Send letter to journal:
Re: Adrenal crisis due to inhaled steroids not underestimated

Dear Editor

In response to comments by Pearce and Mabin on Professor Russell’s editorial[1] on our paper.[2]

They doubt that our survey underestimated the true scale of the problem. I can inform them that this is not the case. Since our survey was completed we have been notified of a further 7 cases (5 children, 2 adults). All but one of the children had been taking fluticasone in similar dosages to those reported in our survey. Three of these were critically ill in intensive care and an 8-year-old girl died due to adrenal crisis. The remaining child was only 20 months old and had been given budesonide in extremely high doses of 2000-8000mcg/day.[3] Both adults had been taking fluticasone (1000mcg/day, 2250mcg/day).

Case reporting clearly plays a much greater role than clinical studies in post license surveillance of new drugs. In an international 20 year study of drug safety discontinuations, nearly all occurred as a result of case reporting. Despite studies the authors concluded that “it is impossible to know fully all the facts about a drugs effects both beneficial and harmful at the time of approval”.[4] Further, it is incorrect for Pearce and Mabin to say that “studies show no increased risk of hypothalamic pituitary axis (HPA) suppression with fluticasone propionate when compared with other inhaled steroids”. There are many studies arguing against this assertion (e.g. [5-9]). Actually, there is a serious disparity between the results of different safety studies involving fluticasone which requires explanation. While the product monograph claims “mean plasma cortisol concentrations remained within the normal range for adults and children demonstrating that, even at high doses (2000mcg), fluticasone propionate is well tolerated with regard to side effects”,[10] many studies suggest otherwise. For example, as little as 88mcg/day of fluticasone can produce 10% adrenal suppression [11] and 704mcg/day can produce 50% adrenal suppression, a considerably greater degree than the equipotent dosage of beclometasone,[9] leading those authors to conclude that “increasing the dose beyond this point of maximum efficacy... resulted in increasing systemic effect, especially with fluticasone metered dose inhaler with its CFC propellant”- exactly what we have reported.

Pearce and Mabin correctly state that “individuals have differing sensitivities to inhaled corticosteroids. Idiosyncratic responses to inhaled corticosteroids may occur even at licensed doses”. I agree, however, such patients “disappear” in large multi-centre studies, particularly when the pharmaceutical company will not make available data on individual patients.[12] This is of concern as there is evidence that fluticasone is associated with significantly more individual abnormally low cortisol values than other inhaled steroids.[13] Also, over 75% of our patients developed adrenal crisis greater than one year after starting fluticasone, and it is known that length of time taking inhaled steroids is a major factor in determining the frequency of side effects.[14] How many studies of fluticasone have lasted greater than one year?

Pearce and Mabin correctly state that in recent years, when paediatricians decide that high doses of inhaled corticosteroids are necessary, more are choosing to prescribe fluticasone propionate. However, they need to explain why only 2 cases of adrenal crisis (both adults) in over 30 years of prescribing inhaled corticosteroids had ever been reported in literature before the introduction of fluticasone propionate allowing Russell to make a claim in 1994 that “there is no firm evidence that any child has ever come to harm as a result of adrenal suppression induced by inhaled corticosteroid therapy”.[15] Further, some cases reported in our survey had previously been taking very high doses of either beclometasone or budesonide but only developed adrenal crisis some time after changing to fluticasone.[16]

Finally, it is unfair to blame doctors for prescribing fluticasone “off label”. Almost half of all drug prescriptions for children in hospital are either unlicensed or off label.[17] Prescribers have every right to expect a reasonable margin of safety with a drug should they decide that off label dosages are necessary in children. Bearing in mind that there have now been 2 reported deaths and many intensive care cases, the risks of prescribing fluticasone off label appear greatly to exceed any possible benefits for patients, and will have serious medico-legal implications for doctors, particularly when there is not a single study showing better efficacy for fluticasone compared with other available inhaled corticosteroids.[18]

References

(1) Russell G. Inhaled corticosteroids and adrenal insufficiency. Arch Dis Child 2002;87:455-456.

(2) Todd GRG, Acerini CL, Ross-Russell R, Zahra S, Warner JT, McCance D. Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom. Arch Dis Child 2002;87:457-461.

(3) Dunlop KA, Carson DJ, Shields MD. Hypoglycaemia due to adrenal suppression secondary to high-dose nebulised corticosteroid. Ped Pulmonology 2002;34:85-86.

(4) Bakke OM, Manocchia M, de Abajo F, Kaitin KI, Lasagna L. Drug safety discontinuations in the United Kingdom, the United States, and Spain from 1974 through 1993: a regulatory perspective. Clin Pharmacol Ther 1995;58:108-117.

(5) Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a systemic review and meta-analysis. Arch Intern Med 1999;159:941-955.

(6) Clark DJ, Lipworth BJ. Adrenal suppression with chronic dosing of fluticasone propionate compared with budesonide in adult asthmatic patients. Thorax 1997;52:55-58.

(7) Casale TB, Nelson HS, Stricker WE, Raff H, Newman KB. Suppression of hypothalamic-pituitary-adrenal axis activity with inhaled flunisolide and fluticasone propionate in adult asthma patients. Ann Allergy Asthma Immunol 2001;87:379-385.

(8) Eid N, Morton R, Olds B, et al. Decreased morning serum cortisol levels in children with asthma treated with inhaled fluticasone propionate. Pediatrics 2002;109:217-221.

(9) Szefler SJ, Martin RJ, King TS, et al. Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol 2002;109(3):410-418.

(10) Allen & Hanburys. Product Monograph Flixotide. HS3151. Mar 1993.

(11) Martin RJ, Szefler SJ, Chinchilli VM, et al. Systemic effect comparisons of six inhaled corticosteroid preparations. Am J Respir Crit Care Med 2002;165:1377-1383.

(12) Herxheimer A. Commentary: Dosage needs systematic and critical review. BMJ 2001;323:256.

(13) Wilson AM, Lipworth BJ. Adrenocortical activity in asthmatic patients receiving intranasal corticosteroids. Thorax 1999;54:20-26.

(14) Brown PH, Blundell G, Greening AP, Crompton GK. Hypothalamic- pituitary-adrenal axis suppression in asthmatics inhaling high dose corticosteroids. Resp Med 1991;85:501-510.

(15) Russell G. Inhaled corticosteroid therapy in children: an assessment of the potential for side effects. Thorax 1994;49:1185-1188.

(16) Todd GRG, Acerini CL, Buck JJ, Murphy NP, Ross-Russell R, Warner JT, McCance DR. Acute adrenal crisis in asthmatics treated with high-dose fluticasone propionate. Eur Respir J 2002;19 :1207-1209.

(17) Conroy S, Choonara I, Mahn A, et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. BMJ 2000;320:79-82.

(18) The use of inhaled corticosteroids in childhood asthma. Drug and Therapeutic Bulletin 1999;37(10):73-75.

Send letter to journal:
Re: Use of inhaled corticoseroids in children

Dear Editor

I read with interest the article Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom by Todd et al. and the accompanying editorial in the December issue of Archives of Disease in Childhood.

In the reported cases, the children had been administered substantially (up to 5 times) higher than the Glaxo SmithKline Core Data Sheet recommended Flixotide dose of 400 mcg/day and use of FP at such doses is certainly not endorsed by GSK. Within the recommended doses, there are a wealth of data from controlled clinical trials that Flixotide is a well tolerated and effective drug in adults and children.[1-5] There are a number of recent studies in children which identified no cases of adrenal crisis and no effect on growth following 12 months treatment with FP at licensed doses.[6-8]

There are also a number of methodological deficiencies in this survey, the most important being that the survey is not case-controlled and lacks information on true incidence against the overall FP use or exposure. In addition, it is unclear from the survey what attempts were made to closely monitor any adrenal suppression with increasing doses of FP or whether patients were down-titrated to the lowest effective FP dose, as routinely recommended.

The survey data also imply that fluticasone has been implicated in the great majority of cases of adrenal failure even though it is the least frequently prescribed form of inhaled corticosteroid. Prescribing data in relation to fluticasone from the UK DINLINK (Doctors Independent Network) database, shows that it is in fact the most commonly prescribed inhaled corticosteroid in children with moderate and severe asthma.[9] DINLINK is an amalgamated database of the anonymised computer records of a panel of 300 General Practitioners spread across the UK selected to represent the demographic population of the UK.

In addition, the authors’ contention that adrenal effects with FP are due to its greater lipophilicity and hence accumulation over prolonged periods is misconceived and inaccurate. There are studies to show that there is no accumulation of FP at a steady state.[10] It is the clearance value which determines the amount of FP in the body at steady state, and lipohilicity per se in not a relevant factor.[11]

I also wanted to take this opportunity to comment on the editorial by Dr Russell. The last line of the editorial recommends that if high dose inhaled corticosteroid is considered necessary, that it is advisable not to use fluticasone. The recent publication by the CSM "Current Problems in Pharmacovigilance"[12] states that adrenal suppression is a dose related class effect of inhaled steroids, and that all inhaled corticosteroids are associated with an increased risk of adrenal crisis when used at higher than licensed doses.

In conclusion, inhaled corticosteroids have an important place in asthma management throughout the world, and this paper by Todd et al. should be reviewed in this context. Any inhaled corticosteroid used at such high doses has the potential to cause systemic effects, and paediatricians should be encouraged to treat their patients using the lowest effective dose, down-titrating as appropriate.

Dr Mike Devoy VP, Europe
Glaxo SmithKline

References

(1) Barnes NC, Hallett C, Harris TAJ. Clinical experience with fluticasone propionate in asthma: a meta-analysis of efficacy and systemic activity compared with budesonide and beclomethasone dipropionate at half the microgram dose or less. Respir Med 1998;92:95-104.

(2) Ferguson AC, Spier S, Manjra A et al. Efficacy and safety of high-dose inhaled steroids in children with asthma: a comparison of fluticasone propionate with budesoinde. J Pediatr 1999;134: 422-427.

(3) Roorda RJ, Mezei G, Bisgaard H et al. Response of preschool children with asthma symptoms to fluticasone propionate. J Allergy Clin Immunol 2001; 108:540-6.

(4) Rao R, Gregson RK, Jones AC et al. Systemic effects of inhaled corticosteroids on growth and bone turnover in childhood asthma: a comparison of fluticasone with beclometasone. Eur Respir J 1999;13: 87- 94.

(5) De Benedictis FM, Teper A, Green RJ, Boner AL, Williams L, Medley H. Effects of 2 inhaled corticosteroids on growth: Results of a randomized controlled trial. Arch Pediatr Adolesc Med 2001;155(11):1248-1254.

(6) Bidat E, Desfougeres J, Minini P, Kolta S, Roux C. Equivalent bone safety and better efficacy of fluticasone propionate compared to nedocromil sodium in asthmatic children. Results of a 2-year randomised study. ERJ 2002;20(Suppl 38):1443.

(7) Bisgaard H, Allen D, Milanowski J, Kalev I, Davies P, Willits L. Evaluation of long-term safety, growth and efficacy of fluticasone propionate 100mcg bd compared with sodium cromoglycate 5mg qds in asthmatic children aged 12-47 months. ERJ 2002;20(Suppl38):1444.

(8) De Benedictis Fm Teper A, Green R, Boner A, Williams L, Medley H. Effects of 2 inhaled corticosteroids on growth: Results of a randomized controlled trial. Arch Pediatr Adolesc Med Nov 2001;1551248- 1254.

(9) DIN-LINK Data, CompuFile Ltd, (March 2002).

(10) Meibohm B, Mollmann H, Wagner M, Hochhaus G, Mollmann A, Derendorf H. The clinical pharmacology of fluticasone propionate. Rev Contemp Pharmacother 1998; 9: 535-549.

(11) Mackie AE, Falcoz C, McDowall JE, Moss J, Ventresca GP, Bye A. Pharmacokinetics of fluticasone propionate inhaled from the Diskhaler and the Diskus powder devices in healthy subjects. Br J Clin Pharmacol 1997; 43: 540P-541P.

(12) Committee on the Safety of Medicines. Inhaled corticosteroids and adrenal suppression in children. Current Problems in Pharmacovigilance 2002; 28: 7.

Send letter to journal:
Re: Adrenal axis suppression in children with long term inhaled corticosteroids treatment

Dear Editor

With reference to the recent article of Todd et al.[1] about adrenal crisis associated with inhaled corticosteroids, we report two cases of adrenal axis suppression in children with this treatment.

The first one[2] is a 18 months boy, who had been diagnosed of bronchial hyperresponsiveness, and was in treatment with high dose of inhaled fluticasone (FP) (1000 mcg/day) since he was 9 months old; 1 month before the admission he had treatment with oral prednisone starting with 1 mg/kg/day, and a reduction of the dose until a total of 10 days of oral treatment. He went to the casualty department because he presented vomits, slight dehydration and bewilderment. A hypoglycaemia (2 mmol/l) was detected, he was treated with IV rehydration and he was discharged at 36 hours. After that, we received a plasmatic levels of cortisol of 37 ng/ml (normal values: 130-260 ng/ml) and ACTH of 6 pg/ml (normal values: 5-60). Two months later, in the course of a cold, he was readmitted with vomits and weakness and he required parenteral corticosteroids. After that the dose of FP was gradually reduced, until 500 mcg/day.

The second case is an adrenal axis suppression without adrenal crisis. The patient is a 9 years old boy, diagnosed of bronchial hyperresponsiveness, in treatment with inhaled FP at dose of 500 mcg/day for 19 months, and then 250 mcg/day during the last 7 months. In a control test we detected a suppression of the adrenal axis (cortisol: 53 ng/ml; ACTH: 27 pg/ml). The corticosteroid dose was gradually reduced; at the moment he has budesonide (320 mcg/day) and the hormonal levels have improved ( cortisol: 90 ng/ml; ACTH: 35 pg/ml).

Children with adrenal suppression due to inhaled corticosteroid often are asymptomatic[3] and, in other cases, they have an unexpected mode of presentation.[4] We underline the importance of a control of the adrenal axis in children with long term inhaled corticosteroids; not only with doses so high like the published by Todd ( FP > 400 mcg/day) but also with lower doses.

References

(1) Todd GRG, Acerini CL, Ross-Russell R, Zahra S, Warner JT, McCance D. Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom. Arch Dis Child 2002;87:457-461.

(2) García García E, López-Siguero JP, Pérez Frías J, Pérez Ruiz E, Martínez Valverde A. Insuficiencia suprarrenal secundaria a dosis altas de fluticasona inhalada. Ann Esp Pediatr 2000;52:476-478.

(3) Perry RJ, Findlay CA, Donaldson MDC. Cushing Syndrome, growth impairment, and accult adrenal suppression associated with intranasal steroids. Arch Dis Child 2002;87:45-48.

(4) Patel L, Wales JK, Kibirige MS, Massarano AA, Couriel JM, Clayton PE. Symptomatic adrenal insufficiency during inhaled corticosteroid treatment. Arch Dis Child 2001;85:330-334.