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Pramipexole _Sifrol_ for severe

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                                                                                                                           ISSN 1832-3596

Timely, independent information about new drugs

                                Desvenlafaxine (Pristiq) for major depressive disorder
                                New product PBS listed February 2009

                                Pramipexole (Sifrol) for severe primary restless legs syndrome
                                New indication PBS listed April 2009

                                Valsartan (Diovan) and combinations with hydrochlorothiazide
                                (Co-Diovan) or amlodipine (Exforge)
                                New products PBS listed March 2009

                                In Brief
                                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.
        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

       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).

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
   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

                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.
                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)

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)
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)

            Valsartan reduces blood pressure to a similar extent as other angiotensin II-receptor

            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

            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
and Prescribing Practice Review 38.8,9
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
treating people with heart failure, refer to NPS News 57
and Prescribing Practice Review 41.11,12
Valsartan reduces blood pressure                                     -10                                                   12
to a similar extent as other angiotensin                             -11
II-receptor antagonists                                              -12
A meta-analysis of 46 short-term trials showed that
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
                                         –7                                                                                                 –8
                     –8                                                                                                                                                     –8
           –10                –10                                                      –10                   –10   –10                                                            –11         –11                             –10

                                 –16           –15         –15
           –15                                                                                               –15   –15                                                                                                        –15
           –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
                                                           –9                     –9
           –10      –10               –10       –10                                                          –10   –10                                                -8                                                      –10
                                                                                             –11                                                       -9                         -8   -8
                              –12                                                                                                                                                   –9
                                                     –13                                                                                                               -10
                                         –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

     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).
                                                                     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).
     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).

                                                                                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
     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
     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
         (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,
   (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: info@nps.org.au l web: www.nps.org.au
                                                                                                                                                      NPSB0921 APR09

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