Pharmacology

Drug subsidy recommendations should be informed by active assessment of current evidence and emerging treatments Decisions about which medicines should be subsidised by the Australian Government on the Pharmaceutical Benefits Scheme (PBS) are based on recommendations made by the Pharmaceutical Benefits Advisory Committee (PBAC) — an independent statutory body appointed by the government.1 The PBAC lists among its goals maximising the “value” that Australia derives from its health expenditure and “meet[ing] the health needs of the majority of the Australian community”.2 While the PBAC is generally thought to have in place good processes for working towards these goals, its decisions are increasingly contested by consumers, governments, clinicians and the pharmaceutical industry.3 For example, concern has been expressed about the PBS’s subsidisation of ranibizumab (Lucentis), a vascular endothelial growth factor (VEGF) inhibitor used for the treatment of wet age-related macular degeneration (AMD), when a far cheaper and probably equally effective alternative — bevacizumab (Avastin), a VEGF inhibitor listed for cancer but not for AMD — was available.4 The listing of ranibizumab, it was argued, was inconsistent with the goals of the PBAC and PBS because it is about 40 times more expensive than bevacizumab, and costs taxpayers over $200 million each year (second only to atorvastatin and rosuvastatin). A recent development has brought the issue to light once again: Bayer Healthcare and Regeneron Pharmaceuticals are, together, likely to seek PBS listing for yet another VEGF inhibitor, aflibercept (VEGF Trap-Eye), recently approved by the Therapeutic Goods Administration,5 to treat wet AMD. Although aflibercept has not been shown to have greater efficacy than ranibizumab, patients only need an injection every 2 months, compared with monthly for ranibizumab.6 But even if this did provide some benefit to patients and reduced the cost of therapy, which it is only likely to do by a small degree, it would still leave bevacizumab unlisted, and taxpayers would still be paying significantly more than they need to, overall, to cover the cost of treatment for wet AMD. One possible explanation for such a situation is that the PBAC currently relies entirely upon interested parties putting forward submissions for listing, rather than proactively seeking submissions in the public interest. In practice, this means that almost all submissions come from commercial sponsors, and the agenda of the PBAC is largely determined by the interests of the pharmaceutical industry. This is potentially problematic, because commercial sponsors are unlikely to go to the trouble of listing medicines for indications that are not commercially attractive. In theory, there is nothing to stop professional societies or consumer organisations from making their own submissions to the PBAC in the public interest. However, non-commercial organisations seldom have the resources and expertise to conduct and synthesise the research into clinical effectiveness, cost-effectiveness and the broader impacts of health technologies that is needed to make a case for PBS listing. But need this be the case? Some overseas agencies charged with health technology appraisal (eg, in the United Kingdom7 and Canada8) place more emphasis on setting their own priorities for health technology assessment than does the PBAC. We suggest that it may be possible to expand the role of the PBAC so that it has the power to, first, identify emerging or established pharmaceutical agents that might require evaluation on the basis of likely public interest (“horizon scanning”); second, invite professional societies to prepare submissions in these priority areas; and, third, provide the necessary financial and scientific support to these organisations so that they do not need to be burdened by prohibitive costs or legal liability. Orphan drug provisions, which allow the PBAC to waive submission fees for medicines that have no sponsor or are not commercially viable,9 go some way towards redressing the imbalance between commercial and non-commercial interests; but, even here, the onus is on professional and consumer organisations to initiate and prepare submissions. In this regard, it is noteworthy that, in Australia, efforts have been made to initiate horizon scanning for non-pharmaceutical health technologies through the Australia and New Zealand Horizon Scanning Network (ANZHSN), which makes recommendations to the Medical Services Advisory Committee (MSAC).10 Horizon scanning may: identify new technologies with major implications for the health system; control the adoption and use of technologies; and, identify underused technologies, as might be the case with the listing of bevacizumab for the treatment of AMD.10 Expanding the role of the PBAC would not be easy. It would probably require the establishment of a separate government-funded body that would conduct horizon scanning, make recommendations to the PBAC, seek submissions from relevant professional organisations and provide these organisations with the financial and administrative support that they would need to conduct or commission the necessary health technology assessments. A subcommittee of the PBAC, to whom the horizon-scanning body could make its recommendations, would probably also need to be formed. And even if such a mechanism could be established, questions would remain, such as: Who should set priorities for seeking PBS listings? What criteria should be used for prioritising potential listings (eg, novelty, financial impact, clinical impact, disease burden)? What processes should be used to identify areas of need (eg, specialty mapping, forecasting, public ranking exercises)? And how can such processes be inclusive and transparent?8,10 Such practical difficulties are evident in the non-pharmaceutical medical technology sector in Australia, where, despite the existence of a separate government-funded horizon-scanning body, the impetus for the MSAC to conduct a health technology assessment almost always stems from an application by a commercial sponsor.10 But, unless steps are taken in this direction regardless of such difficulties, the PBAC will be unable to reach its full potential as an agency committed to universal benefits and the systematic application of evidence-based decision making.11

Wendy L Lipworth MB BS, MSc, PhD · Ian Kerridge MPhil, FRACP, FRCPA · Richard O Day MD, FRACP

To the Editor: In Australia, when melatonin is requested in doses higher than those available in preprepared formulations, in different dosage forms, or for people under 55 years of age, private prescriptions and extempora-neous preparations are often used. There is evidence of efficacy of melatonin in shiftwork-related sleep disorders, jet lag, circadian rhythm disorders, and for older people with chronic insomnia, but not for insomnia generally.1-3 There is concern over increasing use of melatonin in children, but no current data exist for actual melatonin usage patterns in Australia. In September 2010, we conducted a 2-week prospective drug use audit of melatonin prescriptions dispensed to patients by Australian compounding pharmacies. All pharmacies of the Professional Compounding Chemists of Australia (PCCA) (n = 153) received audit forms and explanatory information sheets, followed up by two telephone calls. The audit form requested patient details, the melatonin prescription, prescriber, dose amount and formulation prescribed, directions on prescription, and purpose of medication. This study was approved by the Human Research Ethics Committee of the University of Sydney. Forty-one pharmacies completed 228 audits, a response rate similar to recent pharmacy-based surveys.4 Also, 42 pharmacies estimated melatonin prescriptions in the audit period without completing patient details. The demographic details of respondents (Box) were similar to those in a previous survey of Australian compounding pharmacies.5 A total of 1463 melatonin prescriptions were reported as dispensed in the 2 weeks by 83 pharmacies (17.63 per pharmacy). In the detailed audit, the median age of people for whom melatonin was prescribed was 12 years; 56.4% (128/227) were male; the average dose prescribed was 4.3 mg ± 2.5 mg (range, 0.5 mg–20 mg); the most common reason for prescribing melatonin was to help sleep in cases of attention deficit hyperactivity disorder (ADHD); and paediatricians were the most common prescriber (43.0%; 96/223). Analysis of the non-responders showed that responders were not different to non-responders in age, sex, years of experience or pharmacy prescription volume. Extrapolating the results, 70 132 prescriptions (17.63 × 26 × 153) are estimated to be compounded in the 153 compounding pharmacies annually. This staggering figure does not include non-PCCA pharmacies, compounding hospital pharmacies, melatonin purchases without prescription (generally via the internet), or Circadin (Neurim Pharmaceuticals) prescriptions. Circadin was not included in our study as it was introduced in mid 2010 and there had been only a few sales by September 2010, and it is approved only for people over 55 years of age with primary insomnia. In conclusion, we found that melatonin was frequently dispensed, with many cases of off-label use, to both adults and children, particularly for insomnia in children with ADHD and autism. Melatonin has limited long-term safety data, and the long-term effect on gonadal development, particularly with high doses, is unclear. The efficacy and safety of melatonin in children will only be established through well designed trials of high methodological quality and sufficient sample size. Melatonin prescription details for 227 patients Demographic details of patients and prescribers Proportion or mean ± SD (range) (n = 227) Details of patients for whom melatonin was prescribed Age (years) 22.8 ± 20.9 (1–83) Age bracket 0–2 years 1.4% 3–5 years 10.1% 6–10 years 32.0% 11–18 years 19.6% 19–34 years 8.7% 34–55 years 19.6% > 55 years 8.2% Male 56.7% New prescription 29.1% (42.3% using > 6 months) Details of prescribers (from 227 audit forms*) Type of prescriber General practitioner 41.4% Paediatrician 43.2% Sleep specialist 5.7% Psychiatrist 4.8% Other specialist 3.5% Reason for prescription† Primary insomnia 26.4% Secondary insomnia 14.5% Jet lag, travelling, shift worker, CRD 12.8% Help sleep in children with ADHD 24.2% Help sleep in children with autism and behaviour problems other than ADHD 19.4% Anxiety, trauma, stress and sleep problems 3.5% Sleep problems related to pain and cancer 0.8% Sleep problems related to other comorbidities (gastro-oesophageal reflux disease, Grave’s disease) 0.8% Unsure of reason 0.8% Dose (mg) (n = 213) 4.3 ± 2.5 (0.5–20) Total amount prescribed for liquid formulations (mL) (n = 99) 55.2 ± 53.2 (5–300) Total amount prescribed for solid formulations (number of capsules, tablets, troches) (n = 123) 72.9 ± 37.9 (15–300) Repeats authorised (n = 221) 2.3 ± 2.1 (0–10) Prescription duration (months) (n = 200) 7.9 ± 9.7 (0–60) Formulation prescribed† Tablets 3.5% Capsules, slow release capsules 49.7% Liquids (suspension, oral, sublingual drops) 43.5% Troches 2.6% CRD = circadian rhythm disorder. ADHD = attention deficit hyperactivity disorder. * Some data missing on one record of 228, so 227 used for tabulation. † Percentages may not add to 100% because of some missing data, and some patients may have reported two reasons.

Jane Nikles · Victor Lo · Jennifer A Giam · Bandana Saini

Recent federal trade policy commitments could protect Australia’s tobacco control legislation and the Pharmaceutical Benefits Scheme in the Trans-Pacific Partnership Agreement negotiations In its Trade Policy Statement of April 2011, the Australian Government committed to “preserve the right of Australian governments to make laws in important public policy areas” and to reject provisions in trade agreements that could “limit its capacity to put health warnings or plain packaging requirements on tobacco products or its ability to continue the Pharmaceutical Benefits Scheme”.1 One forum in which this resolve is likely to be tested is the Trans-Pacific Partnership Agreement (TPPA) negotiations. The TPPA is a proposed regional free trade agreement between Australia, Brunei, Chile, Malaysia, Peru, Singapore, New Zealand, the United States and Vietnam — a diverse assortment of countries from several continents around the Pacific rim. The TPPA differs from existing bilateral and regional free trade agreements in its sheer size and geographic diversity. It has the potential to restrict national policy space — “the freedom, scope and mechanisms that governments have to choose, design and implement public policies to fulfil their aims”2 — on an unprecedented scale. This article explores the potential for the TPPA to constrain Australia’s national health policy space through two illustrative case studies: tobacco plain packaging and the Pharmaceutical Benefits Scheme (PBS). Investor–state dispute settlement and plain packaging of tobacco productsDuring 2011, the Australian Government introduced legislation requiring tobacco products to be packaged in plain paper (with graphic health warnings, but minimal branding). This represents an important assault on one of the last bastions of tobacco marketing — the appeal to personal identity.3 Strong tobacco control policies such as Australia’s tobacco plain packaging laws are consistent with a substantial body of scientific literature and the World Health Organization’s Framework Convention on Tobacco Control, but they can be challenged under international trade and investment agreements, which are driven by economic rather than public health goals. Philip Morris Asia (PMA) — a subsidiary of Philip Morris International (PMI) — has launched an investor–state dispute against the Australian Government over its tobacco plain packaging legislation. While several tobacco companies have taken their complaints to the High Court, PMA has also been able to pursue its case in international arbitration (where it has a greater chance of success) through an investor–state dispute settlement (ISDS) clause in a bilateral investment treaty signed between Australia and Hong Kong in the early 1990s. This is the second investor–state dispute to arise over tobacco labelling; PMI is bringing a similar case against Uruguay through a Swiss subsidiary.4 PMI has also been prominent in calling for an ISDS provision in the TPPA.4,5 Ironically, the corporate restructuring that has allowed PMI to access the Hong Kong bilateral investment treaty (PMA was made the sole shareholder in Philip Morris Australia in February 2011) has also significantly weakened its claims. This is because the investment was made with the company’s full knowledge that the plain packaging legislation was being developed.6 The government has a strong case. Nevertheless, the dispute with PMA highlights broader problems of including ISDS provisions in trade treaties, and demonstrates why it is important that they be excluded from the TPPA. The arbitration rules that govern PMA’s dispute with the Australian Government are those of the United Nations Commission on International Trade Law. The case will be decided by a tribunal made up of three members: one chosen by PMA, one chosen by Australia, and a third, mutually agreed upon, which will act as president. This method of appointing arbitrators has been described as neither independent nor impartial.7 In sharp contrast to domestic forms of adjudication, individuals can serve as a legal representative in one ISDS case and an arbitrator in another, further undermining their ability to act without bias. Furthermore, although the arbitrators will be experts in international investment law, they may have little or no experience with specific fields of public policy such as tobacco control. While the public has a stake in investor–state disputes, confidentiality is a dominant principle in investment arbitration. Hearings are rarely opened to the public unless both parties agree, and investors have opted for closed hearings in several recent cases concerning public policy. In this regard, it is commendable that the Australian Government has adopted a high standard of transparency in advance of the commencement of formal proceedings by posting PMA’s claims and their response on a public website.8 The arbitration will be expensive for Australian taxpayers, although the government may be able to recoup some of the costs if it prevails. In several investor–state disputes to date, legal fees alone have amounted to over US$4 million and in one case have exceeded US$13 million.9 There are also arbitrator’s fees, administration fees and additional costs for involving experts and witnesses. Even more significant are the awards in investor–state cases, which are widely enforceable.7 The Czech Republic was obliged to pay more than US$350 million in compensation to a Dutch investor, which according to one report meant a near doubling of the country’s public sector deficit.10 It can readily be seen how insertion of a TPPA ISDS mechanism into Australia’s national health policy space might skew legislation away from the public interest towards supranational corporate interests. This is why it is significant that the government has vowed to no longer include provisions on ISDS in the bilateral and regional trade agreements that it signs.1 Australia’s refusal to consent to ISDS in the TPPA is a significant step towards limiting the encroachment of international trade agreements into our national health policy space and retaining our sovereign right to regulate significant areas of public health policy. US proposals for medicines policy in the TPPAChallenges to Pharmaceutical Benefits Advisory Committee processesThe PBS is another area of domestic health policy that the Australian Government has committed to protect in international trade agreements. However, US TPPA negotiators are seeking substantial changes to Australia’s laws and administrative processes. Certain draft TPPA provisions relate to the PBS directly and also indirectly, by seeking to prolong pharmaceutical patents and minimise exceptions to them made in the public interest. We examine these proposals as another instance of how the TPPA may promote incursions into our national health policy space. In October 2011, a draft annex to the transparency chapter of the TPPA was leaked.11 Under the rubric of transparency and procedural fairness, this TPPA annex seeks to impose new restrictions on the operation of national pharmaceutical reimbursement and pricing schemes (Box 1). It is an annex because it is not designed to apply to the US, as it would if it was in the body of the treaty. Clause (d) of paragraph X.3 of the draft annex would require countries to reimburse pharmaceutical companies based on “competitive market-derived prices in the Party’s territory”, or other benchmarks that “appropriately recognize the value” of the patented product. This wording represents a shift away from the more science-based standard in Annex 2-C of the Australia–United States Free Trade Agreement (AUSFTA), which refers to the “objectively demonstrated therapeutic significance” of the new patented pharmaceutical (http://www.dfat.gov.au/fta/ausfta/final-text). This provision includes no mechanism for proving that prices are derived from “competitive” markets. It undermines the world-class science-based mechanisms used by the Pharmaceutical Benefits Advisory Committee (PBAC) to determine whether a new patented medicine has sufficient health innovation to be listed on the PBS (based on a determination of cost-effectiveness, as well as efficacy, quality and safety). Paragraph X.3 of the draft annex seeks to impose a new independent appeals process on determinations by government bodies such as the PBAC (Box 1). This is contrary to what was decided (after prolonged and acrimonious negotiations) under Annex 2-C of the AUSFTA, which only provides for independent expert review as a quality improvement exercise for the PBAC. The threat and the use of an independent appeals process would increase the capacity of the pharmaceutical industry to lobby against PBAC decisions and undercut their expert-informed determinations. Paragraph X.4 of the draft annex requires parties to permit pharmaceutical companies to disseminate information to health professionals and consumers via the internet — a practice that is not permitted for prescription drugs in Australia due to concerns about overprescribing. This is also contrary to Annex 2-C of the AUSFTA, which makes the direct advertising of pharmaceuticals subject to Australia’s domestic laws, regulations and procedures. There is a consensus against such advertising in the Australian national policy space, chiefly because of its capacity to increase lobbying of the medical profession for purposes of corporate gain rather than public health benefit. While the effect of US TPPA proposals on Australia’s PBS would be economically damaging and reduce the affordability of medicines in Australia, the effects on access to medicines in other TPPA countries could be far more severe, particularly for developing countries and those required to make greater changes to their domestic laws.12 Extending intellectual property rightsUS TPPA proposals on intellectual property applying to patents13,14 (Box 2) would also add to the cost of medicines overall, affecting the sustainability of the PBS. Non-government organisations have undertaken extensive analyses of these proposed provisions,12,15 and have shown areas where TPPA provisions extend patent protection beyond comparable AUSFTA patent provisions and existing Australian law.15 For example, proposed article 8.1 of the intellectual property (IP) chapter of the TPPA provides patent protection for new forms, uses or methods of using a known product, whereas article 17.9.1 of the AUSFTA does not require patent protection to be provided for new forms of existing drugs.15 Although, in practice, new forms are sometimes patented, the TPPA proposals would restrict efforts to tighten patenting standards in future. Proposed IP article 8.2 requires patenting of diagnostic, therapeutic and surgical methods, whereas article 17.9.2 of the AUSFTA allows for its exclusion.15 This change could restrict expeditious patient access to new clinical developments and substantially add to health care costs. Proposed IP article 8.7 would also eliminate pre-grant opposition to patent applications by third parties, a safeguard provided for in the Australian Patents Act 1990, which is designed to prevent unwarranted patents from being granted.15 Most concerning are the provisions for data exclusivity periods — where generic manufacturers cannot use clinical trial data to prepare and register their products for springboarding after patent expiry. Proposed IP article 9.214 provides an additional 3 years of data exclusivity for new uses of existing pharmaceutical products, on top of the 5 years of data exclusivity already permitted under article 17.10.1 of the AUSFTA. There is also a placeholder for specific provisions for biologics (medicines produced from biological products, which are not currently dealt with separately in Australia). US pharmaceutical companies are reportedly lobbying for 12 years of data exclusivity for biologics. If adopted, these proposals would lead to higher costs to the PBS (as drugs stay under patent for longer periods) and delayed entry of cheaper generic medicines into the market. The US TPPA proposals for extended intellectual property rights and data exclusivity for pharmaceutical companies would require changes to Australian laws and administrative processes. They would also conflict with the spirit of the Intellectual Property Laws Amendment (Raising the Bar) Bill 2011, which is currently before the Senate and seeks to raise patent standards and facilitate faster regulatory approval for generic medicines. ConclusionRecent Australian trade policy commitments to exclude ISDS and provisions that would affect the PBS from the TPPA are a positive step towards preserving sovereign, democratic and science-based control over our national health policy space. It is important that Australia continues to insist that future trade agreements, including the TPPA, do not extend the intellectual property privileges of patent holders, interfere with the operation of the PBS or provide foreign corporations with ISDS rights to challenge domestic public health policies. 1 Leaked United States demands for changes to schemes such as Australia’s Pharmaceutical Benefits Scheme Pharmaceutical Benefits Advisory Committee (PBAC) recommendations to be based on competitively derived market forces or systems that appropriately value patented pharmaceuticals (no mention of “objectively derived therapeutic significance” as in the Australia–United States Free Trade Agreement) Appeals process able to challenge PBAC recommendations Heightened capacity for direct-to-patient pharmaceutical advertising 2 Some United States proposals for extensions to intellectual property rights applying to patents Patent protection for new forms of existing drugs Patenting of diagnostic, therapeutic and surgical methods Elimination of pre-grant opposition Extensions to data-exclusivity periods for some drugs

Deborah H Gleeson BSc(MLS), MPH, PhD · Kyla S Tienhaara PhD · Thomas A Faunce BA LLB(Hons), BMed, PhD

Veterinary pharmacologist Stephen Page believes that antibiotic use in animals benefits human and animal health While antibiotic use in livestock has the potential to cause harm to human health, the likelihood of harm arising from the use of antibiotics under current Australian practices is highly unlikely. There is ample independent evidence supporting the long history of appropriate use of antibiotics in Australian livestock. For example, the past six annual reports of the National Residue Survey contain the results of tests for the presence of up to 38 antibacterial agents in the edible tissues of cattle, pigs, poultry and sheep.1 Almost 400 000 assays were performed and compliance with Australian standards was at or above 99.99% for each of the four species tested. Given the high morbidity and mortality associated with many of the diseases of livestock (eg, necrotic enteritis and coccidiosis in poultry, bovine respiratory disease and mastitis in cattle, and post-weaning diarrhoea and porcine respiratory disease in pigs), prevention of infectious diseases is of fundamental importance. Judicious use of antibiotics in integrated animal health plans has an important role to play in protecting the health and welfare of animals and in contributing to the safety and quality of the food that is produced. Only 39 antibacterial agents are approved and available for use in Australian livestock, six of which are from classes with no human medical use counterpart. As an example of contemporary patterns of use, a recent survey of the use of antimicrobial agents in the Australian pig industry found most use was for control of infections with Lawsonia intracellularis, Mycoplasma hyopneumoniae and Escherichia coli and relied on sulfonamides, tetracyclines and penicillins2 — all drugs considered by the Expert Advisory Group on Antimicrobial Resistance to be of low importance to public health.3 What led the Australian Department of Health and Ageing to conclude that “Australia’s food supply is one of the safest and cleanest in the world”4? In 2008, Food Science Australia was commissioned to survey the presence of bacteria with antimicrobial resistance in samples of raw whole poultry, beef mince and pork chops collected from shops in Melbourne, Sydney, Brisbane and Perth. Among the isolates of Campylobacter jejuni, Salmonella and E. coli that were collected, no fluoroquinolone or ceftiofur resistance was identified. No Enterococcus faecium was isolated and all Enterococcus faecalis isolates were susceptible to ampicillin, penicillin and vancomycin; only one of 300 E. faecalis isolates was resistant to gentamicin. In contrast, Denmark, despite being recognised as having one of the most regulated and conservative approaches to the use of antibiotics in livestock, noted significant antibiotic resistance in their most recent antimicrobial resistance monitoring report: fluoroquinolone-resistant C. jejuni in 17% of broiler meat samples; high-level gentamicin resistance in E. faecalis from pork samples; vancomycin-resistant E. faecium in 47% of isolates from broiler chickens; extended-spectrum β-lactamase producing E. coli (ceftriaxone resistant) in 27% of broiler cloacal swabs and 9% of broiler meat samples; fluoroquinolone-resistant Salmonella enterica subspecies enterica serovar Enteritidis in 8% of sporadic cases of human salmonellosis; multiresistant Salmonella enterica subspecies enterica serovar Typhimurium definitive type 104 (DT104) in 7% of isolates from pigs; and ceftiofur-resistant E. coli in 1% of domestic pork and broiler meat samples.5 OzFoodNet (http://www.ozfoodnet.gov.au) was established by the Australian Government in 2000 to enhance surveillance of foodborne disease. It has published eight annual reports, which do not identify any cases of domestically acquired foodborne illness caused by infections with Salmonella, Campylobacter or Shiga toxin-producing E. coli complicated by antibiotic resistance of livestock origin. By contrast, a number of human cases of fluoroquinolone-resistant Campylobacter infection and S. Typhimurium DT104 infection have been described, but each originated from overseas (especially South-East Asia) or from imported food. Since 2001, the Australian Salmonella Reference Centre has tested more than 18 000 Salmonella isolates from cattle, pigs, sheep, chickens (broilers and layers), raw meat and eggs. No fluoroquinolone-resistant isolates were found and only nine isolates (most of which were submitted before 2004) were phenotypically resistant to cefotaxime at 1 g/mL. Australians should be reassured that food safety is the highest priority in livestock production. The Australian Veterinary Association is currently updating a series of guidelines for responsible use of antibiotics, the poultry industry is supporting leading edge research to develop a vaccine to prevent necrotic enteritis, and the pig industry has spent over $7 million on projects to refine and replace the use antibiotics and has committed to halving antibiotic use by 2018. Antibiotics used prudently and selectively can clearly benefit animal health and welfare, leading to overall human health benefits, not risks.

Stephen W Page BVSc(Hons), MVetClinStud, MAppSci(EnvTox)

To the Editor: After our recently published article1 and subsequent criticism2 that shortages in benzylpenicillin were a “storm in a teacup”, we would like to detail the increasing number of drug shortages at John Hunter Hospital. Not only does this pose increasing costs to pharmacy but there are escalating threats to patient care. As part of our routine formulary management, records are kept on drug shortages, collected to communicate urgent pharmaceutical issues and not designed as a research tool (Box). All shortages recently experienced in this hospital have been in generic medicines, particularly injectables, although any drug is potentially vulnerable. There are shortages that recur; thiopentone has twice been in short supply in recent months, noradrenaline has had recurrent periods of short supply, and intravenous labetalol is currently critically low and has previously been discontinued by a supplier in Australia, requiring a new manufacturer to be found. At the time of writing, midazolam 5 mg/5 mL injection is in short supply despite there being three generic brands in Australia, suggesting that all products come from the same source. The shortages we are experiencing are similar to but less extensive than those described in the United States.3 However, our list is far from complete as we cannot detect suppliers’ shortages that are resolved before our hospital shelves are affected. Hospitals cope in the usual ways — stockpiling (which protects some networks and harms others), switching to alternatives where possible, and finding new suppliers. Not only does this directly compro-mise patient care, it has been shown that subsequent changes in formulary increase medication errors4,5 — not to mention the economic impact, which is not known in Australia but has been estimated to cost $216 million each year in the US.3 Governments in the US and United Kingdom are taking decisive action to rectify this problem. However, the issue remains unrecognised in Australia and the Therapeutic Goods Administration has indicated to the authors that monitoring shortages is not its legislative responsibility. In the interests of national health care security, this issue needs to be resolved immediately by the federal government. Urgent action must be taken to identify medicines that are “essential” and to safeguard their supply through all possible avenues to ensure short-term health care sustainability. Number of different medicines in short supply at John Hunter Hospital, 2006–2011

Robert Pearce · Simon Quilty · Jacqueline Kewley · Lisa M Harris

To the Editor: As an author, researcher and lecturer on the safety of drugs used in the obstetric setting for over 30 years — during which I participated in successive Medicines in Pregnancy Working Parties of the Australian Drug Evaluation Committee and Therapeutic Goods Administration (TGA) — I share Kennedy’s concerns about the alphabetical drug categorisation system currently used in Australia.1 I am also concerned that, since the demise in 2008 of the Prescribing Medicines in Pregnancy TGA Advisory Group (which provided ongoing external clinical expertise to the TGA), there has been a complete lack of action, preparation and consultation with external sources of expertise and experience by the TGA with regard to the safety of drugs used in pregnancy. Expert consultation would be invaluable in preparing for the overseas “game-changing” developments in labelling relating to safety of drugs used during pregnancy, as identified by Kennedy. These changes in labelling are primarily being driven in the United States, with the aim of providing definitive, well substantiated advice to patients and health professionals — advice that reflects the consensus of expert opinion in a way that the alphabetical system, by its inherent structural and functional limitations, is unable to do.

Ronald P Batagol

To the Editor: Kennedy highlights a major source of frustration for mothers and health professionals — the accuracy of information regarding the safety of medications in pregnancy.1 The current categorisation system is inaccurate and outdated. Labetalol, used safely throughout pregnancy to treat hypertension for more than 30 years, has a Category C label because atenolol was associated with intrauterine growth retardation in one study.2,3 Proton pump inhibitors remain in Category C despite large studies demonstrating their safety in pregnancy.4 Hydroxychloroquine is in Category D despite extensive use in pregnancy without any adverse effect.5 The present A to X system could be simplified to three categories — safe, uncertain and definite risk, with a brief description of the information available, together with the references on which the evaluation is made. This could be freely available online and regularly updated as new information is published. In addition, more rapid accumulation of evidence regarding the safety of newer medications in pregnancy and lactation is needed. At present, we rely on the publication of case reports and case series by single institutions. It would be valuable if a national or international database of de-identified information could be kept on mothers and babies who are exposed to drugs for which the safety is uncertain, so that outcomes may be followed, to better guide future parents and their health professionals regarding the safety of these medications in pregnancy and lactation.

Adam P Morton

In reply: As a practising physician, Morton clearly understands the issues faced by prescribers and consumers regarding drug categorisation in pregnancy.1 Currently, the Therapeutic Goods Administration provides no references for the data on which it bases its drug categorisations for pregnancy. It is therefore left to the conscientious prescriber to try to find the data (not always easy or obvious) and then attempt to interpret it in a clinically relevant way. The more narrative approach suggested by Morton is an improvement but would still need clinical context and interpretation for optimal use. The system proposed by the United States Food and Drug Administration (FDA) would provide appropriate referenced data so that clinicians and consumers could see the latest available evidence (and not, as Morton points out, just the limited studies performed up to 30 years ago) about the safety (or otherwise) of medication to enable rational decision making regarding medication use during pregnancy and breastfeeding. The FDA’s proposed new labelling would include contact details of any pregnancy registries, if applicable, for the agent in question.2 At present, there are over 20 pregnancy registries collecting prospective data on the effects of exposures, including antiepileptic drugs and vaccines, as well as registries for pregnant women being treated for chronic medical conditions such as rheumatoid arthritis and HIV/AIDS.3 It is unfortunate that Australian regulators have not properly discussed these issues with interested professionals in the past few years. Even if we cannot remain world leaders in this field, it behoves us to at least embrace innovation occurring in other parts of the world.

Debra S Kennedy

Objective: To explore the current use of conventional and complementary medicines in Australians aged ≥ 50 years.Design, setting and participants: Cross-sectional postal survey sent to a random sample of 4500 Australians aged ≥ 50 years between June 2009 and February 2010.Main outcome measures: Prevalence of medicines use, reasons for medicines use and sources of medicines.Results: Response rate was 37.3%. Medicines use was very common; 87.1% of participants took one or more medicines and 43.3% took five or more in the previous 24 hours. Complementary medicines were used by 46.3% of participants, 87.4% of whom used both conventional and complementary medicines. The most commonly used medicines were antihypertensive agents (43.2% of participants), natural marine and animal products including fish oil and glucosamine (32.4%) and lipid-lowering agents (30.4%). Doctors recommended 79.3% of all medicines and 93.0% of conventional medicines. Pharmacists commonly recommended occasional medicines (ie, as needed), while friends, family and media most often influenced use of complementary medicines.Conclusions: The use of multiple medicines is common and higher than reported in the 1995 National Health Survey. Today, much medicines use is to prevent future disease by influencing risk factors. High levels of polypharmacy highlight the need to support the safe and effective use of medicines in the community. Although doctors recommend or prescribe most medicines, self-directed medication use is common. This highlights the need for consumer access to accurate information and strategies to improve health literacy about medicines.

Tessa K Morgan BSc, BA, MPH · Margaret Williamson BPharm, MPH, GradDipEpi · Marie Pirotta MB BS, MMed, PhD · Kay Stewart BPharm(Hons), PhD · Stephen P Myers PhD, BMed, ND · Joanne Barnes BPharm(Hons), PhD, MRPharmS

We need an urgent review of medicines labelling in Australia and New Zealand Almost 25% of patients admitted to hospital a decade ago received inappropriately prescribed medicines.1 As 40% of patients aged over 70 years receive more than five medicines, they are increasingly vulnerable to medication errors.1 Increasing brand substitution due to the proliferation of generic medicines adds to the potential for consumer and practitioner confusion and the likelihood of medication misadventure.2 Clinical scenario: Ms M J, aged 79 years, when questioned about her current prescribed medicines by her physician during an initial consultation, produced a list that included an angiotensin-converting enzyme (ACE) inhibitor, a selective serotonin reuptake inhibitor, a benzodiazepine, an anticonvulsant, and both Oroxine 100 μg and Eutroxsig 100 μg daily; the latter two preparations are both thyroxine sodium. Brand substitu-tion by her pharmacist was confirmed as the cause. There is anecdotal evidence that the progressive increase in innovator (new medicines) and especially generic brand names is associated with inappropriate prescribing and medicine use.3,4 Furthermore, the widespread practice of brand substitution by pharmacists, in which one brand (innovator or generic) is substituted for another, increases confusion, particularly among consumers but also among doctors, nurses and pharmacists. In some cases, such as the above, it can lead to duplicate prescriptions of a medicine.5 Juliet’s reflection in Romeo and Juliet, “What’s in a name? That which we call a rose by any other name would smell as sweet”, may be true for flowers, but clearly not pharmaceuticals. Brand name proliferationAlthough the increasing number of pharmaceuticals has obvious health benefits, the potential for confusion resulting from the thousands of associated brand names requires action. Some prescribers and consumers find brand names more convenient than generic names, but the frequent absence of any relationship between a brand name and the active ingredient or the condition being treated is problematic. Antihypertensive agents illustrate the breadth of brand proliferation. Eight different ACE inhibitors are used in Australia, excluding combinations, whereas 81 brands have Therapeutic Goods Administration (TGA) approval (Box). Enalapril maleate, which has been available for decades, is available in 12 brands, and only six of these use the active ingredient as part of their brand name. While prescribers and dispensers will recognise the active ingredient in these names, many consumers might consider Enalapril-DP and Enalapril Winthrop to be different, and would not necessarily know that Auspril and Alphapril are the same. The proliferation of brands today contrasts sharply with the situation 20 years ago, when only three ACE inhibitor preparations, Capoten, Amprace and Renitec — representing two individual medicines — were available. Even a relatively new generic medicine such as amlodipine is now available in 10 brands, excluding combinations, and many prescribers would be challenged to define the active ingredient of Ozlodip (amlodipine) from its name. Newer brand names of other antihypertensive agents such as Deralin (propranolol), Fibsol (lisinopril), Tryzan (ramipril) and Nyefax (nifedipine) clearly do not contribute to the quality use of medicines. Although there may be marketing sense behind the choice of a catchy name for a new product, generic brands are rarely marketed to prescribers, and pharmacists’ decisions are more likely to be based on cost, not persuasive advertising. Consequently, as a first step, companies that use the active ingredient name within their brand name should be supported. Some companies market the same active ingredient under different brand names but use identical tablet colours and shapes, which may limit brand confusion. However, it is worth noting that Oroxine and Eutroxsig are concomitantly used in the clinical scenario above, and are manufactured by the same company. Consequences of labelling confusionConsumer confusion and adherence problems are related not only to names but also shape, colour, taste, packaging, printing and excipients. The Second national report on patient safety noted that “look-alike or sound-alike” medicine names cause errors and system failures in hospitals and the community.7 The United States Institute for Safe Medication Practices reported that about 25% of serious complications relating to use of medicines resulted from name confusion, with another 25% due to labelling and packaging confusion.8 Another recent US study demonstrated poor emergency department patient knowledge concerning paracetamol in over-the-counter and prescription analgesics: for example, 49% of patients did not know that Tylenol, a commonly used US analgesic, contained paracetamol.9 Lack of knowledge about the paracetamol content of commonly used over-the-counter preparations (including combination products) given to children by parents and carers has resulted in many cases of paracetamol overdose and toxicity in young children.10 Generic brand substitutionAlready a common occurrence in hospitals, generic brand substitution is increasingly practised by community pharmacies. A recent study, which evaluated three major classes of Pharmaceutical Benefits Scheme medicines, found that about 20% of patients switched brands two or more times over 12 months, with the likelihood of substitution directly related to the number of available brands.2 Dealing with brand proliferation and confusionIn 2006, the Australian Pharmaceutical Advisory Council submitted a safe and effective brand substitution policy to government, promoting the use of active ingredient names.11 Unfortunately, this recommendation was not implemented, nor was a subsequent compromise agreement established by the Joint Expert Committee on Labelling Requirements for Medicines. The Pharmacy Guild of Australia has stated that “Medicine naming and packaging is a quality use of medicine issue and requires a systems/continuous quality improvement approach”.12 A recent editorial in the Journal recommended strategies to reduce medication confusion, including clear medicine labels with the active ingredient being displayed with equal or greater prominence to the brand names,13 and this was supported by the Advisory Committee on Prescription Medicines.14 Current TGA labelling guidelines recommend that Both the product name and the active ingredient names and strength should be prominently and equally displayed . . . To distinguish between the product name and the active ingredient name, the first letter of the product name should be in upper case and of the active ingredient name in lower case with a different colour for each. Fonts may be used to differentiate, but all fonts should be clearly legible.15 Guidelines are voluntary and our conclusion is that industry compliance is low. Solutions to the problemWe call on the responsible authorities, as a matter of urgency, to amend Australian and New Zealand drug labelling laws to ensure the active ingredient or generic name is displayed more prominently and in a larger font than the brand name on all pharmaceutical labels, whether prescribed or over-the-counter. This should apply to both innovator and generic products. In addition, to further distinguish between brand and generic names, we propose that the font and colours used for generic names should be unique and comparable for all medicines so as to aid consumer recognition. Brand confusion is a patient safety and a quality use of medicines concern,16 which will only worsen with time if no action is taken. National awareness and incentive campaigns funded by government and industry to ensure that all prescribers and consumers have access to electronic medicines information, including electronic health records, will be a complementary strategy to achieve quality use of medicines for all. Angiotensin-converting enzyme inhibitors available in Australia, 20106 Name No. of brands Captopril 6 Enalapril 12 Fosinopril 6 Lisinopril 17 Perindopril 10 (erbumine 9; arginine 1) Quinapril 9 Ramipril 13 Trandolapril 8 (8 active ingredients — 81 brands)

Shane L Carney MB BS, PhD, FRACP · Madlen Gazarian MB BS(Hons), MSc(ClinEpi), FRACP · Justin T Denholm BMed, MBioethics, FRACP · David M Reith FRACP, PhD · Robert K Penhall MB BS, FRACP, FRCP · Christine R Jenkins MB BS, MD, FRACP · Kay A Wilhelm MD, BS, FRANZCP · Paul A Komesaroff MB BS PhD · Mary M Osborn MPH · Richard O Day MD, FRACP

Pregnant women and their health care providers deserve better drug labelling, so that risks and benefits of medications can be weighed up rationally Given that over 80% of women use at least one prescribed or over-the-counter medication (typically one to three) at some time during their pregnancy, most medical practitioners who treat women of reproductive age can expect frequent questions about the use of medications during pregnancy and breastfeeding.1 In addition, as the average age of women having babies increases, their likelihood of having medical disorders that complicate pregnancy (such as hypertension) or chronic conditions also increases. A recent Australian study found that 322 of 819 pregnant women (39.3%) reported a chronic health condition during pregnancy, the most common being asthma, blood-related disorders (eg, thrombosis, haemorrhage and/or anaemia) and diabetes.2 Of concern, 107 out of 181 of those who reported a chronic health condition and use of regular prescribed medication (59.1%) reported non-adherence to medication for a number of different reasons. Most of the participants had “some concerns” about using any medicine during pregnancy and almost one-third believed that natural remedies were safer than other medicines during pregnancy. Complementary medicines include nutritional supplements, vitamin and mineral preparations, and herbal, aromatherapy and homoeopathy products, and an estimated $1.3 billion was spent by Australians on such products in 2004.3 In an Australian study completed between 2005 and 2007, about one-third of pregnant women reported taking complementary and alternative therapies to treat common complaints during pregnancy (eg, vitamins and minerals to treat colds and leg cramps, yoga and aromatherapy).4 Complementary medicines are included on the Australian Register of Therapeutic Goods as listed (low-risk) or registered (higher-risk) medicines, but most complementary medicine products do not carry a pregnancy risk category, even though some may have significant effects on pregnancy or fetal development. Since the 1960s and the birth of babies in Australia and Europe with severe birth defects following early pregnancy exposure to thalidomide, there has been a general reluctance on the part of doctors to prescribe, and women to take, medications during pregnancy because of fears about potential teratogenic effects. In 1963, as a direct consequence of the thalidomide tragedy, the Commonwealth Department of Health established the Australian Drug Evaluation Committee (ADEC) as an independent committee to advise on the safety of new drugs being introduced into Australia and to monitor and evaluate potential adverse effects of drugs already in use. In 2010, ADEC was replaced by the Advisory Committee on Prescription Medicines. An ad hoc working party of ADEC published a unique Australian categorisation of the risk of drugs in pregnancy (Categories A, B1, B2, B3, C, D and X). In the United States, the Food and Drug Administration (FDA) adopted a labelling format for safety of drugs in human pregnancy in 1979, and other countries developed their own categorisations. The ADEC categorisation is similar to the Swedish system and, although it shares the same letters as the FDA categorisation, there are some notable differences (particularly the Australian B1, B2 and B3 categories). The first Australian Medicines in pregnancy booklet was published in 1989. The last hard copy (fourth) edition, retitled Prescribing medicines in pregnancy, was published by the Therapeutics Goods Administration (TGA) in 1999.5 This resource subsequently went online, and the currently available Prescribing medicines in pregnancy database was revamped in May 2011.6 Unfortunately, the content of the data on drug safety in pregnancy and reliance on the categories did not change. A recent audit of practice of 80 general practitioners and 50 pharmacists by MotherSafe (a counselling service for women and health care providers who are concerned about exposures during pregnancy and breastfeeding) found that both groups were generally very conservative regarding advice about medications during pregnancy and breastfeeding, relying heavily on the ADEC categorisation and company product information listed in MIMS (the Monthly Index of Medical Specialties).7 The survey found that 80% of pharmacists and GPs used MIMS (ie, the categorisations and product information, where pregnancy and lactation are almost without exception included under special precautions or contraindications) as their primary source of information on medication safety in pregnancy. While 25% of pharmacists used the Australian medicines handbook, only 4% of pharmacists and 2% of GPs used the TGA’s Prescribing medicines in pregnancy booklet. Almost half of Australian drugs fall into one of the B categories because of the paucity of available human pregnancy data. Undoubtedly the most problematic of the Australian categories is B3 — limited use by pregnant women and women of childbearing age, without an increase in the frequency of harmful effects on the fetus, but with animal data showing increased occurrence of fetal damage. If the definition of the B3 category were explained to an average pregnant woman, she would probably never take a B3 drug because of anxiety about what this could mean for her baby. However, the data regarding many B3 drugs (such as combinations of long-acting β-agonists plus inhaled corticosteroids) are limited but reassuring, and uncontrolled asthma in pregnancy is a significantly greater risk than the potential risks (derived from animal data) posed by these medications.8,9 The biggest problem of the ADEC system is its alphabetical nature, which implies (incorrectly) that there is a gradation of risk, with the B category being “worse” than the A category, and so on. Confusingly, some publications that list the categories alphabetically (eg, MIMS) add a note explaining that “allocation of a B category does not imply greater safety than the C category” — counterintuitive and distinctly unhelpful to say the least. Unfortunately, the apparent simplicity of the categories means that clinicians tend to use it as a “bible”, rather than as a guide, which can result in misinterpretation of risk. The ready availability of the categories means that practitioners would rarely critically assess the quality or content of the original studies on which the categorisation was based and, therefore, would not consider the complexities involved in balancing the risks and benefits of using or not using a particular drug for a specified indication at a certain stage in pregnancy. There is also an assumption that drugs in the same category carry a similar risk, which is often erroneous. For example, valproate and paroxetine are both in the D category, but the former is associated with a significantly increased risk of birth defects and neurodevelopmental sequelae following use in the first trimester, whereas there are conflicting data about paroxetine being associated with a slightly increased risk of cardiac and other defects. Also, the categories do not take the stage of pregnancy into account. For example, tetracyclines cause tooth discoloration in the fetus when taken after 14 weeks’ gestation, so being categorised D in the first trimester is misleading and unnecessarily worrying. In addition, the categories do not adequately differentiate between different pregnancy situations — planned versus unplanned pregnancy and essential versus non-essential medications. Furthermore, the categories rarely take the dose or route of exposure into account — topical and inhaled exposures are generally less concerning than oral or intravenous exposures as they result in less systemic absorption, lower maternal serum concentrations, and thus minimal transplacental passage and a negligible chance of affecting the embryo. The categories are assigned before drugs are marketed and are often based solely on the results of animal reproductive studies, owing to a general paucity of human pregnancy data. The categories are rarely changed despite new (and often reassuring) evidence because of a general reluctance to advocate the safety of drugs in pregnancy. Other limitations of the ADEC categorisation include the fact that it does not cover environmental agents, chemicals, infectious agents, illicit drugs or complementary medicines and that, contrary to the understanding of many medical practitioners, the categories are not applicable to breastfeeding. In general, recommendations given to women about medications in pregnancy are cautious at best and scaremongering and inappropriate at worst. Unfortunately, the advice given by health care providers is compounded by misleading information obtained from the internet and other lay sources. Misleading advice, often based largely on the ADEC categorisations, can result in significant consequences for both the mother and baby. Some women stop taking essential medication because of fears about fetal safety, thus putting themselves and their baby at risk of an untreated illness (which is often a higher risk than the potential risk posed by the medication). Other women have their medication switched, on misunderstood grounds of fetal safety, from those that are beneficial to those with unknown or less efficacy — for example, switching antidepressants from citalopram (C category) to mirtazapine (B3 category). Equally concerning is that, when pregnant women are told that they should stop their effective, prescribed medications (eg, antidepressants) because of their categorisation, some may self-medicate with complementary medicines (about which there are usually less pregnancy safety and efficacy data) or potentially more harmful substances such as alcohol, cigarettes or illicit drugs. Worse still, some women consider terminating otherwise wanted pregnancies because of perceived safety concerns based on a drug’s categorisation. In a group of 177 of callers to MotherSafe (from 2005 to 2007) who had been considering termination of a pregnancy because of a range of exposures (including drugs, radiation and vaccines), only 30% had been exposed to major teratogens such as retinoids and antiepileptic drugs. Most had received information from other sources (including health care providers and the internet), which had caused them such anxiety that they were considering terminating their pregnancy.10 For several years, concerns have been voiced about the appropriateness of the current system of labelling of drugs for safety in pregnancy in the US.11 In 2008, the FDA proposed major revisions to the labelling of prescription drugs because of these concerns. All labels would include a general statement about the background risk of birth defects for all pregnancies as well as information about whether there was an active pregnancy exposure registry for that particular agent and, if so, how to enrol in it. The new labelling would: remove the letter categorisations; present information regarding fetal risks in a more narrative style; put discussions about risk in the contexts of background risk of birth defects and drug indication; document how the risk was determined (eg, extrapolated from animal data or obtained from human data); and include information (if available) about drug dosing in pregnancy. New and relevant information would be incorporated as it became available.12 As of late 2011, the FDA’s final rule on pregnancy and lactation labelling was in the final writing and clearance process; this promises an exciting new era in the field of rational use of medicine in this important population group. Given that the FDA review has been ongoing for the past 3 years, and it will be several more years before any objective evaluation of the new US system can be made, it may be a long time before Australian regulatory authorities look at the issue of improved labelling of drugs for safety in pregnancy or implement change. I hope that this article will stimulate debate about the direction that Australian regulatory authorities should take to develop an improved, more rational approach to labelling of drugs for safety in pregnancy and breastfeeding in the near future.

Debra S Kennedy MB BS, FRACP, HGSA

To the Editor: Faunce and colleagues wisely called for the introduction of legislation modelled on the United States False Claims Act (FCA) in the Australian health care setting.1 Indeed, whistleblowers require protection and reward.2 The authors stated that the “key strengths of the US qui tam anti-fraud regime ... lie in its recovery of large amounts of public monies, its encouragement of good corporate practice” and noted that it is “largely compensatory or remedial rather than punitive”.2 However, the non-punitive nature of the regime is problematic. Settlements in the US may appear substantial. In 2009, Pfizer paid US$2.3 billion to settle a false claims action against their marketing of Bextra (valdecoxib).1 However, this sum represents only a small proportion of Pfizer’s overall profits, given that Bextra was marketed from 2001 to 2005 and the company’s profit for the first quarter of 2011 was US$2.2 billion.3 Clearly, pharmaceutical companies in the US cope with the FCA — their huge profits largely compensate for the settlements. “While the defense industry used to be the biggest defrauder of the federal government under the FCA ... the pharmaceutical industry has greatly overtaken the defense industry in recent years.”4 Between 1991 and 2010, settlements for criminal and civil monetary penalties reached a total of US$20 billion. Three-quarters of these occurred between 2006 and 2010.4 The message from the US experience is that non-punitive anti-fraud laws do not stop pharmaceutical companies from engaging in fraudulent activities.

Alain Braillon

Recent studies build a strong case to suggest that there is a clear risk Clearly, stroke prevention is preferable to the currently available treatments, particularly for haemorrhagic stroke. The burden of stroke is substantial, so all strategies to reduce risk must be considered. The traditional risk factors, especially hypertension, are well recognised, but there is also increasing interest in identifying and modulating novel risks1 and precipitant causes. In this issue of the Journal, an important article by Caughey and colleagues2 adds to the growing literature concerning the risk of stroke related to the use of non-steroidal anti-inflammatory drugs (NSAIDs), particularly those with selective cyclooxygenase (COX)-2 inhibition. If the use of these agents is a clear and substantial risk, then avoiding such medications, particularly in high-risk patients, may be an important preventive strategy. But is the risk clear and substantial, or are other factors involved? Is there a potential for abandoning useful medications and also creating undue anxiety for patients currently using them to treat painful chronic conditions? The lessons regarding the cardiovascular risk of rofecoxib must be heeded,3 and the pharmacological basis for increased risk of thrombosis and elevation of blood pressure (and thus haemorrhagic stroke risk) is well founded. Surprisingly, recent guidelines4 pertaining to patients with extracranial large arterial stenosis, who are at high risk of stroke, made no specific comment for or against the use of NSAIDs because of a lack of evidence. This was based on some earlier studies5 that did not show increased stroke risk. Two more recent studies6,7 from different populations demonstrated an increased stroke risk, especially for haemorrhagic stroke. Combined with the results of Caughey et al,2 these studies build a strong case to suggest that there is a clear risk. There are consistencies across the studies, including the observation that adverse outcomes seem to vary with different NSAID classes. The population studied by Caughey et al2 was elderly, with comorbidities and, frequently, a combination of arthritis and vascular disease. This is precisely the group of patients where the dilemma commonly arises, making the study clinically valuable. The data appear robust, and feature a sensitivity analysis that strengthens the initial findings. It should be remembered, however, that the conclusions do not apply to younger and healthier populations. Additionally, the absolute stroke risk is small, and may be exceedingly small, particularly if NSAID exposure is brief. What is not clear from these studies is the role of confounding variables. The use of a prescription medication database and hospitalisation codes might suggest an association, but will not provide all the answers to a complex clinical scenario. Although the crude sequence ratio is robust to confounders that are stable within individuals over time, cardiovascular and stroke risk are unlikely to be stable over time and probably fluctuate. Intercurrent infection, inflammation, immune response and blood pressure variability are dynamic factors that may precipitate vascular events, particularly in predisposed individuals. Blood pressure variability8 is under increasing scrutiny as a provoking factor for stroke events. Given the important impact of COX-2 inhibition on increased blood pressure,9 this may be the true link in the relationship. The reasons for NSAID prescription would be of great interest. Suppose, for example, that an NSAID is prescribed for analgesia in an older patient with vascular disease who has a painful arthritic condition. The NSAID may well raise blood pressure, and fluctuations in pain may result in blood pressure fluctuations; thus providing two risks for stroke. Several NSAIDs were shown by Caughey and colleagues2 to carry stroke risk similar to the cardiovascular risk of the now-withdrawn rofecoxib. Low-dose preparations of several NSAIDs are available in Australia without prescription. The findings of Caughey and colleagues further emphasise the need for great care in the use of these agents in patients with hypertension and other stroke risks.

David J Blacker MB BS, FRACP

Pharmacists have an important role in protecting the public from regulatory loopholes If the 2011 Readers Digest survey can itself be trusted, pharmacists are the sixth most trusted profession in Australia, coming in marginally behind nurses (fifth) and before medical specialists (eighth) and general practitioners (ninth), and well ahead of car salesmen (43rd) and politicians (44th).1 What qualities inspire trust? The Concise Oxford dictionary defines trust as “firm belief in reliability, honesty, veracity ...”, so presumably these are the characteristics recognised in pharmacists and applauded by the survey respondents. The advice of community pharmacists in response to customers’ enquiries is widely relied upon, but events in the past few months raise serious questions about the trustworthiness of some in the profession. The first episode involved the marketing of SensaSlim (SensaSlim Australia, Sydney, NSW) a complementary medicine promoted as a new approach to achieving weight loss2 and sold largely through community pharmacies. In September 2010, the Therapeutic Goods Administration (TGA) included the medicine in the Australian Register of Therapeutic Goods (ARTG) as a listed product (labelled with an AUST L number). This means it had been evaluated for quality and safety but not efficacy. The product’s website claimed that a clinical trial involving more than 10 000 patients demonstrated its effectiveness, but requests from many health professionals to SensaSlim Australia failed to produce this evidence. Following complaints from doctors and pharmacists over the ensuing months, SensaSlim was discredited, although the associated legal battles are still unresolved.3 Despite widespread adverse publicity in the media, some community pharmacists continue to promote and sell the product, galvanised perhaps by the 65% profit margin on sales4 rather than the strength of the evidence for efficacy. The second event was the much publicised intention of the Pharmacy Guild of Australia (“the leading advocate for community pharmacy and a vital contributor to improving health outcomes for all Australians”5) to add its “Gold Cross” endorsement to complementary medicines marketed by Blackmores (Sydney, NSW) as “companion products” to prescription medicines for common medical disorders. Justifications for this concept included that some antihypertensive medicines are associated with reduced plasma concentrations of zinc; coenzyme Q10 concentrations are lowered in patients taking statins; hypomagnesaemia has been reported in patients taking long-term proton pump inhibitors; and probiotics might prevent some cases of antibiotic-associated diarrhoea.6 It is a short jump from these observations to the idea that supplements of zinc, coenzyme Q10, magnesium or probiotics should be given routinely when using these medicines. If implemented, this would be a remarkable marketing coup for Blackmores and the community pharmacy. But is there any evidence of possible benefit? A team at the National Prescribing Service published an excellent summary of the available evidence on its website on 30 September.7 They found nothing to support the routine use of these companion products. Under pressure from many pharmacists (including the Pharmacist Coalition for Health Reform) and other health professionals, the Pharmacy Guild announced on 5 October that the plan to endorse the Blackmores products had been dropped. These two disturbing events are symptoms of two underlying problems. First, community pharmacies still rely significantly on product sales for income, rather than a fee-for-service model. This results in a tension between being a health care professional and being a retailer. While recent agreements between the Pharmacy Guild and the Australian Government are trying to address this issue by providing payments to pharmacists for cognitive services such as medication reviews, the uptake of this program has been variable.8 Second, there are regulatory issues around complementary medicines that are yet to be acted upon by the Australian Government and its regulators. For many years, Australia led the world in regulation of complementary medicines. However, the regulations have not kept pace with trends, especially in the case of listed products. In particular, the loophole that allows sponsors to have products such as SensaSlim included on the ARTG without any review of evidence to support their claims is an affront to any regulatory body. When regulation of complementary medicines began in the 1990s, it was agreed that “low-risk” (AUST L) medicines would be allowed onto the market without independent review of efficacy, provided they were safe and of good quality. In 1999, it became a requirement that sponsors of listed products must “hold” the evidence to substantiate their claims. In 2003, a report on complementary medicines in the health system recommended that, as part of the listing process, sponsors should submit a summary of the evidence for efficacy to the TGA.9 The government accepted this recommendation,10 but no implementation has resulted. Enacting this recommendation may protect us from future SensaSlims, and would give a proper basis for the provision of sorely needed evidence-based consumer information about complementary medicines. A positive aspect of the Pharmacy Guild’s forced U-turn is that it demonstrates there are sufficient numbers of alert and concerned people in this country, including many pharmacists, who are prepared to put pressure on the peddlers of untrustworthy proposals. It is presumably these pharmacists who have earned the accolades of trustworthiness for the profession as a whole.

Anthony J Smith BM BCh, DM, FRCP · David A Newby BPharm, PhD

To the Editor: The potential upper gastrointestinal morbidity associated with non-steroidal anti-inflammatory drug (NSAID) misuse is well known.1,2 Recently, Frei and colleagues3 provided an overview of the morbidity and patient characteristics relating to opioid–NSAID misuse; however, they did not identify those patients with NSAID enteropathy (NE). NE is thought to occur via NSAID-induced reduction of endogenous prostaglandin via inhibition of both cyclooxygenase (COX)-1 and COX-2. The result is altered mucosal integrity, which thereby allows exposure to noxious luminal contents leading to inflammation, erosion and ulcers.1 We underscore the importance of identifying this group of patients presenting with anaemia, hypoalbuminaemia, weight loss or abdominal pain that relates to NE. The clinical presentation and small-bowel ulceration that is noted on investigations can often mimic Crohn’s disease.4 As the patient’s drug misuse is not immediately apparent, the diagnosis eludes the treating physician for some time, potentially at the expense of further morbidity from both ongoing medication misuse and the iatrogenic consequences of repeated presentations, investigations and medications that have been initiated to manage Crohn’s disease. Within the Townsville Hospital v(a 460-bed tertiary referral centre for North Queensland), we have observed an increasing number of cases where patients covertly self-medicate with large doses (up to 20 tablets per day) of codeine–ibuprofen analgesics, taken mainly for codeine addiction, subsequently developing small-bowel abnormalities. We present three cases that highlight this problem (Box). In each of these cases, the NSAID use was not immediately apparent. A recent search on the Adverse Drug Reactions Advisory Committee database did not identify any reports of such patients. This may represent significant underreporting of the issue due to lack of physician awareness. In mid-2010, the National Drugs and Poisons Schedule Committee implemented changes to how over-the-counter combination analgesics containing codeine can be accessed.5 Such medications must be accompanied by product and consumer medicine information, and a pharmacist must be involved at every sale to record the customer’s details. Despite these changes, there are still potential pitfalls, as there is no mechanism in place to stop patients from “pharmacy hopping”. It may be necessary to reschedule codeine as a prescription-only substance, and to create real-time databases of over-the-counter sales. While these drugs remain accessible over the counter, patients will continue to use them. Clinicians should therefore be vigilant for evidence of NSAID impact on the gastrointestinal tract. Three patients who self-medicated with large doses of a codeine–ibuprofen analgesic with small-bowel abnormalities consistent with NSAID enteropathy Patient characteristics Presentation Medications Investigations NSAID self-medication 42-year-old man with chronic ankle pain; hypogonadotrophic hypogonadism; diverticulitis with paracolic abscess; cholecystectomy; appendicectomy; excessive alcohol use; depression Recurrent severe hypokalaemia; vomiting, abdominal pain and weight loss; iron deficiency and hypoalbuminaemia; vitamin B12 deficiency Omeprazole 40 mg/day; mirtazapine 15 mg/day; oxycodone 5 mg 4–6 hourly as needed Gastroscopy: antral ulcers; colonoscopy: normal; capsule endoscopy: multiple jejunal ulcers with early structuring consistent with NE; CRP level within RI Ibuprofen 200 mg/codeine phosphate 12.8 mg: 10 tablets/day 41-year-old woman with previous diagnosis of Crohn’s disease elsewhere, not supported by small-bowel resection Abdominal pain, diarrhoea and vomiting; iron deficiency anaemia; hypoalbuminaemia Iron supplement Gastroscopy and colonoscopy: normal; capsule endoscopy: multiple web-like strictures with circumferential ulceration throughout the small bowel consistent with NE; CRP level within RI Ibuprofen 200 mg/codeine phosphate 12.8 mg: 20 tablets/day for 5 years 41-year-old man with Scheuermann’s disease; chronic back pain; melanoma; depression; excessive alcohol use Iron deficiency anaemia; hypoalbuminaemia Omeprazole 40 mg/day; amitriptyline 25 mg/day; as needed: buscopan 20 mg; paracetamol 500 mg/codeine 8 mg; paracetamol 500 mg/codeine 30 mg; tramadol 50 mg Upper endoscopy: small gastric ulcer; push enteroscopy: multiple jejunal ulcers consistent with NE; CRP level within RI Ibuprofen 200 mg/codeine phosphate 12.8 mg: 10–12 tablets/day for more than 5 years CRP = C-reactive protein. NE = NSAID enteropathy. NSAID = non-steroidal anti-inflammatory drug. RI = reference interval, < 5 mg/L.

Rozemary Karamatic · John Croese · Enrico Roche

To the Editor: We agree with Smith and colleagues1 that it is important to raise awareness among health professionals — and consumers — about recently revised dosing recommendations for colchicine. Software decision-support tools have an important role in ensuring safe prescribing of such drugs. However, we have questions about whether this software uses information that is up-to-date with current evidence, particularly in relation to colchicine. We believe that the clinical software systems used by clinicians and pharmacists could better support them in relation to medicines safety issues like this one. First, they could provide up-to-date, evidence-based dosing information. Second, they could warn the user when potentially harmful drug doses are being prescribed or dispensed, or when there are new recommendations about drug therapy. In this case, the situation is not straightforward because there are inconsistencies in the dosing recommendations for colchicine. In 2010, an article in NPS RADAR highlighted new evidence to support the use of low-dose colchicine in acute gout.2 This new dosage regimen was also recommended in the Australian medicines handbook in 2010.3 Nevertheless, higher doses are currently recommended in the Australian approved product information (PI), the consumer medicines information leaflet, and other commonly used medicine reference sources (this raises other issues, including the fact that there is currently no process to ensure that the PI is regularly reviewed, and the role of the Therapeutic Goods Administration4; however, these are beyond the scope of this letter). There is no guidance for clinical software vendors regarding which information to provide, and, at present, drug dosage information in these systems is frequently based on the PI as provided by the manufacturer or sponsor. We examined colchicine dosing information provided at (or accessible from) the point of prescribing or dispensing in a number of commonly used systems, and none showed the recent low-dose recommendations. Nor were any alerts or warnings displayed about potential toxicity specifically related to the dosage regimen for colchicine. Our previous research has shown that, in general, there is little of this type of decision support available in general practice software.5 Guidance for software vendors and high-quality, up-to-date knowledge bases are required to support this functionality. Currently, there is no overarching governance mechanism in Australia to guide the development of decision support, or to ensure that the inclusion of clinical information in software is up-to-date or based on the latest evidence. A coordinated approach to ensure that these systems support safety and quality is long overdue.6

Michelle Sweidan · James F Reeve · Kitty Yu

To the Editor: The letter from Smith and colleagues in the 6 June 2011 issue of the Journal1 highlights the potential toxicity of colchicine, even when used in the therapeutic doses recommended in the current product information (PI).2 This in turn highlights how important it is that all medicines have PI that continues to be maintained with the most clinically accurate and up-to-date information. The current system for maintaining PI seems to break down most significantly with out-of-patent, “grandfathered” and “orphan” medicines.3 During 2009, we identified an important change in the recommended dose in the American PI for colchicine through our usual processes of scanning the medical literature (including the websites of drug regulatory agencies). Colchicine is an out-of-patent medicine. The American study underpinning the American PI changes was sponsored by a different company and used a strength of colchicine tablet (600 μg) not available in Australia.4 The local sponsor companies were contacted at the time, but did not plan to update their Australian PI. Amending a PI is a costly and lengthy process, and the expense is hard to justify for an inexpensive and relatively low-use product. We updated the Australian medicines handbook dosing information5 and then wrote to the Therapeutic Goods Administration (TGA) suggesting the PI change could be initiated by them in the public interest. As yet, we have not received a response from the TGA and the dose in the PI remains unchanged. Despite its limitations in cases such as these,3 the PI forms the backbone of default dosing and drug interaction data in electronic prescribing software in Australia.6 We hope that Smith and colleagues’ letter might not only help prompt a change to the Australian PI for colchicine, but also a reconsideration of whether a more proactive approach is warranted for updating PI dosing and safety information for orphan drugs.

Nicholas A Buckley · Simone O P Rossi

Objective: To determine the risk of stroke associated with non-steroidal anti-inflammatory drug (NSAID) use.Design, setting and participants: Retrospective cohort study of 162 065 Australian veterans with incident dispensing of an NSAID between 1 January 2001 and 31 December 2008, using prescription event sequence symmetry analysis.Main outcome measures: Hospitalisation for stroke, ischaemic stroke or haemorrhagic stroke.Results: The absolute risk of stroke was low: 7.1/1000 people/year. Incident use of NSAIDs was associated with a 1.88 times increased risk (95% CI, 1.70–2.08) of hospitalisation for stroke (ischaemic or haemorrhagic) following first ever dispensing of an NSAID. This equates to an increased absolute risk of 13.4 strokes/1000 people/year. Significant positive associations between starting an NSAID and having a hospitalisation for stroke were found for most NSAIDs, with adjusted sequence ratios ranging from 1.44 (95% CI, 1.16–1.80) for indomethacin to 1.80 (95% CI, 1.59–2.04) for rofecoxib.Conclusions: Incident use of NSAIDs was associated with an increased risk of stroke. Increased awareness of the potential for serious adverse cardiovascular events, together with individual assessment of cardiovascular risk, careful deliberation of the balance between risk and benefits and appropriate supervision, is required when initiating NSAID therapy.

Gillian E Caughey BSc(Hons), PhD · Elizabeth E Roughead BPharm, MAppSc, PhD · Nicole Pratt BSc, PhD · Graeme Killer AO, MB BS, MSc · Andrew L Gilbert BPharm, DipAppPsych, PhD

Health reporter Ray Moynihan explores disturbing new data about the ever-popular pills After analysing antidepressant use among older people in Britain for more than a decade, a team of researchers has come up with some alarming new findings. Released recently, their study barely raised a murmur in Australia, but its implications are potentially enormous.1 If the new data are to be believed, for older people, the most commonly prescribed drugs for depression may be associated with an increased risk of serious health problems and death compared with less common antidepressants or none at all. Conducted as part of the Health Technology Assessment program, this British prospective cohort study investigated the risks associated with antidepressants being used by people aged 65 years or older during the decade or so to 2008. Its database included more than 60 000 people from 570 general practices across the United Kingdom who had been newly diagnosed with depression. Results published in the BMJ show that more than half of the antidepressant prescriptions issued to this group were for drugs from the selective serotonin reuptake inhibitor (SSRI) class, almost a third were for older tricyclics, and just over one in 10 were for other antidepressants.1 Eleven per cent of the people in the study did not take any drugs for depression. For those who did take antidepressants, the median duration of use was 1 year. Interestingly, more than two-thirds of the older people had the severity of their depression classified as mild, a quarter as moderate, and just under 5% as severe — and these proportions were similar for those who were and those who were not prescribed antidepressants. The researchers then compared the adverse events experienced by people during the time they were taking the drugs with those experienced by people during periods when they weren’t taking the drugs, and it was these comparisons that produced the unexpected and disturbing associations. The absolute risk of death from all causes over 1 year was 10.6% for patients taking SSRIs, 8.1% for those taking tricyclics, 11.4% for those taking other antidepressants, and 7.0% for people not taking any antidepressants. Moreover, those taking antidepressants suffered a significantly greater number of serious adverse events: All classes of antidepressant drug were associated with significantly increased risks of all cause mortality, attempted suicide/self harm, falls, fractures, and upper gastrointestinal bleeding compared with when these drugs were not being used.1 Despite being heavily promoted as better than the older medicines, the study found that, compared with tricyclic antidepressants, the newer SSRI class “may be associated with an increased risk of ... all cause mortality, stroke/transient ischaemic attack, falls, fracture, epilepsy/seizures, and hyponatraemia”. The obvious limitation here is that the study was observational, rather than a randomised controlled trial. However, as is made clear in their full 200-page report for the Health Technology Assessment program,2 the researchers went to great lengths to identify a wide range of potentially confounding variables, including age, sex, comorbidities and the severity of depression. Yet after adjusting the results for the confounding variables, key associations were largely unaffected. For example, after adjusting for confounders, taking SSRIs was still associated with a roughly 50% higher chance of death in relative terms, as well as an increased risk of serious adverse events including attempted suicide, falls and fractures, compared with those diagnosed with depression who were not taking antidepressants. In discussing the findings of their observational study, the authors highlight the difficulty of untangling the effect of the drugs from the effect of the underlying condition, particularly as they were unable to adjust for the way the severity of a patient’s depression might have changed during the decade of the study. Putting their results in the context of other data, the researchers conclude that their findings of higher rates of attempted suicide for all classes of antidepressants “suggest an effect of depression itself rather than a direct causal effect” of the drugs.2 By contrast, they conclude their findings of higher rates of falls, fractures and hyponatraemia associated with some antidepressants are generally in line with existing data. Importantly, the study’s limitation is also its strength. Looking at the serious health problems experienced by many thousands of people taking antidepressants over a long period, these real-world results are potentially more relevant than small, short-term, company-funded trials with extensive exclusion criteria, which may lead to overstating benefits and playing down harms of drugs. Whatever your view of the benefits of these heavily marketed medicines, this latest study provides important new information about their associated downsides.

Ray Moynihan BA

High public interest does not guarantee affordability Alcohol dependence is a common, disabling and costly medical condition that affects 4% of Australian adults.1,2 Several pharmacological therapies are now available in Australia to treat alcohol dependence, including disulfiram, acamprosate and naltrexone. While all three medicines are registered in Australia by the Therapeutic Goods Administration (TGA), only acamprosate and naltrexone are listed on the Pharmaceutical Benefits Scheme (PBS). Recent reviews show that supervised administration of disulfiram is both effective and safe. Accordingly, disulfiram should be made more available and accessible through PBS listing. Disulfiram helps to achieve abstinence by inhibiting aldehyde dehydrogenase. This leads to the temporary accumulation of acetaldehyde, which causes a potentially severe aversive reaction with nausea, flushing, agitation and dizziness, thereby usually deterring future drinking. Although the treatment has a logical basis, early studies found only mixed evidence for its efficacy.3 Consequently, disulfiram fell into disfavour. Recently, however, the original studies of the efficacy of disulfiram were reviewed. When studies of supervised and unsupervised dispensing of disulfiram were compared, well supervised treatment was far more effective, often achieving excellent results.4 Indeed, the few available direct comparisons of supervised disulfiram and other medications for alcohol dependence found disulfiram to be more effective.5-7 At first glance, this would seem like unqualified good news: a well known, registered, and relatively inexpensive medicine (costing about $70 per month, including pharmacy dispensing fees) has been found to be effective for a condition that is often ineffectively treated and is estimated to cost Australia as much as $36 billion per annum.2 But the definition of “inexpensive” is a relative one — many of the patients who need disulfiram cannot easily afford even $70 per month, especially on a continuing basis. At present, these patients can access subsidised disulfiram only through ad hoc mechanisms, such as appealing to hospital drug committees. Listing disulfiram on the PBS is the obvious solution — not only because the drug is effective and inexpensive, but because there is reasonable evidence that it is more effective and less expensive than other treatments listed for alcohol dependence. But therein lies the problem: because disulfiram is an inexpensive and old drug, there is little incentive for a pharmaceutical industry sponsor to underwrite the expensive process of applying to the PBS for listing. While professional associations (such as the Australasian Chapter of Addiction Medicine of the Royal Australasian College of Physicians) could submit an application, they too are likely to be deterred by the costs involved. The PBS is also unlikely to take this on, because it has an interest in controlling expenditure and because the cost of applications to the PBS is usually recovered by charges collected from the sponsor of the drug.8 We are left with a situation in which a treatment is not listed on the PBS despite being effective, relatively inexpensive, likely to save health care resources and, somewhat ironically, recommended for use in government-funded treatment guidelines.9 There is, however, a mechanism by which disulfiram could potentially be listed on the PBS that is analogous to the TGA’s “orphan drug” provisions:10 the PBS is willing to list certain drugs in the public interest and waive the associated application costs. For disulfiram to be listed in this way, an economic justification (however crude) would need to be made, support from the relevant clinical organisations would be required, and the sponsor would need to be willing to supply the drug under arrangements proposed by the Pharmaceutical Benefits Advisory Committee that might or might not be commercially appealing. PBS listing of disulfiram would have to be contingent on its proper clinical use. Disulfiram is not a first-line therapy; it should not be used in the elderly or in patients with cerebrovascular or cardiovascular disease; and patients must be able to understand the consequences of drinking alcohol when taking disulfiram. Most importantly, disulfiram is effective only when administered daily under strict supervision (by a health professional, family member, employer, police officer or probation and parole officer) for at least 12 months.4 While we would not wish to discourage the prescribing of disulfiram in general practice and in rural areas, prescribers would need to be familiar with its side effects and able to provide the necessary counselling. We believe that current evidence is more than sufficient to justify listing disulfiram on the PBS, but continued PBS listing of disulfiram would need to be contingent on further evidence demonstrating relative efficacy and cost-effectiveness. Improving treatment outcomes for patients with alcohol dependence is a very worthwhile goal — especially for critical populations such as Indigenous Australians, recidivist drink-drivers, and people with a long history of repeated alcohol-related violence. Increasing the affordability and use of disulfiram, by listing it on the PBS, would be an important step towards this goal.

Wendy L Lipworth MB BS, MSc, PhD · Alex D Wodak FRACP, FAChAM, FAFPHM · Paul S Haber MD, FRACP, FAChAM · Richard O Day MD, FRACP

To the Editor: A daunting idea for health care providers is the statistic that, for many medications, only about half of the patients given standard doses will receive the desired therapeutic benefit.1 In the past decade or so, it has been argued that some of this variation in response may be attributed to genetic differences between individuals in mechanisms responsible for the pharmacokinetics and pharmaco-dynamics of many drugs.2 The disparity in health standards among Aboriginal and Torres Strait Islander people compared with non-Indigenous groups is a cause for concern, and requires a concerted political effort to instigate adequate solutions.3,4 Some of the problems include a higher rate of diseases such as hypertension, diabetes, obesity, cardiac disease and depression.3,4 The range of medicines prescribed for these conditions is broad, and some people may not receive the full therapeutic benefit, or may have more severe side effects compared with others. Genetically determined variables contribute to the pharmacokinetics and pharmaco-dynamics of these drugs. Many medications used to treat such diseases are metabolised by the cytochrome P450 (CYP) hepatic enzyme systems, and/or their pharmacokinetics are altered by drug influx and efflux systems. Many of these mechanisms are under genetic control and their efficiency may vary between individuals. Despite this, there are few data on the pharmacogenetics of Indigenous populations generally, and the data on Aboriginal and Torres Strait Islander populations are particularly scant.5 Of the few genetic studies of Indigenous Australians, one found that CYP2C19 and CYP2D6 allele frequencies in a group from remote north-western Australia differed significantly from those for Australians of European ancestry, but were similar to those for East Asian populations.5 An altered CYP2C19 allele could mean alterations in levels of drugs such as phenytoin and clopidogrel, and an altered CYP2D6 allele could mean alterations in levels of drugs such as tricyclic antidepressants, selective serotonin reuptake inhibitors, codeine and tamoxifen. We urgently need to identify clinically relevant issues relating to the capacity of people from these groups to metabolise certain medicines. Screening for genetic variations in drug metabolism and transport mechanisms may highlight significant variations in capacity. This may influence whether people benefit from or are harmed by commonly prescribed medications for hypertension, type 2 diabetes, cardiac disease and depression. The high and increasing prevalence of these diseases among Aboriginal and Torres Strait Islander populations supports a detailed, methodical assessment of the genetics of their drug-metabolising capacity.

Joseph D Tucci

Australian database linkages could be used for postmarketing surveillance of antidiabetic therapy side effects Several incretin hormone-based therapies for type 2 diabetes are marketed in Australia. These are exenatide (the glucagon-like peptide-1 [GLP-1] analogue) and sitagliptin, vildagliptin and saxagliptin (inhibitors of the enzyme dipeptidyl-peptidase-4 [DPP-4]). These drugs are attractive because they improve blood glucose control without weight gain and with less hypoglycaemia than insulin and its secretagogues. Their distinct mode of action means that they improve glycaemic control when added to more established blood glucose-lowering therapies. This underlies their current Pharmaceutical Benefits Scheme listing as part of dual or, in the case of exenatide, triple therapy with metformin and/or sulfonylurea treatment. With increasing use of these drugs, more data relating to their adverse effects have emerged. A case linking pancreatitis with exenatide therapy was described 5 years ago,1 and further case reports have meant that specific warnings are now included in the product information for all GLP-1 analogues and DPP-4 inhibitors. Animal studies with the GLP-1 analogue liraglutide (registered but not currently available in Australia) raised the possibility of medullary (C-cell) thyroid cancer. Although an increased risk of this tumour was not evident in humans in preregistration trials, liraglutide is contraindicated in patients with a personal or family history of medullary thyroid cancer and in patients with multiple endocrine neoplasia syndrome type 2 (http://www.novo-pi.com/victoza.pdf). Inhibition of DPP-4 may predispose to hypersensitivity reactions through prolonged action of neuropeptides such as substance P,2 and alter immune function, with a possible increased risk of infections.3 However, the relative infrequency of adverse effects such as pancreatitis, C-cell cancer and severe allergy means that large case–control databases are needed to provide accurate estimates of their incidence and predictors. In an attempt to provide better information on incretin therapy-associated adverse effects, United States researchers led by Peter Butler recently used the US Food and Drug Administration (FDA) publicly available Adverse Event Reporting System (AERS). An initial accepted report containing the results of these analyses appeared in February 2011 on the website of the journal Gastroentrology. The main findings were of a significantly increased risk of pancreatitis and pancreatic cancer with exenatide and sitagliptin (the two most-used incretin-based therapies in the US), as well as an increased risk of all thyroid cancer (not just medullary) with exenatide. After the validity of these findings was challenged by the manufacturers,4 the paper was withdrawn but a modified version subsequently reappeared online and in print.5 The use of AERS to identify adverse drug effects is controversial and its substantial limitations are acknowledged by the FDA itself. Reporting is uncontrolled, voluntary, from multiple sources and often incomplete. Overreporting of events for new drugs, especially during the first 2 years and for serious outcomes, is well recognised.6 The choice of comparator treatments, from which odds ratios for the occurrence of index events are generated, has a bearing on the results, as does knowledge of other therapies or patient factors that might also increase the risk of an event. For pancreatitis, this includes the association between diabetes and obesity, as well as drugs that have relatively high use in type 2 diabetes, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins and fibrates. Although mining of data from the AERS has successfully found previously unrecognised adverse effects, a study of 21 unrelated therapies suggests that only about 50% of the signals thus identified subsequently appear in the product information or lead to regulatory actions, while an equivalent number of clinically important signals are missed.7 In the case of incretin-based therapies, the FDA’s automated algorithm Empirica, which is designed to signal AERS safety alerts, did not do so. In addition, one unrelated retrospective analysis of a large US medical and pharmacy claims database, involving 786 656 patients, did not show either exenatide or sitagliptin to be associated with an increased pancreatitis risk.8 The Butler group state that their analyses do not establish that pancreatitis, pancreatic cancer and thyroid cancer are caused by incretin-based therapy but suggest that appropriate studies are required to rule out these associations.5 Accurate incidence of pancreatitis will be difficult to obtain without adequately powered long-term prospective studies, but at least the product information for these drugs warns of this infrequent potential adverse effect. For the possible association between cancer and incretin-based therapy (and since other diabetes treatments including glargine insulin9 and pioglitazone10 might be cancer-promoting), it seems sensible to urgently develop coordinated links between diabetes prescription databases and cancer registries. Available Australian databases and links mean that government agencies could take a lead in this and provide independent, postmarketing observational data for the two incretin-based classes and individual drugs that are more robust than those generated by systems such as AERS. The history of diabetes treatment, from phenformin to rosiglitazone and even newer compounds, illustrates the continuing requirement for comprehensive preclinical and clinical safety and efficacy data before registration. Robust multifaceted postmarketing surveillance and data for important adverse effects, even if they are uncommon, are also necessary. Analyses such as those by the Butler group4 should not direct clinical decision making, but are part of the pharmacovigilance process that aims to provide regulatory authorities, clinicians and patients with the best evidence of the risks and benefits of individual blood glucose-lowering therapies.

Timothy M E Davis MB BS, DPhil, FRACP