In this episode, I’ll discuss the compatibility of nebulized formoterol with other common nebulized medications.
In 2008, an article was published that found admixtures of formoterol with budesonide, ipratropium, cromolyn, or acetylcysteine to be physically and chemically compatible. The study was thorough and used appropriate methods to determine compatibility.
Physical compatibility was determined by visual examination and measurements of pH, osmolality, and turbidity. Chemical stability was evaluated using compendial or in-house–validated high-performance liquid chromatography (HPLC) assay methods.
Despite this, the prescribing information and several tertiary references do not list formoterol as compatible with all of the medications studied.
The reason why might be in the other results found in the same study. In addition to compatibility, the authors examined changes in the fraction of dose delivered when the medications were given alone, in combination, and in sequence. There were significant increases in the amount of formoterol delivered in several of the instances measured.
For example, when formoterol was given alone, about 38% of the dose was delivered.
When it was admixed with budesonide, the fraction delivered jumped to 59%, a 55% relative increase in the amount of formoterol delivered.
When formoterol was given in sequence with budesonide, ipratropium, and N-acetylcysteine, the fraction delivered increased by 58%, 42%, and 32% respectively.
The study was not designed to measure the clinical significance of this increase in the fraction of dose delivered. The authors also concluded that the clinical implications of the in vitro data in patients with COPD have not been determined, and this is likely why the physical and chemical compatibility has not translated into tertiary resources making a recommendation to mix formoterol with other nebulized medications.
What is likely happening that would explain the changes in the dose delivered is that when additional volume from the 2nd medication is added to formoterol, the residual volume left in the nebulizer is no longer purely formoterol, and is partly the 2nd medication. Assuming the residual volume would always be the same, this may explain why more formoterol is delivered.
On one hand, this may be a rational reason to avoid the admixture or sequential nebulization of formoterol with other medications. This is because the prescribing information for formoterol lists the fraction of dose delivered at 37%, almost identical to that which was found with formoterol alone in this study. So the combination of formoterol or sequential administration of it would likely result in doses being delivered that are one-third to one-half as much more as those delivered in clinical trials.
On the other hand, the amount of formoterol delivered from a 12 mcg Foradil inhaler is 10 mcg according to the prescribing information. All combinations studied of formoterol being admixed or administered sequentially with budesonide, ipratropium, or N-acetylcysteine would result in doses equal to or no more than 20% greater than those delivered by the Foradil dry powder inhaler. This information could be used to justify giving formoterol with the other nebulized medications. Such a decision would be best reached by consensus with all stakeholders – pharmacy, respiratory therapy, and pulmonology and incorporated into a local policy rather than an individual clinical making a judgment that is not consistent with existing institutional policies.
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