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Issue No 27
March 2007         

Inhaled corticosteroids: children are at risk from high doses
Development of diabetes with thiazides: what are the consequences?
Grazax▼ sublingual vaccine against grass pollen allergy

Inhaled corticosteroids: children are at risk from high doses

Inhaled corticosteroids (ICS) are safe and effective for the prevention of symptoms of asthma when used at the recommended doses.¹ However, prolonged treatment at high doses carries a risk of systemic side effects and has been associated with adrenal crisis, coma and even death in children.^2,3 In a recent Scottish study, 42% of children prescribed above licensed doses of fluticasone had adrenal suppression.⁴ The Committee on Safety of Medicines (CSM) has advised that the paediatric licensed dosages for ICS (see Table) should not be exceeded.⁷

The British Guideline on the Management of Asthma⁸ recommends that, in children under five years, the dose of ICS should not exceed 400mcg/day beclometasone dipropionate (BDP) or equivalent (e.g. 400mcg/day budesonide, or 200mcg/day fluticasone propionate). In children aged five to 12 years, the dose should not exceed 400mcg/day BDP or equivalent, unless the patient’s asthma remains uncontrolled despite add-on therapy (initially a long-acting ß2-agonist, followed by trials of other therapies e.g. a leukotriene receptor antagonist or sustained-release theophylline). In such cases the dose may be increased to 800mcg/day BDP or equivalent.⁸ However, higher, unlicensed doses of ICS should only be initiated and supervised by specialists, and therapy should be reviewed regularly and titrated down to the lowest dose at which effective control of asthma is maintained.^1,2.

The Commission on Human Medicines (CHM: an amalgamation of the CSM and the Medicines Commission) recently advised that steroid treatment cards should be issued routinely for patients, including children, who require prolonged, high, unlicensed doses of ICS,¹ because they may need corticosteroid cover during an episode of stress (e.g. an operation).²

An observational study,⁹ which looked at asthma prescribing in children in primary care (n=4,332), found that high-dose ICS (>400mcg/day BDP or equivalent) were prescribed to 6% of under-fives, and 10% of children aged 5–11 years, who were treated for asthma. Of these children, 47% of the 5–11 year olds were not prescribed add-on therapy as recommended by the British asthma guideline.⁸ Even more worryingly, ICS doses exceeding 800mcg/day BDP or equivalent were prescribed to 4% of under-fives and 5% of 5–11 year olds. The authors recommended that GPs should audit high-dose ICS and add-on therapy prescribing in children to identify those at risk of adverse outcomes.⁹

References

1. Commission on Human Medicines/Medicines and Healthcare products Regulatory Agency. Current Problems in Pharmacovigilance 2006;31:5. Accessed from www.mhra.gov.uk on 28/02/07
2. Paediatric Formulary Committee. BNF for children. 2006. London: BMJ Publishing Group, RPS Publishing, and RCPCH Publications; 2006. Accessed from www.bnfc.org on 28/02/07
3. Safer Healthcare. Lessons from a fatal accident inquiry. October 2005. Accessed from www.saferhealthcare.org.uk on 28/02/07
4. Paton J, Jardine E, McNeill E, et al. Adrenal responses to low dose synthetic ACTH (Synacthen) in children receiving high dose inhaled fluticasone. Arch Dis Child 2006;91:808–13
5. Summaries of Product Characteristics. Accessed from www.medicines.org.uk on 28/02/07
6. Clenil Modulite^▼. Summary of Product Characteristics. Accessed from www.trinity-chiesi.co.uk/files/Clenil%20Modulite.pdf on 28/02/07
7. Committee on Safety of Medicines/Medicines Control Agency. Current Problems in Pharmacovigilance 2002;28:7. Accessed from www.mhra.gov.uk on 28/02/07
8. Scottish Intercollegiate Guidelines Network/The British Thoracic Society. British Guideline on the Management of Asthma. Revised edition November 2005. Accessed from www.sign.ac.uk on 28/02/07
9. Thomas M, Turner S, Leather D, et al. High-dose inhaled corticosteroid use in childhood asthma: an observational study of GP prescribing. Br J Gen Pract 2006;56:788–90

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Development of diabetes with thiazides: what are the consequences?

In the ALLHAT study, the first-line use of a thiazide diuretic, an angiotensin-converting enzyme (ACE) inhibitor, or a calcium-channel blocker (CCB) for hypertension was similarly effective in reducing the risk of major cardiovascular (CV) events.¹ However, there were significant differences between treatments for some outcomes. Notably, CCBs were less effective in preventing heart failure than thiazide diuretics, whereas development of diabetes (defined as fasting blood glucose levels [FGs] above 6.9mmol/l) was more frequent with thiazide diuretics than with CCBs.¹ When costs associated with these outcomes were factored into the NICE health-economic model, CCBs were identified as the most cost-effective option.² However, this analysis had many limitations, not least whether or not an elevated FG developing as a consequence of drug treatment has the same long-term health impact as diabetes developing in other circumstances.² A recent analysis of the ALLHAT study data provides some insight into this issue.³

This post-hoc subgroup analysis considered non-diabetic patients in ALLHAT who were randomised to initially receive chlortalidone (n=8,419), amlodipine (n=4,958), or lisinopril (n=5,034).³ After two years, mean FGs were raised in all groups — by 0.47mmol/l, 0.31mmol/l and 0.19mmol/l, respectively. New incidences of diabetes were seen in all treatment groups, as would be expected as the study population aged. As diuretics increased blood glucose levels to a greater extent than the other treatments, it is not surprising that more cases of incident diabetes, when defined by a 6.9mmol/l FG threshold, were detected in the chlortalidone group. However, absolute differences between groups in incident diabetes were small (chlortalidone 9.3%, amlodipine 7.2%, lisinopril 5.6%).³ The risk of developing diabetes was lower for lisinopril (odds ratio [OR] 0.55, 95%CI 0.43 to 0.70, P<0.001) or amlodipine (OR 0.73, 95%CI 0.58 to 0.91, P=0.008) compared with chlortalidone.³

Although, there was a significant association between incident diabetes at two years and coronary heart disease (risk ratio [RR] 1.64, P=0.006), the relative risk of coronary heart disease was not significant in the chlortalidone group (RR 1.46, P=0.14).³ There was no significant association between FG changes at two years and any of the study endpoints (death, CV disease or end-stage renal disease), whether analysed for all treatments combined or for chortalidone alone.³

Although requiring a prospective study for confirmation, these findings support the results from the 14-year follow-up of SHEP⁴ and suggest that, even if diabetes does occur during the treatment of hypertension with thiazide diuretics, this does not create any greater cardiovascular risk. It is possible that that the raised FGs that occur with thiazide diuretics arise from mechanisms that are different from those associated with diabetes in other circumstances.³

 References

1. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic. JAMA 2002;288:2981–97
2. National Collaborating Centre for Chronic Conditions. Hypertension: management of hypertension in adults in primary care: partial update. June 2006. Accessed from www.nice.org.uk on 11/01/07
3. Barzilay JI, Davis BR, Cutler JA, et al. ALLHAT Collaborative Research Group. Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment. Arch Intern Med 2006;166:2191–201
4. Kostis JB, Wilson AC, Freudenberger RS, et al. Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes. Am J Cardiol 2005;95:29–35
5. National Prescribing Centre. The management of hypertension in primary care: updated guidance from NICE. MeReC Bulletin 2006;17:1–20. Accessed from www.npc.co.uk/merec.htm on 12/01/07

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Grazax^▼ sublingual vaccine against grass pollen allergy

Grazax^▼ is a once-daily sublingual tablet containing allergen extract of grass pollen. It is licensed for adults with clinically relevant symptoms of pollen allergy who have been diagnosed with a positive skin prick test and/or specific IgE test to grass pollen.¹ It should be initiated by physicians with experience in the treatment of allergic disease. In view of the possibility of local or systemic allergic reactions when first taken, the first dose should be taken under medical supervision (20–30 minutes).¹

There is evidence from a double-blind, randomised controlled trial that Grazax reduces rhinoconjunctivitis symptoms and medication use compared with placebo when initiated at least 16 weeks before, and continued throughout, the whole grass pollen season.² However, the absolute benefits appear very modest, and its clinical efficacy and cost-effectiveness have yet to be established in comparison with subcutaneous allergen immunotherapy.

An extended version of this article is available as a supplement.

References

1. Grazax^▼. Summary of Product Characteristics. October 2006
2. Dahl R, Kapp A, Colombo G, et al. Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006;118:434–40

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