Pharmacology

Parkinson disease (PD) is a multisystem neurodegenerative disorder that affects about 1% of the population over the age of 55 years and has mean age of onset of about 60 years. The Braak hypothesis proposes that the earliest pathological evidence of PD is found in the enteric nervous system, medulla and olfactory bulb, and only subsequently progresses (over years) to the substantia nigra and cortex. Non-motor symptoms, such as constipation, hyposmia and sleep disorders, may precede typical motor features of PD by several years. No treatment has been convincingly shown to slow PD progression (ie, a neuroprotective drug remains elusive). Symptomatic benefit from dopaminergic therapy is usually maintained throughout the course of the disease. The decision as to whether to commence treatment with either levodopa or a dopamine agonist needs to be individually tailored, but long-term outcomes appear to be equivalent. Advanced PD is complicated by the loss of non-dopaminergic neurones, resulting in symptoms that are largely unresponsive to dopaminergic therapy. Treatment with apomorphine, Duodopa or deep-brain stimulation surgery may be beneficial for selected patients with advanced PD. Non-motor symptoms, such as mood disorders, cognitive impairment, autonomic dysfunction and sleep disorders, are responsible for significant morbidity. Management often requires a multidisciplinary approach.

Michael W Hayes MB BS, MSc, FRACP · Victor S Fung MB BS(Hons), PhD, FRACP · Thomas E Kimber MB BS(Hons), PhD, FRACP · John D O’Sullivan MB BS, MD, FRACP

To the Editor: Over-the-counter herbal supplements to promote weight loss have become increasingly popular. Several of these products contain potentially hepatotoxic substances. We present the first reported Australian case of acute hepatotoxicity associated with the weight-loss product Hydroxycut Hardcore (Iovate Health Sciences, Blasdell, NY, USA). Hydroxycut contains various ingredients, including extracts of the herbs Garcinia cambogia and Camelia sinesis (green tea root), and the chromium salt, chromium polynicotinate. A recent review cites these three ingredients as possible causes of Hydroxycut hepatotoxicity.1 A 23-year-old, previously well, construction worker presented to his doctor with a 2-month history of lethargy and jaundice. Test results confirmed serum liver enzyme derangement, and the patient was advised to stop taking the weight-loss supplement. Results of repeat testing a week later showed worsening liver enzyme levels and he was referred to our hospital. On arrival, the patient denied any symptoms except moderate lethargy and icteric sclera. He was usually well with no relevant medical or surgical history. He weighed 83 kg. He denied drinking alcohol, using prescription or non-prescription drugs, or receiving a blood transfusion. He had had unprotected sexual intercourse 2–3 months earlier. A previously obtained tattoo was being extended by a reputable tattoo parlour. He had been using Hydroxycut Hardcore daily for 10 weeks (obtained from his local outlet of a global nutritional products retailer) in an attempt to lose weight and tone muscle. He claimed to have taken the dosage recommended by the manufacturer (six capsules daily); he was taking no other supplements. Physical examination revealed mild jaundice without other features of chronic liver disease or portal hypertension. However, in addition to abnormal blood levels of liver enzymes, bilirubin and iron, results of the patient’s liver biopsy showed severe acute hepatitis (Box). The abnormal test results were consistent with acute drug toxicity. The patient improved without specific treatment and was discharged 8 days after presentation, with near-normal serum liver enzyme levels. He was well on follow-up at 4 weeks. Two reports from the United States link Hydroxycut Hardcore to acute liver injury in otherwise well young males.2,3 The American Food and Drug Administration in May 2009 advised consumers to stop using the product, based on 23 reports linking it to serious injury, including one case of liver failure leading to death.4 In May 2009, Australia’s Therapeutic Goods Administration (TGA) issued a warning to consumers about the product, although noting that no adverse events had so far been reported in Australia.5 In view of this first reported Australian case of Hydroxycut hepatotoxicity, we advise medical practitioners and consumers in this country to be wary of the product, and call on the TGA to re-examine its continued availability. Investigation results for a 23-year-old man with liver dysfunction after using Hydroxycut Hardcore Investigation Result (reference range) Blood tests Aspartate aminotransferase (U/L) 1182 (12–36) Alanine aminotransferase (U/L) 2950 (5–40) Alkaline phosphatase (U/L) 121 (50–140) Bilirubin (µmol/L) 113 (3–18) Prothrombin time (seconds) 13 (11–15) Iron (µmol/L) 68 (11–30) Ferritin (µg/L) 1897 (30–400) Iron saturation (%) 99 (16–50) Paracetamol Not detected Hepatitis A, B, C Negative HIV Negative Autoantibodies Not detected Epstein–Barr virus, cytomegalovirus, toxoplasma, leptospira, coxiella Negative Haemochromatosis genetic testing No abnormality Other tests Abdominal ultrasound No abnormality Percutaneous liver biopsy Severe acute lobular hepatitis with areas of bridging necrosis; no bridging fibrosis or cirrhosis were seen Hepatic iron index 1.1 (< 2.0)

N Nudrat Rashid · Jason Grant

To the Editor: There has been considerable debate about whether selective serotonin reuptake inhibitors (SSRIs) can induce suicidal thoughts and behaviour. Using data from the 2007 National Survey of Mental Health and Wellbeing (NSMHWB),1,2 we examined the relationship between SSRI use and suicidality. The NSMHWB was a nationally representative household survey of 8841 individuals aged 16–85 years. Respondents were interviewed face-to-face and they provided information to assess whether they met International Classification of Diseases (10th revision) criteria for a lifetime affective disorder, and had symptoms in the previous year; had experienced suicidality in the previous year; and had used SSRIs (and/or other psychotropic medications) in the previous fortnight (and, if so, whether they had been taking them for < 1, 1–2, 3–5 or > 5 months). We restricted our analyses to the 555 individuals with symptoms of an affective disorder in the previous year, and examined their suicidality over that year. In our first analysis, we compared those who had used SSRIs in the previous 2 weeks and had been taking them for any duration (n = 109) with those who had not used SSRIs in the previous 2 weeks (n = 446 [respondents in this group were not asked whether they had taken SSRIs at any other time]). Secondly, we compared the subgroup who had been taking SSRIs for more than 5 months (n = 80) with the same non-user group we used in the first analysis. In both analyses, SSRI users were no more likely than non-users to have seriously thought about suicide, made a suicide plan or made a suicide attempt (Box). These findings are consistent with two recent systematic reviews of studies of SSRI use and attempted or completed suicide.3,4 Our study results add to their findings because we considered a fuller range of suicidal thoughts and behaviour. Although the reviews concurred with our findings with respect to adults, they found some evidence for SSRI use increasing the risk of suicidality among children and adolescents. The NSMHWB had limitations, including a potential for recall and misclassification bias, and its inability to account for all possible confounders. Importantly, its cross-sectional nature precluded determining whether an individual’s SSRI use preceded or followed his or her suicidality. By restricting our second analysis to SSRI users who had used SSRIs for more than 5 months, we increased the likelihood that SSRI use occurred first, but we could not determine this conclusively. This would have been a problem had we found an association, because we could not infer the direction of causality. However, with no association demonstrated causality becomes a moot point. Our findings support the contention that SSRI use in adults with affective disorders is not associated with suicide risk. Nonetheless, clinical judgement is required in prescribing SSRIs. Suicidality in the previous year among SSRI users and non-users All users* (n = 109) Non-users† (n = 446) χ2 P Long-term users‡ (n = 80) Non-users† (n = 446) χ2 P Seriously thought about suicide 23% 15% 3.20 0.27 20% 15% 0.83 0.58 Planned suicide 9% 5% 1.76 0.31 4% 5% 0.45 0.41 Attempted suicide 8% 3% 5.23 0.10 2% 3% 0.52 0.52 SSRI = selective serotonin reuptake inhibitor. * SSRI use in previous 2 weeks and for any duration. † No SSRI use in previous 2 weeks (use at other times unknown). ‡ SSRI use in previous 2 weeks and for > 5 months.

Jane E Pirkis · Philip M Burgess · Amy K Johnston · Harvey A Whiteford

Patients often have difficulty remembering drug names accurately. Two instances, from my time as a junior doctor in the United Kingdom in the 1990s, have stayed in my memory. The first occurred during a long and busy night on call. I was admitting an elderly woman and I was tired and fed up. I asked her about her medication and she gave me a handwritten list. Halfway down, in quavery capitals, was FROLIC ACID. It made my night. It also triggered a memory, from several years earlier, of another patient, encountered on a consultant’s ward round. She had been prescribed omeprazole, which was still under patent at the time and marketed under the trade name “Losec”. The consultant asked her if her indigestion had improved. “Oh yes, doctor”, she replied, “it’s been ever so much better since you gave me that Slosex tablet”. We had to stop the ward round for several minutes to compose ourselves. Even though more than 10 years have elapsed, the memory still makes me smile.

Paula H Johnson

To the Editor: A 40-year-old, first-time traveller from the northern hemisphere, on an expedition cruise to the Antarctic Peninsula, experienced thirst, polyuria, fatigue and worsening headaches for several days before embarking on a rough Drake Passage crossing in January 2009. Being well-to-do, fit, and taking no regular medication, he had decided on an adventurous holiday rather than his usual high-end European resort vacation. En route to the expedition vessel in Ushuaia, Argentina, the passenger hurriedly obtained a non-prescribed supply of “adventure travel” medication from a pharmacist acquaintance in the Middle East. To ensure its effectiveness, the passenger had complied with the pharmacist’s recommendation to begin taking the medication prophylactically several days before sailing. On the outbound crossing, the passenger consulted me, the ship’s physician, about the aforementioned unusual constellation of symptoms that he had been experiencing for several days, which were now compounded by severe motion sickness. On examination, he was not confused, had no meningeal irritation, loin percussion tenderness or fever, and was mildly dehydrated. It was soon revealed that he had been using acetazolamide for several days, as recommended. On reflection, I thought the container for acetazolamide that he showed me bore some resemblance to the containers used to store promethazine in the ship’s clinic (similarly sized bottles with similarly coloured lids and labels), with promethazine being well recognised as an effective treatment for motion and sea sickness.1 The symptoms that he had had for several days while taking the “adventure travel” medication before embarking on the expedition vessel are ascribable to acetazolamide.2 The passenger had been given medication on the now apparent misunderstanding that it was for ameliorating symptoms associated with a “high altitude” rather than “high latitude” destination (the bottle had been dispensed after a brief conversation in English — neither party’s first language). The pharmacist had misunderstood, believing that the passenger was travelling to a destination at a high altitude, for which acetazolamide chemoprophylaxis would have been appropriate to reduce risk of high-altitude sickness.3 Polar expedition cruising remains a relatively exclusive though environmentally sensitive pursuit. In the 2008 southern summer season, 34 000 passengers departed for an Antarctic destination by ship;4 most experienced some degree of motion sickness exacted by rough passages across the Drake Passage (the “Drake Shake” rather than the much prayed for and preferred smooth crossing across the “Drake Lake”) to the Antarctic Peninsula. Misunderstanding can occur when high latitude (the Antarctic and Arctic) is confused with high altitude, with the adventurer passenger at risk of being prescribed the wrong chemoprophylaxis. This risk may be accentuated in countries where travel medicine and pharmaceutical dispensing are not well regulated. On another note, in my opinion, it may be helpful to give medication containers and tablets a colour related to their purpose; perhaps bilious green for sea sickness and clear blue for altitude illness.

Joseph Y S Ting

General practitioners hold the key to expanding access to treatment Hepatitis C virus (HCV) is an important cause of morbidity and mortality in Australia. More than 200 000 people are estimated to be living with chronic HCV infection, with over 80% of these infections resulting from unsafe injecting drug use. About 10 000 new infections occur annually, although incidence is thought to be declining.1 Following primary HCV infection, persistent viraemia and chronic hepatitis occurs in 50%–80% of patients; after 20 years approximately 7% develop cirrhosis, and a small proportion of these patients develop hepatocellular carcinoma.1 Treatment of HCV infection has advanced over the past 10 years, leading to improved outcomes; the most effective current treatment is pegylated interferon combined with ribavirin. The aim of treatment is viral eradication, and treatment is deemed successful if a patient has a sustained virological response (SVR).2 The subsequent reduction in liver disease progression in patients who obtain an SVR3 suggests that the burden of advanced liver disease could be reduced if more patients received treatment. Treatment uptake has increased over the past 10 years, but has remained low. The removal of restrictions to prescribing for treatment — including the requirement for patients to have abnormal alanine aminotransferase levels or liver biopsy results (restrictions that were removed in 2005 and 2006, respectively) — has increased access,4 but the total number of individuals being treated for HCV infection in Australia remains low, at around 3500 individuals per year.5 Estimates vary, but recent modelling suggests that at least 6000, and closer to 10 000, people with chronic HCV infection need to be treated annually to reduce the burden of advanced liver disease in the future.1 While we acknowledge that not all people want or can have treatment for HCV infection, the number could be increased. HCV treatment can only be prescribed by certain medical practitioners or specialists, or at liver clinics, and cannot be prescribed by most general practitioners. Opportunities for treatment in tertiary hospitals and opioid pharmacotherapy clinic settings need to be expanded,6 but equally important is increasing GPs’ capacity to manage and treat patients living with HCV. GPs are usually the initial point of contact for patients with or at risk of HCV. It is imperative that GPs provide clear, accurate and up-to-date advice on HCV risk, prognosis and management. Several surveys in the past 10 years have reported that most GPs want further education about treatment, interpretation of test results, pre- and post-test counselling, and referral information.7,8 Many GPs’ knowledge of HCV is limited. A study undertaken in the period 2005–2006 found that, although GPs were aware of which patients are at risk of HCV (injecting drug users in particular), many underestimated the large number of Australians infected with HCV.9 A 2002 study reported that 39% of surveyed GPs mistakenly believed that positive results from HCV serological testing, as opposed to positive results from HCV RNA testing, differentiated current and resolved infection.7 An anti-HCV antibody test only provides information on whether a patient has ever been exposed to HCV — a positive result does not necessarily indicate an ongoing infection. An HCV RNA test is required to determine whether a patient has an ongoing infection or has spontaneously cleared their infection. GPs’ awareness of HCV treatment was also limited. The 2005–2006 study showed that only 42% of surveyed GPs were aware of the effectiveness of current HCV treatment, and only 28% were aware of the eligibility criteria for access to subsidised treatment.9 The 2002 study showed that 52% of GPs were not aware that pegylated interferon–ribavirin combination therapy was the most effective HCV treatment.7 Other studies have shown that fewer than 52% of people living with HCV in Australia had ever been referred to a specialist liver clinic10,11 despite the general acceptance that this should occur for the vast majority of patients with HCV. In addition, many GPs have reported being uncertain about when to refer patients to hepatitis specialists.9 Ongoing education is vital if GPs are to remain up to date on the management of HCV infection. A range of options are required to meet the needs of different GPs and their patients. One option is training GPs to fully manage their own patients, including training to become accredited prescribers of pegylated interferon and ribavirin under the federal government’s Section 100 (s100) Highly Specialised Drugs Program. Currently, the availability of such training is limited and varies between states and territories. A shared care model is a second option. Some GPs could be actively involved in the management and follow-up of patients without being an s100 prescriber. This model could suit GPs who manage only a few patients with HCV infection, as well as nurse practitioners and GPs in rural and regional areas. A specific training program could be developed to provide GPs and nurse practitioners with the necessary knowledge and skills, particularly for managing the side effects of HCV treatment. A third option should be provided to potentially the largest group of GPs — those who have patients at risk of or infected with HCV, but who do not want to be directly involved in HCV management. Through ongoing and regularly updated training programs, these GPs need to stay up to date on who is at risk of HCV infection, what tests should be ordered to diagnose and monitor HCV infection, and when patients should be referred to a specialist. In addition, all GPs need to have a broad understanding of what HCV treatments are available, that current and recent injecting drug users are eligible for HCV treatment, and that a liver biopsy is no longer required for a patient to have access to treatment (Box). Encouraging GPs to undertake HCV training in a setting of competing education priorities is a major challenge. Perhaps the first step should be to highlight that HCV occurs in about 1% of the population and that treatment options and outcomes for their patients have improved considerably during the past 5 years and are likely to continue to do so. Hepatitis C virus (HCV): what general practitioners should know HCV is common — more than 200 000 Australians have ongoing infection. Approximately 25% of people infected with HCV spontaneously clear their infection.12 An anti-HCV antibody test only detects whether a patient has ever been exposed to HCV — it does not detect ongoing infection. An HCV RNA test is required to determine whether a patient has an ongoing infection or has spontaneously cleared their infection. HCV can be successfully treated with pegylated interferon combined with ribavirin. The most common HCV genotypes in Australia are genotype 1 and genotype 3.1 Genotype 1 HCV infection usually requires 48 weeks of treatment, and genotype 3 usually requires 24 weeks of treatment; the chance of successfully clearing the virus with such treatment is approximately 45% and 75%, respectively.13 Treatment is deemed successful if a patient has a sustained virological response — defined as having a negative HCV RNA test result 24 weeks after completion of treatment. After successful treatment, patients will be HCV RNA negative but will remain anti-HCV antibody-positive in the vast majority of cases. Subsidised treatment is available to people older than 18 years who are anti-HCV antibody-positive, have detectable serum HCV RNA levels, have compensated liver disease, and have not had prior treatment with pegylated interferon or interferon alfa.

Margaret E Hellard FRACP, PhD, FAFPHM · Yung-Hsuan J Wang MB BS, FRACGP, MAppEpid

To the Editor: The recent article by Lowthian and colleagues raises some important concerns regarding current management of warfarin therapy in Australia, especially the provision of quality warfarin education.1 While the study focused on the uncertainty surrounding who is responsible for this task, additional barriers to providing warfarin education include limited access to suitable resources and a tendency to rely on a single verbal counselling session and/or the supply of written material, often just before discharge from hospital.2 As Lowthian et al note, it is plausible that warfarin education was provided to the patients interviewed; it may simply have been inadequate to meet their needs or delivered at the wrong time or place. It is not always feasible for health care providers to reliably provide the necessary education in busy health care settings (eg, general practitioners when prescribing warfarin, pharmacists when supplying it). The authors note a potential role for practice nurses in providing this education; we would also like to highlight the role of accredited pharmacists, who can visit patients in their homes and provide targeted medication-related education. An annual Home Medicines Review can be provided for patients taking high-risk medications such as warfarin.3 Under the Fourth Community Pharmacy Agreement Research and Development Program, the Pharmacy Guild of Australia has funded two projects that are attempting to meet the education needs of patients taking warfarin. One project is trialling a comprehensive postdischarge service involving a series of follow-up home visits by trained accredited pharmacists, to provide not only warfarin education but also point-of-care international normalised ratio monitoring, in liaison with the patients’ GPs. The other project is piloting a process whereby community pharmacists can identify potential candidates for patient self-monitoring of warfarin and, with GP collaboration, organise suitable training, with ongoing support from the pharmacist and GP. Patient self-monitoring, although not widely practised in Australia, has been shown to provide the best clinical outcomes for suitable candidates.4 An important component of these two projects is a website, launched in late 2008, containing a range of free, downloadable educational resources for both consumers taking warfarin and health care professionals responsible for its management (http://www.anticoagulation.com.au). Education is crucial in achieving optimal health outcomes for patients taking warfarin, and health care professionals should cooperate to ensure their patients are well educated. This should involve regular reinforcement of consistent messages, and can also involve better use of existing services and educational tools.

Luke R E Bereznicki · Leanne Stafford · Ella C Jeffrey · Gregory M Peterson · Shane L Jackson

In reply: Bereznicki and colleagues have reinforced the importance of patient education in optimising warfarin safety, while highlighting the need for role clarification in its provision. We applaud the Pharmacy Guild of Australia’s sponsorship of research projects trialling different models of service delivery, such as the coordination of postdischarge warfarin home care by pharmacists and support of patient self-monitoring programs, where appropriate. The success of such care models will be enhanced by a collaborative partnership between the patient and all members of the warfarin care team.1 In addition, appraisal of patient suitability for programs such as patient self-monitoring requires systematic and regular evaluation of cognitive function, compliance and health literacy, to reduce the likelihood of adverse events.2-4 Likewise, ongoing education with resources tailored to individual patients’ capabilities will optimise patient safety.5

Judy A Lowthian · Basia O Diug · Sue M Evans · Ellen L Maxwell · Alison M Street · Leon Piterman · John J McNeil

To the Editor: Lowthian and colleagues ask who is responsible for the care of patients treated with warfarin therapy.1 In Melbourne, it seems that this devolves mainly upon the pathology laboratory, whereas in other states, general practitioners manage care for their own patients, in my own experience. Where management of warfarin dosing, based on the international normalised ratio (INR) result, is performed by the laboratory, this is done as a courtesy to GPs. This practice possibly evolved from competition between private laboratories and, as such, may have been intended to induce other pathology requests to the service provider. Larger metropolitan private pathology services may have sufficient pathologists with haematology training to provide warfarin dosing to patients, but this may not always apply in smaller laboratories. In some laboratories, warfarin dosing may be provided to patients by scientific staff. Although warfarin therapy can sometimes be challenging, its difficulties are not usually insurmountable. Problems for pathologists arise because they are expected to give a warfarin dose by telephone to a patient they do not know and have never seen. The patient’s phone number may be not supplied or incomplete, and the call may not be answered. If answered, a brief history of previous INR results, dosages and test intervals may or may not be elicited from a person who may have poor English, who may be the patient, a relative, friend or neighbour; or a message may have to be left. If the message is received, it may not be acted on, depending on memory, understanding or level of compliance. If the message is not received, the patient and the patient’s GP may be unreasonably irate, even though multiple attempts to contact the patient may have been made. It is not hard to understand why some GPs prefer to pass this often frustrating and time-consuming aspect of treatment to pathologists — who may also be pressed for time. Problems are further compounded if warfarin dosing devolves to pathology laboratory scientists, which may be required by their employer. Scientists would be, in effect, performing drug dosing without medical training or medical registration and may be exposing themselves to litigation risk, without carrying medical indemnity. In other Australian states, it seems that GPs do provide treatment and dosing of warfarin for their own patients. In my view, this is the safest and most satisfactory outcome for patients, pathologists and scientists. With the projected advent of point-of-care testing with reliable INR results2 and new anticoagulant alternatives1 that would enable easier management of anticoagulant therapy by GPs, this whole issue could potentially be resolved.

John C Roberts

The relationship between drug dose and clinical outcome has not been established for many medications used to treat chronic disease. Evidence is emerging that chronic diseases can be treated effectively with low doses. Adverse drug reactions account for significant morbidity and mortality and are generally dose related. Optimal drug dose — the best balance of benefit and risk — varies between individuals and may change over time. When treating chronic disease it is important to establish and maintain the optimal dose for each patient by close clinical monitoring.

Simon B Dimmitt MB BS, BMedSc(Hons), FRACP · Hans G Stampfer MB BS, FRANZCP

To the Editor: We wish to call for the removal of scheduling and legislative barriers in Australia that prevent easy access to naloxone for administration by peers to people suffering from a heroin overdose. Use of illicit opioids, typically heroin, remains the major cause of illicit drug-related mortality in this country, with at least one accidental opioid overdose currently occurring each day.1 Although population levels have not reached those seen during the peak in the late 1990s, geographically localised and transient increases in overdoses are evident.2 Death from heroin overdose typically occurs some time after use. In many cases, other people are present, and there is considerable scope for intervention to prevent death.3 Yet, in more than 70% of cases of fatal overdose, there is no intervention, and, where action is taken, calling an ambulance is seldom the first strategy, resulting in even greater risk of death.3 Opioid substitution treatment (with methadone or buprenorphine) is the mainstay of overdose prevention in Australia. Other interventions implemented here include outreach services and education for injecting drug users about the risks of overdose and how to respond to it.3 In 2000, Lenton and Hargreaves summarised the evidence for distributing the opioid antagonist naloxone for administration by peers to prevent deaths from heroin overdose. They concluded that an Australian research trial was needed.4 However, in 2001, the Australian heroin market was disrupted, heroin use and overdoses declined, and the trial did not proceed. Since then, emerging international evidence has demonstrated that injecting drug-using peers, family members and outreach workers can successfully administer naloxone to reverse heroin overdose — with few, if any, adverse effects.5 By December 2008 in the United States, 52 programs distributing naloxone for administration by peers were operating in 17 states, with over 1000 documented overdose reversals resulting from these programs.5 Most concerns about the intervention — such as the possibility of unsafe naloxone administration, reintoxication or more risky drug use — appear to have been unfounded, and naloxone administration by trained peers has been shown to be a remarkably safe intervention.5 In our view, the international evidence clearly indicates that increased naloxone availability will prevent many cases of fatal overdose, that conducting a trial in Australia is now unnecessary, and that naloxone should be made available without delay to be administered by peers in cases of opioid overdose. Careful monitoring and evaluation should be a part of this process. We call on all Australian states and territories to immediately enact Good Samaritan legislation to legally protect laypeople using naloxone in emergency situations. Naloxone should be reclassified from a Schedule 4 (S4) drug (available only on prescription) to S3 or S2 to make it available over the counter. As naloxone is no longer under patent,5 there may be little financial incentive for a drug company to pursue rescheduling. However, it could be rescheduled in Australia under provisions that allow state health authorities, professional associations or the National Drugs and Poisons Schedule Committee to initiate the process. Heroin overdose deaths are preventable. We need to take action now to enable peer-led intervention to reduce this serious outcome.

Simon R Lenton · Paul M Dietze · Louisa Degenhardt · Shane Darke · Tony G Butler

To the Editor: We thank Page and colleagues for their important article considering the sociodemographic correlates of antidepressant utilisation in Australia.1 We note that fewer than 15% of the young people in the study were prescribed fluoxetine, and almost 40% were prescribed sertraline. These rates of antidepressant use contrast with the available evidence on treating young people diagnosed with depression. A recent review examining the effectiveness of selective serotonin reuptake inhibitors (SSRIs) for depression among children and adolescents demonstrated that fluoxetine is the only SSRI with at least some evidence for effectiveness.2 Current clinical guidelines recommend that a young person diagnosed with a major depressive disorder who is to be prescribed an antidepressant should be given fluoxetine in the first instance.3,4 Reasons for the apparent lack of concordance with the guidelines might include treatment of disorders other than depression, or prescriptions for those who have already had an unsuccessful trial of fluoxetine. It would thus be of great interest to learn what proportion of young people are prescribed an antidepressant other than fluoxetine, and what proportion of young people prescribed an antidepressant are concurrently undergoing guideline-concordant psychological treatments, such as cognitive behaviour therapy. The data presented by Page et al draw attention to challenges faced by doctors providing treatment for young people experiencing depression, which include a lack of good evidence about the effectiveness of newer antidepressants for this age group. However, there is an opportunity to support better use of evidence in decisions made about treatment options for young people. The provision of high-quality, evidence-based information for patients and their carers to enable informed decisions is essential, and shared decision making offers a way to enable this.5 By improving the knowledge transfer between doctor and patient, antidepressant prescription can be more judicious.

Magenta B Simmons · Michaela R Willet · Sarah E Hetrick

Clinical record A 66-year-old man with a history of ischaemic heart disease, hypertension and hypercholesterolaemia presented to a rural centre with a 2-week history of malaise, jaundice, right upper quadrant pain and daily rigors. Liver function tests revealed a raised bilirubin level (100 μmol/L; reference range [RR], 1–20 μmol/L) and abnormal levels of liver enzymes (alkaline phosphatase, 357 U/L [RR, 40–135 U/L]; γ-glutamyltransferase [GGT], 687 U/L [RR, 15–73 U/L]; alanine aminotransferase, 344 U/L [RR, 21–72 U/L]; aspartate aminotransferase, 216 U/L [RR, 17–59 U/L]). Results of serology tests for hepatitis B and C were negative. Full blood examination revealed a normal level of total white blood cells and mild thrombocytopenia (platelet count, 124 × 109/L [RR, 150–400 × 109/L]). Results of a computed tomography scan of the abdomen and pelvis were unremarkable. A presumptive diagnosis of acute cholangitis was made, and intravenous ceftriaxone (1 g daily) and metronidazole (500 mg every 8 h) therapy was initiated. The patient had undergone a percutaneous coronary intervention with bare-metal stent placement about 2 months earlier, and had been prescribed clopidogrel (an antiplatelet agent; 75 mg daily) at this time. His other regular medications included aspirin, irbesartan–hydrochlorothiazide, simvastatin and omeprazole. Clopidogrel was ceased on the day of admission to the rural centre because of concern about increased bleeding risk if potential urgent endoscopic or surgical intervention was required. After 24 hours, the patient’s condition had improved markedly, and he was discharged 7 days after admission. Clopidogrel was restarted on the day of discharge from the rural centre. His symptoms returned within 24 hours of discharge, upon which he presented to our tertiary institution. The patient was tachycardic (pulse rate, 114 beats/min), hypotensive (blood pressure, 90/60 mmHg), febrile (temperature, 39.6°C) and jaundiced. The remainder of his physical examination was unremarkable. Results of liver function tests at this time were markedly abnormal (Figure, A). His serum creatinine level was elevated (167 μmol/L; RR, 60–120 μmol/L). His international normalised ratio was 1.3 (RR, 0.8–1.2), with an activated partial thromboplastin time of 35 s (RR, 26–40 s). Abdominal ultrasound and magnetic resonance cholangiopancreatography showed no evidence of gallstones, biliary tree dilatation or choledocholithiasis. He was prescribed intravenous ceftriaxone (1 g daily), ampicillin (1 g every 6 h) and metronidazole (500 mg every 8 h). Clopidogrel was ceased on the day of admission, pending surgical review. His symptoms abated and liver function improved over the next 3 days. Clopidogrel was recommenced on Day 4 of admission. On Day 5 he had a fever of 40°C with rigors, and his liver function deteriorated significantly (Figure, A). Clopidogrel was withheld again in anticipation of surgery, and his antibiotic therapy was changed to intravenous ticarcillin–clavulanate (3 g/0.1 g every 6 h). His condition gradually improved over the next 5 days. Clopidogrel was restarted on Day 10. His condition deteriorated again within 24 hours, with a fever to 39.0°C and rise in GGT to 2205 U/L. His antibiotic therapy was changed to intravenous meropenem (500 mg every 8 h) and endoscopic retrograde cholangiopancreatography (ERCP) was scheduled, prior to which clopidogrel was ceased on Day 11. He suffered ongoing rigors between Days 10 and 17. On Day 17, ERCP revealed a normal intrahepatic and extrahepatic biliary tree. His symptoms and liver function abnormalities persisted; on Day 25, a transjugular liver biopsy revealed scattered poorly formed granulomas within the portal tracts and the hepatic lobules (Figure, B). The granulomas did not involve the interlobular bile ducts. Neutrophils were seen in the bile ductule epithelium, in keeping with acute cholangiolitis (Figure, C). The liver histopathology was initially thought to be consistent with primary biliary cirrhosis, a diagnosis that did not correlate with the clinical presentation. A review of the patient’s medication chart revealed that he had received clopidogrel intermittently since Day 10, despite the treating medical team’s request that it be ceased. Given this new information, the liver histopathology was reviewed and clopidogrel-induced granulomatous hepatitis was diagnosed. Clopidogrel was ceased permanently and he was discharged. At follow-up about 2 months later, his liver function had completely normalised and his symptoms had not recurred. Liver function test results throughout the patient’s tertiary hospital admission (arrows indicate prescribed and documented clopidogrel administration). Section of transjugular liver biopsy specimen (Picro-Mallory trichrome stain, magnification x 100) showing granuloma formation (arrow). Section of transjugular liver biopsy specimen (haematoxylin–eosin stain, magnification x 400) showing neutrophils (arrow) surrounding small bile ducts in the portal tract. The more common adverse effects of clopidogrel include gastrointestinal disturbance, rash and bleeding.1 However, several cases of clopidogrel-induced hepatic injury have been described. In Australia, 15 cases of hepatic injury associated with clopidogrel have been reported to the Adverse Drug Reactions Advisory Committee since the year 2000. Given the widespread use of clopidogrel, this adverse effect appears to be rare. The liver function test derangement associated with clopidogrel use has included hepatocellular2 and mixed hepatocellular and cholestatic3-6 patterns. In our patient, the diagnosis of clopidogrel-induced granulomatous hepatitis was accompanied by the clinical features of the systemic inflammatory response syndrome. The direct temporal relationship between the administration of clopidogrel and the development of symptoms, signs and liver function test abnormalities on three separate occasions during his admission was highly suggestive of causality. In addition, clinical improvement was noted each time clopidogrel was ceased. To our knowledge, this is the second time that the histopathology within the liver of a patient with clopidogrel-induced hepatic injury has been documented; the first was reported in 2006.6 The relatively mild hepatocyte death in contrast to the marked cholangiolitis correlated with the pattern of liver function test derangement. The presence of poorly formed granulomas within the patient’s hepatic lobules was highly suggestive of a drug-related aetiology. The other main differential diagnoses of granulomas in the liver (sarcoidosis, tuberculosis and primary biliary cirrhosis) have different histological characteristics, and are inconsistent with our patient’s clinical presentation. It appears from the emerging number of case reports that clopidogrel-induced systemic inflammatory response syndrome and hepatic injury is a real clinical entity that may be more common than previously suspected. This case demonstrates the importance of considering the possibility of an adverse drug reaction in the differential diagnosis. It also illustrates the potential difficulty and delay in diagnosis that can be encountered when the symptoms and signs of an adverse drug reaction mimic other, more common clinical entities (in this case, cholangitis). Given the increasing evidence for the effectiveness of clopidogrel in a wide variety of cardiovascular disease states, it is important that clinicians are aware of the possibility of this serious adverse effect.

Piers A Blombery BSc(Biomed), MB BS(Hons) · Prudence A Russell MB BS(Hons), FRCPA · John R Daffy MB BS, FRACP

To the Editor: I read with interest the recent case report by Lim and colleagues on Chromobacterium violaceum endocarditis.1 References to the article do not include a report of a similar case published 20 years ago, also in the MJA.2 Perhaps reference searches can be enhanced — otherwise, identifying such similar cases falls to recollected experience (I was the initial treating doctor in the 1988 case) or an improbably capacious memory in the author or reader. What saved the patient in February 19882 were two new antibiotics that were not generally available at the time but were held at Royal Brisbane Hospital — imipenem and ciprofloxacin. Imipenem is a β-lactam antibiotic of the carbapenem subgroup, derived from Streptomyces cattleya, that was developed in 1985.3 Imipenem and other carbapenems including meropenem, as used to treat the patient in the article by Lim et al,1 are now available in Australia but restricted to intravenous use in hospitals. The oral antibiotic ciprofloxacin became generally available with a Pharmaceutical Benefits Scheme authority benefit soon after the 1988 case. I recall a discussion at that time with the late Dr Richard Kemp (then Director of Infectious Diseases at Royal Brisbane Hospital), who told me that C. violaceum infection in humans had been described in the world medical literature only about 10 times, and there had been no eventual survivors. From a general practitioner’s perspective, there was a lesson to be learned from the case: take the time to swab an abscess. The one in question was unusual — volcanic in appearance, indurated and not productive of pus on incision.

Richard N Pearson

New guidelines and a multidisciplinary approach have the potential to help patients in need while minimising inappropriate use of opioids With an estimated community prevalence of about 20%, chronic non-malignant pain represents a significant but neglected and often poorly managed problem in Australia. In 2007, the cost of chronic pain to the community was estimated at $34 billion, which included burden of disease and productivity costs, each accounting for one-third of the total, and one-fifth ($7 billion) attributed to health system costs.1 Its prevalence and associated costs will rise as the population ages. The causes of chronic non-malignant pain are many, including rheumatic disorders, injuries and musculoskeletal degenerative disorders, and vary greatly with age, sex and other demographic characteristics. Many doctors currently approach such pain from a narrow biomedical perspective. This too often defaults to the use of opioids under pressures including time constraints, patient demands, and limited access to supports such as pain clinics and physical therapies. The introduction of sustained-release prescription opioids in Australia two decades ago promised a new era in chronic pain management. These agents were preferred because they offered prolonged analgesia with a potentially lower risk of dependence and drug-seeking behaviour. Previously, short-acting opioids had often been prescribed, causing problems when peak effects of analgesia and euphoria alternated frequently with troughs marked by pain and opioid withdrawal. This created conditions conducive to dose escalation and the eventual development of dependence. The shining promise of the sustained-release prescription opioids has been dulled by two main problems. First, the long-term effectiveness and net benefit of opioids in the management of patients with chronic non-malignant pain remain uncertain, reflecting the biopsychosocial complexity of the underlying conditions and the difficulties of performing clinical trials in such heterogeneous populations.2 Second, increasing consumption of sustained-release prescription opioids has been accompanied by some disturbing developments, first reported from the United States. In 2000, drug overdose deaths from prescription opioids, especially from unsanctioned use, began to outnumber deaths from heroin and cocaine.3 Between 1997 and 2007, admissions for treatment of “abuse” rose by 456% for opioid analgesics and 5% for heroin.4 Australia may be starting to follow these US trends, with substantial increases in consumption of oral prescription opioids since 1990,5 and reports of diversion, injection and related harms.6 However, the extent of inappropriate opioid prescribing and of unsanctioned opioid use in Australia cannot currently be determined. Our information systems are not standardised across jurisdictions, are unable to capture all prescriptions (both private and funded by the Pharmaceutical Benefits Scheme), and are not available to intending prescribers and pharmacists. Three overlapping groups — patients with chronic non-malignant pain, patients with malignant pain, and illicit users (of heroin or prescription opioids) — form a potential common market for opioids, with flow-on effects if any group is inadequately managed. The idea of a continuum between opioid use for pain management and addiction underpins the idea of “universal precautions in pain medicine”.7 Inappropriate prescription can lead to problematic use and opioid dependence. The heroin shortage that started in 2000 in Australia was followed by increasing injection of prescription opioids, especially in rural areas and jurisdictions where heroin was scarcest.8 Increasing demand for prescription opioids may arise where there is unmet demand for opioid substitution treatment with methadone or buprenorphine. People on low incomes may be tempted to request and on-sell prescription drugs to the black market as demand and prices increase. These considerations underpin the desirability of a broader biopsychosocial framework for the assessment of patients with chronic non-malignant pain, and a greater role for non-pharmacological interventions. Such interventions are scarce and underfunded in primary care. Australia has the most developed training program for pain medicine worldwide, but there are too few specialists and there is great demand for pain clinics. In an effort to bring these complex issues to the fore, the Royal Australasian College of Physicians (RACP) has released a prescription opioid policy;9 the Box contains a summary of its recommendations. Reflecting the complex nature of the subject, the report was prepared by an interdisciplinary group, including representatives from the RACP, the Royal Australian College of General Practitioners, the Royal Australian and New Zealand College of Psychiatrists and the Faculty of Pain Medicine of the Australian and New Zealand College of Anaesthetists. The challenge is to provide a better balance between two, sometimes competing, objectives — encouraging more appropriate opioid prescription for patients with chronic non-malignant pain while reducing unsanctioned use of opioids, whether by patients or illicit users. No single health discipline can overcome these complex problems, but a truly multidisciplinary approach has the potential to achieve great advances. The current situation not only results in frustration for patients and families, but also undermines the good standing of the medical profession. The present unhappy cocktail includes patients with chronic, complex painful conditions; doctors who lack succinct uniform guidelines, real-time prescription monitoring information and ready access to relevant specialist advice; and a setting where authorities must minimise diversion of prescription opioids. In 2008, unmet demand for opioid substitution treatment was estimated to exceed the 39 000 patients then in such programs.10 Better tailoring of such treatment to also meet the needs of people dependent on pharmaceutical opioids, many of whom have never previously sought help, may attract and retain more patients in effective treatment. This would most likely decrease the demand for black-market prescription opioids. Australia has a unique opportunity to improve management of patients with chronic non-malignant pain and people who become dependent on opioids; to reduce inappropriate prescribing of opioids; and to avoid the problems that have bedevilled the US. The most important step required is establishing a group with sufficient authority to achieve wide consensus on an action plan and then implement and coordinate national change across jurisdictions, professions and disciplines (especially general practitioners and pharmacists). As most management of chronic non-malignant pain occurs in general practice, little will be achieved unless and until GPs are provided with more support and better linkages to critical specialties. Summary of recommendations of the Royal Australasian College of Physicians report9 1. Establish a national expert advisory group to develop a coordinated approach to implementing the recommendations below, to improve management of chronic non-malignant pain and reduce problematic use of pharmaceutical opioids. 2. Develop guidelines for management of chronic non-malignant pain appropriate for and accepted by general practitioners, integrating non-pharmacological elements of treatment with pharmacological approaches within a biopsychosocial framework, and providing widely accepted standards for audit and feedback. 3. Enhance clinical practice, with improved support for GPs and better linkages to relevant specialties, especially pain medicine and addiction medicine. 4. Improve information systems, with one national, web-based system that includes private and Pharmaceutical Benefits Scheme prescriptions and provides information for prescribers and pharmacists in real time. 5. Standardise regulation and control across jurisdictions. 6. Minimise unmet demand for opioid substitution therapy, and revise it for people dependent on pharmaceutical opioids to decrease the demand for black-market prescription opioids. 7. Improve integration of College training programs in the fields of pain medicine, addiction medicine, psychiatry and general practice. 8. Increase applied research to reduce gaps in knowledge and improve health service delivery.

Alex D Wodak FRACP, FAChAM, FAFPHM · Milton L Cohen MD, FRACP, FFPMANZCA · Malcolm D H Dobbin PhD, FAFPHM, MPH · Richard A Hallinan BMed, FAChAM · Mary Osborn MPubHlth

Objective: To examine the effect of the level of patient copayment on the rate of purchase of inhaled corticosteroids (ICS) by patients with obstructive lung disease.Design and setting: Cross-sectional study of records of all prescriptions for ICS dispensed to general and concessional beneficiaries aged 15 years or over in the period January 2003 to December 2006. Data were obtained from the Pharmaceutical Benefits Scheme, which subsidises medication costs for all Australians.Main outcome measures: The number of prescriptions for ICS dispensed to government concession card holders compared with the number dispensed to general beneficiaries, expressed as a rate ratio.Results: ICS prescriptions were dispensed to over 1.6 million people during the study period. Concession card holders were dispensed ICS prescriptions at a higher rate than general beneficiaries, both overall (43.7 v 9.1 ICS prescriptions per 100 person-years) and in all population subgroups. After adjusting for age, sex, remoteness category and socioeconomic status, people holding a concession card were dispensed over 2.5 times the number of ICS prescriptions (alone or in combination with a long-acting β2-agonist) compared with general beneficiaries. Similar patterns were seen after adjusting for differences between the two groups in the prevalence of obstructive lung disease.Conclusions: As the patient copayment for general beneficiaries is over six times higher than for concession card holders, our findings imply that cost is a barrier to the purchase of ICS prescriptions for obstructive lung disease, independent of socioeconomic status.

Rosario D Ampon BSc, MAppStat · Helen K Reddel MB BS, FRACP, PhD · Patricia K Correll BN, MPH, GradDipAppEpi · Leanne M Poulos BMedSc(Hons), MPH(Hons) · Guy B Marks PhD, FRACP, FAFPHM

A 49-year-old man presented with verapamil toxicity complicated by hypotension and a junctional rhythm, in the context of deliberate self-poisoning with multiple drugs. The patient’s hypotension normalised following the early use of high-dose insulin euglycaemic therapy (HIET), without the need for additional vasopressors; it recurred when HIET was prematurely stopped, and again stabilised when HIET was recommenced. Consideration should be given to the early use of HIET in treating severe calcium channel blocker toxicity, rather than as a last resort after other therapies have failed. (MJA 2009; 191: 350-352) Clinical recordA 49-year-old man presented to a peripheral hospital emergency department 1–1.5 h after deliberately ingesting multiple medications: verapamil (unknown amount), controlled-release morphine sulfate (20 × 30 mg), diazepam (50 × 5 mg) and tramadol (15 × 200 mg). He was a smoker with a history of depression, ethanol misuse, chronic back pain, hypertension and a previous instance of deliberate self-poisoning with multiple drugs. At initial assessment, the patient’s vital signs were: temperature, 36.8°C; pulse, 84 beats/min; respiratory rate, 19 breaths/min; blood pressure (BP), 115/80 mmHg; oxygen saturation, 95% on room air; and Glasgow Coma Scale score, 14/15. He was drowsy, disorientated to time, and had 2 mm pupils that were equal and reactive. He had ataxia, dysarthria and was generally weak. His breath ethanol concentration was 0.172 mg%. Thirty minutes later, the patient was hypotensive (BP, 85/45 mmHg; pulse, 72 beats/min). He was treated with oxygen, 2 L intravenous (IV) 0.9% saline, a naloxone IV infusion (400 μg/h), and 10 mL IV 10% calcium gluconate. He was transferred to a tertiary referral centre and, on arrival (at 2.25 h after initial presentation), his BP was 85/45 mmHg, pulse was 64 beats/min, and an electrocardiogram (ECG) showed a junctional rhythm. Rapid sequence intubation (with propofol 40 mg + 20 mg IV and suxamethonium 100 mg IV) was performed for airway protection and ongoing management of haemodynamic instability, while metaraminol IV boluses (total, 0.7 mg) were administered. Activated charcoal (50 g) was given, and sedation was maintained with a propofol infusion. The patient remained hypotensive (BP, 75/45 mmHg; pulse, 56 beats/min) after intubation, so high-dose insulin euglycaemic therapy (HIET) was commenced at 3.5 hours after presentation. He was given dextrose (50 mL 50% glucose) and a 30 IU short-acting insulin IV bolus (~ 0.5 IU/kg), followed by a further bolus of 50 mL 50% glucose and a short-acting insulin IV infusion (30 IU/h) (Box 1). His BP improved to 110/70 mmHg at 4 hours, with a pulse of 82 beats/min and sinus rhythm on ECG, and he remained stable during transfer to the intensive care unit (ICU). The insulin infusion was abruptly stopped 5.5 hours after presentation, on arrival in the ICU. The patient’s hypotension subsequently recurred (systolic BP, 70 mmHg; pulse, 75 beats/min), prompting administration of 500 mL IV Gelofusine (a colloidal plasma volume substitute; B. Braun, Sydney, NSW) and commencement of an adrenaline IV infusion (20 μg/min). The insulin infusion (30 IU/h) was restarted at 8.5 hours, and his BP again stabilised (Box 1). The propofol IV infusion was gradually increased from 50 mg/h to 150 mg/h between 5.5 hours and 11.5 hours after presentation, and a noradrenaline IV infusion was commenced at 9.5 hours to maintain normotension. At 15.5 hours, pulmonary artery catheter measurements showed a high cardiac index (5.1 L/min/m2; reference range [RR], 2.5–4.0 L/min/m2) and a low systemic vascular resistance index (1047 dynes·s/cm5/m2; RR, 1900–2400 dynes·s/cm5/m2); the patient’s pulse was 85 beats/min and BP was 140/60 mmHg. HIET was continued and the patient remained haemodynamically stable. Adrenaline and noradrenaline were weaned off (at 17.5 hours and 23.5 hours, respectively), despite the propofol infusion rate being increased to 500 mg/h at 18.5 hours. Once sedation was withdrawn, the patient was extubated at 26.5 hours. Insulin was weaned over 5 h and discontinued at 30.5 hours; dextrose was stopped 1 h later. The patient was transferred to the observation ward and discharged well later that day, after psychiatric clearance. During treatment with HIET, the patient’s blood glucose levels were checked hourly and ranged from 6.6 mmol/L to 13.2 mmol/L (RR, 3.5–5.5 mmol/L). He received about 25 g/h of dextrose (mostly as 50% dextrose infusions). Potassium and magnesium levels were also serially monitored; the minimum potassium level was 2.7 mmol/L (RR, 3.5–5.0 mmol/L) at 8.75 hours, and the magnesium level troughed at 0.5 mmol/L (RR, 0.75–1.05 mmol/L) at 15 hours. These were corrected with a total of 200 mmol of potassium chloride and 20 mmol magnesium chloride. DiscussionHIET is an increasingly accepted therapy for calcium channel blocker (CCB) toxicity, but reports of its use are limited and it remains controversial. Indeed, the scarcity of severe CCB poisoning cases means that a randomised controlled trial of HIET may not be feasible.1 Treating clinicians who seek advice from clinical toxicologists are often hesitant about the high doses required and the potential for adverse effects. Such hesitancy is potentially harmful, as a hypotensive patient with a CCB overdose who otherwise appears well is at risk of abrupt lethal cardiovascular collapse.1 HIET is traditionally recommended after other therapies have failed.2,3 This case report aims to raise awareness of HIET for the treatment of CCB toxicity and supports its early use, rather than as a last resort.4 Verapamil binds the alpha-1 subunit of L-type calcium channels, preventing the intracellular influx of calcium.5 These channels are functionally important in cardiac myocytes, vascular smooth muscle cells, and islet beta cells.5 Verapamil’s cardiac toxicity results from excessive negative inotropy, negative chronotropy and negative dromotropy, characterised by myocardial depression, sinus bradycardia, and atrioventricular node blockade.4 Vascular smooth muscle tone is impaired, resulting in decreased afterload, systemic hypotension, and coronary vasodilation.5 Less well known are the metabolic effects of CCBs such as verapamil. Under the stress of the drug-induced shock state, the cardiac myocytes shift from using free fatty acids, their favoured “resting state” energy substrate, to carbohydrates.3,4 CCB toxicity also impairs the uptake of glucose and free fatty acids by cardiac myocytes3,4 and inhibits calcium-dependent mitochondrial activity required for glucose catabolism.3,4 Furthermore, insulin release is dependent on calcium influx into islet beta cells through L-type calcium channels.3,4 Thus, CCB toxicity can cause hypoinsulinaemia,3,4 which, in conjunction with CCB-induced insulin resistance, may lead to hyperglycaemia and a ketoacidotic state.6 Atropine, calcium boluses and infusions, glucagon, inotropes, vasopressors, and cardiac pacing have all been advocated for managing CCB toxicity, despite questionable efficacy.3,4,7-9 For instance, the evidence for glucagon is limited to small, non-blinded animal studies where no survival benefit or improvement in mean arterial pressure was shown, although heart rate improved in some cases.7 Rarely, heroic measures such as extracorporeal circulatory support and intra-aortic balloon counterpulsation have been successfully employed.5,10 HIET was first used to treat verapamil toxicity in humans in 1993, with a favourable outcome.6 Since then, in addition to animal studies, there have been nearly 70 cases reporting the beneficial use of HIET in humans, with an overall survival rate of 85%.8 However, to our knowledge, use of HIET in humans before the administration of glucagon or vasopressors has only been reported once.6 There have been some reports of HIET failure in treating CCB toxicity, although the dosing of insulin was low or uncertain, or it was used late.6,8 Early use of HIET may be more effective than HIET rescue therapy, as CCB-induced insulin resistance is greatest in the first 24 hours2 and the maximal haemodynamic benefit of HIET may not occur immediately.6 HIET may allow the heart to overcome metabolic starvation in CCB toxicity, which compounds the direct CCB impairment of myocardial contractility.3,4 Insulin increases glucose and lactate uptake by myocardial cells and improves function without increased oxygen demand.11,12 It also induces pyruvate dehydrogenase, hastening myocardial lactate oxidation, and helps clear the cytosol of glycolytic byproducts that impair calcium handling and cause diastolic dysfunction.3 Insulin promotes excitation–contraction coupling and contractility because enhanced glycolysis promotes increased sarcoplasmic reticulum-associated calcium ATPase activity and increased cytoplasmic calcium concentrations, and promotes calcium entrance into mitochondria and sarcolemma.3 HIET may be best used adjunctively with other measures such as catecholamines, for two reasons. First, insulin-mediated inotropy is not catecholamine-mediated, and is not affected by β blockers.3 Second, although insulin appears to improve myocardial contractility, it has no chronotropic effect and may cause vasodilation.3,8 HIET is safe, and adverse events are predictable, uncommon, and easily managed.2,8 The maximum safe dose of insulin is unknown, but loading doses of 0.5–1.0 IU/kg followed by infusions of 0.1–2.5 IU/kg/h are typically used.8 Interestingly, neither the inadvertent administration of a 1000 IU insulin loading dose for verapamil toxicity13 nor treatment of toxic cardiogenic shock for 2 days with a 6 IU/kg/h insulin infusion had any adverse effects.14 Adverse effects of HIET include hypoglycaemia, hypokalaemia, hypomagnesaemia, and hypophosphataemia.2,6,8 Although these are rarely clinically significant, they necessitate careful monitoring. Hypoglycaemia (blood glucose < 3.3 mmol/L) occurred in 16% of 55 published cases,8 and no cases of hypoglycaemia within 24 hours of CCB overdose were noted in Greene and colleagues’ series of seven cases.2 Greene et al also reported a mean dextrose requirement of 0.05 g/kg/h (range, 0–0.17 g/kg/h), although the mean blood glucose level exceeded the euglycaemic range.2 Some cases of severe CCB toxicity in patients presenting with hyperglycaemia do not require any additional glucose administration despite high-dose insulin therapy,15 and hypoglycaemia may be more likely in milder cases without marked hypotension.8 In addition, hypokalaemia (potassium < 3.5 mmol/L) was noted in only two patients in Greene et al’s small series, with a minimum potassium level of 2.8 mmol/L.2 Excessive correction of hypokalaemia should be avoided, because it reflects the intracellular shift of potassium from the extracellular compartment due to the action of insulin, rather than a potassium-depleted state.4 Interestingly, hypokalaemia in HIET may augment myocardial contractility by enhancing calcium entry during systole, and increased intracellular potassium may have a membrane-stabilising effect in excitable cells.4,6 In conclusion, we advocate consideration of the early use of HIET (as detailed in Box 2) for the prevention and treatment of life-threatening complications from potentially lethal CCB overdoses. HIET is safe, inexpensive and freely available, and suitable for use even in remote settings before transfer to a referral centre. 1 Early changes in the patient’s systolic blood pressure (SBP) and heart rate, relative to treatment with high-dose insulin and adrenaline infusions Following administration of a 0.5 IU/kg short-acting insulin bolus 3.5 hours after presentation, a short-acting insulin intravenous infusion (0.5 IU/kg/h) was commenced (black line), and the patient’s blood pressure improved. The infusion was abruptly discontinued 2 hours later and the patient again became hypotensive. This resolved following commencement of an adrenaline infusion (20 μg/min) (grey arrow), and the insulin infusion (0.5 IU/kg/h) was restarted 8.5 hours after presentation (black arrow). 2 Recommended high-dose insulin euglycaemic therapy protocol,3,4,9 based on the clinical experience of the Western Australian Toxicology Service, published case reports, reviews and animal studies Commence therapy with: Glucose 25 g (50 mL of 50% solution) IV bolus, unless marked hyperglycaemia (blood glucose > 22 mmol/L) is present Short-acting insulin 1 IU/kg bolus to maximally saturate insulin receptors Continue therapy with: Short-acting insulin infusion starting at 0.5 IU/kg/h and titrated every 30 min to a maximum of 5 IU/kg/h* Dextrose 25 g/h IV infusion titrated to maintain euglycaemia (blood glucose, 5.5–14 mmol/L); central venous access may be required to allow use of concentrated solutions (eg, 50% dextrose) and limit excess volume administration Monitor: Glucose — every 20 min for first hour, then every 1 h Potassium — replace only if < 2.5 mmol/L and there is a source of potassium loss Therapeutic end points: Improvement in myocardial ejection fraction (> 50%); increased BP (systolic BP > 90 mmHg in adults) Adequate heart rate (> 60 beats/min) Resolution of acidaemia; euglycaemia; adequate urine output (1–2 mL/kg/h) Reversal of cardiac conduction abnormalities (QRS interval < 120 ms) Improved mentation Therapy is weaned after the withdrawal of other vasopressors, as cardiotoxicity resolves. Dextrose may be required after cessation of insulin. IV = intravenous. BP = blood pressure. * The maximum safe and effective rate of infusion is unknown but may be even higher than 5 IU/kg/h. In animal studies, insulin infusions as high as 10 IU/kg/h have been safely used.11

Christopher P Nickson MB ChB, DTMH, GCertClinTox · Mark Little FACEM, DTMH, MPHTM

To the Editor: Nordin and colleagues raised important issues about prescribing for osteoporosis.1 We agree that the Pharmaceutical Benefits Schedule guidelines for therapy are imperfect, but they do not necessarily lead, as Nordin et al claim, to inappropriate prescribing. For historical reasons, osteoporosis is held to be synonymous with vertebral fractures, but this misrepresents the epidemiology of fractures. Non-vertebral fractures account for 80% of all fractures and 90% of the loss of quality of life and economic costs. Vertebral fractures contribute only 20% of the burden.2 Most fractures arise in the large population at moderate risk with osteopenia — the “bell” of the Gaussian bone mineral density (BMD) distribution, not its “tail”, which comprises those with osteoporosis (defined by a bone densitometry T-score less than – 2.5). Concentrating on vertebral fractures and screening for osteoporosis with bone densitometry, as recommended by Nordin et al, is no solution to this public health problem. Nutritional change and exercise are appealing because they are safe and cost-effective approaches for early intervention, but are supported only by level D evidence (expert opinion).3 Although these approaches are plausible, no trials demonstrate their antifracture efficacy. There are no means of early identification of individuals who will sustain a fracture. Densitometry is neither sensitive nor specific for fracture; most people with osteoporosis do not sustain a fracture, and most fractures arise in people without osteoporosis, who would, paradoxically, be excluded from treatment by screening.4 Bone densitometry should be more accessible for case finding, but its use for screening does not reduce the fracture burden because of this screening paradox. However, Medicare reimbursement for densitometry is available for high-risk individuals (those with premature menopause, other illnesses or who are taking corticosteroids), not just for those aged over 70 years or those with fractures. Restricting treatment on the basis of BMD results is not advocated by the Australian and New Zealand Bone and Mineral Society precisely because it excludes this moderate-risk group from treatment, particularly those with fractures and osteopenia. There is level A evidence (meta-analysis of multiple randomised trials)5 for the antifracture efficacy of bisphosphonates in patients with osteoporosis, and evidence based on single trials6 of their antifracture efficacy in those with osteopenia and prevalent fractures, whose fracture risk is similar to that of people with osteoporosis and no prevalent fracture. There is limited evidence of antifracture efficacy of bisphosphonates in individuals with osteopenia alone.6 Preventing the first fracture is important, and guidelines are deficient in this way. Case finding to estimate absolute risk is the best approach available at this time, using risk factors, remodelling markers and, more recently, microstructural analysis to improve sensitivity and specificity. Rather than inappropriate or overprescribing, evidence suggests underutilisation of drug therapy for osteoporosis.7,8 Osteoporosis remains underdiagnosed, underinvestigated and undertreated, and limiting access to bone densitometry is not supported by the Australian and New Zealand Bone and Mineral Society.

Ego Seeman · Mark A Kotowicz · Peter T Nash · Philip N Sambrook

In reply: Seeman and colleagues agree that most patients with minimal trauma fractures do not have osteoporosis. The figures are clear: only 13% of patients with a peripheral fracture have a hip bone mineral density (BMD) T-score less than or equal to − 2.5 and only 25% have a score less than or equal to − 1.5. The corresponding figures for vertebral fractures are 25% and 38%, respectively.1 We do not argue that the − 2.5 T-score threshold for defining osteoporosis is sacrosanct, but simply that some bone density threshold be defined for subsidised therapy, for which virtually all the supporting evidence is based on treatment of patients with established osteoporosis. Osteopenia is an artificial concept with an arbitrary definition, but we agree that the T-score threshold for subsidised therapy need not be as low in those with prevalent adult fracture as in those without — perhaps − 1.5, which is the threshold recently adopted for patients receiving corticosteroid therapy. We disagree about the predictive power of bone densitometry; it is comparable to that of blood cholesterol level for heart attacks and blood pressure for stroke.2 It therefore makes sense to measure BMD in all women at menopause and all men at age 60 years to identify those with osteoporosis before they sustain fractures, as well as those with normal but negative T-scores, who have a fracture risk twice that of those with positive T-scores.3 Those with proven osteoporosis could receive subsidised therapy, and those with low normal values could be advised on lifestyle measures, such as calcium supplementation (which significantly delays or prevents bone loss in postmenopausal women).4 People with positive T-scores can be reassured. To suggest that no trials have demonstrated the antifracture efficacy of nutritional measures is to argue against three large meta-analyses showing significant prevention of fractures with vitamin D and calcium supplementation.5-7 The additional cost of confirming low bone density before providing subsidised therapy in fracture cases is likely to be more than offset by the savings from reduced inappropriate therapy; bone densitometry costs about $80 per test, but bisphosphonate therapy costs about $50 a month for each patient. The extra cost of bone densitometry for every woman at menopause and every man at age 60 years could be $20 million a year, but even with subsidised therapy for those without fracture but proven osteoporosis (with a T-score less than or equal to − 2.5, for instance), the cost is also likely to be more than offset in the long term by reducing the enormous cost of osteoporotic fractures ($8 billion annually8). We find it hard to understand why any of our colleagues would not support proposals that would transfer treatment from those who do not need it to those who do.

B E Christopher Nordin · Michael Horowitz

To the Editor: I was interested to read the results of Sweidan and colleagues’ study of drug interaction alerts in prescribing and dispensing software.1 I believe their use of the terms “sensitivity” and “specificity” differ from the standard definitions, which are usually: Sensitivity = true positives ÷ (true positives + false negatives) Specificity = true negatives ÷ (true negatives + false positives)2 To test sensitivity and specificity, one requires a dataset that includes positives and negatives. I do not view “minor interactions” as a complete set of negatives, because a complete set of negatives should include a statistically valid number of randomly chosen drug sets without interactions. Minor interactions do not meet my criteria for “negatives” because, to me, a minor interaction is still an interaction that may sometimes be clinically significant. A true negative should meet the test of “never clinically significant”. Some reported minor interactions would meet that test and some would not. I believe sensitivity and specificity data should be reported for both major and minor interaction alerts. I also believe there should be some alignment of definitions between “drug interaction” research and “adverse drug event” research.3 Bates and colleagues talked about “adverse drug events” and “preventable adverse drug events” in 1995.4 Of most clinical interest are the preventable adverse drug events, which could be minimised by the use of appropriate decision support.5,6 Certainly, there is a need for independent assessment of the quality of electronic prescribing decision support systems. A robust assessment methodology is required to permit potential government regulation of such resources, which are of national and community importance.

Ian R Cheong

To the Editor: As the former Clinical Information Specialist Manager for the MIMS DrugAlert knowledgebase (from 2003 to 2005), I write in response to the study by Sweidan and colleagues examining the quality of drug interaction alerts in prescribing and dispensing software.1 The authors point out that the success of any knowledgebase in providing clear, correct and specific alerts at the point of care is subject to the quality of its technical integration into decision support software. I would like to add that the sensitivity of drug interaction decision support is determined largely by the knowledgebase, while the specificity of the system is subject to the intelligence of the software in which it is employed. I would be interested to know if the low specificity that Sweidan et al found for the MIMS DrugAlert database was due to lack of use of the severity or level of evidence settings, or having these set at inappropriate levels. The MIMS DrugAlert knowledgebase was in some ways a unique decision support database, written by Australian staff for use in Australia and New Zealand. It soon became one of the largest commercially available databases of drug interaction information in the world, covering over 4600 drug-class and individual drug interactions. Its writing alone was a remarkable feat, being completed in a matter of months and further expanded over a subsequent 18-month period. There are significant variations in practical advice between American and European sources of drug interaction information. In writing the MIMS DrugAlert database, we sought to communicate “the right information, at the right time, in the right way” to local professionals. The foundations of MIMS DrugAlert were based on a clear understanding that we would be representing relatively simple pharmacological principles through the structure and content of a relational database. This meant creating interacting drug classes reflective of the pharmacological properties of groups of drugs, rather than simply grouping drugs based on their chemical families alone. Sweidan and colleagues should be congratulated on highlighting the need for comprehensive, accurate and useful information that can reduce medication error and save lives at the point of care. What is lacking is a clinical outcomes-based study focusing on the real-world benefits that can be achieved if the right system can be implemented in the right way, at the right price. Perhaps this type of research would then build on the excellent, basic foundational research carried out by Sweidan et al.

Bryan W Tan

In reply: Cheong notes that the terms “sensitivity” and “specificity” have a slightly different meaning in our study compared with the usual definitions. This was intentional, and the definitions we used are clearly described in our article.1 Our definitions for sensitivity and specificity were based on two important practical considerations. First, an electronic prescribing system should alert the clinician to potentially clinically significant drug interactions (“true positives” by our definition); and second, a system should not inundate clinicians with alerts containing irrelevant or unhelpful information about minor or clinically unimportant interactions (“false positives” by our definition). We know that these latter alerts can cause “alert fatigue” and are a subject of complaint for doctors and pharmacists. We are not aware of there being any problem with prescribing systems producing alerts for pairs of drugs that do not interact at all; hence, we did not investigate this group. Tan questions whether the low specificity we found for the MIMS DrugAlert database may have been due to inappropriate severity level settings. Although it might seem appealing to reduce the number of alerts by allowing users to “switch off” drug interaction alerts that are classified as low severity, there are difficulties in doing this because of a lack of evidence for the application of severity ratings to drug interactions. Severity ratings are subjective — studies have shown there is little consensus on such ratings between major reference sources.2,3 This is not surprising, given that there is little evidence available on adverse clinical outcomes resulting from drug interactions, and also because the clinical outcome is context-dependent according to variables such as patient characteristics and drug dosage. We believe that, rather than relying on software vendors or users to switch off some alerts, drug interaction knowledgebases should include only potentially clinically significant interactions. We tested all systems at the lowest severity setting (if available) for consistency, and to maximise detection of drug interaction alerts. For minor interactions, the rating was based on both presence of the alert and quality of the information — if a minor interaction was either not detected or was detected and provided appropriate information indicating it was minor, then it was a “pass”.

Michelle Sweidan · James F Reeve · Jo-anne E Brien · Pradeep Jayasuriya · Jennifer H Martin · Graeme M Vernon

The Therapeutic Goods Administration is strengthening pharmacovigilance, but strategies to encourage the conduct of pharmacoepidemiological research in Australia are needed For four decades, spontaneous reporting has been the main mechanism by which adverse drug reactions are identified after a medicine is released onto the market, and the Australian program has been exceptionally effective. However, spontaneous reporting programs are limited in their ability to identify an association between a drug and an outcome that is common among the users independent of drug use, and they are not sufficiently sensitive to detect a small increase in the risk of certain rare events. In particular, the increasing long-term use of medication for prevention and control of chronic disease in otherwise healthy individuals presents a challenge to which current postmarketing surveillance mechanisms cannot effectively respond. For example, spontaneous reporting cannot detect an increased rate of myocardial infarction associated with hormone replacement therapy, rosiglitazone or rofecoxib; demonstration of these associations requires large, long-term randomised controlled trials. In recognition of these limitations, the Therapeutic Goods Administration (TGA) recently announced administrative changes that involve a strengthening of pharmacovigilance.1-3 As part of the pre-approval process for a medicine, sponsors will be required to present postmarketing pharmacovigilance and risk minimisation plans. In some cases, the pharmacovigilance plan may simply describe routine passive pharmacovigilance activities. In other cases, where there are important gaps in safety data (eg, groups of potential users for whom documented exposure is inadequate) or where data suggest potentially significant safety issues, the plan will propose studies that specifically address these matters. Studies may use any of the full gamut of epidemiological approaches, including randomised controlled trials, registries of new drug users, and data-linkage and case–control studies. Risk minimisation plans will outline practical steps that will be undertaken to reduce the risk of known safety hazards during the postmarketing period. Possible steps include a small pack size, second-line use only, and advice given in the product information; these measures were available options in the past, but they will now be listed in a single document. Pharmacovigilance and risk minimisation plans may be updated at any time during the postmarketing period, if a need to do so is identified. In addition, sponsors of medicines that are already registered when the new measures are implemented may also be required to draw up suitable plans on a case-by-case basis. These changes bring Australia into line with overseas initiatives, particularly those in the United States and Europe, and involve adoption of guidelines prepared by the European Medicines Agency.4,5 The result has been termed a “whole-of-lifecycle” approach, where active investigation of the safety of a medicine may continue for as long as it is in clinical use.1 A newly constituted medicines safety committee will have responsibility for providing advice on pharmacovigilance and risk minimisation plans, and overseeing the spontaneous reporting program. Medicines prescribed over a long period for disease prevention have typically been approved on the basis of a measured response to a surrogate marker for efficacy, such as improved glucose control, decreased cholesterol level or lowered blood pressure. However, the critical measures of the benefits of such responses to medicines are changes in risk of hard end points, such as myocardial infarction, renal failure and death. These end points are outcomes of the multidimensional effects of medicines — beneficial and adverse — on body systems. Marketing approval of medicines has rarely, if ever, required demonstration of such hypothesised benefits. Under the administrative changes, promising new medicines may still be approved on the basis of surrogate data, but consideration will be given to pharmacovigilance plans that include long-term studies with cohorts that are large enough to determine differences in hard clinical end points and identify any serious adverse effects that may offset benefits. In 2004, Merck Sharp and Dohme precipitately removed rofecoxib from the market worldwide, because evidence of a significantly higher rate of myocardial infarction than with placebo was an incidental outcome of a randomised controlled trial. There had been prior evidence of this association in the VIGOR (Vioxx Gastrointestinal Outcomes Research) study published in 2000.6 At that time, the manufacturer made a small protocol change to the already commenced APPROVe (Adenomatous Polyp Prevention on Vioxx) study, to allow participants to take low-dose aspirin,7 but apparently took no action to verify the association before 2002.8 Under the new procedures, it will be a routine matter for medicine regulators, including the TGA, to ensure that the sponsor conducts suitable studies to clarify safety concerns such as those raised in the VIGOR study. Of critical importance to the success of the expanded approach to pharmacovigilance is the level of resourcing at the TGA. Consideration of requirements must include capacity to: evaluate the suitability of pharmacovigilance plans that are included in applications for marketing approval of medicines; review pharmacovigilance plan updates that are submitted by sponsors; identify areas that require further investigation during the lifecycle of a medicine; and prepare reports for the medicines safety committee. It is disappointing that the initiatives do not include provisions for the TGA to fund, commission or conduct active safety investigations. The US Food and Drug Administration has received a substantial injection of funding for this purpose,4 and Medsafe, the New Zealand medicines authority, is funding product vigilance research through a joint initiative with the Health Research Council of New Zealand.9 Commissioned studies could address questions that sponsors could not reasonably be required to ask, such as those related to genetic markers for hypersensitivity reactions. They could also provide an alternative source of data in cases where the manufacturer chooses not to be transparent about safety matters, as allegedly occurred with rofecoxib10 and cerivastatin.11 As these changes in pharmacovigilance and drug regulation are occurring internationally, in general the TGA will be requiring postmarketing studies in concert with other regulators. In the absence of local initiatives or leadership from the TGA or other federal agencies that encourage the conduct of pharmacovigilance research in this country, Australia may not do much better than to achieve high-level observer status. Linkage of de-identified data from the Pharmaceutical Benefits Scheme and National Cancer Statistics Clearing House, as well as morbidity and mortality data from the Australian Institute of Health and Welfare, would provide a platform for epidemiological studies. Studies using this platform would need to be ones that do not require data on disease severity, concurrent disease, non-subsidised medication or lifestyle factors to control for confounding. While studies using more time-intensive means of data collection should also be encouraged in Australia, the years of inaction with regard to advancing this data linkage cannot be justified.12 The new approach being implemented by the TGA is welcome. Supplementing passive spontaneous reporting with evidence from active pharmacovigilance, in the form of studies designed to address important safety issues associated with medicines, will lead to more timely elucidation of adverse effects, together with reassurance for prescribers and patients. But the failure to include, as an essential part of the proposed changes, a package to ensure that active pharmacovigilance occurs in this country is baffling. This deficiency needs to be addressed urgently, and the matter would benefit from being taken up at a high level of government.

Kathlyn J Ronaldson BSc, MSc, DPhil

Targeted post-exposure prophylaxis represents a more efficient use of the stockpile than treatment alone With the emergence of H1N1 influenza 09 (novel human swine influenza A[H1N1] 2009), efforts to control the spread and mitigate the impact of this virus have been implemented. The Australian health management plan for pandemic influenza (2008)1 (AHMPPI) outlines a range of strategies aimed at eliminating an outbreak where possible (the “Contain” response), or reducing transmission sufficiently to allow distribution of a targeted vaccine (the “Sustain” response). Following evidence of sustained transmission within Victoria in May 2009, state and territory health departments began implementing the Contain response, with a switch to a modified Sustain response in Victoria within weeks. The AHMPPI recommends liberal distribution of the stockpile of neuraminidase inhibitors (oseltamivir, zanamivir) to constrain influenza transmission.1 This policy was based on modelling studies synthesising the best available evidence, including clear demonstration of the efficacy of antiviral drugs to prevent secondary infection in randomised controlled trials.2,3 Notwithstanding revision of the AHMPPI on 17 June 2009 to incorporate the present “Protect” phase, understanding the rationale for and defining the operational implications of the initial recommendations for antiviral drug use are priorities. Translation of evidence from epidemiological trials into pandemic policy is challenging, given the complexity of real-world factors that influence intervention effectiveness. For example, as has been observed with many vaccines, drug effects on transmission have far greater impact when implemented across a whole population. The chosen antiviral deployment strategy needs to take into account not only the direct effects benefiting the treated individual, but also indirect effects due to changes in subsequent transmission. In a rapidly growing epidemic, these secondary effects are critical to determining the optimal deployment strategy. Mathematical modelling provides a way to systematically investigate these issues. Using a diverse set of assumptions and frameworks, models consistently demonstrate that for a country with a sufficiently large stockpile of antiviral drugs, augmenting a patient treatment policy with targeted post-exposure prophylaxis represents a more efficient use of the stockpile than treatment alone.4-6 Modelling performed in the Australian context, where the number of stockpiled antiviral drug courses is 40% of the population size, has demonstrated that extensive drug distribution for preventive purposes does not compromise the ability to treat infected patients.6 It was therefore recommended in the AHMPPI that prophylaxis should be provided to as many readily identifiable contacts as possible during the Contain response, with continued provision to household contacts during the Sustain response. Provision of continuous pre-exposure prophylaxis to health care workers was also recommended, as this additive burden on the stockpile would not substantially impede efforts to delay the pandemic. Lessons learned so far in the effort to implement these recommendations have highlighted the importance of clear case definitions to guide treatment, particularly when disease is mild. Delays in confirming infection, associated with finite laboratory resources, posed significant challenges for front-line health care workers. This practical issue must be addressed should deployment of existing stockpile reserves be recommended in coming years, as potentially more virulent variants of the present pandemic strain arise. Meanwhile, further research and policy development are required on a largely unaddressed issue. A transmissible drug-resistant variant of the pandemic strain may arise either by de-novo mutation or by reassortment with drug-resistant seasonal strains (eg, the oseltamivir-resistant 2008 seasonal H1N1 strain carrying the H274Y mutation [histidine-to-tyrosine mutation at codon 274]), and its spread would be favoured by widespread antiviral use. The effort to delay the appearance of such a variant might stimulate a change to the recommended strategies for antiviral deployment. To date, novel H1N1 viruses demonstrating oseltamivir resistance have been isolated from individuals in Denmark and Japan.7 Several published models have been used to investigate the potential consequences of antiviral drug resistance and all demonstrate that emergence of a transmissible drug-resistant variant will reduce the effectiveness of antiviral distribution strategies, with obvious consequences for their utility in “buying time” before a targeted vaccine becomes available. Two recent studies have investigated strategies for reducing the negative impact of drug resistance.8,9 Both considered the case where the main stockpile (ie, oseltamivir) is supplemented with a smaller secondary stockpile of another drug (eg, zanamivir). One study considered four strategies for antiviral drug distribution when both drugs are available for treatment and prophylaxis.8 It was concluded that a strategy whereby the smaller stockpile (drug B) is reserved for treatment, while the main stockpile (drug A) is used for prophylaxis, will most effectively delay the peak of the epidemic and result in the lowest overall level of drug resistance. Alternative strategies of random allocation of drug A or drug B to each individual who is prescribed an antiviral drug, or use of drug B followed by drug A, were also shown to have significant benefits over a single-drug policy. Cycling between one drug and the other over a period of weeks or months was shown to be a high-risk strategy and cannot be recommended. Treatment strategies were also considered in the other study, which demonstrated that using a small amount of drug B followed by drug A will reduce the overall attack and greatly reduce the resistant attack rate.9 In addition, the global implications of a two-drug strategy were considered, taking into account regular entry of infectious individuals into countries and regions over the course of a pandemic. It was shown that if the primary source country implements a strategic two-drug distribution policy, any country into which strains are subsequently introduced will gain a significant benefit from implementing a similar policy. Both these studies provide strong evidence for jurisdictions to consider acquisition of a secondary drug to supplement their primary drug stockpile. Whether the stockpiles are deployed in order (drug B, then drug A) or separated for use as treatment only and prophylaxis only would largely depend on logistical constraints and overall feasibility of the alternative strategies. Either strategy is likely to provide significant benefits compared with deployment of a single drug. In a climate of great uncertainty surrounding characteristics of the current influenza outbreak,10 the challenge worldwide is for jurisdictions to implement flexible evidence-based policies for antiviral stockpile distribution that maximise their effectiveness.

James M McCaw BSc, PhD · James G Wood BSc, PhD · Emma S McBryde MB BS, PhD, FRACP · Terry M Nolan MB BS, PhD, FRACP · Joseph T Wu PhD · Marc Lipsitch DPhil · Jodie McVernon BMedSc, MB BS, PhD

The complete, up-to-date guidelines can be found at: http://www.mja.com.au/ public/rop/cheng/che10661_fm.html Since the initial reports of H1N1 influenza (human swine influenza; caused by influenza A/2009/H1N1/swl) in Mexico and the United States in mid April 2009, many thousands of cases have been reported worldwide. At the time of writing, community transmission is becoming established in many areas in Australia, but the number of reported cases is likely to be an underestimate of the true incidence due to policies for testing. These guidelines provide advice to clinicians on the use of antiviral agents for this newly emerged influenza virus. A full version of these guidelines, including all references, has been previously published online (http://www.mja.com.au/public/rop/cheng/che10661_fm.html). Recommendations for diagnosis of influenzaIn areas with established community transmission, patients presenting with an acute febrile respiratory illness (fever with cough and/or sore throat) are considered to have H1N1 influenza 09 and testing is generally not recommended. Early in the course of the pandemic, timely influenza diagnostic tests can be used to enable targeted antiviral treatment, but will be less useful once community transmission is widespread. Health care workers performing nose swabs or other high-risk aerosol-generating procedures (eg, suctioning, bronchoscopy or intubation) should use a particulate respirator (N95, P2 mask or equivalent), eye protection, impervious gowns, gloves, and, where possible, carry out the procedure in a negative pressure room. The use of nasopharyngeal aspirates are not recommended because of the risk to staff. The use of a combined nose–throat swab is recommended for diagnosis. Specimens for viral nucleic acid detection and culture at reference laboratories should be taken for epidemiological surveillance and to monitor for drug resistance. Once the pandemic is established, this is best facilitated through existing sentinel surveillance systems. Recommendations for treatment using antiviral agentsAntiviral treatment has been shown to reduce the duration of symptoms and may also reduce the incidence of lower respiratory tract infection. Neuraminidase inhibitors (oseltamivir and zanamivir) are the antiviral agents of choice for H1N1 influenza 09. Dose recommendations for treatment and prophylaxis are provided in Box 1 and Box 2, respectively. The decision to treat an individual patient, particularly before the results of confirmatory testing are available, depends on three factors: An assessment of the likelihood of influenza, based on the known prevalence of infection in the region, a history of contact and the characteristics of the illness. An assessment of the likely benefits of treatment (Box 3), based on the presence of established complications, comorbidities and risk factors (Box 4), and the time since onset of the illness. The phase of the pandemic and the public health policies regarding distribution of the national stockpile (Box 5). Recommendations for treatment in adultsAntiviral treatment should only be given to patients with confirmed or suspected influenza within 48 hours of symptom onset, except in cases of severe influenza. Treatment should be prioritised for patients with risk factors for poor outcomes, such as the morbidly obese, pregnant women, those with chronic disease (including asthma, cardiorespiratory disease, diabetes and renal failure) or immunosuppression, and those presenting with severe disease. Recommendations for treatment in childrenAntiviral treatment can be given to children as young as 1 year. Parents should be warned of the possibility of rare neuropsychiatric symptoms related to oseltamivir use in children and adolescents. There is a concern regarding central nervous system accumulation of neuraminidase inhibitors in infants aged under 1 year, based on animal data; a treatment decision must balance the potential benefits of treatment with potential toxicity. Recommendations for treatment in pregnant womenAntiviral treatment should be offered to pregnant women with suspected or confirmed influenza because of the risk of severe disease in this group. Oseltamivir and zanamivir are in the Australian Drug Evaluation Committee category B1, with limited evidence suggesting safety. Recommendations for treatment of severe influenzaAntiviral treatment should be given to hospitalised patients with severe influenza infection (especially pneumonia), even if commenced more than 48 hours after the onset of symptoms. Antibiotic treatment should not be given routinely for influenza-like illness, but antibiotic treatment should follow established national guidelines for treatment of community-acquired pneumonia. Recommendations for prophylaxis with antiviral agentsLong-term prophylaxis can be given to first-responder health care workers for up to 6 weeks for oseltamivir and up to 4 weeks for zanamivir. Use of antiviral prophylaxis for these groups should be in the context of agreement to use the national stockpile. Antiviral prophylaxis can be given to health care workers and close contacts of patients with influenza following exposure, and to residents of institutions to terminate outbreaks. Contacts not provided with prophylaxis should have access to early treatment with antiviral agents, where indicated. Updated informationWe acknowledge that the evidence on which these recommendations are based is rapidly changing. In particular, estimates of disease severity and case fatality, and risk factors for severity are poorly defined at present and may influence clinical decision making. We therefore include some resources for further information. Updates to these clinical guidelines will be posted on the websites of the Australasian Society for Infectious Diseases (ASID) (http://www.asid.net.au), the Thoracic Society of Australia and New Zealand (TSANZ) (http://www.thoracic.org.au) and the MJA (http://www.mja.com.au). Australian resources for pandemic influenza, including links to clinical and infection control guidelines (http://www.flupandemic.gov.au) and current information on the H1N1 outbreak (http://www.healthemergency.gov.au and http://www.influenza specialistgroup.org.au). For information on accessing personal protective equipment and antiviral medication, see links below: http://www.emergency.health.nsw.gov.au/swineflu/professionals/index.asp (New South Wales) http://humanswineflu.health.vic.gov.au/practitioners/index.htm (Victoria) http://www.health.qld.gov.au/swineflu/html/hc_resources.asp (Queensland) http://flu.sa.gov.au/Swineflu/InformationforGPs.aspx (South Australia) http://www.public.health.wa.gov.au/3/952/3/human_swine_flu_health_providers.pm (Western Australia) http://www.pandemic.tas.gov.au/what_does_it_mean_to_you/health_sector (Tasmania) http://www.health.nt.gov.au/H1N1_Influenza/General_Information_Resources/index.aspx (Northern Territory) http://health.act.gov.au/c/health?a=da&did=11044035&pid=1242181681 (Australian Capital Territory). 1 Dose recommendations for treatment of influenza Treatment Dose, interval, duration Oseltamivir Adults; children > 13 years 75 mg, twice daily orally, 5 days Renal impairment* 75 mg, daily orally, 5 days Children aged 1–13 years < 15 kg 30 mg, twice daily, 5 days 15–23 kg 45 mg, twice daily, 5 days 23–40 kg 60 mg, twice daily, 5 days > 40 kg 75 mg, twice daily, 5 days Zanamivir Adults 10 mg (2 inhalations), twice daily, 5 days Children > 5 years 10 mg (2 inhalations), twice daily, 5 days * Creatinine clearance, 10–30 mL/min. 2 Dose recommendations for prophylaxis against influenza Prophylaxis Dose, interval, duration Oseltamivir Adults; children > 13 years 75 mg, daily, 10 days Renal impairment* 75 mg, alternate days, 10 days Children aged 1–13 years < 15 kg 30 mg, daily, 10 days 15–23 kg 45 mg, daily, 10 days 23–40 kg 60 mg, daily, 10 days > 40 kg 75 mg, daily, 10 days Zanamivir Adults 10 mg (2 inhalations), daily, 10 days Children > 5 years 10 mg (2 inhalations), daily, 10 days * Creatinine clearance, 10–30 mL/min. 3 Factors to consider in deciding on likely benefits of treatment for H1N1 influenza 09 (human swine influenza) infection Established complications Hospitalised patients Patients with respiratory compromise Patients with pneumonitis or secondary bacterial pneumonia High risk of complications Pregnant women Patients with morbid obesity Indigenous Australians Patients with chronic respiratory disease; other comorbidities (see Box 4) Potential for transmission to others Health care workers and first responders (eg, paramedics) Household contact or carer of high-risk patient Low risk of complications Healthy adults Low likelihood of benefit Presentation > 48 hours after onset of illness High prevalence of circulating influenza strains with resistance to neuraminidase inhibitors Potential risks of treatment Infants < 1 year 4 Patients at risk of complications from influenza infection* Pregnant women Indigenous Australians Patients with: chronic respiratory disease (including asthma and chronic obstructive pulmonary disease); cardiac disease; morbid obesity; chronic diseases (eg, diabetes, chronic metabolic diseases, chronic renal failure, haemoglobinopathies); chronic neurological disorders; or impaired immunity, including HIV infection Homeless people Residents of nursing homes and long-term care facilities Children aged 6 months – 10 years on long-term aspirin therapy Older people (> 65 years) Children < 5 years * Adapted from the Australian immunisation handbook.1 5 Indications for antiviral treatment and prophylaxis for H1N1 influenza 09 (human swine influenza) infection, depending on likelihood of benefit and stage of pandemic Pandemic phase Delay Contain Sustain Protect Epidemiological setting Little or no community transmission; cases identifiable via exposure history Limited community transmission; cases not identifiable via exposure history Community transmission in some regions Widespread community transmission Treatment Patients with established complications Clinically presumed or laboratory-confirmed Clinically presumed or laboratory-confirmed Clinically presumed or laboratory-confirmed Clinically presumed or laboratory-confirmed Groups at risk of complications* Clinically presumed or laboratory-confirmed. Consider treatment > 48 h after onset if severe or not improving Clinically presumed or laboratory-confirmed. Consider treatment > 48 h after onset if severe or not improving Clinically presumed or laboratory-confirmed. Consider treatment > 48 h after onset if severe or not improving Clinically presumed or laboratory-confirmed. Consider treatment > 48 h after onset if severe or not improving Health care workers, carers for patients at risk of complications within 48 h of onset of illness Clinically presumed or laboratory-confirmed Clinically presumed (if appropriate exposure history) or laboratory-confirmed Clinically presumed or laboratory-confirmed Clinically presumed or laboratory-confirmed Otherwise healthy adults and children > 5 y within 48 h of onset of illness Clinically presumed or laboratory-confirmed Laboratory-confirmed Clinically presumed (depending on rationing policy and virulence) Not generally indicated Infants < 1 y Depends on clinical scenario Depends on clinical scenario Depends on clinical scenario Depends on clinical scenario Low likelihood of benefit (> 48 h after presentation, known high prevalence of resistance) Not indicated, unless severe infection present. Consider zanamivir if oseltamivir-resistant Not indicated, unless severe infection present. Consider zanamivir if oseltamivir-resistant Not indicated, unless severe infection present. Consider zanamivir if oseltamivir-resistant Not indicated, unless severe infection present Prophylaxis following exposure Groups at risk of complications* Indicated Indicated Indicated (depending on rationing policies) Not generally indicated, except immunosuppressed patients and closed communities Health care workers, carers for patients with comorbidities Indicated Indicated Indicated (depending on policy for national stockpile) Not generally indicated (depending on hospital policy) Healthy adults and children > 5 y within 48 h of exposure Indicated Indicated Not indicated (depending on rationing policy and virulence) Not indicated Children < 1 y Not generally indicated Not generally indicated Not generally indicated Not generally indicated Low likelihood of benefit (> 48 h after exposure) Consider up to 7 days after exposure to prevent transmission Depends on observed incubation period and public health policy Consider early treatment if symptoms develop Not indicated * Such as pregnant women, patients with comorbidities or immunosuppression, and Indigenous Australians (Box 4).

Allen C Cheng FRACP, MPH, PhD · Dominic E Dwyer MD, FRACP, FRCPA · A Thomas C Kotsimbos MB BS, FRACP, MD · Mike Starr MB BS, FRACP · Tony M Korman MB BS, FRACP · Jim P Buttery MB BS, MSc, FRACP · Christine R Jenkins MD, FRACP · Vicki L Krause MD, FAFPHM, DTM · Paul D R Johnson MB BS, PhD, FRACP