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DTB Select: 3 | March 2014 Every month, DTB scans sources of information on treatments, disease management and other healthcare topics for key items to bring to our readers’ attention and help them keep up to date. To do this, we produce succinct, contextualised summaries of the information concerned. We also include comments on, for example, the strengths of the information, whether it contains anomalies, ambiguities, apparent error or omissions, or whether or how it affects current practice.

Further restrictions on the use of strontium ranelate The European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) had recommended that strontium ranelate should no longer be used to treat osteoporosis.1 In the UK, it is licensed for the treatment of severe osteoporosis in postmenopausal women at high risk for fracture to reduce the risk of vertebral and hip fractures, and for the treatment of severe osteoporosis in adult men at increased risk of fracture.2 In April 2013, after a routine assessment of the risks and benefits, the EMA recommended that the use of strontium ranelate should be restricted to reduce the risk of heart problems but called for a more in-depth review before making final recommendations. 3 The review has now been concluded. Strontium ranelate has a modest benefit in people with osteoporosis. For every 1,000 patients treated for 1 year, the drug prevents about 5 non-spinal fractures, 15 new spinal fractures and 0.4 hip fractures. However, the Committee noted that for the same treatment period, strontium ranelate was associated with four additional serious cardiac adverse events (including myocardial infarctions) and four additional thromboembolic events compared with patients prescribed a placebo. In addition, strontium ranelate is associated with serious skin reactions, disturbances in consciousness, seizures, liver inflammation and “reduced number of blood cells”. 1 The review questioned whether having a prescribing restriction in place would reduce these excess risks and whether such restrictions would be practical in clinical practice. Instead, the review found that the risk benefit balance no longer favoured strontium ranelate, and determined that its use be suspended until more favourable data emerge in a defined patient group. However, following its meeting on 21 February 2014, the Committee for Medicinal Products for Human Use (CHMP) recommended that there should be further restrictions on the use of strontium ranelate to patients who cannot be treated with other medicines approved for osteoporosis.4 In addition, patients treated with strontium ranelate should be evaluated regularly and the drug stopped if heart or circulatory problems develop.4 Comment: In England in 2012, over 300,000 prescriptions for strontium ranelate were dispensed. 5 Prescribers need to be aware of the recommendations made by PRAC. Further information is available from the EMA's website ( 1. European Medicines Agency, 2014. PRAC recommends suspending use of Protelos/Osseor [online]. Available: jsp?curl=pages/news_and_events/news/2014/01/news_detail_002005. jsp&mid=WC0b01ac058004d5c1 [Accessed 19 February 2014]. 2. Protelos. Summary of product characteristics, EU. Servier Laboratories Limited, December 2013.


3. Medicines and Healthcare products Regulatory Agency. Strontium ranelate (Protelos): risk of serious cardiac disorders—restricted indications, new contraindications, and warnings. Drug Safety Update 2013; 6 (9): S1 [online]. Available: CON266148 [Accessed 19 February 2014]. 4. European Medicines Agency, 2014. European Medicines Agency recommends that Protelos/Osseor remain available but with further restrictions [online]. Available: events/news/2014/02/news_detail_002031.jsp&mid=WC0b01ac058001d126 [Accessed 24 February 2014]. 5. Health and Social Care Information Centre, 2013. Prescription cost analysis England 2012 [online]. Available: pres-cost-anal-eng-2012a-rep.pdf [Accessed 19 February 2014].

Acid-suppressing medicines associated with an increased risk of vitamin B12 deficiency Some acid-suppressing drugs may have an impact on vitamin B12 absorption, concludes a case-control study that showed an association between vitamin B12 deficiency and long-term prior use of proton pump inhibitors (PPIs) and H2 receptor antagonists (H2RAs).1 The study included 25,956 patients with a diagnosis of vitamin B12 deficiency and 184,199 patients without B12 deficiency. Researchers analysed patients’ records to find which patients had been prescribed either PPIs or H2RAs for at least 2 years, and estimated odds ratios (ORs) for risk of vitamin B12 deficiency during the 14.5-year study. Among patients with vitamin B12 deficiency, 21,749 patients (83.8%) did not receive prescriptions for either PPIs or H2RAs. However 3,120 patients (12.0%) were dispensed PPIs and 1,087 (4.2%) were dispensed H2RAs. Patients who were dispensed PPIs or H2RAs for 2 or more years had an increased risk of vitamin B12 deficiency compared with patients who had never been prescribed either drug (OR PPIs, 1.65 [95% CI 1.58 to 1.73]) (OR H2RAs, 1.25 [95% CI 1.17 to 1.34]). An increased risk of vitamin B12 deficiency was also associated with higher doses of PPIs, based on a calculation of ‘mean daily dose’. Mean doses of more than 1.5 PPI ‘pills per day’ were more strongly associated with vitamin B12 deficiency (OR, 1.95 [95% CI 1.77 to 2.15]) than mean doses of less than 0.75 ‘pills per day’ (OR, 1.63 [95% CI 1.48 to 1.78]). Additionally, the research identified a link between the decrease in incidence of vitamin B12 deficiency and discontinuation of acid-inhibitor therapy. The effect of residual confounding can’t completely be ruled out as an explanation for these findings, including the increased likelihood of diagnosis of vitamin B12 deficiency in those already seeking or receiving a prescription. But the researchers argue that several aspects of their results—such as the strength of the association, the evidence

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of a dose response and the temporality of the effect—suggest the relationship between acid-suppressing drugs and vitamin B12 deficiency may be a causal one. Comment: It’s not clear if the association is sufficient to warrant screening and monitoring of patients on acid-suppressing drugs for vitamin B12 deficiency. However, healthcare professionals should be aware of the association between use of PPIs and H2RAs and vitamin B12 deficiency. 1. Lam JR et al. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA 2013; 310: 2435-42.

Drug-driving law has implications for prescribers The Medicines and Healthcare products Regulatory Agency (MHRA) has issued advice to holders of Marketing Authorisations of medicines controlled by the Misuse of Drugs Act in connection with a new criminal offence of drug driving, due to become law in summer 2014.1 Although the principal target of the legislation is dangerous drivers who are impaired as a result of illicit drug use, the list of substances that can lead to prosecution includes some prescription medications (including morphine, methadone and benzodiazepines). The legislation is due to be debated in parliament in the coming months, but the exact nature of the offence is likely to be defined as: driving, attempting to drive or being in charge of a vehicle, with a specified controlled drug in the body above a specified level for that particular drug. The MHRA considers it important for prescribers to be aware that there will be a legitimate legal defence for people charged under the legislation who have taken medicines prescribed for them, provided they have done so in accordance with the prescriber’s and the Marketing Authorisation Holder’s (MAH) instructions. Patient information leaflets and drug packaging will be modified, where appropriate, to stress that it may be an offence to drive while under the influence of the medication if it affects a person’s ability to drive safely. The full list of affected drugs can be found in the MHRA advice.1 Comment: Healthcare professionals should routinely advise patients about possible impairment with certain drugs, and about not exceeding the prescribed dose. The information provided by the manufactures will stress the importance of telling patients if a medicine is likely to affect their ability to drive, that they must not drive until they know how the medicine affects them and that it is an offence to drive if the medicine affects their ability to drive safely. 1. Medicines and Healthcare products Regulatory Agency, 2013. New drug driving offence—implications for medicines packaging [online]. Available: http://www. pdf [Accessed 19 February 2014].

New US hypertension guideline The panel members appointed to the Eighth Joint National Committee ( JNC 8) have published a new guideline for treating hypertension in adults.1 In addition to general guidance, the committee has produced specific guidance, stratified on age and ethnicity. The Committee produced nine recommendations based on three questions that address thresholds and objectives for pharmacological treatment:

• Does initiating antihypertensive pharmacologic therapy at specific blood pressure thresholds improve health outcomes? • Does treatment with antihypertensive pharmacologic therapy to a specified blood pressure goal lead to improvements in health outcomes? • Do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes? The evidence base for the guideline was restricted to randomised controlled trials, as other types of studies were considered more sensitive to bias. In addition, only trials with primary outcomes related to morbidity and mortality, rather than to specific reductions in blood pressure, were included. The outcomes assessed included: overall mortality and mortality related to cardiovascular disease or chronic kidney disease; cardiovascular outcomes including myocardial infarction and heart failure; progression to revascularisation; and renal outcomes including end-stage renal disease. The committee commented that strong evidence is still limited for some patient groups and emphasised that the guidelines are not a substitute for clinical judgement. Treatment decisions should be based on the characteristics and circumstances of individual patients. Strength of evidence was graded according to the strength of the recommendation and the degree of certainty of the net benefit of the intervention (benefits minus harms). The general recommendations for blood pressure goals are 150/90mmHg in people aged 60 years and over, and 140/90mmHg in people aged 18–59 years. However, owing to the lack of good evidence in the latter group, the systolic target is based on expert opinion. These targets are the same for patients with diabetes or non-diabetic chronic kidney disease. In the general non-black population, including those with diabetes, the guidelines recommend that initial antihypertensive treatment should include a thiazide-type diuretic, calcium channel blocker (CCB), angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-II receptor antagonist (AIIRA). In the general black population, including those with diabetes, initial treatment should include thiazide-type diuretic or CCB. If the target blood pressure is not reached within 1 month of treatment, the guideline recommends increasing the dose of the drug or adding a second drug (thiazide-type diuretic, CCB, ACEI or AIIRA). A third drug from the group could be added if the goal was not reached. Patients should not be treated with an ACEI and AIIRA concomitantly. However, these recommendations were based on expert opinion and uncertain net benefit. Unlike previous JNC reports, this guidance has not been sanctioned by the US National Heart, Lung, and Blood Institute (NHLBI). The committee’s decision to restrict the evidence base to randomised controlled trials has been seen as controversial and the difficulties involved in developing national guidance have been highlighted.2 One area of debate has focussed on the decision to raise the threshold for treating patients over the age of 60 years. 3 Comment: Of note is the emphasis that the guidance placed on targeting blood pressure control rather than use of a specific agent to achieve that control. 1. James PA et al. Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee ( JNC 8). JAMA [Epub ahead of print] 18 December 2013; DOI:10.1001/ jama.2013.284427. 2. Bauchner H et al. Updated guidelines for management of high blood pressure recommendations, review, and responsibility. JAMA 2014; 311: 477-8. 3. Peterson ED et al. Recommendations for treating hypertension - what are the right goals and purposes? JAMA 2014; 311: 47-6.

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SIGN issues guideline for management of chronic pain The Scottish Intercollegiate Guidelines Network (SIGN) has issued a new evidence-based guideline for the management of nonmalignant chronic pain in adults in non-specialist settings.1 The guideline is aimed at all healthcare professionals involved in the assessment and management of patients with chronic pain, including GPs, pharmacists, anaesthetists, psychologists, psychiatrists, physiotherapists, rheumatologists, occupational therapists, nurses, patients, carers and voluntary organisations with an interest in chronic pain. From a starting point of assessment and planning of care, it covers treatments including supported self-management, pharmacological and psychological management, and physical, complementary and dietary therapies. Unlike current National Institute for Health and Care Excellence (NICE) guidance, which examines the management of pain of specific types or for specific conditions separately, the SIGN guideline features more general evidence-based advice across a range of common causes of chronic pain, including low back pain, osteoarthritis, fibromyalgia and neuropathic pain. However, the guideline is careful to stress the difficulties of generalised approaches to a chronic problem—citing that a marked individual response to a given treatment may become insignificant in an averaged study. Add to this the lack of good evidence for some treatments and conditions, and the difficulties of interpreting the results of pain trials, and the authors are keen to emphasise the importance of the development of individualised care plans for patients, management of access to other services, and the monitoring and re-assessment of those needs. The authors highlight some key recommendations for pharmacological interventions: • Patients using analgesics to manage chronic pain should be reviewed at least annually, and more frequently if medication is being changed or the pain syndrome and/or underlying comorbidities alter. • Strong opioids should be considered as an option for pain relief for patients with chronic low back pain or osteoarthritis, and only continued if there is ongoing pain relief. Regular review is required. • Specialist referral or advice should be considered if there are concerns about rapid-dose escalation with continued unacceptable pain relief, or if a dose equivalent to >180mg/day of morphine is required. Comment: The use of opioids in the management of chronic pain is a particular challenge for prescribers. The guidance stresses the importance of regular review and appropriate referral and follow-up. 1. Scottish Intercollegiate Guidelines Network, 2013. Management of chronic pain [online]. Available: [Accessed 19 February 2014].

MHRA: screen all patients for hepatitis B before starting rituximab The Medicines and Healthcare products Regulatory Agency (MHRA) has amended its advice on the use of the biologic treatment rituximab (MabThera). Rituximab is licensed for the treatment of non-Hodgkin’s


lymphoma, chronic lymphocytic leukaemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis. Recent reports show that rituximab has been associated with re-activation of the hepatitis B virus when used for cancer and rheumatoid arthritis. (Rituximab was associated with virus reactivation in patients with positive HB surface antigen, and in those with negative HB surface antigen and positive HB core antibody.) As a result, the MHRA says prescribers should screen all patients for hepatitis B before they begin treatment.1 The advice applies for any indication of rituximab. Previous advice was that only those at risk of infection needed to be screened. The agency advises that people with active hepatitis B infection should not be treated with rituximab. People with positive serology but no active disease should be referred to a specialist in liver disease for monitoring and management during their treatment. Comment: Although rituximab is usually prescribed by specialists, healthcare professionals should be aware of the risk of hepatitis B re-activation, and of the need for continued monitoring and appropriate management for patients with positive serology during treatment to prevent reactivation of the hepatitis B virus. 1. Medicines and Healthcare products Regulatory Agency. Rituximab: screen for hepatitis B virus before treatment. Drug Safety Update 2013; 7 (5): A1 [online]. Available: [Accessed 19 February 2014].

Duration of common symptoms in children with RTIs The duration of symptoms of the common cold and earache are often longer than is described in UK guidance given to parents, according to a systematic review.1 Concerned parents often ask healthcare professionals for an estimate of how long the symptoms of their child’s respiratory tract infection (RTI) are likely to last. Accurate information is needed to be able to answer this question, manage parents’ expectations and inform parents’ decisions about when and whether to reconsult. This systematic review of 23 randomised controlled trials and 25 observational studies considered outcomes for children with four symptoms of RTI—sore throat, cough, common cold and earache. The outcomes studied were time taken to achieve resolution of symptoms or duration of symptoms. Such measures included time taken for specified proportions of symptoms to have resolved, the proportion of children with unresolved symptoms at follow-up, or mean or median duration of symptoms. Among the five studies that reported the mean duration of earache, symptoms lasted from 0.5 to 9 days. Based on the pooled results of 10 studies, 50% of children’s symptoms had resolved at day 3 and 90% by day 8. Four studies reported the mean duration of common cold symptoms. These lasted from 7 to 15 days. Based on pooled data from five studies, about 50% of children had improved by day 10. Researchers estimated 90% of children would have improved after 15 days. However, the mean duration of symptoms of sore throat, acute cough, bronchiolitis and croup were more consistent with guidance. In over 90% of cases symptoms of sore throat had improved by

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2–7 days, croup by 2 days, bronchiolitis by 21 days, acute cough by 25 days and non-specific RTI symptoms by 16 days. In most (90%) children earache was resolved by 7–8 days, sore throat by 2–7 days, croup by 2 days, bronchiolitis by 21 days, acute cough by 25 days, common cold by 15 days and non-specific RTI symptoms by 16 days Comment: Some of the estimates are much longer than the currently cited average duration of 4-days duration of earache symptoms and 10–11 days for common cold symptoms in current guidance.2 Such information is important to guide parents on the likely duration of symptoms and to inform decisions on follow-up and appropriate use of antibiotics. 1. Thompson M et al. Duration of symptoms of respiratory tract infections in children: systematic review. BMJ 2013; 347: f7027. 2. National Institute for Health and Care Excellence, 2008. Respiratory tract infections—antibiotic prescribing: prescribing of antibiotics for self-limiting respiratory tract infections in adults and children in primary care [online]. Available: [Accessed 19 February 2014].

Does vitamin E slow decline in mild to moderate Alzheimer’s disease? The authors of a large randomised controlled trial have suggested that vitamin E is effective in slowing functional decline in mild to moderate Alzheimer’s disease.1 The trial examined whether 2,000IU/day of vitamin E (alpha tocopherol), 20mg/day of memantine, or the combination of both slows decline in patients with Alzheimer’s disease with a Mini-Mental State Examination (MMSE) score of 12–26. Researchers randomised 613 patients with Alzheimer’s disease (97% male) to one of these treatments or placebo. All participants were already taking an acetylcholinesterase inhibitor. The primary outcome was change in the Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) inventory. The ADCS-ADL inventory score ranges from 0 to 78 with lower scores indicating worse function. There is no agreement on a minimum clinically significant change in score, but it has been suggested that a difference of two points may be meaningful as it can potentially represent the loss of dressing or bathing independently, for example. Over a mean follow-up of 2.27 years, participants taking alpha tocopherol showed a significantly slower functional decline than those taking placebo. In the group taking alpha tocopherol, the least squares mean change in ADCS-ADL score was 13.8 compared with a reduction of 17.0 with placebo (from a baseline of 57). The mean decline was 3.2 points lower in the alpha tocopherol group than in the placebo group (95% CI 0.92 to 5.39). This finding translated into a slowing in functional decline of 19% per year compared with placebo, or a delay of 6.2 months over the study period (95% CI 5.4 to 7.4). The trial found no significant difference in functional decline among the groups taking memantine, or memantine plus alpha tocopherol,

compared with placebo. In safety analyses, there were no significant variations among all the groups in all-cause mortality and adverse events, with the exception of a higher rate of ‘infections or infestations’ in the memantine and combination groups. Comment: This trial has a complicated statistical analysis using a “longitudinal repeated-measures mixed-effects model”. In addition, it should be noted that the trial was originally planned to recruit 840 patients in order to be able to detect a four-point mean difference with a mean of 2.5 years follow-up. However, as a result of difficulties in recruiting participants, the parameters were changed to a median follow-up of 3 years to allow for the reduction in sample size to 600. Furthermore, the absolute change in score between the groups was less than the estimated four-point mean difference. The trial may not have been large enough to detect uncommon but potentially significant adverse effects. Whilst the results raise some interesting questions, the argument for the routine use of vitamin E in patients with Alzheimer’s disease is not yet made. 1. Dysken MW et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA 2014; 311: 33-44.

MHRA: rare adverse effect of clopidogrel The oral anticoagulant clopidogrel may give rise to acquired haemophilia, the Medicines and Healthcare products Regulatory Agency (MHRA) warns.1 The agency says the marketing authorisation holder had received 12 reports of acquired haemophilia, two of which were considered life threatening. Haemorrhage is a well-recognised risk with clopidogrel, arising from its platelet-inhibiting action, and potentially masking this very rare condition. Acquired haemophilia generally occurs in older people and is thought to affect between one and four people per million. Characteristics include bleeding into the soft tissues and skin. Bleeding into joints, a characteristic of inherited haemophilia, is less common. The agency says that the condition should be considered in patients taking clopidogrel in the event of isolated prolonged activated partial thromboplastin time. Such patients should have clopidogrel discontinued, and require specialist management. Comment: While this potential adverse effect is rare, clopidogrel is becoming much more widely used. The MHRA has stressed that, although a rare complication, it is important for physicians to be aware of the potential for acquired haemophilia in patients treated with clopidogrel, aside from the more common risk of bleeding. 1. Medicines and Healthcare products Regulatory Agency. Clopidogrel: risk of acquired haemophilia. Drug Safety Update 2013; 7 (5): A2 [online]. Available: [Accessed 19 February 2014].

DOI: 10.1136/dtb.2014.3.0239

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DTB 2014 52: 26-29 originally published online February 28, 2014

doi: 10.1136/dtb.2014.3.0239 Updated information and services can be found at:

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DTB Select: 3 | March 2014.

Every month, DTB scans sources of information on treatments, disease management and other healthcare topics for key items to bring to our readers' att...
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