There Has Been Chatter A...
Highlights
- There has been chatter and perhaps some confusion floating around about norepinephrine, salt formulations, and dosing.
I discussed it in a recent @yourICM letter. I’ll break it down here in a 🧵
1/
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- 2/ but first, what is a “salt formulation”?
It is an anionic or cationic salt conjugated form of a molecule.
For e.g., the sulfate salt formulation of magnesium is “magnesium sulfate” commonly used intravenously in humans.
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- 4/ salt formulations are often necessary for medicinal products in order to facilitate production of “dosage forms”, that is, products that are suitable for human use, e.g., tablet, injectable, etc.
Simply put, this is taking “a molecule to a drug”
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- 5/ these salt formulations are needed to address a variety of biological and physiochemical issues with medicinal products including stability, absorption, toxicity, manufacturing, etc.
https://t.co/IQmTa8cNKV (View Tweet)
- 6/ but most commonly, they are needed to increase aqueous solubility of medicinal molecules.
This is precisely the case with norepinephrine, a trihydroxy substituted phenethylamine.
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- 7/ norepinephrine is poorly soluble in water, alcohol, and ether, but very solubly in acid
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- 8/ hence the salt formulations of norepinephrine are those produced from solubilizing it in acids (hence also the risk of tissue necrosis with intravenous extravasation). One of the most common examples is using tartaric acid to produce norepinephrine bitartrate
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- 9/ this of course isn’t the only way to produce a salt form. Indeed, there are numerous different anions and cations that are used to make salt formulations of drugs
https://t.co/epEaIjF8X2
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- 10/ actually, about half of the commercially produced drugs in the US are present in a salt formulation
https://t.co/epEaIjF8X2
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- 11/ and when you look at just the injectables, they are even more common with about 2/3 of injectable drugs present in a salt formulation!
https://t.co/epEaIjF8X2
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- 12/ clearly the story about norepinephrine is not unique. But, @MarcLeone8 elegantly identified this as a potential problem
https://t.co/Obid9wFZeB
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- 13/ you may be thinking to yourself…after all, we just titrate norepinephrine infusions to desired hemodynamic and perfusion endpoints, so who cares? It surely must be just a “semantics” or “academic” problem. Well, here’s a few reasons why you should care (View Tweet)
- 14/ first, research studies of vasopressors and anti-shock treatments often use formulae that attempt to quantify total vasopressor load to assess effectiveness of an intervention (such as the “norepinephrine equivalent dose”)
https://t.co/gdwpk69E6A
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- 15/ second, these formulae are also used for prognostication such as this recent elegant example from @siddharth_dugar in @journal_CHEST
https://t.co/eetKKsBBHA
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- 16/ third, these formulae are also used in clinical trials that provide a basis for regulatory drug approvals, such as in 2017 with a synthetic version of angiotensin II @KhannaAshishCCM
https://t.co/Utyj9IgjgY
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- 17/ fourth, norepinephrine is used in pivotal trials, such as VASST published in 2008, as a treatment assignment to compare to an intervention. Inaccurate characterization of dosage may lead to differences in how patients are treated
https://t.co/8pgnaVQ5q3
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- 18/ and the list goes on. But most importantly, research findings are used to inform intensive care practice. They also serve as a basis for clinical practice guideline recommendations such as the surviving sepsis campaign
https://t.co/dj7aOpOebD
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- 19/ let’s get back to the salt formulations…is it actually a problem?
🧐 I reviewed 97 regulatory documents of drug approvals across 32 countries (US, UK, Canada, Australia, and those under the European Medicines Agency) to find out
(see supplement)
https://t.co/ia20P8JeNB (View Tweet)
- 20/ in most cases (28 out of 32 countries), the physical label on the product directly reflected the amount of “norepinephrine base”, i.e., the active pharmaceutical ingredient (molecule)
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- 21/ the four outliers were France, Italy, Malta, and Portugal. In these countries the package label reflected the amount of norepinephrine conjugated salt
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- 22/ to add confusion to this, in France and Portugal, the prescribing leaflets outline dilution instructions for preparing compounded infusions. In these instructions they describe resultant concentrations in norepinephrine base (molecule)
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- 23/ what was most shocking to me in this exercise was that there were 2 European manufacturers (Laboratoire Aguettant 🇫🇷, AS Kalceks 🇱🇻) that labeled products by norepinephrine base in some countries (e.g., 🇦🇹,🇩🇰,🇩🇪) but salt formulation when sold in France and Italy.
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- 24/ this discrepancy to me indicates there may potentially be some sort of regulatory requirement at the national level of certain countries that require a specific way of product labeling. (View Tweet)
- 25/ overall, it’s unclear if these labeling differences actually result in differences at the research data level. I suggest a task force of international experts and individuals with knowledge of local products to evaluate to ensure we have standardization. (View Tweet)
- 26/ thanks for reading this thread! Here is a link to my letter in @yourICM
https://t.co/rgxBLh8gN2
/fin (View Tweet)