note Aerosolized medications
Mixing and compatibility guide for commonly used
aerosolized medications
DaviD K. Burchett, William DarKo, James Zahra, John noviasKy,
luKe ProBst, anD aDrienne smith
Purpose. A mixing and compatibility guide
and respiratory therapists who administer Compatibility references of i.v.
aerosolized medications. The authors of a recently published evaluation of the com- Summary. Compatibility guides for inject-
patibility of common inhalation solutions able drugs are available as a reference for table. This table served as a template to hospitals and other health care institutions and compatibility guide in the form of an easy-to-use reference chart, which includes compatibility of frequently used intrave- additional agents, compatibility references nous medications. Respiratory therapists on the chart, and compatibility information for pharmacists, nurses, physicians, and often faced with the challenge of uncertain Conclusion. A compatibility guide for
limited data regarding the compatibility of these aerosolized admixtures. After a care- ful review of the literature, a compatibility Index terms: Aerosols; Compounding;
significant value to pharmacists, nurses, Am J Health-Syst Pharm. 2010; 67:227-30
Trials are heterogeneous, and results can be confusing, even contradic-tory.3 A careful review of which inha-lation admixtures were tested and the cal Pharmaceutics Database6 provide relatively unfamiliar to nurses, re-methods used for testing is critical comprehensive data on several aero- Trissel’s Stability of Compounded ibility and stability data for various counterpart to the parenteral i.v. ad- Formulations5 and Trissel’s 2 Clini- admixtures. These references are mixture chart.
DaviD K. Burchett, Pharm.D., was Pharm.D. Candidate, Albany Department of Pharmaceutical Care Services; and aDrienne smith, College of Pharmacy, Albany, NY, at the time of writing. William Pharm.D., BcoP, was Assistant Professor of Medicine, Department DarKo, Pharm.D., is Assistant Professor of Medicine, Department of of Medicine, Section of Clinical Pharmacology, and Department of Medicine, Section of Clinical Pharmacology, and Adjunct Associate Pharmaceutical Care Services, SUNY Upstate Medical University Professor of Pharmacy Practice, Department of Pharmaceutical Care Hospital, Syracuse, at the time of writing.
Services; James Zahra, B.s.Pharm., is Adjunct Assistant Professor of Address correspondence to Dr. Darko at SUNY Upstate Medi- Pharmacy Practice, Senior Pharmacist, and Intravenous Laboratory cal University Hospital, 750 East Adams Street, Syracuse, NY 13210 Coordinator, Department of Pharmaceutical Care Services; John noviasKy, Pharm.D., is Assistant Professor of Medicine, Depart- The authors have declared no potential conflicts of interest.
ment of Medicine, Section of Clinical Pharmacology, and Associate Director, Clinical Services and Research, Department of Pharma- Copyright 2010, American Society of Health-System Pharma- ceutical Care Services; luKe ProBst, Pharm.D., BcPs, is Assistant cists, Inc. All rights reserved. 1079-2082/10/0201-0227$06.00.
Professor of Medicine, Department of Medicine, Section of Clinical Pharmacology, and Associate Director, Pediatric Clinical Services, Am J Health-Syst Pharm—Vol 67 Feb 1, 2010 Figure 1. Compatibility guide for commonly used inhalation solutions and suspensions. Dark green shading with corresponding letter C indicates that there is evidence in the form of
clinical studies confirming the stability and compatibility of the particular admixture. Light green shading with corresponding letter C indicates that there is evidence from manufacturers’ reports confirming the stability and compatibility of a particular admixture3; in many instances, these studies were unavailable for review and were confirmed either by reference in the package insert or direct communication with the manufacturer. Red shading with corresponding letter X indicates that there is evidence confirming or suggesting that a particular admix-ture is not compatible. Yellow shading with corresponding letters NI indicates that there is insufficient evidence to evaluate compatibility and should be avoided unless future evidence becomes available. Blue shading with corresponding letters CD indicates that there are conflicting data regarding compatibility of the combination. The following information should be considered when determining the feasibility of preparing drug combinations for inhalation: (1) all admixtures should be prepared from formulations that do not contain preservatives, (2) The United States Pharmacopeia requirements state that the particle size of the delivered drug must be carefully controlled and the average diameter must be <5 mm, (3) physical and chemi- Aerosolized medications
cal compatibilities do not describe possible effects on aerodynamic behavior, (4) decreases in temperature can occur in certain nebulizers, and the effect of such decreases on compatibility has not been studied, (5) mixing solutions or suspensions increases total volume, and the relationship between the volume fill, total mass output, and inhaled mass of nebulized drug must be considered, and (6) if admixtures are to be stored, sterility issues must be addressed. References should be consulted to verify drug concentrations are compatible.
Albuterol Arformoterola Epinephrineb Formoterol Levalbuterolc Metaproterenold Budesonide Cromolyne Ipratropium Acetylcysteinef Colistimethateg aNo safety and efficacy studies available for admixtures of arformoterol with other drugs; physical and chemical compatibility studies with acetylcysteine, ipratropium, budesonide, and tiotropium have indicated compatibility of concentrations studied (Quon CL, Sepracor, personal communication, 2009 Sep 24).
bEpinephrine is readily destroyed by oxidizing agents or alkali (e.g., sodium bicarbonate, halogens, permanganates, chromates, nitrates, nitrites) and salts of easily reducible metals (e.g., iron, copper, zinc).7cNo safety and efficacy studies available for admixtures of levalbuterol with other drugs; physical and chemical compatibility studies with budesonide, cromolyn, and ipratropium have indicated compatibility of concentrations studied (Quon CL, Sepracor, personal communication, 2009 Sep 24).
dNo safety and efficacy studies available for admixtures of metaproterenol with other drugs available from manufacturer (Lee S, Dey Laboratories, personal communication, 2009 Sep 24).
eCompatibility of cromolyn (Intal, King Pharmaceuticals) with albuterol (Ventolin, GlaxoSmithKline), fenoterol (Berotec, Boehringer Ingelheim), metaproterenol (Alupent, Dey Laboratories), and terbutaline (Bricanyl, fAcetylcysteine (Mucomyst, Sandoz Pharmaceuticals) has been reported to be compatible with netilmicin or betamethasone.3 The manufacturer reports that acetylcysteine is incompatible with amphotericin B, tetracyclines, erythromycin, or ampicillin; also incompatible with any oxidizing agent, iodized oil, trypsin, chymotrypsin, and hydrogen peroxide.8 gColistimethate sodium (available as an injectable formulation in the United States; dosage expressed in terms of colistin) is not approved for inhalation via a nebulizer; a case of acute respiratory failure and subsequent death of a cystic fibrosis patient who received premixed colistimethate sodium via nebulization has been reported.9 The prescribing information for a formulation available outside of the United States (Colistin, Grunenthal) states that precipitation may occur in admixtures with other nebulized antibiotics.3 hTobramycin solution for oral inhalation should not be diluted or mixed with other drugs in the nebulizer. Based on protocols used in clinical studies evaluating tobramycin solution for oral inhalation in cystic fibrosis patients, it has been recommended that patients receive doses of inhaled bronchodilators first, then dornase alfa, then chest physiotherapy, and then tobramycin.10 iAdmixtures of albuterol, cromolyn, and ipratropium appear to be stable, with ipratropium as the limiting component.3jAlbuterol and ipratropium are available as a combination solution for nebulization (Duoneb, Dey Laboratories, Napa, CA).
kAlbuterol containing benzalkonium chloride (1 mL) mixed with 1 mL colistin (Coly-Mycin M Parenteral, 33.3 mg/mL, King Pharmaceuticals) resulted in immediate cloudiness, which was believed to be due to interaction of benzalkonium chloride with colistin (effect on aerodynamics unknown); colistin mixed with preservative-free unit-dose albuterol inhalation solution was chemically stable for one hour.3 No additional information available from manufacturer (Guinto A, JHP Pharmaceuticals, personal communication, 2009 Sep 24).
lManufacturer of budesonide (Pulmicort, Astra Zeneca GmbH, Wedel, Germany) stated that cloudiness occurred in mixtures of budesonide with cromolyn (Intal), but information is not included in the prescribing mPrescribing information for ipratropium (Atrovent, Boehringer Ingelheim) states that it should not be mixed with cromolyn because precipitation can occur. It has been reported that cromolyn mixed with ipratropium instantly produced cloudiness, which was attributed to the effect of an unknown excipient in the cromolyn formulation; the manufacturer attributed the cloudiness to benzalkonium chloride in the formulation. However, ipratropium mixed in a nebulizer with cromolyn sodium solution for oral inhalation also has been reported to be stable for one hour.3 nAcetylcysteine sodium solution (10%) for oral inhalation and colistin 37.5 mg/mL have been reported to be compatible, with immediate use recommended.3 note Aerosolized medications
Table 1.
Inhaler Device Recommendations for Aerosolized Medications20-23
Recommended Inhaler
Medication and Concentration
Albuterol Nebulized solution: 0.63 mg/3 mL, 1.25 mg/3 mL, administer solution immediately after removal from foil pouch Levalbuterol Aerosol inhaler: 45 mg/actuation Nebulizer solution: 0.31 mg/3 mL, 0.63 mg/3 mL, Metaproterenol Aerosol inhaler: 0.65 mg/actuation Nebulizer solution: 4 mg/mL (0.4%), 6 mg/mL chloride injection to 0.2–0.3 mL of drug for nebulization Budesonide Nebulizer solution: 0.25 mg/2 mL, 0.5 mg/2 mL, Powder inhaler: 90 mg/actuation, 180 mg/actuation Cromolyn sodium Aerosol inhaler: 800 mg/actuation Ipratropium bromide Aerosol inhaler: 17 g/actuation Acetylcysteine 100 mg/mL (10%), 200 mg/mL (20%) undiluted; dilute 20% solution with sodium chloride or sterilized water for inhalation Colistimethate 150 mg powder for reconstitution to 75 mg/mL with sterile water for injection (2 mL) 0.9% sodium chloride injection can be nebulized; immediate use after mixing recommended Sodium chloride solution 0.9%, 3%, 7%, 12% Am J Health-Syst Pharm—Vol 67 Feb 1, 2010 note Aerosolized medications
Development of the compatibility nurses, pharmacists, and respiratory 9. Food and Drug Administration. FDA
A review of the practices at our sive. Respiratory therapists often pre- institution for mixing aerosolized pare respiratory admixtures without medications revealed several areas of proper understanding of what can be concern. First, no hospital-approved mixed safely. In an effort to correct 10. McEvoy GK, ed. Tobramycin. In: AHFS protocol existed for preparing these our own knowledge deficiencies, we admixtures. Second, the document developed an easy-to-use compat- used by our respiratory therapists ibility chart to guide pharmacists, 11. Lesko LJ, Miller AK. Physical-chemical monly aerosolized drugs with only therapists in the mixing and admin- solution admixtures. Ann Allergy. 1984; “yes/no” information on admixtures istration of respiratory admixtures. and no references establishing the Users of the information in the com- 12. Bonasia P, Cook C, Cheng Y et al. Com- validity of the information. Third, patibility chart should recognize the patibility of arformoterol tartrate inhala- tion solution with three nebulized drugs. Curr Med Res Opin. 2007; 23:2477-83.
rected to mix aerosolized drugs with ibility determination.
13. Dey Laboratories. Napa, CA. 2007 Nov. stability, safety, or efficacy. Fourth, Conclusion
fenoterol and ipratropium. Am J Health- nel (including pharmacists) about for use by staff who administer these 15. Ameredes B, Calhoun W. (R)-Albuterol the stability, safety, and efficacy of agents.
for asthma: pro [a.k.a. (S)-albuterol for asthma: con]. Am J Respir Crit Care Med. for the compatibility of respiratory References
16. Falagas M, Kasiakou S, Tsiodras S et al. 1. Trissel LA. Handbook on injectable drugs. tions in critically ill patients: a review of 2. King JC. King guide to parenteral admix- the recent literature. Clin Med Res. 2006; tures [electronic version]. Napa, CA: King 17. Rau J. The inhalation of drugs: advan- 3. Kamin W, Schwabe A, Krämer I. Inhala- tages and problems. Respir Care. 2005; tion solutions: which ones are allowed to 18. Rieutord A, Arnaud P, Dauphin J et al. ity of drug solutions in nebulizers. J Cyst Stability and compatibility of an aerosol netilmicin and betamethasone. Int J sion with four nebulizing solutions. Ann reference chart (Figure 1)3,7-14 that in- Pharmacother. 2004; 38:967-72.
treatment of cystic fibrosis. Ann Pharma- 20. McEvoy GK, ed. AHFS drug information 6. Trissel LA. Trissel’s 2 clinical pharmaceu- 21. Boe J, Dennis JH, O’Driscoll BR et al. Eu- tics database [electronic database]. http:// ropean Respiratory Society guidelines on the use of nebulizers. Eur Respir J. 2001; 22. O’Donohue WJ Jr. group. Guidelines for the use of nebulizers in the home and at domiciliary sites. Report of a consensus conference. Chest. 1996; 109:814-20. 8. McEvoy GK, ed. Acetylcysteine. In: AHFS 23. Dolovich MB, Ahrens RC, Hess DR et al. Am J Health-Syst Pharm—Vol 67 Feb 1, 2010 Copyright of American Journal of Health-System Pharmacy is the property of American Society of Health System Pharmacists and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for


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