Therapeutics Today May 2014

Number 5

For personal use only. Not to be reproduced without permission of the editor.

Restrictions on use of domperidone-containing medicines: Domperidone-containing medicines have been authorised in most EU Member States via national authorisation procedures since the 1970s. They are widely available as over-the-counter (OTC) or prescription-only medicines (POM) and are available as tablets, an oral suspension and suppositories. Domperidone acts by blocking dopamine neurotransmitters in the gastrointestinal tract and brain and is used for symptoms including nausea and vomiting. Due to concerns regarding cardiac adverse effects associated with domperidone use, an evaluation of the available evidence on the benefits

and risks of domperidone was recently undertaken by the Pharmacovigilance Risk Assessment Committee (PRAC) in the European Medicines Agency (EMA). After evaluation of the safety and efficacy data of domperidone from various sources (non-clinical and clinical data - both published and unpublished), PRAC confirmed that there was a small increased risk of serious cardiac adverse effects associated with use of domperidone, including QT prolongation, torsades de pointes, ventricular arrhythmia and sudden cardiac arrest. This risk was higher in patients > 60 years, adults taking daily oral doses of >30 mg and those concomitantly taking QT prolonging medicines or CYP3A4 inhibitors. There remains a positive benefit-risk balance for domperidone for the treatment of nausea and vomiting but not for other indications such as dyspepsia and gastro-oesophageal reflux. It is recommended that domperidone is used at the lowest effective dose for the shortest possible period (not exceeding 1 week). The new recommended dose of domperidone in adults is 10 mg orally up to 3 times daily or 30 mg twice daily as suppositories. The recommended dose of domperidone for children is 0.25mg/kg bodyweight up to 3 times daily orally (oral suspensions should be given in adapted graduated syringes). Domperidone is contraindicated in patients with severe hepatic impairment, conditions where cardiac conduction is or could be impaired, patients with underlying cardiac disease and when co-administered with QT prolonging medicines or potent CYP3A4 inhibitors. Other recommendations include the withdrawal of formulations not consistent with the new dosage recommendations from the market. The medicines regulatory body representing the EU member states (the Co-ordination Group for Mutual Recognition and Decentralised Procedures [CMDh]) endorsed the PRAC recommendations to restrict the use of domperidone containing medicines. The CMDh position will be sent to the European Commission, which will take an EU-wide legally binding position. The product information will then be amended appropriately to reflect this. [Editors note: Further information on this review is available on the EMA website www.ema.europa.eu]

Irish Malaria Surveillance Data: The Health Protection Surveillance Centre (HPSC) recently published Irish malaria surveillance data, providing an opportunity to remind healthcare professionals of the risk of malaria for Irish residents travelling to malarious countries (Epi-Insight April 2014;15(4)). Globally, Africa is the most highly malarious area, however countries in Asia and South America also pose a risk. In 2010, Ireland had the third highest incidence rate for imported malaria in the European Union. There were 71 cases of malaria notified in Ireland in 2013 which is an increase of 9% on those notified in 2012. The highest number of cases occurred among males aged 35-54 years and there were 12 paediatric cases. Where the reason for travel

was reported, the most common reasons were: visiting family in the country of origin (n=33) [all of whom travelled to Africa], followed by business/professional travel (n=3) and foreign visitor ill in Ireland (n=3). The most common infecting species was Plasmodium falciparum (89%) and there was one case each of Plasmodium ovale and Plasmodium vivax. It is important that malaria prevention messages are targeted to tourists, business travellers and other travellers with little previous exposure to malaria. Children in particular are at risk; people born in Western and Central Africa currently resident in Ireland who return to their country of origin should be informed that their Irish-born children have no inate immunity to malaria and are particularly at risk. Travellers should be advised that they must complete their full course of chemoprophylaxis and take steps to avoid mosquito bites. [Editors note: The HPSC have resources including a poster available for display in surgeries and leaflets for patients intending to travel on http://www.hpsc.ie/A-Z/Vectorborne/Malaria/LeafletsandPosters/]

Patient empowered education reduces benzodiazepine use: The use of benzodiazepines (BZD) particularly in older patients is discouraged due to the risk of cognitive deficits and the risk of falls and hip fractures. Physicians are advised not to use BZD as first-line treatment for insomnia in older patients although BZD account for up to 25% of inappropriate prescriptions in the elderly. Educational interventions aimed at promoting patient empowerment regarding their medication could reduce the prescribing of BZD. The EMPOWER (Eliminating Medication Through Patient Ownership of

End Results) was a 2-arm, parallel-group cluster randomised trial conducted in Montreal, Canada, which compared the effect of a direct patient educational intervention against usual care on BZD discontinuation in older adults living in the community (JAMA Intern Med. doi:10.1001/jamainternmed.2014.949). The study included 30 community pharmacies which were randomly allocated to the intervention or control arm. Eligible patients were identified from the pharmacy database and included those ≥ 65 years who were receiving a minimum of 5 active prescriptions, one of which was an active BZD prescription. Exclusion criteria included a diagnosis of severe mental illness or dementia, an active prescription for an anti-psychotic or dementia medication in the preceding 3 months and residence in a long-term facility. Patients who met the criteria were contacted by their pharmacists asking if they would be interested in participating in a medication safety study for older adults. Those who agreed had a home visit with a research assistant, where baseline data was collected from eligible patients. Within 1 week of randomisation, an 8 page booklet which described the risks of BZD and included a patient assessment component and a stepwise tapering protocol, which patients were advised to discuss with their physician and/or pharmacist, was mailed to the intervention group. The control arm received usual care. The primary outcome was complete cessation of BZD (absence of any BZD prescription) in the 6 months following randomisation and a secondary outcome was drug reduction which was defined as a ≥ 25% dose reduction compared with baseline sustained for ≥ 3 consecutive months. There were 303 patients randomised to the study of which 261 (86%) were available for 6-month follow-up. The most common self-reported indications for taking a BZD were insomnia (60%) and/or anxiety (48%); patients had used BZD for a mean duration of 10 years. Complete cessation was achieved in 27% of the intervention group and 5% of the control arm; the adjusted odds ratio was 8.3 (95% CI, 3.3-20.9) for discontinuing BZD in the intervention group. An additional 11% of individuals achieved dose reduction in the intervention group; the number needed to treat for any discontinuation or dose reduction was 3.7. At a 6-month follow-up interview with those completing the study in the intervention group (n=123), 62% said they had discussions with their physicians/pharmacists about discontinuing BZD and 58% had attempted to stop the BZD. Of the 71 participants who attempted cessation, 54% were successful, 22% achieved a dose reduction and 24% were unsuccessful. Of the 52 patients who elected not to taper, the reasons given were: discouragement by their physician/pharmacist (33%), fear of withdrawal symptoms (25%), lack of concern about taking BZD (23%) and difficult life circumstances (12%). Limitations to the study included the short follow-up period of 6 months following the intervention. The authors of the study concluded that their findings suggest that direct patient education successfully leads to discussion with physicians/pharmacists to stop unnecessary or harmful medication.

Triptans for treatment of migraine: Migraine is a common clinical condition with a global prevalence of 15%. The triptans are selective 5-hydroxytryptamine (5HT) receptor agonists used for the symptomatic treatment of migraine since the 1990’s; their use was recently reviewed (BMJ 2014;348:g2285). They have high affinity for the 5HT1B (stimulation causes vasoconstriction) and 5HT1D receptors (stimulation blocks the release of vasoactive peptides and neurotransmitters). There

are seven triptans currently available; sumatriptan, naratriptan, zolmitriptan, rizatriptan, eletriptan, frovatriptan and almotriptan. Various formulations include nasal spray, rapid melt tablet, oral tablet and subcutaneous (SC) injection (not currently authorised here). A number of reviews evaluating sumatriptan versus placebo/other treatments found that the number needed to treat for a pain-free response at 2 hours were 6.1 for the sumatriptan 50 mg tablet, 4.7 for the 100 mg tablet, 2.3 for the 6 mg SC injection and 4.7 for the 20 mg nasal spray. Evidence shows that all seven triptans are superior to placebo for the acute treatment of migraine. They are recommended alone or in combination with a non-steroidal anti-inflammatory drug or paracetamol for acute migraine. Triptans should be taken as early as possible after the onset of the headache. Patient preference and characteristics of migraine attacks should be considered when recommending a particular formulation; for example patients with severe nausea and vomiting might find the nasal spray more helpful than tablets and those where nausea is exacerbated by fluids might find the orally dissolving tablet helpful. Individual patients respond differently to the various triptans; if a patient does not respond to one triptan, another triptan should be tried for future attacks. Triptans are well tolerated, however they are contraindicated in patients with coronary artery disease, cerebrovascular disease, peripheral vascular disease and uncontrolled hypertension, as 5HT1B receptors are present on coronary arteries. They are contraindicated with ergotamine and monoamine oxidase inhibitors. Other potential drug interactions occur with selective serotonin reuptake inhibitors and serotonin/noradrenaline reuptake inhibitors. They should be used for no more than 9 days per month due to concerns of medication overuse headache; this may develop from regular overuse of triptans for ≥3 months. Patients with migraine with typical aura can take triptans, which may be more effective if taken at the onset of pain rather than earlier in the aura. Caution is advised in patients with complex aura presentations due to potential difficulties in differentiating early stroke symptoms from migraine aura.

Every effort has been made to ensure that this information is correct and is prepared from the best available resources at our disposal at the time of issue. References are available on request. This newsletter is produced by the National Medicines Information Centre, St. James’s Hospital (SJH) Dublin 8 and Dept of Therapeutics Trinity College, Trinity Centre, SJH. Tel: Direct Line (01) 473 0589 or 1850 727 727 Fax: (01) 473 0596 Email: nmic@stjames.ie