at sources of drug information that are truly independent of drug companies, such as the Australian Medicines Handbook (www.amh.net.au), Australian Prescriber (www.australianprescriber.com) and Therapeutic Guidelines (www.tg.com.au).

Agnes I Vitry · Eve Hurley

To the Editor: We agree that the "what", "how" and "who" of guideline development all deserve equal, explicit and systematic attention.1 A fundamental task for architects of consensus guidelines is to get the "what" right first. Agreement about the importance of the topic and the objective of the exercise is crucial to its ultimate success. Edmonds and colleagues state that "formulation of precise indications for the use of NSAIDs [non-steroidal anti-inflammatory drugs] rather than CSIs [COX-2-specific inhibitors] (or vice versa) would generate interminable controversy".2 The foundation for this assertion is not clear and the authors do not present data about the level of agreement on this by the experts initially assembled. The NSW Therapeutic Assessment Group (NSW TAG) believes that providing timely, independent and evidence-based guidance to clinicians about the place in therapy for such new drugs is extremely important. The membership of NSW TAG identified this as a priority soon after the marketing of celecoxib in Australia, and agreed unanimously to develop evidence-based recommendations on indications for the use of this drug. Our consensus development process involved a wide variety of experts in therapeutics and was successfully completed without generating "interminable controversy".3 We wonder whether our different experiences may be partly related to a difference in the initial level of consensus on the importance of the chosen topic. The "how" of the process followed by Edmonds et al is not described in sufficient detail to enable systematic evaluation of its validity. How systematic was the search for evidence or the process for inclusion or exclusion of studies? What was the level of evidence on which final recommendations were based? Importantly, high quality guideline development processes require a "balance of healthcare disciplines in the guideline development group".4 Getting the right "who" is a prerequisite for getting the "how" right. Edmonds et al state that membership was arbitrary, with predominant representation from rheumatologists and relevant pharmaceutical companies. Given the problems associated with physician–industry interactions,5 it has been suggested that authors with significant conflicts of interest should be excluded from participating in guideline development.6 The rationale for arbitrary selection of members and inclusion of members from the pharmaceutical industry is not explicitly stated. These issues may have contributed to the difficulties the group experienced, and may detract from the validity of their recommendations. Future trips down the "road to consensus" should run more smoothly after careful consideration of the "what", "how" and "who" at the outset — no "ifs and buts" about it.

Madlen Gazarian · Karen I Kaye

In reply: Both Vitry and Hurley and Gazarian and Kaye would have had our consensus group address different or broader issues than safe prescribing and use of COX-2-specific inhibitors (CSIs). Indications for use, leakage and cost effectiveness are important issues, but our goal, clearly stated in our article,1 was different and, we believe, important: if a clinician has decided to use a CSI, what considerations are needed to prescribe the drug safely? Disagreements in reaching consensus were not, as suggested by Gazarian and Kaye, due to confusion about the aim of the exercise, but to differences in interpreting evidence and expressing conclusions in simple and direct terms. It would have been easy to avoid these problems by limiting participants to a small group of like-minded colleagues, but we chose to involve a broad range of people who may represent a more realistic spectrum of attitudes and approaches. We find Vitry and Hurley gratuitously pejorative in their description of the participants in this exercise. With the exception of two rheumatologists with epidemiological expertise (who did not sign off on the position statement2), all the rheumatologists involved were members of one or both advisory boards. They were a relevant group precisely because this role should involve a responsibility to provide sound advice to the industry paying for it, and equally to the profession, both in the interests of good patient care. "Current financial links" is not the way such a consultancy is usually described. They call the exercise "at best a tight collaboration between some healthcare professionals and drug companies" and "at worst . . . as the 'happy end' of a successful marketing campaign". Given that one of the two pharmaceutical companies involved declined to sign off on the statement, as did two rheumatologists who were advisory board members for the other company, this is a curious outcome of "tight collaboration". With respect to the relative safety of selective versus non-selective COX inhibitors, our considerations were based on data available from peer-reviewed studies published to the end of May 2001 and available on the United States Food and Drug Administration website, as indicated in the position statement2 and the accompanying article.1 A number of the references quoted by Vitry and Hurley became available after May 2001. Renewed scrutiny and analysis of existing datasets is interesting, but the results are best used to decide whether unresolved issues are of sufficient importance to justify further studies, and how these could be designed to deliver evidence that will convince us all, one way or the other. We made the point at the conclusion of the position statement that this is an evolving field and that conclusions may well change with emerging data.3 We consider the statements made in the considerations article1 represent a fair expression of our assessment of the data available to us. Not everyone in the group agreed. In publishing the position statement with the list of participants who endorsed it and those who did not, and by adding an article on the process we adopted, we hoped to highlight the fact that there are controversies and uncertainties about aspects of CSIs which require careful consideration in clinical use and further high quality data to resolve currently unresolvable issues.

John P Edmonds · Richard O Day · James V Bertouch

Re "Thiazolidinediones and type 2 diabetes: new drugs for an old disease", the New Drugs, Old Drugs article by Trisha M O'Moore-Sullivan and Johannes B Prins in the 15 April issue of the Journal (Med J Aust 2002; 176: 381-386), in which an editing error resulted in the word "tryglyceride" replacing "total cholesterol". Thus, on page 383, the first sentence in the second dot point under the subheading "Both drugs increase HDL and LDL and decrease FFA levels; pioglitazone lowers triglyceride levels", the sentence should read "Rosiglitazone also tends to increase total cholesterol level and studies have reported variable effects on ratios of total cholesterol to high-density lipoprotein (HDL) and of LDL to HDL." The html and pdf versions of this article were corrected on Monday 30 September 2002.

Trisha M O'Moore-Sullivan MB BS, FRACP · Johannes B Prins MB BS, PhD, FRACP

Antibiotic resistance is a consequence of antibiotic use — we need to use antibiotics less and to use them prudently. Plans to combat antibiotic resistance were recently proposed by the World Health Organization, a United States interagency taskforce and the Australian Joint Expert Technical Advisory Committee on Antibiotic Resistance. Prudent antibiotic use includes not using antibiotics when benefit is minimal (eg, in many respiratory tract infections), using narrow-spectrum antibiotics whenever possible and using optimal dosages and regimens. The need for antibiotic therapy can be reduced by preventing infections through vaccination, infection control measures and improved sanitation. Surveillance of antibiotic resistance is needed to target interventions for minimising antibiotic use. More research is needed into new antibiotics and regimens and into improving medical devices and protocols to prevent infection.

Series Editors:

To the Editor: Linezolid is the first of a new class of oxazolidinone antibacterials which was first registered in Australia in September 2001. It represents an important advance in the treatment of infections caused by some enterococci resistant to vancomycin and staphylococci resistant to methicillin.1 In clinical trials, the most commonly reported drug-related adverse events which led to discontinuation of linezolid therapy were headache, diarrhoea, nausea and vomiting.2 We describe a patient who developed peripheral and optic neuropathy while being treated with linezolid. A 76-year-old man was hospitalised in November 2000 for the third revision of a left total hip joint prosthesis. This was complicated by infection with methicillin-resistant Staphylococcus aureus (MRSA) isolated from hip joint washout. The organism was sensitive to vancomycin, teicoplanin, rifampicin and fusidic acid, and resistant to ciprofloxacin. Vancomycin therapy was commenced, but had to be replaced by rifampicin and fusidic acid when the patient developed fever (40°C), rigors, rash and eosinophilia. However, the patient developed severe, generalised pruritus. Therapy with rifampicin and fusidic acid was ceased and oral linezolid (600 mg twice daily) was given. Linezolid was initially well tolerated. However, about six months after starting treatment with the antibiotic, the patient presented to his general practitioner with numbness of his hands, feet and legs below the knee, intermittent sharp pain in both feet and blurred vision. He was hospitalised and linezolid therapy ceased. On admission, peripheral sensory loss in a glove-and-stocking distribution was noted. Nerve-conduction studies showed severe sensory-motor axonal neuropathy, more severe in the lower limbs than the upper limbs. Formal visual field testing showed patchy field damage, suggestive of drug-induced toxicity. The patient declined further ophthalmological review. Five months after he stopped taking linezolid, he reported subjective resolution of visual impairment, but the peripheral neuropathy persists. The patient's alcohol intake had been negligible. Ongoing medications include digoxin, irbesartan, frusemide, omeprazole, piroxicam and diazepam. We are not aware of any published articles describing peripheral or optic neuropathy associated with linezolid therapy. This information was not included in the original product information, but has been added to the revised version under the heading "Post-marketing surveillance".3 Up to June 2002 there had been only 13 reports of adverse reactions to linezolid to the Australian Adverse Drug Reactions Advisory Committee (ADRAC). Four of these, including our report, describe peripheral neuropathy and involve adult males who had received 1.2 g of linezolid daily for six to nine months. No patient's neuropathy had resolved at the time of reporting. Moreover, linezolid was the sole suspected drug in all four reports. It is important to note that the maximum duration of treatment with linezolid in clinical trials has been 28 days. Reports of neuropathy received by the manufacturer have primarily involved patients treated for longer than 28 days.3 Our report highlights the importance of postmarketing surveillance and reporting of adverse drug reactions, especially when a drug is used outside original indications or duration.

Carmela E Corallo · Amalie E Paull

To the Editor: The recent article by Chapman et al1 and a case report published some years previously in the Journal2 indicated that hyponatraemia may occur during indapamide therapy. However, it should be noted that the data came from spontaneous adverse drug reaction reporting, and therefore can give no indication of the incidence or relative risk of hyponatraemia compared with other diuretics. Nor can it give the incidence of hyponatraemia as a proportion of side effects occurring during indapamide therapy. The presentation of these data appears to cause some confusion, including an interpretation that hyponatraemia was more common with indapamide therapy than other diuretics.3 However, adverse events may be more likely to be reported for drugs which are usually well tolerated. Hyponatraemia led to discontinuation of therapy in only eight out of 3000 patients in the PROGRESS study.3,4 Previous controlled studies of indapamide (2.5 mg or sustained-release 1.5 mg daily) have found no significant overall changes in serum sodium levels.3 Hyponatraemia associated with indapamide therapy may occur with a recommended dose of 2.5 mg, which does not have a significant diuretic effect. Indapamide appears to be useful for treating central diabetes insipidus, raising the possibility that hyponatraemia occurs because of an inappropriate antidiuretic hormone secretion syndrome.6 Indapamide-related hyponatraemia may be more common in elderly women,1 as is the case for hyponatraemia associated with selective serotonin reuptake inhibitors. Hyponatraemia associated with indapamide therapy appears to be sporadic and uncommon and may be avoided by appropriate monitoring of serum electrolyte levels.

Laurence G Howes · John McEwen · John E Marley

In reply: Howes writes that previous studies have not shown significant hyponatraemia with indapamide. Our article highlighted that hyponatraemia was reported in a much larger proportion of all types of adverse drug reactions to indapamide than to chlorothiazide in Australia. As we clearly acknowledged, "Voluntary reporting systems do not provide a basis for calculating incidence or robust risk estimates". In the PROGRESS study, 1770, and not 3000, participants were exposed to 2–2.5 mg of indapamide.1 The mean age of participants given active therapy in that study was 64 years and 30% were women. Details of the eight patients withdrawn because of hyponatraemia were not published. Importantly for indapamide, chlorothiazide and the other comparator (hydrochlorothiazide with amiloride), more than 80% of the patients with hyponatraemia in our study of Australian adverse reaction reports were aged 65 years or older (mean age for indapamide, 69.3 years, unpublished data), and at least 78% were female. Given that indapamide formulations have been promoted as a replacement for chlorothiazide notwithstanding the acknowledged limitations of the data, our article was appropriate in alerting practitioners to the possibility of hyponatraemia, particularly in elderly women.

Laurence G Howes MB BS, PhD, FRACP · John McEwen MB BS, MSc, MPS · John E Marley MD, MB ChB

Infectious diseases physicians, clinical microbiologists and hospital pharmacists tend to have a love–hate relationship with the antibiotic ceftriaxone and its stablemate cefotaxime. These potent third-generation cephalosporins have an important place in every Australian hospital formulary, and boast numerous entries in the current edition of Therapeutic guidelines: antibiotic (AG).1 Third-generation cephalosporins (3GCs) are the antibiotics of choice for several life-threatening infections including bacterial meningitis. They are convenient to administer and are among the safest antibiotics available. Yet, these drugs have become the bête noire of hospital epidemiologists. So, what's the problem? The problem is the increasing burden of resistant bacteria arising from the constant selective pressure exerted by our extensive use of antibiotics, especially very broad-spectrum agents such as 3GCs. Cefotaxime and ceftriaxone are now known to be associated with the emergence of vancomycin-resistant enterococci, resistant gram-negative bacteria, and Clostridium difficile-associated diarrhoea.2-6 They also likely contribute to the emergence of resistant pneumococcus and the ongoing spread of methicillin-resistant Staphylococcus aureus (MRSA).7,8 Third-generation cephalosporins are active against a wide range of gram-positive and gram-negative bacteria and have the added advantage that they penetrate into cerebrospinal fluid and other normally sterile sites, enabling a number of invasive infections to be treated. However, they have only limited activity against anaerobes and staphylococci and are inactive against MRSA. They are also inactive against Pseudomonas, Listeria, and enterococci — all causes of potentially life-threatening infections in immunocompromised patients. In Australia, we have an antibiotic guidelines handbook that is clear, concise, accurate, extensively peer-reviewed, regularly updated, and, from my own experience, extremely useful! Yet, in this issue of the Journal, Robertson and colleagues (page 524)9 have identified a widespread prescribing problem — and one that probably extends far beyond 3GCs. In a study involving most Victorian hospitals, they found extensive inappropriate use of cefotaxime and ceftriaxone. Three areas of prescribing deserve particular mention. About half of all use of these antibiotics involved empiric treatment of respiratory tract infections, and over three-quarters of these courses were not in concordance with the then current edition of AG. This is despite the fact that simpler regimens are likely to be at least as effective.10 The two other key problem areas found by the authors were inappropriate use for surgical prophylaxis and for treatment of skin and soft tissue infections. As Robertson and colleagues state, improving concordance in surgical prophylaxis should be readily amenable to intervention by withdrawing 3GCs from operating theatres. However, improving concordance in empiric therapy of respiratory and skin and soft tissue infections will require a truly concerted educational effort. A perusal of the current edition of AG1 reveals that 3GCs don't rate a mention in the first-line regimens for empiric treatment of many common infections in non-penicillin-allergic patients. They are not included in any of the first-line regimens for community-acquired or hospital-acquired pneumonia, and not included at all for the treatment of cellulitis or erysipelas or postoperative wound infections. They have virtually no role in surgical wound infection prophylaxis. Clearly, there is discordance between guidelines and practice. After 11 editions of AG in Australia, what more can be done to curb the high rate of inappropriate use of important antibiotics? The United States Centers for Disease Control and Prevention recently highlighted 12 clinicians' "action steps" for preventing antimicrobial resistance in hospitals (Box).11 Improved implementation of clinical guidelines is implicit in these steps. Although the steps highlight inter alia the role of vancomycin in the emergence of antimicrobial resistance, similar recommendations could be applied to 3GCs. Implementation of guidelines must be multifaceted and preferably supported by published evidence.12 In Australia, we must first ensure there is comprehensive and practical access to endorsed guidelines among Australian doctors. No recent surveys of access to AG have been conducted, but they appear to be widely available — almost 20 000 copies of the current edition have been sold to date (Mary Hemming, Chief Executive Officer, Therapeutic Guidelines Limited, personal communication). The Australian medicines handbook13 is also a valuable emerging resource now in its third edition. Given that many of the concordance issues highlighted by Robertson and colleagues also apply to other areas of prescribing, universal access to a range of appropriate prescribing guidelines is an essential and logical complement to the training and continuing education of all doctors in Australia. At the very least, 24-hour paper and electronic access to appropriate guidelines should be available to every public hospital doctor and medical student. Personal digital assistants are also emerging as a major practical platform that should expand access to clinical reference programs.14 Improved and adequate access to clinical guidelines is, however, only the first step to control of inappropriate use of 3GCs. Adherence to guidelines requires the support and endorsement of opinion leaders and medical educators and, in particular, obliges senior clinicians to set an example through sensible prescribing. Pharmacists should be given a greater educational role in both hospital and community practice through academic detailing, surveillance of prescribing patterns, feedback to doctors, participation in clinical decision making, and provision of relevant guidelines to specific clinical groups. Most hospital drug committees attempt to adapt generic guidelines to local conditions, which generally involves imposing restrictions on the prescribing of 3GCs and other broad-spectrum antibiotics. Their efforts are supported by the many studies that attest to reductions in the incidence of resistant bacteria and C. difficile following institution of programs to reduce use of 3GCs.8,15,16 Drug committees also have an important role in monitoring the influence of pharmaceutical industry promotions on local prescribing practice. Recent advances in medical informatics herald exciting new approaches to prescribing in Australia over the forthcoming decade. A range of opportunities is emerging for computerised integration of prescribing guidelines with clinical decision making. Although the main aims are to prevent errors, improve quality of care and reduce costs,17 there is obvious opportunity for benefit at the community level by reducing the burden of resistant bacteria through appropriate prescribing of antibiotics. Many general practitioners in Australia are already using integrated electronic prescribing programs such as Medical Director (Healthcare Portal) and pathology reports have become integrated with prescribing guidelines. The major challenge now is applying computerised prescribing decision-support programs for real-time guideline implementation in hospital wards and emergency departments.18,19 Their application to desktop computers is certainly feasible. Their application to personal digital assistants as a real-time, remote, wide-area data-access and decision-support device is an evolving challenge that will require a major change in the way we approach drug prescribing in hospitals. The report by Robertson and colleagues is not only a timely reminder of the importance of regular evaluation of drug use, but should also inspire us to seek and embrace opportunities to improve antibiotic prescribing in this country. Twelve "action steps" for preventing antimicrobial resistance in hospitals Step 1: Vaccinate — get influenza vaccine; give influenza and Streptococcus pneumoniae vaccine to at-risk patients before discharge. Step 2: Get the catheters out — use catheters only when essential; remove catheters when no longer essential. Step 3: Target the pathogen — grow cultures from the patient; target empiric therapy to likely pathogens; target definitive therapy to known pathogens. Step 4: Consult the experts — consult infectious diseases experts for patients with serious infections. Step 5: Practice antimicrobial control — engage in local antimicrobial control efforts. Step 6: Use local data — know your antibiogram. Step 7: Treat infection, not contamination. Step 8: Treat infection, not colonisation. Step 9: Know when to say "no" to vanco(mycin). Step 10: Stop antimicrobial treatment when the infection is treated or unlikely. Step 11: Isolate the pathogen — use standard infection control precautions; contain infectious body fluids (airborne/droplet/contact precautions); when in doubt, consult infection control experts. Step 12: Break the chain of contagion — stay home when you are sick; keep your hands clean; set an example!

D Ashley R Watson MB BS, MPH, FRACP

Objective: To determine patterns of use of ceftriaxone and cefotaxime (CEFX) in Victorian hospitals and to identify areas for improvement.Design, patients and setting: A concurrent, observational evaluation of CEFX use in patients commencing a course of these drugs between 8 and 14 September, 1999, in 51 Victorian hospitals.Main outcome measures: Proportion of patients treated with CEFX; indications; duration of use; concordance with recommendations of national antibiotic guidelines (Therapeutic guidelines: antibiotic, 10th edition [AG10]).Results: 671 patients were treated with CEFX. The overall rate of use was 43 patients per 1000 inpatient separations. Treatment of respiratory tract infection accounted for 352 patients (52%) and surgical prophylaxis for 99 patients (15%). Treatment of skin/soft tissue, urinary tract and gastrointestinal tract infections accounted for about 7% of patients each. The median duration of CEFX courses was 3.0 days. The overall rate of concordance with indications recommended in AG10 was 27%. The rate of concordance for empirical treatment of respiratory tract infection was 24%. Of the 195 patients treated empirically with CEFX for community-acquired respiratory tract infection and assessed as non-concordant, 64% did not have radiological evidence of pneumonia, and a further 30% did not fulfill the criteria for severe pneumonia. All courses given for surgical prophylaxis were non-concordant.Conclusions: CEFX is widely used in Victorian hospitals, mostly to treat lower respiratory tract infection and in surgical prophylaxis of infection. The rate of concordance with AG10 is low. Potential areas for intervention include empirical treatment of respiratory tract infection and use in surgical prophylaxis.

Marion B Robertson BPharm, MSc · Jonathan G A Dartnell BPharm, PhD · Tony M Korman FRACP · Lisa L Ioannides-Demos BPharm, PhD · Sue W Kirsa BPharm, GradDipHospPharm · Julie A V Lord BPharm · Liliana Munafo BPharm · Graham B Byrnes BSc, PhD

To the Editor: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for patients with cardiovascular disease, including those taking perhexiline for severe ischaemic heart disease. Elevated serum perhexiline concentrations have been observed during therapy with the SSRIs fluoxetine and paroxetine, which are known to be strong inhibitors of cytochrome P450 2D6, the enzyme system responsible for the hepatic metabolism of perhexiline.1 The Adverse Drug Reactions Advisory Committee has received five reports of a possible interaction between perhexiline and SSRIs, but none of these involved the SSRIs citalopram or fluvoxamine, which are generally considered to be weak inhibitors of cytochrome P450 2D6. I describe here a case of perhexiline toxicity that occurred within 10 days of starting citalopram therapy. An 82-year-old man was admitted to hospital for drainage of a femoral abscess. His medical history included bilateral hip replacements, ischaemic heart disease, hypertension, renal artery stenosis, renal calculi, gout, gastroesophageal reflux disease and prostate cancer. His medications included (daily) aspirin 100 mg, isosorbide mononitrate 120 mg, pravastatin 40 mg, allopurinol 300 mg, celecoxib 200 mg, lorazepam 2 mg, nitrazepam 10 mg; (twice daily) perhexiline 100 mg; and paracetamol and tramadol as needed. On Day 51 after admission the patient underwent first-stage revision of an infected hip implant under general anaesthesia, and on Day 60 citalopram was commenced (10 mg daily for four days, then 20 mg daily). On Day 70, the patient complained of diarrhoea, nausea and dizziness. Citalopram was discontinued but the nausea was slow to settle. After a perhexiline assay on Day 75 revealed a high serum concentration (see Box), the perhexiline dose was reduced to 100 mg daily and the patient's nausea settled. Previous perhexiline concentrations on a dose of 100 mg twice daily had ranged from 0.29 to 0.34 mg/L over a two-year period. Tests of renal and hepatic function were normal throughout the patient's hospital stay. While in hospital, the patient was given celecoxib (a cytochrome P450 2D6 inhibitor) at a constant dose between Days 1 and 95, and meropenem (not a documented cytochrome P450 2D6 inhibitor) between Days 51 and 95. These patterns of administration suggest that neither of these drugs had a significant effect on perhexiline concentration. On the other hand, the laboratory evidence of a marked inhibition of perhexiline metabolism during treatment with citalopram suggests that caution is required when prescribing citalopram (or any other SSRI) for a patient taking perhexiline.2 Serum concentrations (mg/L) of perhexiline and perhexiline metabolite Day 48 Day 75 Day 95 Perhexiline (therapeutic range, 0.15–0.60 mg/L) 0.37 0.82 0.27 Perhexiline metabolite 3.53 0.37 2.22 Ratio of perhexiline to perhexiline metabolite 0.10 2.22 0.12

Karin Nyfort-Hansen

To the Editor: A potentially important, if somewhat crude, means of suicide prevention involves restricting the availability of commonly used methods. In 1967, for example, restrictions on barbiturate prescribing in Australia led to declines in its use for suicide and in overall suicides.1 A crucial concern with this approach is that distressed individuals might use alternative, more lethal, methods. In Britain, there is just such a concern in relation to recent legislation restricting the availability of paracetamol.2 Analysis of the natural experiment investigated by Balit and colleagues3 does not, however, provide useful insights into the impact of paracetamol sales restrictions. Their most consistent finding was that, despite restricted availability for the period studied, paracetamol accounted for about 10% of all contacts with the two poisons information centres in both time periods. In Britain, in 1998, paracetamol purchases from chemists and supermarkets were restricted rather than banned.4 Up to 16 g (32 tablets) may be purchased from pharmacies and 8 g from supermarkets. The aim was not to prevent overdose but to reduce its severity. Presumably, over the periods studied by Balit et al, paracetamol was simply unavailable. As their analysis is based on calls to poisons information centres rather than on the clinical records of people presenting to hospital, they could not assess whether changes in paracetamol availability influenced indicators of severe poisoning — death and liver damage. A decline in the number of severe paracetamol poisonings, without a change in total episodes of paracetamol overdose, might be considered the most important end-point. Attention is drawn to statistically significant rises in calls concerning ibuprofen in one centre and aspirin in the other. The clinical significance of these observations is questionable. Overdoses of ibuprofen are less harmful than paracetamol,5 and the significant rise in aspirin overdose represents an increase from two calls per year to five per year — an increase of only three calls. Of note is the fact that the largest absolute decline in calls related to paracetamol (from 423 per year in 1997–1999 to 370 per year in 2000). Furthermore, as only two time points are compared, it is impossible to determine whether the increases reflect year-on-year changes in use of particular drugs for overdose, as might occur with increased ibuprofen sales. Legislation seeking to influence patterns of harm through changing the availability of drugs which are beneficial when used safely should be monitored carefully.4 Balit et al do not provide convincing evidence concerning the effects of paracetamol sales restrictions on population health.

Corrine R Balit BPharm · Geoffrey K Isbister BSc, MB BS · Andrew H Dawson FRCP(Ed), FRACP · Ian M Whyte MB BS, FRACP

To the Editor: In their recent article,1 Balit et al concluded "restriction of paracetamol-containing products may inadvertently increase poisoning with potentially more toxic agents". As manufacturers of one brand of ibuprofen tablets and the only brand of ibuprofen suspension in Australia, we would like to comment on the article and its conclusion. We understand that the objective of the audit was to determine whether the occurrence of paracetamol and non-paracetamol analgesic deliberate self-poisoning and accidental paediatric poisoning was affected by two periods of recall of paracetamol products. However, our concern is that the article's conclusion — "may inadvertently increase poisoning with potentially more toxic agents" — is not linked to any long term outcomes nor any follow-up regarding ongoing sequelae. This conclusion might give the impression that ibuprofen is more toxic than paracetamol when taken in an overdose situation, whether deliberate or accidental. It might also give the impression that overdoses of ibuprofen leave the patient with ongoing morbidity. In addition, we note that the percentage change in deliberate self-poisonings at both the NSW Poisons Information Centre (PIC) and the Hunter Area Toxicology Service for the periods when paracetamol was restricted, although seemingly large and statistically significant for the PIC, both came from a very low base (0.9% and 0.8% of all calls, respectively).

David Gunnell · Anthea Steans

In reply: There appears to be some misunderstanding about both the conclusions and the methodology of our study.1 We showed that when the availability of one analgesic (paracetamol) decreased, the use of the next most available analgesic increased in deliberate and accidental self-poisonings. We did not look at the relative toxicity of the analgesics, but referred to the published literature on acute paracetamol and ibuprofen overdoses in children, noting that serious complications of acute overdose in children have only been reported with ibuprofen.2-4 Data reported in the study not only included a poisons information centre, but also included data from hospital presentations. The Hunter Area Toxicology Service (HATS) manages all patients with poisoning in the Newcastle region and is based at the Newcastle Mater Misericordiae Hospital. The limitation of the small sample size in the HATS data was discussed in the article, highlighting the fact that, as this was an opportunistic study, it was not possible to increase the sample size. However, the conclusions drawn were based on two different data sets, with a much larger sample size for the NSW Poisons Information Centre data. Overdose is a significant public health problem that requires appropriate post-marketing vigilance. For drugs that are commonly taken in overdose, it is important to take advantage of opportunities to assess the potential effect of any change in availability.

David Gunnell

The great majority of smokers are chronically dependent on tobacco. This dependence arises from the rituals and sensory associations of smoking that are reinforced, within seconds, by a rapid burst of nicotine from the cigarette. All forms of nicotine replacement therapy (NRT) — gum, patches and inhaler — and bupropion are safe and effective for increasing smoking cessation rates in the short and long terms. Other than those who are minimally dependent, all patients willing to quit should be offered one of these therapies unless contraindications exist. The effectiveness of drug treatments is multiplied when associated with effective counselling or behavioural treatments. While NRT is not recommended during pregnancy or in patients with cardiac disease, if the alternative is smoking NRT is almost certainly safe. Combination NRT (more than one therapy) may be indicated in patients who have failed monotherapy in association with withdrawal symptoms. There are some specific contraindications to the use of bupropion. Its subsidised availability should not influence prescribers to ignore these.

Matthew J Peters MD, FRACP · Lucy C Morgan BMed, FRACP

Non-sedating antihistamines are available as "over-the-counter" preparations and have been widely promoted in public advertisements. However, two such antihistamines, terfenadine and astemizole, have been withdrawn in Australia and overseas. Their use was associated with ventricular arrhythmias — QT-interval prolongation on the surface electrocardiogram (ECG) and polymorphic ventricular tachycardia ("torsade de pointes").1-3 We report a case of ventricular tachycardia (VT) which was probably "torsade de pointes" following ingestion of a single tablet of loratadine. Clinical recordA 43-year-old woman presented after her identical twin died suddenly, presumably from cardiac arrhythmia. The patient was asymptomatic, had no other risk factors and was not taking any regular medication. Clinical examination showed evidence of mitral valve prolapse, with normal left ventricular function and trivial mitral regurgitation on echocardiography. Several ECGs (Box 1a) and her biochemical profile were normal. An electrophysiological study did not show inducible ventricular arrhythmias with standard stimulation testing or adrenaline provocation. Atrial fibrillation was induced during catheter introduction into the right atrium, with ventricular rate less than 130/minute. A prophylactic automatic implantable defibrillator (Medtronic Micro Jewel 7221) was subsequently inserted. Transient prolongation of the QT interval was noted on ECG monitoring in association with non-sustained VT (Box 1b) within 48 hours of the implant. Two years later, the patient had an episode of presyncope, interrupted by a spontaneous defibrillator shock, about 90 minutes after taking a single 10 mg tablet of loratadine for minor symptoms of nasal congestion; this was the patient's first exposure to this drug. She was reviewed on the following day, when the defibrillator device history revealed a rapid ventricular rhythm with changing axis of the intracardiac ventricular electrogram, with a cycle length of 320–230 ms (average rate, 250/minute; Box 2), successfully terminated by a 31-Joule biphasic discharge. The patient was not taking other medications at the time. DiscussionThe term "torsade de pointes" describes polymorphic ventricular tachycardia where the QRS axis appears to be twisting around a baseline. It is associated with prolongation of the QT interval, usually greater than 500 ms (normal is less than 440 ms). A pattern of long–short cycle length in the beats immediately before tachycardia is typical of torsade de pointes (Box 3). It is only possible to diagnose probable "torsade de pointes" in our case, as the defibrillator placed in the patient recorded only a brief snapshot after the device had made the diagnosis of a treatable arryhthmia, so the initiating beats were not recorded. Further, the tracing that the device makes is a ventricular electrocardiogram without any atrial tracing, and the intracardiac QT is not generally accepted as a valid measure of the QT interval. However, the rate of the arrhythmia and its twisting morphology, together with the previous brief episode of prolonged QT interval, make any other diagnosis unlikely. If we could have made a definite diagnosis, this would be the first documented case of torsade de pointes following ingestion of the non-sedating antihistamine loratadine. In this patient's case, the family history of sudden death and the prior history of transient QT-interval prolongation suggests a possible congenital predisposition to the deleterious effects of a drug with potential to prolong the QT interval. Prolongation of the QT interval and torsade de pointes can result from a variety of drug therapies. The likelihood of developing deleterious cardiac reactions to drugs that can prolong the QT interval can be enhanced under certain conditions (Box 4).4-6 Two non-sedating antihistamines (terfenadine and astemizole) were withdrawn after reports of sudden cardiac death.7,8 They were found to block the channels that regulate entry of potassium into cardiac cells during the repolarisation phase of the action potential. Blockade of these channels produces lengthening of the action potential duration.1,2 This is expressed as QT prolongation on ECG and is associated with the development of early after-depolarisations which can give rise to polymorphic VT and, in turn, degenerate into ventricular fibrillation. Loratadine has been retained because of favourable laboratory and clinical data.7 Although cardiac deaths have been reported in relation to this drug,3 no life-threatening arrhythmias have been documented. However, a mechanism for susceptibility to ventricular arrhythmias is suggested by a recent report demonstrating blockade of the human ether-a-go-go-related potassium channel in a similar manner to terfenadine in an animal preparation.9 ConclusionThis case suggests the need for caution in administering loratadine in patients with a predisposition to arrhythmias. Patients should be cautioned to report symptoms such as palpitations, presyncope or syncope after exposure to this drug. As QT-interval prolongation may be intermittent, routine ECG screening may not accurately identify susceptible patients. 1: Electrocardiograms from the patient before (a) and after (b) implantation of an automatic implantable defibrillator (a) ECG strip showing sinus bradycardia (rate, 50/min) and a normal QT interval (420 ms). (b) ECG monitor strip showing QT prolongation (560 ms) and a run of non-sustained ventricular tachycardia (arrow). 2: Intracardiac electrogram obtained following spontaneous discharge of the implanted defibrillator VS = ventricular sensed beat; FS = ventricular beat within the fibrillation zone. Numbers at the bottom denote the tachycardia cycle length in milliseconds. 3: Electrocardiogram rhythm strip illustrating torsade des pointes (not from this patient) ECG shows classical torsade de pointes with long QT interval (a), long–short initiating cycles and twisting QRS complexes (b). 4: Factors predisposing to QT-interval prolongation Electrolyte abnormalities: hypokalaemia, hypocalcaemia, hypomagnesaemia Metabolic disturbance: hypothyroidism, hypothermia, anorexia Drugs: class I and class III antiarrhythmics, antihistamines (eg, astemizole, terfenadine), psychiatric drugs (eg, tricyclic antidepressants, haloperidol, lithium, prochlorperazine, sertindole), antimicrobials (eg, macrolides, ketoconazole, chloroquine, halofantrine), cisapride Structural heart disease: left ventricular hypertrophy or failure Severe renal or hepatic dysfunction Congenital long-QT syndrome

Dennis L Kuchar MD, FRACP · Bruce D Walker MB BS, PhD, FRACP · Charles W Thorburn BM, FRACP, MA

The recent AusDiab data show that 7.2% of Australians over 25 years of age have type 2 diabetes mellitus and a further 16.1% have impaired glucose tolerance. In fact, 20% of Australians over 65 years have type 2 diabetes and it is well known that morbidity and mortality are significantly increased in affected patients.1,2 However, there is evidence from the United Kingdom Prospective Diabetes Study (UKPDS) that good glycaemic control can improve morbidity by improving microvascular complications of type 2 diabetes, such as retinopathy, nephropathy and neuropathy3 (E2). (See Box 1 for an explanation of level-of-evidence codes.) There is a well-recognised and strong association of type 2 diabetes with obesity and the insulin resistance syndrome. "Syndrome X"5 refers to a collection of pathophysiological sequelae resulting from insulin resistance and includes type 2 diabetes, as well as hypertension, dyslipidaemia, hyperuricaemia and elevated plasminogen-activator-inhibitor-1 levels.6 Pathophysiologically, type 2 diabetes is characterised by defects in insulin action (ie, insulin resistance) and secretion (ie, β-cell dysfunction), and increased hepatic glucose output.2 It is also well established that type 2 diabetes is a progressive condition, and that β-cell failure ensues in many patients. The UKPDS showed that, although monotherapy with sulfonylureas, metformin or insulin can achieve good glycaemic control initially, sustained control with these agents fails in 50% of patients after three years. Most patients will require multiple therapies to obtain adequate long term glycaemic control (E2).7 Currently available therapiesCurrently available therapies for type 2 diabetes include various oral agents such as sulfonylureas, metformin, α-glucosidase inhibitors (such as acarbose) and insulin. These agents can be used as monotherapy or in combination therapy. They have been used extensively, are efficacious and have a low incidence of serious adverse events. Recently, a new class of oral agents, the thiazolidinediones (TZDs), which act to improve the insulin sensitivity of peripheral tissues, has become available for use in clinical practice. Troglitazone was the first agent in this class and was effective, but was withdrawn because of severe and unpredictable hepatic failure. Newer TZDs such as rosiglitazone and pioglitazone are now available and have been approved by the Therapeutic Goods Administration (TGA) for use as monotherapy in patients with type 2 diabetes inadequately controlled by lifestyle measures, and also for use in combination with sulfonylureas or metformin in patients with inadequate glycaemic control.8,9 Pioglitazone is also licensed for use in combination with insulin.9 To date, hepatotoxicity does not appear to be a significant problem with these newer agents. Neither drug is listed on the Pharmaceutical Benefits Scheme yet. A profile of these two drugs is shown in Box 2. Thiazolidinediones and peroxisome proliferator-activated receptor γTZDs reduce hyperglycaemia by improving insulin sensitivity in a manner distinct from that of metformin. These drugs increase peripheral glucose utilisation in skeletal muscle and adipose tissue, reduce hepatic glucose output, increase fatty acid uptake and reduce lipolysis in adipose cells. This ultimately leads to a reduction in fasting and post-prandial plasma glucose, insulin and circulating free fatty acid (FFA) levels.10 TZDs are believed to exert most of their effects through binding to and activation of the gamma isoform of the peroxisome proliferator-activated receptor (PPARγ). PPARγ is a member of the steroid hormone nuclear receptor superfamily, and is found in adipose tissue, cardiac and skeletal muscle, liver and placenta. On activation of this nuclear receptor by a ligand such as a TZD, PPARγ–ligand complex binds to a specific region of DNA and thereby regulates the transcription of many genes involved in glucose and fatty acid metabolism.10 An endogenous ligand for this receptor has not been identified. Activation of PPARγ also leads to stimulation of adipogenesis,11 and this occurs more so in the subcutaneous rather than the omental fat depot.12 There are other isoforms of PPAR, and one of these, PPAR-α, is predominantly expressed in liver and is activated by hypolipidaemic agents such as fibrates. It mediates the triglyceride-lowering and high density lipoprotein (HDL)-raising effects of fibrates. Recent research has identified agents which are capable of activating PPARγ and PPARα simultaneously, and which could potentially have even greater beneficial effects than current TZDs. The development of TZDs has also led to the identification of non-TZD compounds which are capable of acting as full or partial agonists or as antagonists of PPARγ, depending on the tissue type and the specific target gene, in a manner analogous to the selective oestrogen receptor modulators (SERMs). It is therefore possible that future agents will be more selective and specific in their effects and potentially safer and more efficacious.13 Clinical trialsAlthough the evidence for therapy with these two agents is Level II, some of the data have either been published in abstract form only, or are only available from pharmaceutical company sources or websites or other organisations like the United States Food and Drug Administration (FDA). There are few studies which directly compare these agents as monotherapy or combination therapy with current standard treatment regimens. There are also no long term data on safety or effects on morbidity or mortality related to diabetes and cardiovascular disease. There are no studies directly comparing rosiglitazone and pioglitazone. The clinical trial data are summarised below. ◆ Both drugs lower HbA1c and fasting plasma glucose (FPG) levels when used as monotherapy8,9,14-22 (E2)For rosiglitazone, there was a dose-dependent reduction in HbA1c. The greatest effect was seen with a divided dose of 4 mg twice daily. In the various studies, this resulted in a reduction in HbA1c level of between −0.6 and −0.8 percentage points compared with baseline, and −1.5 to −1.8 compared with placebo. The FPG level was reduced by 2.3–3.6 mmol/L compared with baseline and 3.4–4.6 mmol/L compared with placebo. For pioglitazone, there was also a dose-dependent reduction in HbA1c level of −0.9 percentage points compared with baseline, and −1.6 compared with placebo, for patients taking 45 mg per day. The FPG level was reduced by 3.1 mmol/L compared with baseline, and 3.6 mmol/L compared with placebo. For both drugs, patients who were already receiving treatment with other agents at recruitment into the studies responded less well when swapped to monotherapy with the TZD than drug-naïve patients. ◆ Rosiglitazone and pioglitazone lower HbA1c and FPG levels when used in combination with a sulfonylurea or metformin8,9,23-26 (E2)Rosiglitazone (2 mg twice daily) added to various sulfonylureas over 26 weeks resulted in a reduction in HbA1c level of −0.8 percentage points compared with baseline, and −1.0 compared with placebo plus sulfonylurea. The FPG level was reduced by 2.09 mmol/L. When added to metformin (2.5 g), rosiglitazone (8 mg per day) reduced the HbA1c level by −0.78 percentage points and the FPG level by 2.7 mmol/L compared with baseline, and reduced the HbA1c level by −1.2 percentage points and the FPG level by 2.9 mmol/L compared with placebo plus metformin. Pioglitazone (30 mg) added to sulfonylurea reduced the HbA1c level by −1.3 percentage points compared with baseline and the FPG level was reduced by 2.9 mmol/L. When pioglitazone was added to metformin, the HbA1c level was reduced by about −0.7 percentage points, and the FPG level fell by 2.4 mmol/L compared with baseline. Compared to placebo plus metformin, pioglitazone (30 mg) plus metformin reduced the HbA1c level by −0.83 percentage points and the FPG level by 2.1 mmol/L. ◆ Rosiglitazone and pioglitazone lower HbA1c and FPG levels when used in combination with insulin8,9,27,28 (E2)Rosiglitazone (4 mg or 8 mg per day) added to insulin reduced HbA1c levels by −0.6 and −1.2 percentage points (respectively) compared with baseline and −0.7 and −1.3 compared with placebo plus insulin. Congestive heart failure was reported in two patients in each rosiglitazone group (comprising 106 and 103 patients) and one in the placebo group (103 patients). Rosiglitazone is not registered for use in combination with insulin.27 Pioglitazone (15 mg or 30 mg) per day added to insulin reduced HbA1c levels by −0.99 and −1.26 percentage points (respectively) compared with baseline and −0.73 and −1.00 compared with placebo plus insulin. Sixteen per cent of patients in the 30 mg pioglitazone plus insulin group had a reduction in their insulin dose of more than 25%.28 In these two studies, the incidence of oedema was significantly increased in the groups treated with TZD plus insulin.27,28 ◆ Both drugs lower fasting insulin and C-peptide levels when used as monotherapy or in combination therapy8,9,14-26 (E2)The significant reduction in insulin and C-peptide levels is consistent with the mechanism of action of these drugs as insulin sensitisers. ◆ Both drugs increase HDL and LDL and decrease FFA levels; pioglitazone lowers triglyceride levels8,9,14-32 (E2)Rosiglitazone significantly increased low-density lipoprotein (LDL) levels (mean increase, 15%–20%29) compared with baseline and controls, whereas, although pioglitazone increased LDL levels compared with baseline, there was no difference compared with controls. Rosiglitazone also tends to increase total cholesterol level and studies have reported variable effects on ratios of total cholesterol to high-density lipoprotein (HDL) and of LDL to HDL. In patients taking rosiglitazone, the ratios are either unchanged or increased. In studies over six months, the ratios tended to be unchanged because LDL reached a plateau and HDL continued to increase. There is a trend for these ratios to decrease in patients treated with pioglitazone. A recent, small, non-randomised and unblinded study suggested that pioglitazone increased levels of HDL to a greater, and LDL to a lesser, extent than rosiglitazone30 (E4). No randomised comparative study has been undertaken. It is known that modest increases in LDL levels correlate with increased cardiovascular risk. However, as has been reported for troglitazone,6 the increase in LDL level associated with rosiglitazone and pioglitazone is mainly in the larger, more buoyant and less atherogenic particles of LDL.31,32 Pioglitazone significantly reduced triglyceride levels. The long term effects of these alterations in lipid profile are unknown. Comparison with current antidiabetic drugsIn a published abstract and in the product information, rosiglitazone (2 mg twice daily and 4 mg twice daily) was directly compared with glibenclamide (or glyburide) at "optimally titrated dose". Patients in all three groups showed a statistically significant improvement in glycaemic control. The HbA1c level fell 0.27% and 0.53%, respectively, for the two rosiglitazone groups and 0.72% for the glibenclamide group at one year.8,33 Rosiglitazone was said to be "statistically equivalent" to glibenclamide at lowering HbA1c at one year, although the mean dose of glibenclamide is not stated (but, according to the FDA website, is 7.5 mg/day),29 and the graph in the product information shows that there was a deterioration in glycaemic control in the first six months in the two rosiglitazone groups. There was no statistical analysis provided for any time points other than one year. Rosiglitazone at 4 mg twice daily resulted in a significantly greater reduction in FPG level at one year than glibenclamide (−2.3 mmol/L v −2.0 mmol/L, respectively; P < 0.033).33 A study comparing rosiglitazone with metformin has not been published, but some information can be accessed through the FDA website.29 Patients were placed on metformin therapy at recruitment and the dose was increased to 2.5 g per day. They were then randomly allocated to continue to take metformin, to stop taking metformin and start taking rosiglitazone (4 mg twice daily) or to add rosiglitazone (4 mg twice daily) to their metformin therapy. The combination of the two agents was better than either used as monotherapy, but there was also a subset of patients in the group converted from metformin to rosiglitazone monotherapy who showed an abrupt deterioration of glycaemic control over the 24 weeks.29,34 However, no statistical analysis is provided. There are no similar studies published for pioglitazone. DeFronzo has reviewed studies of monotherapy with conventional agents and compared the efficacy of sulfonylureas, metformin, acarbose and troglitazone. From a similar starting HbA1c level, sulfonylureas and metformin reduced the HbA1c level by 1.5%–2.0% and the acarbose level by 0.7%–1.0%. Troglitazone reduced the HbA1c level by 1%–1.2%.2 The monotherapy studies described above indicate that the reduction in HbA1c level with rosiglitazone and pioglitazone is probably less than that with sulfonylureas or metformin. Concerns about hepatotoxicityTroglitazone was the first agent in this class to be marketed in the United States and was withdrawn by the FDA in March 2000 because of severe and unpredictable hepatotoxicity and 61 related deaths.35 The incidence of troglitazone-induced acute liver failure is estimated to be 1 in 8000 to 1 in 20 000 patients treated.36 The side chain of troglitazone, an α-tocopherol (vitamin E) moiety, or its quinone metabolites, may be the reason for its hepatotoxicity, and therefore this may not represent a class effect.17 To date, there have been three case reports of hepatotoxicty potentially caused by rosiglitazone and one potentially caused by pioglitazone. The agent was not proved to be the cause in any of these cases, all of which resolved with supportive care and withdrawal of the agent.37-40 In clinical trials, asymptomatic, reversible elevations of hepatic enzymes during treatment with both drugs have been noted, but rates were similar to those with placebo and resolved without withdrawal of the drug.41 The product information for both drugs states that these agents are contraindicated in patients with alanine aminotransferase (ALT) levels more than 2.5 times the normal level at baseline. Caution should be exercised when using these drugs in patients with hepatic enzyme level elevations of 1–2.5 times normal at initiation. It is also recommended that liver function tests (LFTs) be performed at baseline and every second month for the first year of therapy, and then periodically thereafter. If symptoms of liver dysfunction occur, LFTs should be checked. If the ALT remains elevated to more than three times the normal level, with or without symptoms, the drug should be discontinued.8,9 Adverse reactions and side-effectsIn all clinical trials for both rosiglitazone and pioglitazone, the incidence of adverse events, with the exception of weight gain and peripheral oedema, was similar to placebo. As monotherapy, neither drug caused hypoglycaemia, but in combination therapy mild hypoglycaemia has been reported and, in some cases, the dose of sulfonylurea, insulin or metformin was reduced8,9,23-28 (E2). Dose-dependent weight gain of 0.5–3.7 kg has been noted in the clinical trials and seems to be a class effect. The least weight gain was seen when used in combination with metformin.8,9,14-17,20-28 Weight gain is likely to be multifactorial in nature and could be the result of increased adipogenesis, increased appetite and oedema.11-15 Despite the weight gain, there are clearly improvements in insulin sensitivity and glycaemic control. Some studies report that the weight gain is associated with a reduction in waist : hip ratio, supporting the theory that there is a "shift" in fat distribution from visceral to subcutaneous fat depots, which confers less cardiovascular risk.15 In all studies, oedema occurred more frequently in the TZD treatment groups, although it was generally mild and did not lead to withdrawal from treatment. The incidence of oedema is about 3%–5%, although, when rosiglitazone or pioglitazone was combined with insulin therapy, the incidence rose to 13%–16%, compared with 5%–7% in the group receiving insulin plus placebo.8,9,14-17,20-28 There is also an increase in plasma volume of 6%–7%, and patients with New York Heart Association Class III and IV cardiac status were excluded from the studies (both drugs are contraindicated in these patients). This increase in plasma volume is also likely to be responsible for the mild reduction in haemoglobin level seen with all TZDs.6 PrecautionsThere are no data on the use of these drugs in pregnancy or lactation. In animal studies both drugs cross the placenta, and fetal loss, retarded fetal development and suppression of postnatal growth have been seen in rats.8,9 There were no significant effects on levels of the oral contraceptive pill in healthy women taking rosiglitazone, and the drug's manufacturer reports that no impairment of efficacy would be expected.8,42 There is no similar study for pioglitazone, but the product information recommends that alternative modes of contraception be used.9 Women with polycystic ovarian syndrome and insulin resistance should be advised that treatment with TZDs may result in resumption of ovulation and advice regarding suitable contraception should be given.8,9 Both drugs are contraindicated in moderate to severe liver dysfunction. Dose reduction is not required in elderly patients or those with renal impairment.8,9 Although animal studies have shown tumour-inducing effects for familial adenomatous polyposis and sporadic colon cancer in mice, there are no clinical data yet.43 However, mutagenicity and carcinogenicity studies have not raised any other significant concerns.8,9 These agents should be avoided in patients with significant cardiac dysfunction. There are no data in humans under 18 years of age. Conclusions and recommendationsThe thiazolidinediones are a unique class of drugs for the management of type 2 diabetes and they act to improve insulin resistance. Current evidence suggests that they are effective in the treatment of type 2 diabetes, but there is no evidence to suggest that they are better than currently available drugs and no data on long term safety or effects on morbidity and mortality related to diabetes and cardiovascular disease. Since the mechanism of action of TZDs is different from other currently available antidiabetic agents, it seems logical that they would be useful in combination therapy. So far, there are no studies assessing the effect of the TZDs when added to the combination of sulfonylurea and metformin, or to insulin combined with sulfonylurea or metformin. There is little difference between the two agents, although pioglitazone may have a more favourable effect on lipid profile than rosiglitazone. There are some data that show that these drugs may preserve beta-cell function, and it has been suggested that they should therefore be used early in the disease process, but there are no studies to support this hypothesis. Until there are more data available, these agents should probably be reserved for use in combination therapy in patients who are unable to be managed with current standard treatment combinations (ie, metformin, sulfonylurea, acarbose and insulin),44,45 and who fulfil the current prescribing guidelines. The development of thiazolidinediones has opened the door to some exciting research and to the development of other new agents for the treatment of type 2 diabetes mellitus. Important messages for patients are shown in Box 3. 1: Level-of-evidence codes Evidence for the statements made in this article is graded according to the NHMRC system4 for assessing the level of evidence. E1 Level I: Evidence obtained from a systematic review of all relevant randomised controlled trials. E2 Level II: Evidence obtained from at least one properly designed randomised controlled trial. E31 Level III-1: Evidence obtained from well-designed, pseudo-randomised controlled trials (alternate allocation or some other method). E32 Level III-2: Evidence obtained from comparative studies with concurrent controls and allocation not randomised (cohort studies), case–control studies, or interrupted time series without a parallel control group. E33 Level III-3: Evidence obtained from comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group. E4 Level IV: Evidence obtained from case-series, either post-test, or pre-test and post-test. 2: Drug profile of rosiglitazone and pioglitazone Action: TZDs activate peroxisome proliferator-activated receptor γ (PPARγ) and thereby regulate a number of genes involved in glucose and lipid metabolism. They act to improve insulin sensitivity. Onset: Both rosiglitazone and pioglitazone are rapidly absorbed and have high bioavailability. The timing of dose in relation to food does not significantly affect absorption or serum levels. Changes in fasting plasma glucose may start to be seen within two weeks, but maximal effects on glycaemic control may not be evident until 6–14 weeks after commencement of therapy. Dosing: Both rosiglitazone and pioglitazone are available as oral formulation. Rosiglitazone comes in 2 mg, 4 mg and 8 mg tablets and pioglitazone in 15 mg, 30 mg, and 45 mg tablets. No dosage adjustment is required for renal impairment. Recommended dose for rosiglitazone (Avandia; GlaxoSmithKline) — Commence at 4 mg per day, and, if necessary, increase to 8 mg per day after 6–8 weeks as a single or divided dose given with or without food. There is no additional benefit from doses higher than 8 mg per day. The largest dose given in combination with sulfonylurea in clinical studies was 2 mg twice daily. Recommended dose for pioglitazone (Actos; Eli Lilly) — Commence at 15 mg per day, and, if necessary, increase to 30 mg per day up to a maximum of 45 mg per day after 4–6 weeks. Give as a single dose with or without food. The largest daily dose used in clinical studies of pioglitazone in combination with insulin or sulfonylurea was 30 mg. Metabolism: Both drugs are extensively metabolised by hepatic cytochrome P450. Rosiglitazone metabolites are essentially inactive and mainly excreted in the urine. Some of the pioglitazone metabolites are active and are excreted in faeces and urine. Neither drug inhibits cytochrome P450. Although no significant drug interactions have so far been identified, prescribers should be vigilant for possible interactions, especially with drugs metabolised by or affecting the cytochrome P450 system. Adverse effects: Both drugs are well tolerated. There have been some case reports of hepatic dysfunction in patients taking the two drugs but causation was not definite. The incidence of elevations in enzyme levels on liver function tests was the same in treatment and placebo groups. The most common adverse effects include weight gain, oedema and dilutional anaemia. Because of fluid retention, these drugs may exacerbate heart failure and should not be prescribed to patients with New York Heart Association III-IV cardiac status. The drugs are also contraindicated in pregnancy and lactation and have not been tested in children. In women with polycystic ovarian syndrome with insulin resistance, treatment with these drugs may restore ovulation and appropriate advice regarding contraception should be given. When used in combination with other antidiabetic drugs, rosiglitazone and pioglitazone have been associated with mild hypoglycaemia requiring dose reduction of sulfonylurea, metformin or insulin. 3: Important messages for patients Thiazolidinediones (TZDs): Are a new type of drug for the treatment of type 2 diabetes. Improve diabetic control by increasing the body's sensitivity to insulin. Can cause mildly low blood sugar levels if they are used in combination with other medications for diabetes. Can cause some weight gain and mild fluid retention. Should not be taken if you are pregnant or breastfeeding or if you have significant heart or liver problems. Your doctor may need to advise you about methods of contraception, as you should not become pregnant while taking these medications. You will need to have regular liver function tests.

Trisha M O'Moore-Sullivan MB BS, FRACP · Johannes B Prins MB BS, PhD, FRACP

To the Editor: One concern that medical practitioners and pharmacists have about patient counselling is the uncertainty about the amount of information which should be given to patients, especially regarding possible adverse reactions to medications.1 Studies have found that providing information on possible adverse reactions can affect patients' willingness to take the medication.1 Research in cognitive psychology provides clear evidence that the order in which information is presented has a significant influence on judgement. Information received first is likely to have a disproportionately large effect on judgement, the "primacy effect".2-4 Despite clear evidence supporting the "order effect" in diverse areas, research has not been undertaken to investigate whether the order effect is present in medication information. To test the hypothesis that differently ordered sequences of the same information about a drug can result in different judgements,5 804 subjects were presented with a short description of a fictitious medication. The descriptions were presented in one of two formats (Box): (A) positive–negative (therapeutic benefits followed by potential adverse reactions) or (B) negative–positive order (potential adverse reactions followed by therapeutic benefits). The surveys were randomly distributed to university students, mindful of the limitation of extrapolating the data to the general population. Subjects rated the medication (from very bad to very good) and the likelihood of taking the medication (from very unlikely to very likely) on seven-point Likert scales. For analysis, we used the independent sample t test, which is robust and therefore considered suitable for this analysis. Two descriptions of a fictitious medicine for treatment of diabetes A: Diabetic MedicationThis medication is effective; it lowers sugar levels. It makes one feel better and boosts energy. It may cause nausea and headache. B: Diabetic MedicationThis medication may cause headache and nausea. It boosts energy and makes one feel better. It is effective; it lowers sugar levels. Of the 804 completed questionnaires, 403 were in the positive–negative order and 401 were in the negative–positive order. Participants given the positive–negative description of the medication rated it more positively (mean, 4.43; SD, 1.02) than those given the negative–positive description (mean, 3.70; SD, 1.62) (P < 0.001). Similarly, participants reported a higher likelihood of taking the medication when information was presented in the positive–negative order (mean, 4.23; SD, 1.62) compared with the negative–positive order (mean, 3.54; SD, 1.66) (P < 0.001). We found that the order of presentation of medication information significantly affected judgement of the medication. Subjects rated the medication more favourably when positive information was presented first. These results suggest a potential benefit in presenting medication benefits before discussion of possible adverse effects. Such an approach might apply to medical practitioners and other healthcare professionals when counselling patients. It might also be a consideration in the format of written information, such as Consumer Medicine Information.

Abilio C de Almeida Neto BScPsychol(Hons), PhD · Timothy F Chen BPharm, DipHPharm · Joyce H L Chan BPharm(Hons)

The majority of the "Australian COX-2-Specific Inhibitor (CSI) Prescribing Group" endorse the following points: CSIs are equivalent to non-steroidal anti-inflammatory drugs (NSAIDs) as anti-inflammatory agents. CSIs and NSAIDs modify symptoms but do not alter the course of musculoskeletal disease. CSIs do not eliminate the occurrence of ulcers or their serious complications, but are associated with considerably fewer peptic ulcers, slightly fewer upper GI symptoms and, according to published reports, fewer serious upper GI complications, notably bleeding, than NSAIDs. CSIs and NSAIDs have similar effects on renal function and blood pressure. Whether any CSI poses a risk to cardiovascular safety remains subject to debate. Comorbidities and coprescribed drugs must be considered before initiating CSI (or NSAID) therapy. Patients prescribed CSIs (or NSAIDs) should be reviewed within the first few weeks of therapy to assess effectiveness, identify adverse effects and determine the need for ongoing therapy

The Australian COX-2-Specific Inhibitor (CSI) Prescribing Group*

To the Editor: The review by Brodaty and colleagues1 on drug treatment of Alzheimer's disease provides a good, concise and balanced overview. However, Pfizer takes issue with some of the referenced safety data. In Box 3 of that article (Profiles of cholinesterase inhibitors), in reference to adverse effects of donepezil (Aricept, Pfizer), it is stated that "At 10 mg/day, nausea (17% of patients), diarrhoea (17%) and vomiting (10%) may occur.49" Reference 49 at this point appears to be an incorrect citation. The figures of 17%, 17% and 10% for nausea, diarrhoea and vomiting, respectively, appear to have been taken from an article by Rogers and Friedhoff.2 It is important to note that this was a non-comparative, open-label extension study, and these incidences of gastrointestinal adverse events are inconsistent with data presented in the Australian Product Information for donepezil,3 which quote rates of nausea, diarrhoea and vomiting of 11%, 10% and 5%, respectively. These incidences are derived from a patient cohort of 1102 patents who participated in appropriately designed comparative (active and placebo) pre-registration studies of donepezil. These data have recently been confirmed in a one-year, randomised, placebo-controlled study of donepezil in patients with mild to moderate Alzheimer's disease.4 Incidences of 11.3%, 7.0% and less than 5% for nausea, diarrhoea and vomiting, respectively, are quoted in that study. We contend that, while the citation referenced by Brodaty et al was incorrect, the figures quoted for the gastrointestinal safety incidences for donepezil are also inconsistent with the Product Information and current published data.

William Lam MB ChB, PhD

In reply: We thank Lam for pointing out an error in the referencing in Box 3 of our article1 regarding the figures for adverse events for donepezil. The correct reference was number 48 in our list, not 49, and was to Rogers, Farlow, Doody et al,2 not to Rogers and Friedhoff,3 as suggested by Lam. The other references in Box 3 were given as 20, 21, 23 and 48, but should have been listed as 19, 20, 21 and 47, respectively. Secondly, issue is taken with the rates of 17%, 17% and 10% for nausea, diarrhoea and vomiting, respectively, in people taking donepezil. We agree with the overall tenor of this letter that rates of side effects are generally lower in everyday practice. The figures we quoted for adverse events are higher than the 11%, 10% and 5% cited in the Australian Product Information for donepezil,4 as the article by Rogers and colleagues2 refers to rates of adverse events experienced by those on the 10 mg dose, after a forced titration after only one week on 5 mg. We presented data for adverse events at the 10 mg dose, as this was the dose recommended for donepezil given the findings of greater benefit on the higher dose. The Australian Product Information does not indicate whether the rates of adverse events refer to the 5 mg or 10 mg dose. Usual clinical practice, which is to start with 5 mg daily and increase to 10 mg after 4–6 weeks, results in fewer adverse events. The figures of 11.3% for nausea, 7% for diarrhoea and less than 5% for vomiting presented in the Nordic study,5 in which over 80% of patients were taking 10 mg of donepezil daily, with a more flexible titration schedule, appear to be more realistic.

Henry Brodaty AO, MB BS(SYD), MD(NSW), FRACP, FRANZCP · Jane R Hecker MB BS(Hons), FRACP · John A Snowdon MPhil, MD, FRCPsych, FRACP, FRANZCP · David J Ames BA, MD, FRCPsych, FRANZCP

Objectives: To review Australian adverse drug reaction reports describing hyponatraemia and hypokalaemia attributed to indapamide and compare the characteristics of the patients with those in Australian reports implicating two other diuretic products (hydrochlorothiazide and amiloride hydrochloride; chlorothiazide).Design: Descriptive analysis using reports from the database of the Adverse Drug Reactions Advisory Committee (ADRAC).Main outcome measures: Numbers of reports of hyponatraemia and hypokalaemia; proportion of such reports in total reports of adverse reactions to each drug; severity of electrolyte disturbances.Results: Between August 1984 and September 2000, 84 Australian reports of hyponatraemia and 87 reports of hypokalaemia, in which indapamide was the sole suspected drug, were submitted to ADRAC. Most reports involved an indapamide dose of 2.5 mg daily. There was a significantly greater proportion of reports of hyponatraemia with indapamide and with the hydrochlorothiazide and amiloride combination than with chlorothiazide; hypokalaemia was significantly more common for indapamide than for the other two drugs. Of the 87 reports of hypokalaemia with indapamide, 35 patients also had hyponatraemia. For all three drugs, at least 80% of reports of hyponatraemia were in people aged 65 or over, and electrolyte disturbance was most commonly reported in elderly women.Conclusions: Hyponatraemia and hypokalaemia have been described in 20.9% and 21.7%, respectively, of reports to ADRAC in which indapamide was the sole suspected drug. The electrolyte disturbances can be severe.

Michael D Chapman · Ross Hanrahan · John McEwen MB BS, MSc, MPS · John E Marley MD, MB ChB