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April ISSN 1832-3596 09 www.npsradar.org.au Timely, independent information about new drugs Desvenlafaxine (Pristiq) for major depressive disorder 02 New product PBS listed February 2009 Pramipexole (Sifrol) for severe primary restless legs syndrome 05 New indication PBS listed April 2009 Valsartan (Diovan) and combinations with hydrochlorothiazide 11 (Co-Diovan) or amlodipine (Exforge) New products PBS listed March 2009 In Brief 16 Clopidogrel (Iscover, Plavix) PBS listing extended to include acute coronary syndrome (ACS) in combination with aspirin — Ziprasidone (Zeldox): another atypical antipsychotic listed for acute mania in bipolar disorder — Sublingual desmopressin PBS listed: where does desmopressin fit in primary nocturnal enuresis? — Risedronate (Actonel and Actonel Once-a-Week) for corticosteroid-induced osteoporosis — Zoledronic acid (Aclasta) listing extended to osteoporosis in postmenopausal women NPS is an independent, non-profit organisation for Quality Use of Medicines, funded by the Australian Government Department of Health and Ageing. NPS RADAR provides timely, independent, evidence-based information on new drugs, research and PBS listings for general practitioners, specialists, pharmacists and other health professionals. It won't be a surprise to readers to learn that of the desvenlafaxine (Pristiq). Desvenlafaxine and venlafaxine newly PBS-listed products that NPS RADAR has covered have very similar pharmacological activity, and there's over 5 years, more than a third are very close cousins no reason to expect that desvenlafaxine will offer any of drugs already available.* advantage in efficacy or tolerability over venlafaxine. 01 It's clear that many of the 'new' products listed on the Theoretically desvenlafaxine is less likely than venlafaxine PBS aren't particularly novel — for example, isomers, to interact with other drugs because, unlike its parent, combination products, modified-release formulations, it is not metabolised by CYP2D6. But because the new routes of delivery and metabolites of existing product information for venlafaxine notes no drug drugs. And that's placing 'me-too' drugs — analogues interactions mediated by CYP2D6 that have clinical in an existing therapeutic class — to one side. consequences, this theory does not appear to translate to a practical difference. These variations have the potential to produce differences of practical significance to prescribers Compelling advantages for patients are hard to find. and patients: there may be theoretical reasons why Both the new and the old drug are once-daily tablets and a pure isomer or an active metabolite might have both require tapering to avoid discontinuation effects. fewer adverse effects or drug interactions than its The cost to patients of a PBS prescription is currently parent drug, and combinations or modified-release equivalent. However, if generic versions of venlafaxine formulations can reduce the number of tablets or become available, there may be less expensive choices doses for patients. For a pharmaceutical company, available for patients, and the price of venlafaxine to such reborn drugs can also be a means of 'lifecycle the federal government will fall by 12.5%. management' to extend the profitable life of a product We hope you find this issue informative. Look out nearing the end of its patent. for our next print issue in August, and keep up to date Whatever the rationale for these products, the with information about important new and revised PBS questions that prescribers need to consider are the listings in the interim by visiting www.npsradar.org.au. same as for any other new drug: does the new drug have demonstrable advantages or disadvantages — Medicine Update — independent assessments in safety, tolerability, cost, convenience or effectiveness of new medicines and PBS listings for consumers — compared with existing therapies? Medicine Update helps consumers to ask the right On page 2 of this issue, we look at a metabolite of questions about new medicines. To find out more venlafaxine that was PBS listed for depression in February: and download issues of Medicine Update, visit *Even excluding new members of an existing class www.nps.org.au/consumers. NPS RADAR articles may be updated when there is new evidence about safety or efficacy, or in case of regulatory or PBS listing changes. Please refer to www.npsradar.org.au for the most recent version as well as any supplementary information. Timely, independent information about new drugs National Prescribing Service Limited National Prescribing Service Limited (NPS) is an independent, non-profit organisation for Quality Use of Medicines. We provide accurate, balanced, evidence-based information and services to help people choose if, when and how to use medicines to improve their health and wellbeing. We are member-based and work in partnership with health professionals, government, pharmaceutical industry and consumers. NPS is funded by the Australian Government Department of Health and Ageing. April 2009 Desvenlafaxine (Pristiq) for major depressive disorder (des-VEN-la-FAX-een) Summary Desvenlafaxine is the active metabolite of venlafaxine. There is no evidence that desvenlafaxine is more effective, safer or better tolerated than venlafaxine or other antidepressants. Doses above 50 mg/day are unlikely to provide further clinical benefit and are associated 02 with a higher incidence of adverse effects. Common adverse effects include nausea, headache, dizziness, dry mouth and diarrhoea. Desvenlafaxine should not be used in children and adolescents. Reduce the dose slowly to avoid discontinuation symptoms. PBS listing antidepressant or has any particular advantage over venlafaxine. Restricted benefit Desvenlafaxine is the major active Desvenlafaxine (Pristiq) 50 mg and 100 mg tablets can metabolite of venlafaxine be prescribed on the Pharmaceutical Benefits Scheme (PBS) for people with major depressive disorder.1 O-desmethylvenlafaxine (desvenlafaxine) is the major active metabolite of venlafaxine and has similar The 50 mg and 100 mg tablets are listed as a month's pharmacological activity to that of venlafaxine. Both supply with 5 repeats. venlafaxine and desvenlafaxine contribute to the pharmacological effect of venlafaxine.3 Reason for PBS listing Venlafaxine is metabolised to desvenlafaxine The Pharmaceutical Benefits Advisory Committee by cytochrome P450 2D6 (CYP2D6). Desvenlafaxine recommended desvenlafaxine for listing on a cost- is not metabolised by CYP2D6 and is excreted minimisation basis — that is, similar efficacy and cost unchanged or after conjugation. — compared with its parent drug, venlafaxine, for the Using desvenlafaxine rather than venlafaxine avoids treatment of major depressive disorder.1,2 This decision CYP2D6 metabolism. Theoretically, desvenlafaxine has was based upon an indirect comparison in which lower potential than venlafaxine for drug interactions randomised trials of desvenlafaxine and randomised with substrates and inhibitors of CYP2D6. However, trials of venlafaxine were compared using placebo this does not appear to confer any particular advantage as the common comparator.2 to desvenlafaxine — the product information for venlafaxine notes that dose adjustment is not required Place in therapy when venlafaxine is used with drugs that inhibit or are metabolised by CYP2D6.3 Desvenlafaxine is a serotonin and noradrenaline reuptake inhibitor (SNRI). The other SNRIs are No evidence that desvenlafaxine venlafaxine and duloxetine. is more effective than venlafaxine Desvenlafaxine does not have a novel mechanism of or other antidepressants action; it is the active metabolite of venlafaxine. It has No studies have been powered to directly compare been formulated as a prolonged-release tablet. There the efficacy of desvenlafaxine with venlafaxine or any is no evidence that it is more effective than any other other antidepressant. An indirect comparison was made April 2009 Desvenlafaxine (Pristiq) Report suspected adverse reactions to the Therapeutic Table 1: Mean changes in HAM-D17 scores in studies of 50 or 100 mg/day desvenlafaxine Goods Administration (TGA) online (www.ebs.tga.gov.au [then click 'Adverse reaction to a medicine' at left]) or Mean change from baseline by using the 'Blue Card' distributed with Australian Placebo 50mg 100mg Prescriber. For information about reporting adverse Leibowitz4 –9.5 –11.5* –11.0 reactions, see the TGA website (www.tga.gov.au). Boyer5 –10.7 –13.2* –13.7* Adverse effects increase with dose 03 DeMartinis6 –7.65 — –10.6* Common adverse effects at the 50 mg dose include * Significant improvement over placebo nausea (22%), headache (20%), dizziness (13%), dry mouth (11%) and diarrhoea (11%).10 Other potential in the PBAC submission, comparing randomised trials of adverse effects include insomnia, increased blood desvenlafaxine against randomised trials of venlafaxine, pressure, sexual dysfunction and increases in blood using placebo as the common comparator (see Reason pressure, heart rate, cholesterol and triglycerides.7,10 for listing).2 Nausea is less commonly reported after the first week of therapy.4,6 Desvenlafaxine improves depression scores The incidence of adverse effects increase with dose. At doses of 50 or 100 mg/day, desvenlafaxine improves Based on pooled trial data, nausea was reported in scores on the Hamilton Rating Scale for Depression 22% of trial participants using 50 mg/day but rose (HAM-D17). In most studies the 50 mg and the 100 mg to 26% in those using 100 mg/day and 36% in those doses improved HAM-D17 scores significantly more — using 200 mg/day.10 by 1.5 to 3 points — than placebo (Table 1). Desvenlafaxine may increase blood pressure Doses above 50 mg day are unlikely and cholesterol to provide further clinical benefit Statistically significant increases in blood pressure The recommended dose of desvenlafaxine is 50 mg/day. and total cholesterol concentration were observed Higher doses do not appear to improve clinical efficacy.6,7 in a small number of trial participants using 50 mg However, adverse effects are more common at higher or 100 mg desvenlafaxine.4,5 In trials using 50 mg/day doses (see Safety issues). There is no evidence as to the maximum increase in mean systolic and diastolic whether an individual patient who does not respond blood pressure was 3.3 mmHg and 2.1 mmHg, at the 50 mg dose will respond at a higher dose and respectively.11 Consider whether more frequent no studies have been designed to evaluate this. monitoring of blood pressure is needed. The lowest effective dose of desvenlafaxine is still being investigated. A US Food and Drug Administration Desvenlafaxine precautions are similar analysis did not find any advantage to increasing the to those of other antidepressants dose above 50 mg/day and suggested the efficacy of As with other SNRIs: a dose of 25 mg/day should be investigated.8 This trial • Monitor all people prescribed desvenlafaxine for is currently underway.9 clinical worsening and suicidality during the early stages of treatment and during dosage adjustment.7,12 Safety issues • Do not use desvenlafaxine in children and Desvenlafaxine's adverse-effect profile appears to be adolescents, as its safety and efficacy has not been similar to that of venlafaxine.3,10 However, information established and it is not approved for use in these on its full adverse-effect profile will only be established groups.7 See the NPS RADAR review Selective after more widespread and long-term use in a broader serotonin re-uptake inhibitors in child and adolescent patient population. depression (available at www.nps.org.au). Increasing the dose of desvenlafaxine increases • Desvenlafaxine should be avoided in combination the incidence of adverse effects without improving with other drugs that can increase serotonin levels. clinical efficacy. These include SSRIs, venlafaxine, duloxetine, tricyclic April 2009 Desvenlafaxine (Pristiq) antidepressants, monoamine oxidase inhibitor (MAOI) and confusion. Slower dose tapering may be needed antidepressants (including moclobemide), triptans, for patients who experience these symptoms. tramadol, pethidine, fentanyl, St John's wort and the illicit drugs MDMA ('ecstasy'), cocaine and LSD.7,13 Information for patients Advise patients that the benefits of using desvenlafaxine Dosing issues may take a few weeks to manifest and they should The recommended dose is 50 mg once daily.7,12 Doses continue with treatment even when they feel better. above 50 mg per day are unlikely to provide further 04 Advise patients: clinical benefit.7 • to take desvenlafaxine at the same time each day No dose adjustment is required in hepatic impairment. and to swallow the tablet whole and not to break, For people with renal impairment the dose may need chew or crush it to be adjusted according to the level of impairment. See • that the tablet casing may be visible in the faeces the Pristiq product information for further information. • that side effects such as nausea, headache and Reduce the dose slowly to avoid dizziness are common. Nausea is less common after discontinuation symptoms the first week of therapy. When stopping desvenlafaxine, gradually taper the • to check with their doctor or pharmacist before using dose (by asking the patient to take it less frequently — any prescription medicines (e.g. tramadol), over-the- i.e. every other day) over at least 1–2 weeks to avoid counter medicines or herbal medicines (e.g. St John's discontinuation symptoms.10,12 These include dizziness, wort), as interactions may occur. sensory disturbances including paraesthesia, anxiety Discuss the Pristiq consumer medicine information and agitation, sleep disturbances, tremor, sweating (CMI) leaflet with the patient (this is available on the NPS website). References 1. Pharmaceutical Benefits Advisory Committee. Positive 4. Liebowitz MR, et al. Curr Med Res Opin Medicine, 2008. http://www.clinicaltrials.gov/ct2 Recommendations made by the PBAC — November 2008;24:1877–90. /show?recr=open&intr=%22O-desmethylvenlafaxine 2008. Canberra: Australian Government Department 5. Boyer P, et al. Int Clin Psychopharmacol 2008;23:243–53. %22&rank=2 (accessed 22 December 2008). of Health and Ageing, 2008. http://www.health.gov.au 6. DeMartinis NA, et al. J Clin Psychiatry 2007;68:677–88. 10. Wyeth Pharmaceuticals Inc [USA]. Pristiq /internet/main/publishing.nsf/Content/pbacrec-nov08- (desvenlafaxine) Extended-Release Tablets full 7. Wyeth Australia Pty Ltd. Pristiq product information. positive (accessed 24 December 2008). prescribing information. April 2008. 30 July 2008. 2. Pharmaceutical Benefits Advisory Committee. 11. Center for Drug Evaluation and Research. Pristiq 8. Center for Drug Evaluation and Research. Pristiq Public summary document for desvenlafaxine succinate, (Desvenlafaxine Succinate) Extended Release Tablets — (Desvenlafaxine Succinate) Extended Release Tablets — tablet, (extended release), 50 mg and 100 mg (base), Application Number: 21–992. Medical Review(s) Application Number: 21–992. Summary Review. 2008. Pristiq November 2008. Canberra: Australian Government Part 1. 2008. http://www.fda.gov/cder/foi/nda/2008 http://www.fda.gov/cder/foi/nda/2008 Department of Health and Ageing, 2009. /021992s000_MedR_P1.pdf (accessed 9 December 2008). /021992s000_SumR.pdf (accessed 9 December 2008). http://www.health.gov.au/internet/main/publishing.nsf 12. eTG complete [CD-ROM]. Melbourne: Therapeutic /Content/pbac-psd-desvenlafaxine-nov08 (accessed 9. ClinicalTrials.gov. Study evaluating desvenlafaxine succinate sustained release (DVS SR) in the treatment Guidelines Limited, December 2008. 9 March 2008). of major depressive disorder. US National Library of 13. Rossi S. Australian Medicines Handbook, 2008. 3. Wyeth Australia Pty Ltd. Efexor-XR product information. 5 May 2008. Date published: March 2009 The information contained in NPS RADAR is derived from a critical analysis of a wide range of authoritative evidence and is current at the time of publication. Any treatment decisions based on the information provided in NPS RADAR should be made in the context of the clinical circumstances of each patient. NPS RADAR articles may be updated when there is new evidence about safety or efficacy, or in case of regulatory or PBS listing changes. Please refer to www.npsradar.org.au for the most recent version as well as any supplementary information. April 2009 Pramipexole (Sifrol) for severe primary restless legs syndrome (pram-i-PECKS-ole) Summary Pramipexole is a non-ergot-derived dopamine agonist that is also approved for treating Parkinson's disease. Pramipexole reduces the symptoms of restless legs syndrome for some people and is PBS listed for severe primary cases. Diagnose restless legs syndrome by confirming that the patient meets all 4 clinical criteria. Grade severity using the IRLS rating scale. 05 Consider possible causes of secondary restless legs syndrome, including iron deficiency, pregnancy or renal failure and differential diagnoses such as muscle cramps, arthritis, neuropathy or drug-induced akathisia. Try non-drug measures, including exercise and sleep hygiene. Consider pramipexole for severe frequent symptoms. Nausea and somnolence are common but are generally mild and transient. Sudden-onset daytime sleep (sleep attacks) can occur and rare cases of compulsive behaviour have been reported. Evidence for efficacy beyond 3 months is limited and observations suggest that it declines over time. PBS listing In response to an earlier submission, the PBAC rejected the claim that pramipexole was superior overall to Restricted benefit levodopa with benserazide, noting that pramipexole was associated with higher rates of nausea and other Severe primary (idiopathic) restless legs syndrome with an gastrointestinal adverse events, while levodopa with International Restless Legs Syndrome Study Group Rating benserazide was associated with more nervous system Scale (IRLS) score ≥ 21 before starting pramipexole.* adverse events.2 Patients must meet all 4 of the diagnostic criteria for restless legs syndrome (see Box 1). Place in therapy Pramipexole is not PBS subsidised for restless legs Pramipexole is the only dopamine agonist currently syndrome secondary to other causes. PBS listed for treating the symptoms of restless legs syndrome. It may be useful if frequent symptoms Reason for PBS listing severely affect a patient's quality of life and non-drug The Pharmaceutical Benefits Advisory Committee (PBAC) measures prove ineffective. Modest symptomatic recommended listing pramipexole for severe primary benefits need to be weighed against common adverse restless legs syndrome on the basis that it was no worse effects, as well as the possibility of sleep attacks or than levodopa with benserazide in effectiveness and other less common serious problems. Evidence for safety for the same cost. The comparison was based efficacy beyond 3 months is limited and observations on 1 unpublished randomised controlled trial.1 suggest that it declines over time. * The date and IRLS score must be recorded when starting pramipexole. April 2009 Pramipexole (Sifrol) Restless legs syndrome is an idiopathic Guidelines recommend levodopa with either carbidopa sensorimotor disorder or benserazide for occasional use in intermittent restless legs syndrome3, but augmentation limits levodopa's Restless legs syndrome consists of a pattern of usefulness for treating daily symptoms. symptoms involving an urge to move the legs because of unpleasant sensations. Symptoms are worse or only Diagnose from symptoms and medical history present at rest, worse or only present in the evening or Patients must meet all 4 diagnostic criteria, assessed night-time, and are relieved by movement (see Diagnose on patient report of symptoms (see Box 1). Exclude from symptoms and medical history). The diagnosis differential diagnoses, consisting of other conditions covers a spectrum from mild and harmless to severe that cause discomfort or involuntary movements and distressing. As the pathology is unknown and no of the limbs. These include leg cramps, positional objective test exists, diagnosis is based on patient discomfort, arthritis, neuropathy, and drug-induced report of symptoms, according to consensus criteria. akathisia (e.g. as side effects of antipsychotics, Pramipexole is a non-ergot-derived metoclopramide, or antidepressants).4,7,8 06 dopamine agonist If there is doubt about the diagnosis, refer to Pramipexole is a dopamine agonist, first developed a neurologist with an interest in movement disorders, for treating Parkinson's disease. Although it has been or a sleep specialist. registered in Australia for this indication for some time, Many people with restless legs syndrome also it has been marketed only since June 2008. Pramipexole experience periodic limb movements in sleep (PLMS), and ropinirole, another non-ergot-derived dopamine possibly with associated sleep disturbance. However, agonist, are the first drugs approved by the TGA for periodic limb movements in sleep are not sufficient restless legs syndrome. Currently only pramipexole is to diagnose restless legs syndrome and do occur PBS subsidised for restless legs syndrome. independently of it.3 Pramipexole may be useful for severe restless legs syndrome Box 1: Consensus essential diagnostic criteria for restless legs syndrome9 If the patient reports significant distress from restless legs syndrome that cannot be managed by non-drug 1. An urge to move the legs, usually accompanied or caused measures (see Suggest non-drug measures), consider by uncomfortable and unpleasant sensations in the legs drug treatment in the context of a full discussion about (sometimes the urge to move is present without the the potential symptomatic benefit and possibility of uncomfortable sensations and sometimes the arms or other adverse effects. body parts are involved in addition to the legs). Australian guidelines recommend a non-ergot-derived 2. The urge to move or unpleasant sensations begin or worsen dopamine agonist for pharmacotherapy of restless legs during periods of rest or inactivity such as lying or sitting. syndrome when symptoms are frequent (e.g. daily).3 3. The urge to move or unpleasant sensations are partially or Indirect and unpublished data, together with experience totally relieved by movement, such as walking or stretching, with other dopamine agonists, suggest that pramipexole at least as long as the activity continues. is less likely than levodopa preparations to worsen 4. The urge to move or unpleasant sensations are worse symptoms with long-term use (a phenomenon known in the evening or night than during the day or only occur as augmentation), but that levodopa preparations are in the evening or night (when symptoms are very severe, better tolerated.4,5 Refer to a specialist if initial the worsening at night may not be noticeable but must treatment is not effective.3 have been previously present). The safety and efficacy of pramipexole have not been Supportive clinical features: evaluated in children and adolescents under 18 years • Positive family history of restless legs syndrome old.6 Children and adolescents with restless legs syndrome that cannot be managed by non-drug • Response to dopaminergic drug treatment measures should be assessed by a specialist. • Periodic limb movements. April 2009 Pramipexole (Sifrol) Grade severity with the IRLS Rating Scale Pramipexole is modestly effective To assess the severity and significance of restless In one 12-week double-blind trial in people with leg symptoms, and to determine eligibility for PBS- moderate to severe restless legs syndrome, the treating subsidised drug treatment, use the International physicians rated 66% of participants receiving Restless Legs Syndrome Study Group Rating Scale pramipexole as 'much' or 'very much' improved, questionnaire. Scores on this scale correlate with compared with 40% of participants receiving placebo.13 the subjective clinical global impression (CGI) ratings Other placebo-controlled trials reported similar results.14 of expert examiners (correlation coefficient r = 0.74).10 While trials consistently found improvements in patient- The questionnaire consists of 10 items asking reported sleep quality, daytime sleepiness was not the patient to report the severity of the primary improved significantly.13,15,16 symptoms, sleep quality and day-to-day disability. Scores on the scale range from 0–40, with scores Effectiveness of pramipexole may decrease 07 of 11–20 designated moderate, 21–30 designated over time severe, and 31–40 designated very severe. In non-comparative trials of up to 9 months, most The questionnaire is freely available for individual patients continued to respond to pramipexole.6 While clinical practice after completing a user agreement efficacy did not decrease over periods up to 12 weeks form. The form and questionnaire are available on-line in randomised controlled trials, observations suggest to be printed out and administered by GPs. See that pramipexole becomes less effective over time. www.mapitrust.org/services/questionnairelicensing Meta-regression analysis of short-term trials, as well /cataloguequestionnaires/65-irls as an unpublished 46-week non-comparative trial found that symptoms became worse with time during Investigate possible causes of secondary pramipexole treatment.14,17 Increasing pramipexole restless legs syndrome doses were recorded in 1 of 2 case series during long- Known reversible causes of restless legs syndrome term treatment.18,19 include iron deficiency, pregnancy and renal failure.3 Chronic dopaminergic therapy can cause Test serum ferritin concentration. Iron-replacement augmentation of symptoms therapy may benefit individuals with low-normal serum ferritin concentrations. Guidelines suggest a cut-off Augmentation is a common consequence of chronic of 50 micrograms/mL.8 use of levodopa in restless legs syndrome, and can also occur with dopamine agonists. Augmentation typically Suggest non-drug measures involves daytime symptoms becoming more frequent or intense than they were before treatment began, Many people manage their restless leg symptoms or shifting to an earlier time in the day.9 using a variety of non-drug measures (see Box 2).4 The efficacy of these measures has not been assessed Refer patients experiencing augmentation to rigorously, but they are largely low cost and low risk. a specialist. Most cases can be reversed with a change One small randomised controlled trial found that in dosing frequency, by lowering the dose, by switching a 12-week program of regular aerobic exercise and drugs or by stopping dopaminergic therapy.3 lower-body resistance training significantly improved Controlled trials of pramipexole have been too short restless legs syndrome symptoms.11 to establish how often augmentation occurs or how More than a third of patients in clinical trials of to manage it.6 In a retrospective case-series analysis, pharmacological treatments had a major improvement over an average of 2 years of pramipexole treatment, in restless leg symptoms while receiving placebo.12 one-third of patients developed augmentation, on average 9 months after starting treatment.19 Discuss sleep hygiene measures if restless leg symptoms are causing insomnia.3 April 2009 Pramipexole (Sifrol) Safety issues Nausea is very common, especially early in treatment The adverse-effect profile of pramipexole is largely a consequence of its activity at dopamine receptors. Among people receiving pramipexole in clinical trials, 16% The frequency of adverse events increases with dose20 reported nausea, and 1% discontinued treatment because (note that doses are higher in Parkinson's disease than of it. The symptoms were generally mild and transient.6 in restless legs syndrome). There was 1 report of Nausea and fatigue were reported by women more often hallucinations in clinical trials for restless legs syndrome than men.23 In one case series, 5% of patients received from a total of 889 people who received pramipexole.6 a prescription for domperidone (Motilium) for nausea.18 Postural hypotension was not significant in trials, but Dopamine agonists may cause blood pressure monitoring may be required, especially at compulsive behaviours the start of therapy and in severe cardiovascular disease.6 There have been several reports of pathological Report suspected adverse reactions to the Therapeutic gambling by people taking pramipexole for restless legs Goods Administration (TGA) online (www.ebs.tga.gov.au 08 syndrome.24,25 The risk may be lower than in Parkinson's [then click 'Adverse reactions to a Medicine']) or by using disease where higher doses of dopamine agonists are the 'Blue Card' distributed with Australian Prescriber. used. Other compulsive behaviours that occur rarely For information about reporting adverse reactions, see with dopamine agonists prescribed for Parkinson's the TGA website (www.tga.gov.au). disease include hypersexuality and binge eating.26 Pramipexole can cause somnolence Inform patients and carers that there is a small risk and sleep attacks but that the consequences can be serious, and to seek Somnolence was a common drug-related adverse effect medical advice if concerned.6 in restless legs trials.6 Sudden onset of sleep during Theoretical risk of retinal degeneration daily activities — in some cases without awareness or warning signs ('sleep attack') — has been reported in Pramipexole caused retinal degeneration in albino people with Parkinson's disease receiving pramipexole21, rats during preclinical safety testing. Similar tests as have a few cases during clinical trials for restless legs with pigmented rats found no effect, and assessment syndrome.6,16,17,22 of a group of Parkinson's disease patients treated with pramipexole for an average of 4 years found Advise patients not to drive or perform other no increased rate of retinal degeneration.6 dangerous tasks until they are used to the effects of pramipexole. Dosing issues Patients who have a sleep attack should refrain from driving and other dangerous activities until they For restless legs syndrome, pramipexole is taken receive medical advice (see Information for patients). as a single daily dose 2–3 hours before bedtime. Consider dose reduction or discontinue pramipexole The starting dose is pramipexole 125 micrograms daily. in these cases.6 Increase as required every 4–7 days to a maximum of 750 micrograms daily.6 Note that even the lowest dose Pramipexole is not recommended significantly reduces symptoms, and that there is in pregnancy or breastfeeding no documented increase in response rate with doses There is a lack of clinical data in pregnancy, along with higher than 500 micrograms daily.15,23 evidence that pramipexole impairs implantation and Lengthen the time between titration steps to 14 days disrupts early pregnancy in rats (ADEC Category B3).6 for people with creatinine clearance 20–60 mL/minute.23 Pramipexole is expected to inhibit lactation because of Assess response to treatment regularly (e.g. after its effects on prolactin. It may be excreted into breast 3 months) to decide if pramipexole should be stopped milk and should not be used during breastfeeding.6 or the dose adjusted to improve the balance of efficacy April 2009 Pramipexole (Sifrol) and adverse effects. If initial treatment is not effective, • to take the tablets with water, with or without food, refer to a specialist.3 2–3 hours before bedtime Centrally active dopamine antagonists (i.e. antipsychotics • that nausea and sleepiness are common side effects, or metoclopramide) diminish the effect of pramipexole. but these may decrease with time These drugs should not be used with pramipexole.6 • not to drive or perform dangerous tasks requiring Some renally excreted drugs may interact with constant attention until accustomed to the side effects pramipexole, with reduced clearance of either or both • that sedatives or alcohol may worsen any drowsiness drugs. This group consists of drugs that inhibit the • to contact their doctor if their symptoms worsen.27 active renal tubular secretion of basic (cationic) drugs and drugs that are eliminated by this pathway, and Discuss the Sifrol consumer medicine information (CMI) includes amantadine, cimetidine, digoxin, diltiazem, leaflet with the patient. quinine, ranitidine, triamterene, trimethoprim, and verapamil. Consider dose reductions when Discuss non-drug approaches to managing 09 restless leg symptoms administering these drugs with pramipexole, and observe for signs of dopamine overstimulation, See Box 2 for examples. Patient support groups such such as dyskinesias, agitation or hallucinations.6 as Restless Legs Syndrome Australia can offer advice At the usual doses for restless legs syndrome, and support, including suggestions for useful coping pramipexole can be stopped without tapering. However, strategies and non-drug measures. See www.rls.org.au some patients in clinical trials experienced a worsening for details. of symptoms after stopping pramipexole abruptly. Box 2. Commonly used low-risk measures to manage Most cases of worsening resolved within a week.6 restless leg symptoms9,28 Information for patients • Very hot or very cold baths Advise patients: • Physical activity, particularly involving the limbs, just before bedtime (excessive exercise may increase symptoms) • that pramipexole may cause sudden attacks of sleepiness in some people • Stretching • if they have a sleep attack at any time to refrain • Massage from driving and contact a doctor • Relaxation techniques (e.g. biofeedback, meditation, • that pramipexole could make them more susceptible or yoga) to compulsive behaviours • Engrossing mental activity (e.g. reading, doing needlework, or playing video games) April 2009 Pramipexole (Sifrol) References 1. Australian Government Department of Health and 10. Walters AS, et al. Sleep Med 2003;4:121–32. 22. Boehringer Ingelheim International GmbH. Trial Ageing. Public summary document for pramipexole, 11. Aukerman MM, et al. J Am Board Fam Med number 248.518 Tabulated Study Report. 2005. tablet, 125 micrograms and 250 micrograms, Sifrol 2006;19:487–93. http://trials. boehringer-ingelheim.com/res/trial/data/pdf November 2008. http://www.health.gov.au/internet 12. Fulda S, Wetter TC. Brain 2008;131:902–17. /248.518_new.pdf (accessed 22 December 2008). /main/publishing.nsf/Content/pbac-psd-pramipexole- 23. Boehringer Ingelheim Pharmaceuticals Inc [USA]. 13. Ferini-Strambi L, et al. Sleep Med 2008;9:874–81. nov08 (accessed 6 March 2009). Mirapex (pramipexole) prescribing information. 14. Baker WL, et al. Ann Fam Med 2008;6:253–62. 2. Australian Government Department of Health and Ageing. 31 December 2008. http://www.fda.gov/cder/foi Public summary document for pramipexole, tablet, 15. Partinen M, et al. Sleep Med 7:407–17. /label/2006/020667s011s013lbl.pdf (accessed 125 micrograms and 250 micrograms, Sifrol July 2007. 16. Winkelman JW, et al. Neurology 2006;67:1034–9. 20 February 2009). http://www.health.gov.au/internet/main/publishing.nsf 17. Boehringer Ingelheim International GmbH. Trial 24. Quickfall J, Suchowersky O. Parkinsonism Relat Disord /Content/pbac-psd-pramipexole-hydrochloride-july07 number 248.520 Tabulated Study Report. 2005. 2007;13:535–6. (accessed 10 December 2008). http://trials. boehringer-ingelheim.com/res/trial/data 25. Tippmann-Peikert M, et al. Neurology 2007;68:301–3. 3. Psychotropic writing group. Therapeutic Guidelines: /pdf/248.520__ U05-1394-01_new.pdf 26. Medicines and Healthcare Products Regulatory Agency Psychotropic. Melbourne: Therapeutic Guidelines (accessed 22 December 2008). [UK]. Dopamine Agonists: Pathological Gambling and Limited, 2008. 18. Montplaisir J, et al. Eur J Neurol 2006;13:1306–11. Increased Libido: Public Assessment Report. 4. Hening W, et al. Sleep 1999;22:970–99. 19. Winkelman JW, Johnston L. Sleep Med 2004;5:9–14. http://www.mhra.gov.uk/Safetyinformation/Safetywarnings 5. Trenkwalder C, et al. Mov Disord 2007;22:696–703. 20. European Medicines Agency. European Public Assessment alertsandrecalls/Safetywarningsandmessagesformedicines 6. Boehringer Ingelheim Pty Limited. Sifrol product Report for Mirapexin. EMEA/H/C/134/II/36. 6 April 2006. /CON2025151 (accessed 16 December 2008). 10 information. 11 August 2008. Scientific Discussion. http://www.emea.europa.eu 27. Boehringer Ingelheim Pty Limited. Sifrol consumer 7. Hening WA, et al. Sleep Med 2009 /humandocs/PDFs/EPAR/Mirapexin/Mirapexin-H-C-134- medicine information. 23 October 2008. doi:10.1016/j.sleep.2008.09.015. II-36-SD.pdf (accessed 15 December 2008). 28. Thorpy MJ. Neurology 2005;64:S28–33. 8. Silber MH, et al. Mayo Clin Proc 2004;79:916–22. 21. Homann CN, et al. BMJ (Clinical Research edn) 2002;324:1483–7. 9. Allen RP, et al. Sleep Med 2003;4:101–19. Date published: April 2009 The information contained in NPS RADAR is derived from a critical analysis of a wide range of authoritative evidence and is current at the time of publication. Any treatment decisions based on the information provided in NPS RADAR should be made in the context of the clinical circumstances of each patient. NPS RADAR articles may be updated when there is new evidence about safety or efficacy, or in case of regulatory or PBS listing changes. Please refer to www.npsradar.org.au for the most recent version as well as any supplementary information. April 2009 Valsartan (Diovan) and combinations with hydrochlorothiazide (Co-Diovan) or amlodipine (Exforge) (val-SAR-tan) Summary Valsartan reduces blood pressure to a similar extent as other angiotensin II-receptor antagonists. If blood pressure is not controlled by valsartan 160 mg, add a second drug rather than increasing the dose to 320 mg. Increasing the dose from 160 mg to 320 mg provides marginal additional blood pressure reduction. Establish the effective dose using individual drugs before prescribing the appropriate combination. Check electrolytes and renal function before and 1–2 weeks after starting valsartan, after each dose increment or if changed clinical circumstances are likely to worsen renal function (e.g. dehydration). 11 Avoid angiotensin II-receptor antagonists (including valsartan) in combination with a nonsteroidal anti-inflammatory drug and a diuretic (including hydrochlorothiazide) — particularly in elderly people or people with pre-existing renal impairment — because combining these 3 drug classes increases the risk of acute renal failure. PBS listing The PBAC recommended valsartan with hydrochloro- thiazide or amlodipine for listing on a cost-minimisation Valsartan (Diovan) — unrestricted benefit basis compared with the corresponding strengths of the individual drugs given concomitantly.3,4 Valsartan is listed on the Pharmaceutical Benefits Scheme (PBS) as an unrestricted benefit1, as are other angiotensin II-receptor antagonists.2 Place in therapy Valsartan with hydrochlorothiazide Valsartan is an angiotensin II-receptor antagonist (Co-Diovan) or amlodipine (Exforge) — that has been available overseas for several years. restricted benefit Angiotensin II-receptor antagonists have similar blood pressure reducing effects to those of other major Valsartan with hydrochlorothiazide (Co-Diovan) antihypertensive drug classes.5,6 This class of drugs is or amlodipine (Exforge) is restricted for people an option for initial therapy for people with hypertension with hypertension not controlled with valsartan, and may be useful for those with particular comorbidities hydrochlorothiazide or amlodipine monotherapy.3,4 (e.g. diabetic nephropathy) or intolerances (e.g. angiotensin-converting enzyme [ACE] inhibitor-induced Reason for PBS listing cough). Other options for initial therapy include low- The Pharmaceutical Benefits Advisory Committee dose thiazide diuretics, dihydropyridine calcium-channel (PBAC) recommended valsartan for listing on a cost- blockers or angiotensin-converting enzyme inhibitors.7 minimisation basis — that is, similar efficacy and cost — with irbesartan. The equi-effective doses were taken to be valsartan 320 mg and irbesartan 300 mg.1 April 2009 Valsartan (Diovan) If blood pressure is not controlled by valsartan 160 mg, Figure 1: Mean reduction in trough systolic/diastolic add a second drug from a different pharmacological blood pressure (mmHg) with valsartan.13 class rather than increasing the valsartan dose to 320 mg,7 and consider comorbidities when choosing Systolic BP reduction (mmHg) the second drug (see Add a second drug for people Diastolic BP reduction (mmHg) with hypertension not controlled by monotherapy). For more information about managing hypertension Valsartan dose (mg) as a cardiovascular risk factor, refer to NPS News 52 80 160 320 0 and Prescribing Practice Review 38.8,9 -1 Valsartan is also indicated for people with heart failure -2 (New York Heart Association Class II–IV) unable to -3 tolerate an angiotensin-converting enzyme inhibitor, -4 and to improve survival after myocardial infarction in -5 people who are clinically stable and have left ventricular mmHg -6 failure or dysfunction.10 For more information about -7 treating people with heart failure, refer to NPS News 57 -8 and Prescribing Practice Review 41.11,12 -9 Valsartan reduces blood pressure -10 12 to a similar extent as other angiotensin -11 II-receptor antagonists -12 -13 A meta-analysis of 46 short-term trials showed that -14 all 9 angiotensin II-receptor antagonists assessed — including valsartan — reduced trough blood pressure to a similar extent: on average, systolic blood pressure Add a second drug for people with was reduced by about 8 mmHg and diastolic blood hypertension not controlled by monotherapy pressure by about 5 mmHg. However, the true blood pressure reduction may be less because the meta- If target blood pressure reduction is not achieved with analysis showed some publication bias. Up to 70% monotherapy, guidelines suggest adding a second drug of trough blood pressure reduction achieved by (from a different pharmacological class (e.g. thiazide angiotensin II-receptor antagonists occurs at the diuretic, calcium-channel blocker) at a low dose rather recommended starting doses.13 than increasing the dose of the first drug. This maximises blood pressure reduction while minimising Increasing the dose of valsartan from adverse reactions.7 Combining valsartan with 160 mg to 320 mg provides marginal hydrochlorothiazide or amlodipine achieves significant additional blood pressure reduction additional blood pressure reduction (Figures 2, 3). Consider the combination of an angiotensin II-receptor Valsartan reduces blood pressure across its dose range, antagonist(e.g. valsartan) with a: though an 80 mg dose achieves near maximal blood pressure reduction.13 Increasing the valsartan dose from • thiazide diuretic (e.g. hydrochlorothiazide) for people 160 mg to 320 mg provides marginal additional blood with hypertension and heart failure pressure reduction (see Figure 1). This is unlikely to be • calcium-channel blocker (e.g. amlodipine) for people clinically meaningful and increasing the dose increases with hypertension and diabetes. the risk of adverse reactions.13,14 April 2009 Valsartan (Diovan) Figure 2: Placebo-adjusted mean reduction in sitting systolic and diastolic blood pressure (mmHg) at week 8: valsartan and hydrochlorothiazide*.15,16 Systolic Diastolic hiaz ide Valsartan hiazide Valsartan Hydrochlorot Hydrochlorot dose (mg) dose (mg) dose (mg) dose (mg) 25 320 160 25 320 160 placebo 12.5 80 placebo placebo 12.5 80 placebo 0 0 0 0 –4 –3 –5 –5 –5 –5 –5 –5 –5 –5 –7 –8 –8 –8 –9 –10 –10 –10 –10 –10 –11 –11 –10 –10 –16 –15 –15 –15 –15 –15 –15 –19 –19 –20 –21 –20 –20 –20 13 –25 –25 –25 –25 * Mean sitting diastolic blood pressure inclusion criteria for the two trials were slightly different, so these figures are an average15,16 Figure 3: Placebo-adjusted mean reduction in sitting systolic and diastolic blood pressure (mmHg) at week 8: valsartan and amlodipine.17 Systolic Diastolic Amlodipine Valsartan Amlodipine Valsartan dose (mg) dose (mg) dose (mg) dose (mg) 5 10 320 160 5 10 320 160 80 80 placebo 2.5 40 placebo placebo 2.5 40 placebo 0 0 0 0 -3 -3 –5 –5 –5 -5 -4 -5 –5 –6 -7 -7 -7 -4 -7 –7 –7 -8 –8 –9 –9 –10 –10 –10 –10 –10 –10 -8 –10 –11 -9 -8 -8 –12 –9 –13 -10 –13 –16 –15 –15 –15 –15 –15 –16 –16 N/A N/A N/A N/A –20 –20 –20 –20 April 2009 Valsartan (Diovan) Consider a fixed-dose combination for people Report suspected adverse reactions to the Therapeutic on stable doses of the individual drugs Goods Administration (TGA) online (www.ebs.tga.gov.au) or by using the 'Blue Card' distributed with Australian Fixed-dose combination therapy may be a more Prescriber. For information about reporting adverse convenient option for people who have inadequate reactions, see the TGA website (www.tga.gov.au). blood pressure control with monotherapy and whose doses of the individual drugs in combination are stable. Compared with taking valsartan, hydrochlorothiazide Dosing issues or amlodipine as separate tablets, the combination In hypertension, the usual dose of valsartan is 80 mg tablets allow people to take fewer tablets each day once daily. Maximum blood pressure reduction is seen and are cheaper because only one co-payment is required after 4 weeks: if necessary, increase to 160 mg once daily. for both medicines. However, the usual considerations that apply to combination tablets remain important.18 Add a second drug for people whose blood pressure is Do not start valsartan, amlodipine or hydrochlorothiazide not controlled by valsartan 160 mg once daily. Increasing therapy with a fixed-dose combination. Establish the once daily dose from 160 mg to 320 mg provides the effective dose using the individual drugs before marginal additional blood pressure reduction. prescribing the appropriate combination.7 Consider Lower starting doses and maximum doses are whether the available strengths of the combination recommended for people aged over 75 years, allow the same doses of valsartan, hydrochlorothiazide people with mild to moderate hepatic impairment or amlodipine to be given: not all strengths of each drug 14 or a creatinine clearance < 30 mL/minute.5,10 are available in a combination tablet (see Table 1). Consider prescribing the appropriate combination when valsartan has been added to hydrochlorothiazide Safety issues or amlodipine and the effective doses have been Some common adverse effects for valsartan include established and are stable (Table 1). dizziness, hypotension and hyperkalaemia.10 In heart failure or after myocardial infarction, valsartan As for all angiotensin II-receptor antagonists: is given twice daily, usually starting with a lower dose than for hypertension.5,10 • stop potassium supplements and potassium-sparing diuretics before starting valsartan5 Table 1: Dose strengths, appearance and availability on • valsartan can worsen renal impairment10 and increase the PBS of valsartan, valsartan with hydrochlorothiazide the risk of renal failure5 and valsartan with amlodipine10,21,22 • check electrolytes and renal function before and Doses Packet colour Tablet colour, shape 1–2 weeks after starting valsartan, after each dose valsartan increment or if changed clinical circumstances are 40 mg light blue yellow, oval, scored likely to worsen renal function (e.g. dehydration)6 80 mg light medium blue pale red, round, scored • valsartan is contraindicated in pregnant women and 160 mg medium blue grey-orange, oval, scored women planning to become pregnant because it may 320 mg dark medium blue grey-violet, oval cause foetal and neonatal morbidity and death10 valsartan with hydrochlorothiazide • avoid valsartan in breastfeeding women (there are 80 mg/12.5 mg pink light orange, oval no data for this group)5 160 mg/12.5 mg red dark red, oval • avoid angiotensin II-receptor antagonists (including 160 mg/25 mg red brown-orange, oval valsartan) in combination with a nonsteroidal valsartan with amlodipine anti-inflammatory drug and a diuretic (including 80 mg/5 mg dark blue with dark yellow, round hydrochlorothiazide) — particularly in elderly people an orange stripe or those with pre-existing renal impairment — 160 mg/5 mg dark blue with dark yellow, oval because combining these 3 drug classes increases a light blue stripe the risk of acute renal failure.19,20 160 mg/10 mg dark blue with light yellow, oval a red stripe April 2009 Valsartan (Diovan) Information for patients • to have their renal function and electrolytes (including potassium) checked 1–2 weeks after starting therapy Advise patients: and at each dose change • to take valsartan or valsartan-containing combination • to tell their doctor or pharmacist that they are tablets at about the same time each day taking valsartan with hydrochlorothiazide if they • which of their existing medicines are being replaced need medicines to treat pain (e.g. nonsteroidal by valsartan or valsartan-containing combination anti-inflammatory drugs). tablets and to discard the unneeded medicines Discuss the Diovan, Co-Diovan or Exforge consumer • that some common adverse effects for valsartan medicine information (CMI) leaflet with the patient. include dizziness, hypotension and hyperkalaemia References 1. Pharmaceutical Benefits Advisory Committee. Positive 8. National Prescribing Service. Managing hypertension as 13. Heran BS, et al. Cochrane Database Syst Rev recommendations made by the Pharmaceutical Benefits a cardiovascular risk factor. NPS News 52. Sydney: 2008;4:CD003822. Advisory Committee (PBAC) in July 2008 relating to the National Prescribing Service, 2007. 14. Medicines and Healthcare Products Regulatory Agency. listing of drugs on the Pharmaceutical Benefits Scheme http://nps.org.au/health_professionals/publications/nps_ Diovan 320 mg tablets PL00101/0726 UKPAR. London: 15 (PBS). Canberra: Australian Government Department of news/current/nps_news_52/managing_hypertension_as MHRA, 2008. http://www.mhra.gov.uk/home/groups/l- Health and Ageing, 2008. http://www.health.gov.au/ _a_cardiovascular_risk_factor (accessed 29 October 2008). unit1/documents/websiteresources/con2033064.pdf internet/main/publishing.nsf/Content/pbacrec-jul08- 9. National Prescribing Service. Managing hypertension as (accessed 29 October 2008). positive (accessed 29 October 2008). a cardiovascular risk factor Prescribing Practice Review 15. Benz JR, et al. J Hum Hypertens 1998;12:861–6. 2. Department of Health and Ageing. PBS for Health 38. Sydney: National Prescribing Service, 2007. Professionals. Canberra: Australian Government, 2008. http://nps.org.au/health_professionals/publications 16. Pool JL, et al. Clin Ther 2007;29:61–73. www.pbs.gov.au (accessed 29 October 2008). /prescribing_practice_review/editions/current/prescribing _practice_review_38/managing_hypertension_as_a_ 17. Philipp T, et al. Clin Ther 2007;29:563–80. 3. Pharmaceutical Benefits Advisory Committee. Public cardiovascular_risk_factor (accessed 29 October 2008). 18. Moulds RFW. Aust Prescr 2001;24:127–9. summary document: valsartan with hydrochlorothiazide, tablets, 80 mg-12.5 mg, 160 mg-12.5 mg and 160 mg- 10. Novartis Pharmaceuticals Australia Pty Limited. Diovan 19. Adverse Drug Reactions Advisory Committee. Australian 25 mg. Canberra: Australian Government Department product information. 21 May 2008. Adverse Drug Reactions Bulletin 2006;25:18. of Health and Ageing, 2008. http://www.health.gov.au/ http://www.novartis.com.au/products_healthcare.html internet/main/publishing.nsf/Content/pbac-psd- (accessed 3 November 2008). 20. Adverse Drug Reactions Advisory Committee. Australian valsartan-july08 (accessed 6 November 2008). Adverse Drug Reactions Bulletin 2003;22:14–5. 11. National Prescribing Service. Improving outcomes in 4. Pharmaceutical Benefits Advisory Committee. Public chronic heart failure by early detection, drug therapy 21. Novartis Pharmaceuticals Australia Pty Limited. summary document: amlodipine besylate with valsartan, and patient support. NPS News 57. Sydney: National Co-Diovan product information. 23 June 2008. tablet, 5 mg-80 mg, 5 mg-160 mg, 10 mg-160 mg. Prescribing Service, 2008. http://www.novartis.com.au/products_healthcare.html Canberra: Australian Government Department of Health http://nps.org.au/health_professionals/publications (accessed 3 November 2008). and Ageing, 2008. http://www.health.gov.au /nps_news/current/nps_news_57/improving_outcomes_ 22. Novartis Pharmaceuticals Australia Pty Limited. Exforge / internet/main/publishing.nsf/Content/pbac-psd- in_chronic_heart_failure_by_early_detection,_drug_the product information. 21 May 2008. amlodipine-july08 (accessed 6 November 2008). rapy_and_patient_support (accessed 29 October 2008). http://www.novartis.com.au/products_healthcare.html 5. Australian Medicines Handbook, 2008. 12. National Prescribing Service. Improving outcomes in (accessed 3 November 2008). chronic heart failure. Prescribing Practice Review 41. 6. Therapeutic Guidelines: Cardiovascular. Version 5. Sydney: National Prescribing Service, 2008. 7. National Blood Pressure and Vascular Disease Advisory http://nps.org.au/health_professionals/publications Committee. Guide to management of hypertension /prescribing_practice_review/editions/current/prescribing 2008: assessing and managing raised blood pressure in _practice_review_41/improving_outcomes_in_chronic_ adults. Sydney: National Heart Foundation, 2008. heart_failure (accessed 29 October 2008). http://www.heartfoundation.org.au/Professional_Information /Clinical_Practice/Hypertension/Pages/default.aspx Date published: March 2009 The information contained in NPS RADAR is derived from a critical analysis of a wide range of authoritative evidence and is current at the time of publication. Any treatment decisions based on the information provided in NPS RADAR should be made in the context of the clinical circumstances of each patient. NPS RADAR articles may be updated when there is new evidence about safety or efficacy, or in case of regulatory or PBS listing changes. Please refer to www.npsradar.org.au for the most recent version as well as any supplementary information. April 2009 In Brief A digest of news items about NPS RADAR, new drugs and changes to PBS listings. Clopidogrel (Iscover, Plavix) PBS listing In the CLARITY study, in which 3491 patients were extended to include acute coronary followed for 30 days, there was an absolute risk syndrome (ACS) in combination with aspirin reduction of 6.7% in the primary outcome (occluded infarct-related artery on angiography, death or recurrent Clopidogrel and aspirin can now be prescribed MI before angiography) in patients receiving clopidogrel in combination for acute coronary syndrome (ACS) and aspirin, compared with those receiving aspirin alone.3 as an authority (streamlined) item on the Pharmaceutical Benefits Scheme (PBS). The extended listing, which came In the CURE study, 12562 patients were randomised into effect on 1 February 2009, includes the treatment to receive clopidogrel and aspirin, or aspirin alone, of myocardial infarction (MI) or unstable angina to for 3–12 months (mean treatment duration 9 months). prevent early and long-term atherothrombotic events. The absolute risk of death from cardiovascular causes, non-fatal MI or stroke was reduced by 2.1% in patients The Pharmaceutical Benefits Advisory Committee receiving clopidogrel and aspirin, compared with those (PBAC) agreed that clopidogrel plus aspirin is more receiving aspirin alone.2 effective in ACS than aspirin therapy alone, but is associated with a higher risk of bleeding.1 In clinical Optimal duration of clopidogrel therapy is unknown trials of patients with ACS, the benefit of combined The optimal duration of clopidogrel therapy in ACS therapy exceeded risk.2,3 In summary: is unknown. It will depend on individual medical • there is a higher risk of bleeding with combined therapy circumstances and may be influenced by the category of ACS index event, type of stent implanted (if relevant), • for about every 3 serious cardiovascular events 16 the absolute risk of further ischaemic events and the risk prevented in ACS patients without ST-segment- of bleeding (see Potential risk for major bleeding). elevation, 1 patient will experience a major bleed The decision to discontinue antiplatelet therapy after requiring transfusion2 ACS or stent implantation, including discontinuation • there is a possibility of rebound cardiac effects after for surgery, should be made in consultation with the stopping clopidogrel patient's cardiologist.7,8 After withdrawing clopidogrel, • the optimal duration of combined therapy is unknown, low-dose aspirin (unless contraindicated) should be and should be determined on an individual basis. continued indefinitely.6 Current Australian guidelines recommend clopidogrel Place in therapy 75 mg daily in addition to aspirin in the medical Consider clopidogrel in combination with aspirin for management of high-risk non-ST-segment elevation ACS patients with ACS (unstable angina, non-ST-segment- (duration of therapy not specified).6 Patients with ST- elevation MI or ST-segment-elevation MI).4,5 If possible, segment-elevation MI should take clopidogrel (75 mg clopidogrel should be discontinued 5 days before coronary daily) for at least 1 month after fibrinolytic therapy, artery bypass surgery, and avoided in patients likely to and for up to 12 months after stent implantation*.6 undergo emergency coronary artery bypass surgery.6 The optimal duration of clopidogrel therapy may be Clopidogrel prevents thrombotic events and deaths greater in patients treated with a drug-eluting stent, compared with those treated with a bare metal stent.7,9 The extended listing was informed by two randomised, double-blind clinical trials. One study (CLARITY) enrolled Formal studies assessing extended or indefinite periods patients with ST-segment-elevation MI3 and the other of clopidogrel therapy, tapering of clopidogrel therapy, (CURE) enrolled patients with ACS without ST-segment- or bridging of clopidogrel cessation to transient high-dose elevation.2 aspirin have not been conducted in patients with ACS. * Depending on the type of stent and circumstances of implantation. April 2009 In Brief Potential risk for major bleeding stopping clopidogrel and was nearly twice that found in the following 3 months. However, the absolute risk Combined therapy is associated with a small absolute in the first 3 months after stopping was small; 0.57 increased risk of bleeding. However, in clinical trials deaths or acute MIs per 1000 patient days of follow-up the benefit of clopidogrel and aspirin in patients with in PCI-treated patients and 1.31 in medically treated ACS with or without ST-segment-elevation outweighed patients. The rate of events in medically treated patients the risk of major bleeding. during the first 3 months after stopping clopidogrel Data from the CURE study indicate that for about treatment was higher than that for the first 3 months every 3 serious cardiovascular events prevented in ACS of clopidogrel treatment, and the subsequent 9 months patients without ST-segment-elevation, 1 patient will of treatment. experience a major bleed requiring transfusion.2 Any decision to discontinue clopidogrel therapy The risk of any major bleeding* in patients receiving should be made in consultation with the patient's clopidogrel and aspirin therapy was small, but it was cardiologist and include an assessment of the individual higher than that of patients receiving aspirin alone risk of recurrent vascular events against the risk of at 12 months.2 major bleeding. In the CLARITY study, the incidence of major bleeding was not significantly greater in patients receiving Reason for PBS listing clopidogrel and aspirin than those receiving aspirin The PBAC recommended a streamlined authority alone during the day after angiography or at 30 days.3 listing of clopidogrel for the treatment of ACS in The CURE trial excluded patients at high risk for severe combination with aspirin. The decision was reached heart failure or bleeding (not otherwise specified), on the basis of acceptable cost-effectiveness compared and those taking oral anticoagulants. Therefore, use with aspirin alone. clopidogrel with caution in this population and inform Information for patients and carers 17 patients that bleeding may take longer than usual to stop while taking clopidogrel. Monitor patients for signs Advise patients and carers of the following: of bleeding, particularly during the first few weeks • clopidogrel and aspirin can be used together for heart of treatment and after invasive procedures or surgery. attack or unstable angina Advise patients or carers to immediately report unusual • both medicines can cause bleeding, and the risk bleeding or bruising, abnormal nose bleeds or bloody of major bleeding is increased when they are or black bowel motions.4,5 used together Risk of rebound cardiovascular events on cessation • immediately report unusual bleeding or bruising, A retrospective study found an increased risk of abnormal nose bleeds or bloody or black bowel motions death or acute MI (rebound effects) after stopping • aspirin must be continued, even if clopidogrel clopidogrel.10 The absolute increase in risk was small. is stopped. This effect has not been confirmed in a randomised controlled trial, and it is not known how the increased References risk after stopping clopidogrel compares to that 1. Pharmaceutical Benefits Advisory Committee. March 2008 PBAC outcomes — positive recommendations. http://www.health.gov.au/internet/main/publishing.nsf/Content of patients who have never received clopidogrel. /pbacrec-mar08-positive (accessed 24 June 2008). 2. Yusuf S, et al. N Engl J Med 2001;345:494–502. The cohort study included 3137 patients who received 3. Sabatine MS, et al. N Engl J Med 2005;352:1179–89. percutaneous coronary intervention (PCI) or medical 4. sanofi-aventis Australia Pty Ltd. Plavix product information. 21 August 2007. treatment (mean duration of clopidogrel 302 and 278 5. Bristol-Myers Squibb Australia Pty Ltd. Iscover product information. 21 August 2007. 6. Acute Coronary Syndromes Guidelines Working Group. Med J Aust 2006;184:S1–32. days, respectively) for ACS. The risk of death or acute 7. Department of Veterans' Affairs. Doctors Therapeutic Brief 13 — Aspirin and MI was greatest during the first 3 months after clopidogrel in cardiovascular disease. http://www.dva.gov.au/health/veteransmates /modules.htm#13 (accessed 24 September 2008). 8. Jackowski L, et al. Aust Fam Physician 2008;37:721–6. * Major bleeding episodes were defined as substantially disabling bleeding, intraocular 9. Australian Medicines Handbook, 2008. bleeding leading to the loss of vision, or bleeding necessitating transfusion of at least 10. Ho PM, et al. JAMA 2008;299:532–9. 2 units of blood. April 2009 In Brief Ziprasidone (Zeldox): another atypical Evidence of efficacy in acute mania, antipsychotic listed for acute mania in not for maintenance therapy bipolar disorder The evidence for ziprasidone for reducing symptoms Ziprasidone (Zeldox) was PBS listed on 1 April 2009 for of acute mania comes from 2 short (3 week) blinded treating acute mania or mixed episodes in people with randomised controlled trials.6,7 Like many trials in bipolar I disorder. The streamlined authority listing allows bipolar disorder, generalisability is hampered by small ziprasidone monotherapy for up to 6 months. Ziprasidone sample size, numerous exclusion criteria (e.g. people with was previously PBS listed for schizophrenia only. cardiovascular disease) and high dropout rates — in one Mood stabilisers (e.g. lithium) remain the mainstay trial, 50% of all patients did not complete the study.7 for treatment and maintenance (prophylaxis) of mania The evidence base for 'real life' effectiveness is limited. in bipolar disorder. Atypical antipsychotics are sometimes Evidence for maintenance therapy or adjunctive use recommended, particularly for severe episodes of acute (e.g. with lithium) is lacking, and ziprasidone is not mania, because of their faster onset of effect currently TGA approved for either indication.8 One (1–2 days).1–4 unpublished trial failed to find a benefit when ziprasidone was added to lithium therapy.8 Approved indications and PBS listings differ between antipsychotics Dosing is twice daily with food Acute mania: quetiapine (Seroquel) and risperidone Unlike most other atypical antipsychotics, ziprasidone (Risperdal) are the other atypical antipsychotics PBS must be taken twice daily with food. Absorption of listed for acute mania.5 Of these, only risperidone ziprasidone may be significantly reduced if taken can currently be prescribed on the PBS as adjunctive without food.8 Ensure that people taking ziprasidone therapy (see Table 1). are aware of these requirements, especially if switching from another antipsychotic, most of which are dosed 18 Mixed episodes: ziprasidone is PBS-listed for use once daily without food. Check compliance before in mixed episodes of bipolar 1 disorder. increasing dose if symptoms do not improve. Maintenance therapy: olanzapine is currently the only atypical antipsychotic with a PBS listing Safety issues for maintenance therapy in bipolar disorder. Common adverse effects with ziprasidone include headache, sedation, somnolence, dizziness, Table 1. Indications and PBS listings for atypical extrapyramidal symptoms and nausea.8,9 antipsychotic drugs in bipolar I disorder Safety data on use in mania beyond 3 weeks is limited ACUTE MANIA MAINTENANCE and can only be extrapolated from longer term studies TGA PBS TGA PBS of ziprasidone in schizophrenia.10,11 More experience Drug approved listed approved listed is needed to adequately characterise its adverse effect Olanzapine Yes Yes Yes profile relative to other atypical antipsychotics. (Zyprexa) (monotherapy or adjunctive Metabolic effects and diabetes therapy) Metabolic effects such as weight gain and lipid changes Quetiapine Yes Yes Yes appear less likely with ziprasidone than with other (Seroquel) (monotherapy (monotherapy) (adjunctive antipsychotics.9,10 Whether this means that ziprasidone or adjunctive therapy only) has a lower risk of new-onset diabetes is uncertain. therapy) Observational studies have found an increased incidence Risperidone Yes Yes (adjunctive of new type 2 diabetes with other atypical antipsychotics (Risperdal) therapy only) (olanzapine, quetiapine, risperidone and clozapine) Ziprasidone Yes Yes compared with conventional antipsychotics.12–14 While (Zeldox) (monotherapy), (monotherapy) no increased risk with ziprasidone has been observed mixed episodes to date, fewer epidemiological data are available April 2009 In Brief because ziprasidone is a newer drug.12 The exact A small but increased risk of sudden cardiac death mechanism by which antipsychotics increase diabetes has been observed for all antipsychotics — consider risk is uncertain and it is not clear if weight gain alone the individual's cardiovascular risk profile before is the causal factor.12 prescribing an antipsychotic, and an ECG before and shortly after starting antipsychotic treatment.17,18 Extrapyramidal symptoms References Extrapyramidal symptoms (EPS) occur with short-term 1. National Institute for Health and Clinical Excellence. Bipolar disorder: the management ziprasidone use — 11% of patients with acute mania of bipolar disorder in adults, children and adolescents, in primary and secondary care. developed EPS, compared with 2% for placebo in one Clinical Guideline No. 38. 2006. http://www.nice.org.uk /download.aspx?o=CG038NICEguideline (accessed 9 October 2007). 3-week trial.6 EPS may be more likely in short-term use 2. Pyle DI, Mitchell PB. Australian Prescriber 2007;30:70–3. for mania than with some other atypical antipsychotics, 3. Singh A, Berk M. Australian Prescriber 2008;31:73–6. but better data are needed to be sure.15 In an 18-month 4. eTG complete [CD-ROM]. Melbourne: Therapeutic Guidelines Limited, July 2008. schizophrenia trial, there were similar rates of EPS-related 5. Australian Government Department of Health and Ageing. Schedule of Pharmaceutical Benefits, 1 Feb 2009. http://www.pbs.gov.au/html/healthpro/home (accessed 5 Feb 2009). discontinuations between atypical antipsychotics 6. Potkin SG, et al. J Clin Psychopharmacol 2005;25:301–10. (4% with ziprasidone and 2% to 3% with olanzapine, 7. Keck PE, Jr., et al. Am J Psychiatry 2003;160:741–8. risperidone and quetiapine)* and no difference was 8. Pfizer Australia Pty Ltd. Zeldox product information. 3 April 2008. found between antipsychotics in EPS symptom ratings.10 9. Lieberman JA, et al. New England J Med 2005;353:1209–23. 10. Bagnall A-M, et al. Ziprasidone for schizophrenia and severe mental illness. Cochrane All atypical antipsychotics can cause EPS, although to Database Syst Rev 2000. http://www.mrw.interscience.wiley.com/cochrane a lesser extent than conventional antipsychotics such /clsysrev/articles/CD001945/frame.html (accessed 5 Feb 2009). 11. Consensus development conference on antipsychotic drugs and obesity and diabetes. as haloperidol.4,16 Diabetes Care 2004;27:596–601. 12. Guo JJ, et al. Journal Clin Psychiatry 2006;67:1055–61. QT prolongation 13. Lambert BL, et al. Am J Epidemiol 2006;164:672–81. 14. Gao K, et al. J Clin Psychopharmacol 2008;28:203–9. Before prescribing, consider whether the patient has 15. Scherk H, et al. Arch Gen Psychiatry 2007;64:442–55. 19 risk factors for QT prolongation. Ziprasidone prolongs 16. Ray WA, et al. New Engl J Med 2009;360:225–35. the QTc interval.8,9 The clinical significance of this effect 17. Schneeweiss S, Avorn J. New Engl J Med 2009;360:294–6. is currently not fully known. While clinical trials have not detected clinically significant QT prolongation8, Sublingual desmopressin PBS listed: there have been postmarketing reports of torsades de where does desmopressin fit in primary pointes in patients with multiple risk factors taking nocturnal enuresis? ziprasidone.8 Ziprasidone is contraindicated in significant cardiovascular disease, including arrhythmias, Desmopressin sublingual wafer (Minirin Melt, and in people with other conditions or taking other 120 micrograms) is available as a streamlined authority drugs that may prolong the QT interval (including listing for primary nocturnal enuresis from 1 April 2009. some antibiotics, antifungals, antidepressants and Similar to desmopressin tablets and nasal spray, the anti-arrhythmic agents).8 Ziprasidone may not be listing for desmopressin sublingual wafers is restricted appropriate for people at risk of electrolyte imbalances to children aged ≥ 6 years with primary nocturnal (e.g. hypokalemia, people taking diuretics), which may enuresis refractory to an enuresis alarm, or when increase the risk of QT prolongation. For those at risk an enuresis alarm is contraindicated.1 of electrolyte imbalances, measure potassium and Enuresis alarms are the most effective treatment magnesium levels both before starting ziprasidone and during treatment.8 for bedwetting An enuresis alarm is the first choice for primary nocturnal enuresis. Alarms are at least as effective *Statistical significance was not reported for ziprasidone discontinuations compared with other atypical antipsychotics. as desmopressin, more likely to have a sustained effect, and do not have the risk of serious hyponatraemia.2,3 April 2009 In Brief Although alarms require close involvement from and vomiting, difficulty concentration, confusion, lethargy, a parent or carer in the first few weeks of use, about agitation, headache, and seizures.11 two-thirds of children with nocturnal enuresis become Use the nasal formulation only when oral or sublingual dry at night when using an enuresis alarm, and about desmopressin use is not feasible for primary nocturnal half of children stay dry when the alarm is withdrawn.2,4 enuresis.12 Children taking nasal desmopressin for Alarms are usually withdrawn after 14 consecutive dry primary nocturnal enuresis are heavily represented nights and may be trialled for up to 12–16 weeks.5 in reports of severe hyponatraemia and seizures with Several different enuresis alarms are available: pad-and- desmopressin.11,13 bell alarms that are placed on the bed, and personal Minimise risk of hyponatraemia with desmopressin alarms that are worn between pairs of underpants. Choice is determined by the child's preference and If prescribing desmopressin for primary nocturnal enuresis: by cost — there is insufficient evidence to show any • use cautiously and monitor serum sodium levels one alarm is more effective than another.2 in children with conditions that may increase the risk Desmopressin acts faster than alarms at reducing the of hyponatraemia or water intoxication (e.g. systemic number of wet nights in the first week of treatment, infections, gastroenteritis, syndrome of inappropriate but this advantage does not persist.6 Relapse rates ADH secretion [SIADH])10 after stopping desmopressin are similar to those for • reserve the nasal formulation for when an oral placebo and higher than for alarms.6 Desmopressin or sublingual formulation is not feasible11,12 may have a role in special circumstances, such as short- term use when sleeping away from home.3,5 • avoid concomitant use with medicines known to induce SIADH (eg, tricyclic antidepressants, selective serotonin Discuss simple behavioural strategies with the child reuptake inhibitors, chlorpromazine, carbamazepine).10 and their parent or carer. Although there is insufficient • avoid NSAIDs, as they may induce water retention10 evidence to prove effectiveness, some of these may 20 help, are not associated with side effects, and may • advise children and their parents or carers that they be preferred by children and parents.7,8 can help to minimise the risk of hyponatraemia by: — limiting the child's fluid intake for 1 hour before Sublingual wafers may be easier to take and 8 hours after taking desmopressin10 — than oral tablets parents or carers may need to closely watch Desmopressin sublingual wafer can be taken without the ingestion of fluid by their child after dosing water, which may make it easier for some children — avoiding excessive fluid ingestion at all times3 to take.9 A single desmopressin 120 micrograms sublingual wafer has an equivalent bioavailability10 — stopping the medicine if the child develops and efficacy to that of a single desmopressin 200 symptoms of water retention (eg, headache, micrograms tablet.9 There is no difference in the safety nausea, vomiting, weight gain or convulsions) profile for the two formulations at recommended doses.9 and reporting these promptly to their doctor14 — stopping the medicine temporarily if the child Reserve nasal desmopressin for when oral develops vomiting or diarrhoea from any cause, or sublingual formulations cannot be taken to allow recovery of normal fluid balance.3,10 The nasal formulation of desmopressin is more likely to cause hyponatraemia and seizures than oral Review need for desmopressin within 3 months formulations (15 cases versus 6 cases per 100,000 years of starting treatment of patient exposure for nasal versus oral formulations).11 The benefit of desmopressin is not sustained after Hyponatraemia is a rare but serious adverse effect stopping, but spontaneous remission of bedwetting of desmopressin, which may present as anorexia, nausea does occur. Assess for remission regularly to determine April 2009 In Brief the need for ongoing treatment. The intended duration Risedronate (Actonel, Actonel Once-a-Week) of desmopressin sublingual wafer for primary nocturnal for corticosteroid-induced osteoporosis enuresis is up to 3 months.10 Consider capping the The PBS listing for risedronate (Actonel and number of repeats to ensure an assessment takes place Actonel Once-a-Week) and risedronate with calcium within this period. To assess whether bedwetting has (Actonel Combi) has been extended to people with resolved, stop desmopressin and wait a week before corticosteroid-induced osteoporosis (CIO) who are reviewing the number of dry nights.3 on long-term high-dose corticosteroid therapy. Eligible Resources on bedwetting for parents and children people must have been taking high-dose corticosteroids (≥ 7.5 mg/day prednisolone or equivalent) for at least Resources for parents and children on the 3 months and have a bone mineral density (BMD) management of bedwetting are available at T-score of ≤ –1.5. www.bladderbowel.gov.au. These include a series of booklets, updated in 2008 (Sleepover, Watertight, Bone loss is worst in the first year of corticosteroid and The Dry Night), which provide advice on behavioural therapy.1,2 To minimise bone loss, use the smallest therapies, alarms, and the place of medicines. possible dose of corticosteroid for the shortest possible time.1,2 Prescribe at least 1000 mg calcium daily and References ensure adequate vitamin D intake.3 1. Pharmaceutical Benefits Advisory Committee. July 2008 PBAC outcomes - positive recommendations. Canberra: Department of Health and Ageing, 2008. The risk of a vertebral or hip fracture increases rapidly http://www.health.gov.au/internet/main/publishing.nsf/Content/pbacrec-jul08-positive (accessed 19 January 2009). after beginning corticosteroid treatment but declines 2. Glazener CM, et al. Cochrane Database Syst Rev (Online) 2005:CD002911. within a year of stopping therapy.1,2 3. Rossi S, ed. Australian Medicines Handbook [online]. Adelaide: Australian Medicines Handbook Pty Ltd, 2009. Limited data on fracture prevention in people 4. Glazener CM, et al. J Wound Ostomy Continence Nurs 2004;31:223–34. with corticosteroid-induced osteoporosis 5. Caldwell PH, et al. Med J Aust 2005;182:190–5. 21 6. Glazener CM, Evans JH. Cochrane Database Syst Rev (Online) 2002:CD002112. No trial in people with corticosteroid-induced 7. Glazener CM, Evans JH. Cochrane Database Syst Rev (Online) 2004:CD003637. osteoporosis has used fracture as a primary endpoint 8. Fritz G, et al. J Am Acad Child Adolesc Psychiatry 2004;43:1540–50. 9. Lottmann H, et al. International journal of clinical practice 2007;61:1454–60. or reported a significant reduction in incident fracture 10. Ferring Pharmaceuticals Pty Ltd. MINIRIN Melt product information. 15 October 2008. among people taking risedronate, compared with 11. Adverse Drug Reactions Advisory Committee. Desmopressin and hyponatraemia. placebo.4–7 However, meta-analysis of fracture data 2008;27:14–6. http://www.tga.gov.au/adr/aadrb/aadr0808.pdf (accessed 20 January 2009). shows a significant decrease in vertebral fracture risk 12. Ferring Pharmaceuticals Pty Ltd. MINIRIN nasal spray product information. (relative risk 0.33, 95% confidence interval 0.14 18 November 2008. to 0.80) among people with corticosteroid-induced 13. US Food and Drug Administration. Information for Healthcare Professionals Desmopressin Acetate: FDA alert [12/4/2007]. Rockville, MD: FDA, 2007. osteoporosis taking risedronate 5 mg daily.8 There http://www.fda.gov/cder/drug/InfoSheets/HCP/desmopressinHCP.htm was no significant reduction in vertebral fracture risk (accessed 20 January 2009). 14. Ferring Pharmaceuticals Pty Ltd. MINIRIN Melt consumer medicine information. among people taking risedronate 2.5 mg daily or in October 2008. non-vertebral fracture risk in people taking either 2.5 mg or 5 mg daily.8 April 2009 In Brief Risedronate can maintain or improve BMD Zoledronic acid (Aclasta) listing extended in people using corticosteroids to osteoporosis in postmenopausal women In clinical trials, BMD levels deteriorated among people From 1 April 2009 the PBS listing for zoledronic acid taking placebo but remained steady, or occasionally (Aclasta) will include treatment of osteoporosis in any improved, among those taking risedronate 2.5 mg postmenopausal woman aged ≥ 70 years who has a or 5 mg.4–7 People taking risedronate 5 mg appear bone mineral density (BMD) T-score ≤ –3.0. Previously, to be more likely to have significantly higher BMD values the listing was only for osteoporosis in women with than those on risedronate 2.5 mg or placebo.4–7 a fracture, and in men with a hip fracture. One trial followed women taking risedronate 2.5 mg daily An update of the NPS RADAR review of zoledronic for 2 years. Women taking risedronate had significantly acid (Aclasta) for osteoporosis is available on-line higher lumbar spine and femoral trochanter BMD than at www.npsradar.org.au and in Medical Director those receiving placebo. A year after stopping therapy, and Genie prescribing software. the risedronate group still had significantly higher lumbar Zoledronic acid is given as an annual intravenous spine BMD than the placebo group, but femoral infusion. It is important to inform patients starting trochanter BMD was similar to that in the placebo group.5 zoledronic acid that they will need to continue with Minimise gastrointestinal effects daily calcium and vitamin D supplements. with correct administration Before prescribing zoledronic acid, check if patients Instruct patients to take risedronate early in the have already received an infusion (e.g. in hospital). morning on an empty stomach. They should swallow If oral bisphosphonates were previously used, these the risedronate tablet whole with a full glass of water must be stopped before starting zoledronic acid. and remain upright for 30 minutes after the dose to Adverse effects include acute-phase reactions, such minimise adverse gastrointestinal effects.3 as fever, myalgia, flu-like illness and headache, within 22 References 3 days of infusion. Like other bisphosphonates, zoledronic acid may cause hypocalcaemia, and has 1. Romas E. Australian Prescriber 2008;31:45–9. 2. Royal College of Physicians, et al. Glucocorticoid-induced osteoporosis. London: been associated with renal dysfunction, inflammatory Royal College of Physicians of London, 2002. eye disorders, osteonecrosis of the jaw and, possibly, http://www.rcplondon.ac.uk/pubs/books/glucocorticoid/Glucocorticoid.pdf (accessed 25 Sept 2008). atrial fibrillation. 3. eTG complete [CD-ROM]. Melbourne: Therapeutic Guidelines Limited, September 2008. 4. Cohen S, et al. Arth Rheum 1999;42:2309–18. 5. Eastell R, et al. Osteoporos Int 2000;11:331–7. 6. Mok CC, et al. Osteoporos Int 2008;19:357–64. 7. Reid DM, et al. J Bone Miner Res 2000;15:1006–13. 8. Kanis JA, et al. Health Technol Assess 2007;11:iii–iv, ix–xi, 1–231. April 2009 Index of NPS RADAR reviews April 2008 – April 2009 The following NPS RADAR reviews are available on our website, www.npsradar.org.au. Look for the NPS RADAR index in Quick Links. Duloxetine (Cymbalta) for major depressive disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .August 2008 Automatic eGFR reporting — its role in screening for kidney disease and drug-dosing decisions . . .August 2008 Desvenlafaxine (Pristiq) for major depressive disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .March 2009 Escitalopram (Lexapro, Esipram) for generalised anxiety disorder and social anxiety disorder (social phobia) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .August 2008 Fentanyl lozenges (Actiq) for breakthrough cancer pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .April 2008 Memantine (Ebixa) for dementia in moderately severe Alzheimer's disease . . . . . . . . . . . . . . . . . . . .August 2008 Paliperidone (Invega) for schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .April 2008 Pioglitazone (Actos) for type 2 diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .April 2008 Pramipexole (Sifrol) for severe primary restless legs syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .April 2009 Sitagliptin (Januvia) for type 2 diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .August 2008 Once-daily tramadol extended-release (Durotram XR) for pain . . . . . . . . . . . . . . . . . . . . . . . . .December 2008 Valsartan (Diovan) and combinations with hydrochlorothiazide (Co-Diovan) or amlodipine (Exforge) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .March 2009 Zoledronic acid (Aclasta) for osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .April 2009 Visit www.npsradar.org.au to view all NPS RADAR reviews or register for email updates. NPS RADAR reviews are also available in GP prescribing software (Genie and Medical Director 2). NPS is an independent, non-profit organisation for Quality Use of Medicines, funded by the Australian Government Department of Health and Ageing. ABN 61 082 034 393 l Level 7/418A Elizabeth Street Surry Hills NSW 2010 l PO Box 1147 Strawberry Hills NSW 2012 Phone: 02 8217 8700 l Fax: 02 9211 7578 l email: firstname.lastname@example.com l web: www.nps.org.au NPSB0921 APR09
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Laird Technologies Photos
Laird Technologies ReviewsLaird Technologies 71
1 person found this helpful
"Good place to begin "
- Comp & Benefits
- Work/Life Balance
- Senior Management
- Culture & Values
- Career Opportunities
I worked at Laird Technologies full-time (more than a year)Pros
Good work ethics. Get a lot to learnCons
None. A good place to workRecommendsNeutral OutlookNo opinion of CEO
Laird Technologies Interviews
Interview Experience
Interview Experience
Getting an Interview
Getting an Interview
Interview Difficulty
1 person found this helpfulApplication Details
I applied online. The process took 1+ week – interviewed at Laird Technologies in November 2014.Interview Details
Received email from LinkedIn/Glassdoor with job on the list. I clicked it, looked right up my alley, so I applied. Was directed to their job website...create id, the usual.
Answered a bunch of questions (nothing unusual) but could not get it to accept/submit. You MUST fill in ALL fields with N/A. Finally got it to submit. Opinion - very poor HR software.
Received call from HR person in Earth City MO. Asked a few usual questions, limited technical. Was told next step would be technical phone screen.
Email a couple of days later asking me for in person. Arranged time/date.
Was emailed an interview schedule of people/times. Started with VP. Typical upper management overview interview, explaining company and products. Professionally done.
Next was two from SW. One was out and out belligerent. Attacked everything I said, challenged every answer. Was more like an interrogation than an interview. Immediately decided this was one person I would NOT want to work with.
Next was HR person. Standard HR behavioral interview with dealing with workplace conflicts (maybe this guy is known for his problems?), accomplishments, benefits etc. Professionally done.
Project guy was next. Questioned experiences on resume. Nothing difficult. Professionally done.
HW team was next. They were looking for some specific answers which I guess I wasn't giving them regarding competence working with HW. My read was they wanted to make sure every problem wasn't automatically "a hardware bug." Professionally done.
One person on the interview schedule I never saw with no explanation.
Everyone was wearing jackets and sweaters. While it is November in Michigan, it was in the upper 30's. Conclusion- building HVAC has a lot to be desired.
Facility is cramped and dirty. Floors were highly worn and looked like they hadn't seen a mop in a long time.
Given the salary and the oxymoron of "employee benefits", you'd do better getting a job on an automobile assembly line. Better working conditions, more holidays, better medical, better everything.
HW guys were particularly bent on not getting some finger pointing SW guy. I surmised this is a major problem.
Interview was scheduled by HQ and not properly delegated to someone locally. Very haphazardly handled. Other than the VP interview, I was rushed through everything. Promised plant tour never happened. At no time was I ever able to get in a question of my own.
As for the SW belligerent, my take was he dumped me before he got into the room. Whether this was an EEOC problem or he was just a major sphincter, IDK nor do I care. Big shot know it all wanted to just push people around. HR needs a serious talk with that guy. I figure he's the major problem the HW guys were digging at.
After one week, sent a WTH? email. "Still interviewing." Will not bother with sending one further.Interview Questions
No OfferNegative ExperienceDifficult Interview
- Not so much a question but the amount of restraint required to not slap the SW guy. Answer Question
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Laird Technologies feels that the shield is mightier than the sword. The company manufactures electromagnetic interference (EMI) shielding materials such as custom metal stampings, signal integrity components, thermal management products, wireless antennas, and radio frequency modules. It also produces metalized fabric and conductive tape and offers product engineering and testing services. Laird Technologies has two divisions: Performance Materials (handset metals) which includes EMI shields, signal integrity products, and thermal management products; and Wireless Systems... More

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YRP Mardi Gras Celebration and Fundraiser
- Charity & Causes
- The Hotel St. Michael, Prescott AZ
The Dustbowl Revival - An Old Time Medicine Show
Yavapai College Master Chorale
Sunday, October 20, 2013 from 2:00 PM to 5:00 PM (PDT)
October 20 2pm
"An Old-Time Medicine Show" Rolling Stone
" Americana swing so fun I went back to see them again the next day." -- Rob Sheffield, ROLLING STONE
"A nine-piece band replete with tuba, washboard,
accordion, fiddle, mandolin, trumpet and guitar joyously pumped out tunes that would have sounded utterly at home within the hallowed confines of Preservation Hall in New Orleans' French Quarter."
The Master Chorale has been part of Yavapai College for over 20 years and has given hundreds of performances for the Prescott Community and beyond.
They have traveled to Europe and performed for audiences, worldwide.
The Chorale sings a varied repertoire from folk songs to classical music of all types and styles.
In order to purchase these tickets in installments, you'll need an Eventbrite account. Log in or sign up for a free account to continue.