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We are grateful to Dr. Duerden and Dr. Levy for their comments on our paper which highlight the difficulty of comparing doses of ICS steroids when there is no gold standard comparator. Our aim in compiling Table 1 was to point out that the NICE table does not allow for the greater potency of HFA FP compared to HFA BDP. We were concerned that this was a significant safety issue especially in children . In our efforts to simplify this message, we had not fully explained or allowed for some of the other variables.
1. Dr. Levy is correct to point out that the original GINA table (used by NICE) of “Low, medium and high daily doses of inhaled corticosteroid for children 6-11 years” has a statement below indicating that the table is not a table of “dose equivalency”, the term we used in Table 1, but of “estimated clinical comparability”.
2. The GINA table (but not NICE) also has a footnote explaining the inclusion of beclometasone dipropionate CFC (BDP CFC) as a comparison with older literature. CFCs (chlorofluorocarbons), as propellants in metered dose inhalers, were phased out under the Montreal Protocol and were replaced by HFAs (hydrofluorolakanes). However, CFC BDP is still often used as the reference standard when comparing ICS in terms of their potency.
3. Most newer HFA ICSs have been formulated to be equipotent with the CFC ICS they were replacing. As one example, the BTS/SIGN table includes the proprietary HFA BPD, Clenil modulite, commonly us...
3. Most newer HFA ICSs have been formulated to be equipotent with the CFC ICS they were replacing. As one example, the BTS/SIGN table includes the proprietary HFA BPD, Clenil modulite, commonly used in children. Clenil is clinically comparable to the legacy BDP CFC with a recommended starting dose of Clenil 50 2 puffs BD (100ug bd) in children (2). The BTS/SIGN table also includes the HFA BDP, Qvar, which is formulated as an extra-fine particle preparation and is usually considered as effective at half the dose. GINA and NICE give the doses for HFA BDP in children as half those of the BDP CFC but do not specify which preparations of HFA BDP they are referring to in their table.
4. HFA Fluticasone propionate (HFA FP) is as effective as other inhaled steroids at approximately half the microgram daily dose (3). So, for clinical comparability HFA FP should be used at half the dose of HFA BDP, as indicated in the BTS/SIGN table.
5. A further complication is that GINA provides doses as daily doses: BTS/SIGN provides puffs and frequency; NICE only specifies dose (though assumed to be daily dose as the table was taken from GINA). In preparing the table we should have made clear that the doses from the BTS/SIGN table were to be given twice a day.
The challenge was how to explain this simply in limited text and a small table and it was complicated by the other points discussed above. To clarify these issues, we suggest the table should be modified as follows:
Clinical Comparability Table: Children. Comparing NICE, GINA and BTS/SIGN
More fundamentally, this discussion highlights the potential complexity for prescribers from the increasing number of corticosteroid molecules available in an ever-increasing number of devices. If a national guideline body and ‘experts’ who have spent some hours poring over these data struggle to achieve clarity what hope is there for the busy prescriber in clinical practice? Perhaps, this discussion should stimulate regulatory authorities to consider whether manufacturers of inhaled corticosteroids could be required to label their devices as providing doses equivalent to an agreed standard.
Finally, prescribers should always remember that the numbers in all these tables are only a guide. The correct dose of an inhaled steroid is the lowest dose that keeps the patient free of symptoms and that this dose should be adjusted dynamically in response to changes in status in accordance with an agreed action plan.
1. 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 Oct;91(10):808-13.
2. The electronic Medicines Compendium. https://www. medicines. org. uk/ emc/ medicine/30651 (accessed 14 Jan 2018).
3. The electronic Medicines Compendium. https://www. medicines. org. uk/ emc/ medicine/2913 (accessed 14 Jan 2018).
While I agree this paper draws out most of the important issues related to the NICE guideline, I would like to point out that there are inaccuracies regarding the statements and table related to 'dose equivalences' in the GINA document.
In fact reference to equivalence in your article is explicitly contradicted by the statement immediately below GINA table 3-6, which states that 'this is not a table of equivalence, but of estimated clinical comparability'. (1)
Furthermore the GINA table also takes into account the potential for side-effects. For example, BDP HFA causes more adrenal suppression than FP HFA at the same dose. (2)
Of course this is going to get even more complicated with the number of generics now available, as they cannot be assumed to be equivalent to the original product, due to the impact of the inhaler device and additives.
(2) Fowler, S. J., Orr, L. C., Wilson, A. M., Sims, E. J. and Lipworth, B. J. (2001), Dose-response for adrenal suppression with hydrofluoroalkane formulations of fluticasone propionate and beclomethasone dipropionate. British Journal of Clinical Pharmacology, 52: 93-95. doi:10.1046/j.0306-5251.2001.bjcp.1399.x