3 The technologies
3.1 ICSs suppress inflammation in the lungs and are recommended for prophylactic treatment of asthma. In the UK, three ICSs are licensed for use in children: beclometasone dipropionate, budesonide and fluticasone propionate. ICSs are available in both pMDIs and dry powder inhalers (DPIs). pMDIs can either be press-and-breathe or breath actuated, but both contain the drug as either a suspension in a carrier liquid or a solution delivered using a chlorofluorocarbon (CFC) or hydrofluoroalkane (HFA) propellant. It is expected that those using CFC propellants will be phased out in line with the Montreal Protocol. Press-and-breathe pMDIs can be used with spacer devices that enable the drug to be inhaled by breathing normally, thereby removing some of the difficulties with coordinating pressing and inhaling. Spacers also reduce oral deposition of the drug, so they may reduce the likelihood of local adverse effects of corticosteroids such as oral candidiasis. DPIs require less coordination to use, but they require a high flow rate of air through the device to ensure that the drug reaches the lungs.
3.2 Beclometasone dipropionate is licensed for use in children in 10 different products. Three of these products are press-and-breathe pMDIs using a CFC propellant (Beclazone, IVAX Pharmaceuticals; Becotide, GlaxoSmithKline [to be discontinued second quarter 2007]; Filair, 3M Health Care), one of the products is a press-and-breathe pMDI using a HFA propellant (Clenil Modulite, Trinity Chiesi), two products are breath-actuated pMDIs (Aerobec Autohaler, 3M Health Care; Beclazone Easi Breathe, IVAX Pharmaceuticals), and four products are DPIs (Asmabec Clickhaler, UCB; Becodisks Diskhaler, GlaxoSmithKline; Cyclocaps, TEVA; Pulvinal, Trinity Chiesi). The marketing authorisation for beclometasone dipropionate differs depending on the product in which it is available and, within a particular product, not all dose strengths available are recommended for children. The maximum licensed dosage is 400 micrograms per day with no specified lower age limit. Pulvinal and Asmabec are not licensed for children younger than 6 years.
3.3 Budesonide is licensed for use in children in five different products. Two of these products are press-and-breathe pMDIs using a CFC propellant (Pulmicort inhaler, AstraZeneca; Pulmicort LS, AstraZeneca) and three of these products are DPIs (Easyhaler, Ranbaxy; Novolizer, Meda Pharmaceuticals; Pulmicort Turbohaler, AstraZeneca). The marketing authorisation for budesonide differs depending on the product in which it is available and, within a particular product, not all dose strengths available are recommended for children. The maximum licensed dosage is 800 micrograms per day. No lower age limit is specified in the marketing authorisation for the three Pulmicort devices, while the lower age limit for the other two products is 6 years.
3.4 Fluticasone propionate is licensed for children in three different products. One of these products is a press-and-breathe pMDI using a HFA propellant (Flixotide Evohaler, GlaxoSmithKline) and two of these products are DPIs (Flixotide Accuhaler, GlaxoSmithKline; Flixotide Diskhaler, GlaxoSmithKline). The marketing authorisation for fluticasone propionate differs depending on the product in which it is available and, within a particular product, not all dose strengths available are recommended for children. The maximum licensed dosage is 400 micrograms per day and none of the products is licensed for the treatment of children younger than 4 years. Fluticasone propionate is considered nominally clinically equivalent to beclometasone dipropionate and budesonide at half the dose (that is, a ratio of 1:2).
3.5 ICSs are also available in combination with a LABA in a single combination device. Budesonide is available in combination with formoterol fumarate in a DPI (Symbicort Turbohaler, AstraZeneca), and fluticasone propionate is available in combination with salmeterol as a pMDI with a HFA propellant (Seretide Evohaler, GlaxoSmithKline) and as a DPI (Seretide Accuhaler, GlaxoSmithKline). The marketing authorisations for combination devices containing corticosteroids and LABAs differ depending on the product in which they are available, but for all products only the lowest dose strength inhalers are recommended for children, and these are not recommended for individuals with severe asthma. Symbicort is licensed for use in children aged 6 years and older with a maximum recommended dosage of 400/24 micrograms (budesonide/formoterol fumarate) per day. Seretide devices are licensed for use in children aged 4 years and older with a maximum recommended dosage of 200/100 micrograms (fluticasone propionate/salmeterol) per day. For both Symbicort and Seretide, it is recommended that patients are regularly reassessed by their prescriber so that dosing is titrated to the lowest dose at which effective control of symptoms is maintained. The Seretide Evohaler device is the only combination device currently available as a pMDI, and therefore the only one which can be used with a spacer.
3.6 The side effects of ICSs may be local (following deposition in the upper airways) or systemic (following absorption into the bloodstream). Local adverse effects may include dysphonia, oropharyngeal candidiasis, cough, throat irritation and reflex bronchospasm. Local adverse effects can be minimised by optimising inhaler technique and using a spacer with the inhaler device. Systemic adverse effects may include suppression of the hypothalamic-pituitary-adrenal axis, osteoporosis, skin thinning and easy bruising, cataract formation and glaucoma, and growth retardation in children and adolescents. Systemic adverse effects tend to be associated with higher doses of corticosteroids and can differ depending on both the drug and the delivery system. For full details of side effects and contraindications, see the summaries of product characteristics.
3.7 The costs of ICSs vary depending on the product. The costs also vary depending on the dose strength of the inhaler used (for example, 50 micrograms, 100 micrograms or 200 micrograms) and how the recommended dose is achieved (for example, 200 micrograms could be achieved by either 4 x 50 micrograms, 2 x 100 micrograms or more rarely 1 x 200 micrograms). The annual cost of 200 micrograms beclometasone dipropionate equivalent per day ranges from approximately £10 (£25 following the discontinuation of Becotide devices) to £70. The corresponding costs for budesonide range from approximately £35 to £70 and, for fluticasone propionate, they range from approximately £35 to £90. The annual costs for 200 micrograms beclometasone dipropionate equivalent per day in a combination device are £201 per year for Symbicort Turbohaler, £190 per year for Seretide Accuhaler and £115 for Seretide Evohaler. Costs may vary in different settings because of negotiated procurement discounts.
 The Vienna Convention for the Protection of the Ozone Layer and The Montreal Protocol on Substances that Deplete the Ozone Layer (2003) The Montreal Protocol on Substances that Deplete the Ozone Layer. Kenya: United Nations Environment Programme.