Submission to Post-Market Review of PBS Medicines Used to Treat Asthma in Children
Submission 12 - University of Queensland
Submission to PBS Post-Market Review of Pharmaceutical Benefits Scheme Medicines Used to Treat Asthma in Children with regards to item three of the terms of reference.
Oral salbutamol syrup
We contend that oral salbutamol syrup is being used to treat asthma in children and that there is no evidence to support this practice. The PBS indication for oral salbutamol syrup is for patients that are unable to coordinate inhalation devices. The availability of paediatric masks and spacers eliminates this coordination problem.
Salbutamol exhibits molecular chirality, and is administered as a racemic mixture1. This is critically significant, as the bronchodilatory and anti-inflammatory effects of salbutamol are attributed exclusively to the R-enantiomer, while the S-enantiomer is proinflammatory and exacerbates airway resistance2. Oral salbutamol is subject to extensive “first pass metabolism” due to sulphate conjugation by sulphotransferase (SULT) 1A3, predominately in the small intestine and liver3. The SULT 1A3 has genetic polymorphisms, which may cause disparity in the bioavailability of orally administered salbutamol between individuals4. The bioavailability of (R)-salbutamol reportedly varies from 9.4 to 23.8 % for single-dose oral and racemic salbutamol delivered without a spacer, respectively5, while at steady state the bioavailability of (R)-salbutamol is 30 % for orally administered salbutamol6. Inhaled salbutamol avoids this “first-pass” effect by being delivered directly to the target organ..
Clinical trial data also does not support the use of oral salbutamol in the treatment of paediatric asthma. In 2011 a Quality Use of Medicines pharmacy student, during a placement at Mater Children’s Emergency, conducted a search for evidence of effectiveness of oral salbutamol. The search included PubMed, Embase, Google Scholar, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Australian New Zealand Clinical Trials Registry, and ClinicalTrials.gov, and the bibliographies of found articles. The search yielded six relevant publications of oral and inhaled salbutamol use in the treatment of asthma in children.
In two studies nebulised salbutamol demonstrated statistically greater (p < 0.05) improvement in FEV17 and PEFR8 compared with salbutamol tablets. While maximum improvement in PEFR and FEV1 was less distinct in comparisons between salbutamol aerosol9, or inhaled powder8, 10. The therapeutic effect of oral salbutamol took two hours to peak 10. In contrast, the bronchodilatory effect of inhaled salbutamol peaked after 30 minutes10. One study of salbutamol use in exercise-induced asthma concluded that the maximum effect of oral salbutamol on FEV1, which was reached after two hours, was comparable with that reached by inhaled salbutamol after 40 minutes11. These studies did not utilise spacers or paediatric masks, which would likely have improved the efficiency of inhaled administration. Oral salbutamol was also associated with an increased incidence of tremor10, hyperactivity12, and increased pulse rate10.
In the treatment of asthma in children, oral salbutamol is surpassed by inhaled formulations in measures of both effectiveness and tolerability. It is our opinion, therefore, that oral salbutamol, marketed in Australia as Ventolin Sugar Free Syrup, should be removed from the PBS schedule.
Dr David W Herd, FRACP, Staff Specialist, Mater Children’s Emergency Department.
Emma Grove, 4th year pharmacy student, University of Queensland.
Aaron Basing, BPharm, Pharmacist, PhD Candidate, University of Queensland
Professor Keith Grimwood, Queensland Children’s Medical Research Institute.
References
1. Ameredes BT, Calhoun WJ. Levalbuterol Versus Albuterol. Curr Allergy Asthma Rep2009; 9: 401-409
2. Ibe BO, Abdallah MF, Raj JU. Mechanisms by Which S-Albuterol Induces Human Bronchial Smooth Muscle Cell Proliferation. Int Arch Allergy Immunol 2008; 146: 321-333
3. Boulton DW, Fawcett JP. The Pharmacokinetics of Levosalbutamol: What are the Clinical Implications? Clin Pharmacokinet 2001; 40: 23-40
4. Thomae BA, Rifki OF, Theobald MA, Eckloff BW, Wieben ED, Weinshilboum RM. Human catecholamine sulfotransferase (SULT1A3) pharmacogenetics: functional genetic polymorphism. J Neurochem 2003; 87: 809-819
5. Ward JK, Dow J, Dallow N, Eynott P, Milleri S, Ventresca GP. Enantiomeric disposition of inhaled, intravenous and oral racemic-salbutamol in man – no evidence of enantioselective lung metabolism. Br J Clin Pharmacol 2000; 49: 15-22
6. Boulton DW, Fawcett JP. Enantioselective disposition of salbutamol in man following oral and intravenous administration. Br J Clin Pharmacol 1996; 41: 35-40
7. Scalabrin DMF, Naspitz CK. Efficacy and Side Effects of Salbutamol in Acute Asthma in Children: Comparison of Oral Route and Two Different Neublizer Systems. J Asthma 1993; 30: 51-59
8. Grimwood K, Barrett-Johnson JJ, Taylor B. Salbutamol: tablets, inhalational powder, or nebuliser? Br Med J 1981; 282: 105-106
9. Berg IM, Berg T, Ringqvist I. Salbutamol in the treatment of asthmatic children: A comparison of oral and inhalation therapy alone and in combination. Eur J Respir Dis 1982; 63: 305-309
10. Grimwood K, Fergusson DM, Dawson KP. Combination of salbutamol inhalational powder and tablets in asthma. Arch Dis Child 1983; 58: 283-285
11. Francis PWJ, Krastins IRB, Levison H. Oral and Inhaled Salbutamol in the Prevention of Exercise-Induced Bronchospasm. Pediatrics 1980; 66: 103-108
12. Bartfield JM, Boenau IB, Lozon J, Raccio-Robak N. Comparison of metered dose inhaler and oral administration of albuterol in the outpatient treatment of infants and children. Am J Emerg Med1995; 13: 375-377
