5 Facts about Daxxify, the Latest FDA Approved Botulinum Toxin: #5 will SHOCK you!

5 Facts about Daxxify. Latest FDA Approved Botulinum Toxin

Daxxify, the latest FDA-approved botulinum toxin. On Plastic Surgery and Aesthetics podcast, find out about how Daxxify compares with other botulinum toxins on duration, safety, storage, and antibody formation. You’ll also discover a little discrepancy on Daxxify’s package insert.

TIME-STAMPED SHOW NOTES

[01:27] Duration comparison vs. other neurotoxins
[04:15] Safety comparison vs. other neurotoxins
[06:58] Storage & handling vs. other neurotoxins
[07:46] Immunogenicity vs. other neurotoxins
[09:39] Package insert concentration calculation error
[12:39] Summarize our conclusions

Did you know that your Botox, Dysport, and Xeomin injections can also last up to 6 months?

In this blog, we are going to talk about duration, safety profile, storage, immunogenicity, and the fuzzy dilution math of Daxxify versus Botox, Dysport, Xeomin, and Jeuveau.

DURATION:
Daxxify is the FIRST FDA-approved botulinum toxin that can last for 6 to 9 months with a single treatment. Congratulations, Revance, the maker of Daxxify. But for most of us evidence-based medicine aesthetic practitioners, a botulinum toxin that last 6 months is nothing new. If you are finding out now for the first time that Botox, Dysport, and Xeomin can last up to 6 months, then you need to subscribe and follow us as we are starting a series of EBM journal club discussions about aesthetics.

Daxxify, or daxibotulinum toxin A, comes in two sizes 50 units or 100 units. To treat a glabellar line, you inject 0.1mL or 8 units in five sites for a total of 40 units. The injection pattern is similar to Botox, Dysport, Xeomin, and Jeuveau.

Did you catch that? 8 units per injection site for the glabella. Currently, we are injecting 4 units per injection site for Botox, Xeomin, and Jeuveau. Dysport is 10 units per injection point, but most of us believe that Botox to Dysport conversion is 1:2.5. Now you know that “unit” is a measure of the biological effect of a toxin. It is different from mg or mL. As of this recording, November 2022, Revance, the maker of Daxxify, has not published the unit conversion from Daxxify to Botox. It should be noted that Daxxify package insert states the following: “Units of biological activity of DAXXIFY cannot be compared to or converted to Units of any other botulinum toxin products.” But, past research of high-dose botulinum toxin suggests to me that the conversion between Daxxify and Botox MAY be closer to 1:1. In fact, their own phase 2 dose-response study published in 2017 showed that there was little difference in duration between 20U of Botox and 20U of Daxxify (see Table 5 in the Carruthers 2017 paper).

Enough about units and unit conversion. I know that some of you are wondering what is this research that states that high-dose Botox, Dyport, and Xeomin can last 6 months.

Botulinum Toxin Type A for Glabellar Frown Lines: What Impact of Higher Doses on Outcomes?
Published in the Journal of Toxin on July 2021.

The researchers found five published studies that used high-dose botulinum toxins for the treatment of glabellar lines. They wanted to know “whether high doses can prolong response without significantly increasing side effect”. This paper concludes that “Higher doses were associated with longer duration of response.” What were those results you ask?

A median duration of around 6 months was achieved with a 2 to 4-fold increase in Botox.
A median duration of around 9 months was achieved with a 5-fold increase in Xeomin.
A median duration of around 9 months was achieved with a 2 to 2.5-fold increase in Dysport.

This means the following:

If you inject 40 to 80 units of Botox, you’ll get 6 months of glabellar paralysis.
If you inject 100 units of Xeomin, you’ll get 9 months of glabellar paralysis.
If you inject 100 to 125 units of Dysport, you’ll get 9 months of glabellar paralysis.

So, for us aesthetic injectors who are up to date on research papers, when Daxxify comes out and says that their 40 units can last 6 to 9 months, our response is: Botox, Dysport, and Xeomin can also last 6 to 9 months if we inject more of it. Now, I don’t include Jeuveau, because Jeuveau was not included in this high-dose research paper. But, a high dose of Jeuveau will probably prolong the paralysis response in patients.

As a final note, if you have been injecting Botox and didn’t know about this research paper, then you should at least follow the press release by Allergan, the maker of Botox. In September 2018, Allergan released a press release about a higher dose of Botox for the treatment of glabellar lines.
https://www.prnewswire.com/news-releases/allergan-announces-results-of-higher-dose-botox-cosmetic-onabotulinumtoxina-for-the-treatment-of-moderate-to-severe-glabellar-lines-300713102.html

SAFETY
So, then why don’t we inject high-dose Botox, Dysport, Xeomin, and Jeuveau? Well, first of all, this would be considered off-label. Second, an injector might be fearful of the risk of higher complications that comes with higher doses. The same research paper looking at high-dose botulinum toxin also looked at the safety profile and concluded that “there were no new safety concerns identified with the highest doses of each BoNT-A preparation or dose-related increases in ptosis events.” However, footnote, these high-dose botulinum toxin trials did not have such a large patient sample size as the Daxxify trial. The problem is that if your patient gets lid ptosis, then there is a possibility that the lid ptosis will be more severe and last much longer due to the higher dose. We do not know this since we have not had the chance to use Daxxify yet. Therefore, the severity and duration of any side effect of Daxxify is currently unclear.

Let’s compare the adverse reaction of Daxxify versus other botulinum toxins based on the manufacturer’s package insert for the treatment of glabellar lines.

	DAXXIFY	BOTOX	XEOMIN	DYSPORT	JEUVEAU
Eyelid ptosis	2%	3%	0.2%	2%	2%
Headache	6%		5%	9%	12%
Facial paresis “Brow ptosis”	1%	1%	0.7%

As you can see, the eyelid ptosis rate is not higher in the higher dose Daxxify. Whenever I look at this chart, I am surprised to see the extremely low rate of eyelid ptosis with Xeomin compared to other botulinum toxins. Please note that some of the boxes are empty because the side effect was not included within the package insert. The headache rate of the frontalis injection treatment with Botox is 9%, but the package insert does not comment on the rate of headaches for the use of the glabellar lines.

STORAGE & HANDLING

Here are the recommendations based on the package inserts.

	Botox	Dysport	Xeomin	Jeuveau	Daxxify
Unopened	2° to 8°C (36ºto 46ºF)	2° to 8°C (36ºto 46ºF)	at or below 25°C (77°F)	2° to 8°C (36ºto 46ºF)	at room temperature 20°C to 25°C (68°F to 77°F) or refrigerated at2°C to 8° C (36°F to 46°F)
Reconstituted	2° to 8°C (36ºto 46ºF)	2° to 8°C (36ºto 46ºF)	2° to 8°C (36ºto 46ºF)	2° to 8°C (36ºto 46ºF)	2° to 8°C (36ºto 46ºF)
Administer within:	24 hours	24 hours	24 hours	24 hours	72 hours

Botox, Dysport, and Jeuveau have to be refrigerated before and after reconstitution. Unopened Xeomin and Daxxify can be stored at room temperature but needs to be refrigerated after reconstitution. Botox, Dysport, Xeomin, and Jeuveau have to be used within 24 hours after reconstitution with preservative-free 0.9% Sodium Chloride. Daxxify can be used within 72 hours.

IMMUNOGENICITY: ANTIBODY FORMATION
It is well known that some patients may develop antibodies that can neutralize the effectiveness of botulinum toxin. Research data recommends that “using the lowest effective doses that produce a meaningful therapeutic effect and employing the longest inter-injection interval that is clinically acceptable” is a way to reduce immunogenicity. If this is true, then Daxxify has a disadvantage and an advantage over other botulinum toxins.

If the conversion of Daxxify to Botox is 1:1, then injecting 40 units of Daxxify would make this a high-dose botulinum toxin injection. This would put Daxxify at a higher risk of causing immunogenicity. However, Daxxify can last 6 to 9 months, which is 3 to 6 months longer than most botulinum toxins. This longer interval time between retreatment in Daxxify may help decrease the risk of immunogenicity. This is an area that needs further research, but it is concerning that according to the SAKURA 3 trial, “A total of 19 (0.7%) subjects developed binding antibodies against daxibotulinumtoxinA during the course of the study. None of these subjects tested positive for neutralizing antibodies.”

DILUTION WARNING
There is a mathematical discrepancy found in the Daxxify package insert. Daxxify package insert asks you to dilute 1.2mL of Preservative-free 0.9% Sodium Chloride Injection into 100 unit vial of Daxxify. The package insert states the following:
“Glabellar Lines: 0.1 mL (8 Units) by intramuscular injection into each of five sites, for a total dose of 40 Units.”
However, this is inaccurate.

Everyone knows that the package insert recommended dilution of 100 units of Botox is 2.5 mL of Sodium Chloride which yields 4 units per 0.1mL. If you want 8 units per 0.1mL of Botox, then you would dilute with 1.25 mL of Sodium Chloride. But Revance, wants you to dilute 1.2 mL Sodium Chloride per 100 units of Daxxify. This is 0.05 mL less. So what happens when you dilute with 1.2 mL of Sodium Chloride?

Let’s go over the dilution math.
1.2mL = 100 units
0.6mL = 50 units
0.3mL = 25 units
0.1mL = 8.33 units.

So actually 0.1mL = 8.33 units. 0.33 units might not be a big deal for one injection point, but this quickly changes when you add up all 5 injection sites. Why? Well, 5 injection sites of 0.1 mL or 0.5 mL total are NOT 40 units, but 41.66 units of Daxxify (8.33 X 5 injection sites).

This means that if each injection was actually 8 units per injection, then you should be able to inject 12.5 injection points in a vial of 100 units diluted with 1.25 mL of Sodium Chloride (= 100 units divided by 8). But when you use the Daxxify dilution of 1.2 mL of Sodium Chloride in 100 unit vial, you are injecting 8.33 units per injection point, which only give you 12 injection points (= 100 units divided by 8.33 units per injection site).

So financially, you are actually losing 0.33 units per injection or 1.66 units per glabellar treatment in each patient. Therefore, with each vial, you are actually losing 4 units. If you charge your patients by the unit, then this unit charge loss may be insignificant to a small practice, but it will be significant to a larger practice.

As of this recording, since we do not have the pricing for Daxxify, I am unable to comment on the potential financial loss.

However, I am baffled by this discrepancy in units in the package insert. How did this get passed by the FDA? I understand the 0.33 unit per injection site might be within the acceptable range of error. However, when you combine all five injection sites, then it is 1.66 units off. And when you consider the entire vial, then you are 4 units off.

Note, if you actually want to inject 8 units per injection and not 8.33 units per injection site, then you want to reconstitute with 1.25cc of Preservative-free 0.9% Sodium Chloride Injection into 100 unit vial of Daxxify.

SUMMARY:
1
A botulinum toxin that lasts 6 to 9 months is nothing new to the aesthetic community. An FDA approval for a 6 to 9-month indication is something new. However, research since 2015 has stated that higher dose botulinum toxin is “associated with enhanced efficacy and prolonged duration of effect over the on-label dose” for Botox, Dysport, and Xeomin.

2
The package insert of Daxxify, along with the past research on high-dose botulinum toxin, indicates that there are “no new safety concerns identified with the highest doses of each BoNT-A preparation or dose-related increases in ptosis events.”

3
Unopened Daxxify can be stored at room temperature, just like Xeomin. Reconstituted Daxxify must be used within 72 hours when diluted with Preservative-free 0.9% Sodium Chloride Injection.

4
The limited immunogenicity data of Daxxify is very concerning. The label recommends “using the lowest effective doses that produce a meaningful therapeutic effect and employing the longest inter-injection interval that is clinically acceptable.” Some patients developed binding antibodies to both the active core ingredient and the virally-derived peptide excipient after just 3 treatment intervals. We know that immunogenicity is a spectrum, not an all-or-none type of response and that every patient is different. Most patients don’t develop resistance after 3 treatments, and the fact that some patients are already developing an immune response after a few treatments raises concerns with Daxxify. This is an area that needs further research.

5
The dilution calculation error in the package insert of Daxxify has not been widely reported. While the package insert states that 0.1mL of Daxxify is 8 units, the actual dose of 0.1mL is 8.33 units. Therefore, if you follow the package insert and its on-label protocol, then injecting 0.5 mL or “40 units” of Daxxify creates a financial loss of 1.66 units per glabellar area if you charge your patients for 40 units.