Q&A 100.8
Which commonly used nebuliser solutions are compatible?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
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Date prepared:8 January 2016
Background
As administration of one drug by nebulisation can take 15-20 minutes, mixing nebuliser solutions might aid compliance by decreasing nebulisation time (1).
Answer
There is little published evidence on the compatibility of nebuliser solutions. Where available, it is preferable to use licensed combination products.Ipratropium can be combined with a short-acting beta2-agonist in the same nebuliser chamber, for simultaneous administration where co-administration is required (2,3)Similarly, budesonide nebulescan be mixed with terbutaline, salbutamol and ipratropium, however according to the Pulmicort Summary of Product Characteristics (SPC), the admixture should be used within 30 minutes (4,5).Unless specifically stated in theSPC, the manufacturers of nebuliser solutions do not recommend that they are mixed and as such these mixtures are unlicensed.In-house data from manufacturers and the limited published data suggest that two-way mixes of some nebuliser solutions are physically and/or chemically compatible in some cases (6-10),as table 1 shows.
The results of one study investigating the compatibility between budesonide and colistimethate prepared by mixing 2.0 mL Pulmicort with 3.0 mL Colistin CF concluded that the admixtures are compatible but that mixing should take place immediately before administration. Further investigations are needed to determine whether or not drug delivery is affected by mixing the drugs and to ensure simultaneous nebulisation is recommendable (11).
The physical and chemical compatibility of inhalation solutions containing colistimethate and tobramycin was determined in an in vitrostudy in which pH, osmolality and the antibiotic activity of the mixtures were measured (12). Admixtures of colistimethate and tobramycin nebuliser solutions were found to be physicochemically compatible but the effects on drug delivery of mixing these solutions must be determined before it is recommended that the two are mixed in practice (12).The SPCs for tobramycin and colistimethate nebuliser solutionsdo not advise that they are mixed (13,14,15).In general, drugs should not be mixed unless there is firm evidence that they are compatible (16). If mixing is necessary, 0.9% sodium chloride is usually used as a diluent (16). Solutions should be mixed immediately prior to use (1) and using aseptic precautions (16).To maximise nebulised drug, a minimum volume of 3 to 4mL should ideally be nebulised. This volume is required to reduce the amount of drug that may be left in a ‘dead space’ at the end of nebulisation; although this is less with newer nebulisers and no further dilution of commercial nebuliser solutions is necessary (17). If turbidity, colour changes or precipitation occur, the mixture should be discarded (1).Any unused solution should be discarded. Regardless of whether nebulised solutions are mixed, patients should be monitored to ensure that the required clinical response is being obtained (1).
The mixing of nebuliser solutions should only be undertaken in the best interests of the patient and only done by a person competent and willing to do so. The instruction/direction to mix must be in writing and the prescriber should be confident that clinical governance arrangements are in place to ensure that the person who is ‘mixing’ is competent and takes full professional and clinical responsibility for their decisions and actions. The prescriber may be adoctor, dentist, nurse or pharmacist prescriber, ora supplementary prescriber (as part of a clinical management plan for an individual patient); these individuals are also permitted to mix medicines themselves. Any other individual who prepares an unlicensed medicine without written instructions from one of these prescribers has contravened the Human Medicines Regulations. Prescribers should also heed local policy and guidance on the mixing of medicines and prescribing of unlicensed medicines(18).
1
Available throughNICE Evidence Search at
Table 1. Compatibility Table of Commonly Used Nebuliser Solutions
Drug / Budesonide / Fluticasone / Ipratropium / Salbutamol / Terbutaline / Colistimethate / TobramycinBudesonide / N/A / C / C / C / LI / NI
Fluticasone / N/A / C / C / C / NI / NI
Ipratropium / C / C / C / C / NI / NI
Salbutamol / C / C / C / N/A / C† / NI
Terbutaline / C / C / C / N/A / NI / NI
Colistimethate / LI / NI / NI / C† / NI / LI
Tobramycin / NI / NI / NI / NI / NI / LI
CCompatible
LI Limited information (see above)
N/ANot applicable
NINo information
†ensure salbutamol solution or any diluent used is preservative-free
1
Available throughNICE Evidence Search at
Summary
Mixing of nebuliser solutions should only be undertaken in the best interests of the patient and only by a person competent and willing to do so. Instructions for mixing should be in writing.
Two-way mixes of nebuliser solutions have been used for a variety of respiratory medicines. Table 1 indicates those that are deemed to be compatible.
Unless specified in the Summary of Product Characteristics, the manufacturers of nebuliser solutions generally do not recommend that they are mixed and as such these mixtures are unlicensed.
Prescribers should be awareif a medicine is to be used outside its licenceand take responsibility for its use in this manner.
Where available, it is preferable to use licensed combination products.
Two-way mixes should be used immediately, and should be discarded if precipitation, turbidity or colour changes occur.
The mixture may be diluted with 0.9% sodium chloride to a volume of between 3 and 4mL. Any unused solution should be discarded.
Patients should be monitored to ensure continued clinical response to treatment.
Data on other three-way mixes are lacking and therefore cannot be recommended.
Limitations
There is little published evidence on the compatibility of nebuliser solutions (by brand or medicine class).
References
(1)Joseph JC. Compatibility of nebulizer solution admixtures. Ann Pharmacother 1997;31:487-8.
(2)Summary of Product Characteristics - Atrovent® UDVs®. Boehringer Ingelheim Ltd. Accessed via: on 24 Nov 2015 [Date of revision of text July 2014].
(3)Summary of Product Characteristics - Respontin® Nebules®. GlaxoSmithKline UK. Accessed via: on12 Dec 2015 [Date of revision of text 17 Nov 2015].
(4)Summary of Product Characteristics - Pulmicort® Respules®1mg. AstraZeneca UK Ltd. Accessed via: 24 Nov 2015 [Date of revision of text 23 Dec 2014]
(5)Summary of Product Characteristics - Budesonide 0.5mg Nebuliser Suspension (Arrow). Actavis UK Ltd. Accessed via: 12 Dec 2015 [Date of revision of text 11 Mar 2015]
(6)Data on File, Allen & Hanbury’s (PCN102). Obtained June 2005.
(7)Roberts GW and Rossi SOP. Compatibility of nebuliser solutions. Aust J Hosp Pharm 1993; 23: 35-7.
(8)McKenzie JE and Cruz-Rivera M. Compatibility of budesonide inhalation suspension with four nebulizing solutions. Ann Pharmacother 2004; 38: 967-72.
(9)Kamin W, Scwabe A, Krämer I. Inhalation solutions – which ones are allowed to be mixed? Physico-chemical compatibility of drug solutions in nebulizers. J Cyst Fibros 2006; 205-13.
(10)Burchett DK, Darko W, Zahra J, et al. Mixing and compatibility guide for commonly used aerosolized medications. Am J Health-Syst Pharm 2010; 67: 227-30.
(11)Klemmer A, Kramer I, Kamin W. Physiochemical compatibility of nebulizable drug admixtures containing budesonide and colistimethate or hypertonic saline. Int J Pharm Compound 2013, 17:254-261
(12)Wollstadt A, Kramer I, Kamin W. Physicochemical compatibility of nebulizable drug admixtures containing colistimethate and tobramycin. Pharmazie 2013;68:744-8.
(13)Summary of Product Characteristics – Bramitob Nebuliser Solution. Chiesi Ltd. Accessed via: on 24 Nov 2015 [Date of revision of text July 2015].
(14)Summary of Product Characteristics – TOBI® 300 mg/5 mL Nebuliser Solution. Novartis Pharmaceuticals UK Ltd. Accessed via: on 7 Dec 2015 [Date of revision of text 8 Mar 2013].
(15)Summary of Product Characteristics – Promixin 1 Million International Units (IU) Powder for Nebuliser Solution. Profile Pharma Ltd. Accessed via: on 24 Nov 2015 [Date of revision of text 10 Mar 2015].
(16)Harriman A-M, Purcell N, Fleming S, et al. Can we mix nebuliser solutions? Stability of drug admixtures in solutions for nebulisation. Pharm Prac 1996; Oct: 3478.
(17)Gibbs KP, Cripps D. Asthma. In: Walker R and Whittlesea C. Clinical Pharmacy and Therapeutics. 5th ed. Edinburgh. Churchill Livingstone. 2012; p427.
(18)Department of Health. Mixing of Medicines prior to administration in clinical practice: medical and non-medical prescribing. May 2010. [cited 2016 Jan 8] Available from
Quality Assurance
Prepared by
Alex Bailey, Welsh Medicines Information Centre, University Hospital of Wales (based on earlier work by Zainab Alani, Anna Burgess and Gail Woodland)
Date Prepared
8 January 2016
Checked by
Gail Woodland, Welsh Medicines Information Centre, University Hospital of Wales.
Date of check
12 January 2016
Search strategy
Embase (“[fluticasone/ OR salbutamol/ OR ipriatropium bromide/ OR budesonide/ OR terbutaline/ OR colistin/] AND [drug incompatibility/ OR drug combination.exp OR drug compatibility.mp.] AND [inhalational drug administration/ OR nebulisation/]”Limit: yr=2013-current, human)
Medline (“[fluticasone.mp. OR ipratropium bromide/ OR budesonide/ OR colistin/ OR terbutaline/ OR albuterol/] AND administration, inhalation/ AND [drug incompatibility.exp OR drug combinations.exp OR drug compatibility.mp]” Limit yr=2013-current, human)
In-house database (MiDatabank)
Micromedex (DrugDex, Martindale)
Electronic Medicines Compendium
NICE Evidence (nebulis* AND incompatibil*)
1
Available throughNICE Evidence Search at