I will definitely share anything I find. What I'm looking for is actual documentation or a valid technological explanation.
I know that the manufacturers, as well as their legal and scientific teams, would NOT casually state or withhold information in the specs or the white papers for their products.
@Mark
I get the impression that you believe the manufacturers have control over the content of the drug info sheet packaged with insulin. That they can include any information so long as they feel reasonably certain that it is factual & pertinent.
I actually don't know, but I very much doubt that this is the case. So I will also be interested what you find out if you pursue this further.
My speculation is that they are much more limited in the US by FDA rules & regulations in terms of what they can include in those documents. There is probably some sort of established testing procedure that has to be completed, certified, and accepted before they can include "facts" in the document. Just because they tested something in their labs & feel it's factually true is probably insufficient.
My opinion on this comes from similar "nonsense" (IMO) which I have bumped up against while scanning for info on CGMs. Take the sites on a person's body which are "indicated" as acceptable for inserting a CGM.
The official response from the companies usually boils down to inserting on the abdomen and not much else. Why? Well, in the case of Medtronic they say very carefully that these are the best insertion sites based on the US clinical trials for their sensor.
My understanding is that they are not allowed to say other sites might also work, although they certainly do in my own & others experience. In order to do that they probably need to complete another set of clinical trials, something I very much doubt they would do without some revenue generating based reason.
One other example of how unexpectedly convoluted this process is the release of the so-called "enhanced" Enlite glucose sensor. Outside the US Medtronic distributes a slightly better version of their Enlite sensor. They've made small tweaks to its shape, size, and claim to have made the adhesive & sensor chemistry slightly better. For me the bottom line on how minor these changes are is that Medtronic continues to use the same product code for this "new & improved" Enlite as the previous, less special version.
So, small changes to a monitoring device which does not directly affect a person's physiology. Should be a no brainer to certify & release, right? Apparently not. It is still not available in the US. Lord only knows what dance they are required to do before they can sell it in the US.
It gets better. My understanding is that the company's employees can't talk about this tweaked version until after it is approved. It's as though the FDA has no idea that we can use the Internet & Google to get information.
I don't believe you can read drug info sheets with the assumption that the manufacturers are "trying to help". I believe that they are saying primarily what they need to say and also not saying what they could not (easily) get approval to include.
When asking why something is not covered in the drug info sheet, ask yourself what it would take to satisfy a regulatory agency that this information meets the requirements to be included. (And, of course, how much it might cost to satisfy those requirements.)
-iJohn
Iām sure, as you say, John, that the FDA and the politics and finances of drug trials does influence product documentation. But I donāt see how it would profit insulin manufacturers to obscure what I am asking about here. Why would they care to do so? Perhaps theyād make a bit more money by ensuring users only have a certain amount of time to finish an open bottle of insulin kept at room temperature, a time which might be extended if users instead refrigerated said insulin. Perhaps. But the long-term potential for their legal liability I think would outweigh such short-term thinking.
I donāt know anything about the Medtronic situation you describe. That sounds complicated.
I donāt know if I have the attitude that manufacturers are ātrying to helpā exactly with their spec sheets. Iām sure one of their main goals is to increase shareholder profits. But along with having to comply with FDA and other regulations, we as users do have access to said spec sheets, as do our doctors. So I think questions can be asked, and Iām hoping answers will be forthcoming and not obscured by corporate greed or ignorance or regulatory politics.
Another argument against refrigerating insulin has to do with its potency at colder temperatures. Some people might use their insulin right out of the fridge. But at lower temperatures the insulin will not unfold its activity as quickly as it does at room temperature. This might cause higher spikes after meals for example.
Furthermore I found the argument that temperature changes might increase the likelyhood for air bubbles to form in the vial.
Have you heard the rumors about an "optical" (don't ask me how) Enlite sensor (the 3rd iteration)? My trainer mentioned it to me. I tried to get into the trials for it in December but was told by one of the companies involved in trials that MM had delayed it. Everyone is quite tight-lipped about the whole thing, so I gave up trying to get additional information.
I have to be blunt: I am so sick of the corporate greed meme. As someone who's been in sufficiently high management positions in a large corporation to see how these this all works (Hewlett-Packard), it's a bit insulting, and very discouraging, to constantly butt up against this nonsense.
The sole reason information for more sophisticated people is lacking in these documents is for one reason: THE FDA WILL NOT ALLOW IT.
The parameters for insulin are designed around practical use of the drug. This means that once a vial becomes active, convenience dictates that most people will not keep it cooled while they carry it around with them. They also will not be constantly checking the ambient temperature their "kit" is at while sitting in a backpack, purse, briefcase, etc., maybe in the back of a parked car, etc.
These simple realities mean that the instructions must account for this "worst-case" scenario. Try taking your insulin pen and putting it in the sun for an hour a day, and see how long the insulin stays potent. It's this kind of carelessness that needs to be accounted for in the labeling.
Add a statement to the label saying that the insulin will be just fine for 60 days if kept below 72degF, and there will be a lawsuit from a diabetic that went DKA on day 50, insisting they kept it at that temp, either forgetting or not even knowing about some point where it was 100deg in their bag in the sun during that Kindle session on the park bench.
THIS is why the information we are given is so carefully controlled, so filtered. And it's all you're going to get from the manufacturer.
Not because they're greedy profiteers. Rather, because we, society, have made the legal landscape sewn with so many mines that they are utterly shackled from sharing anything not government approved.
Want the answer to why we don't get better info from manufacturers? Look in the mirror.
But I don't see how it would profit insulin manufacturers to obscure what I am asking about here. Why would they care to do so?
Again, I would suggest turning the question around. Ask rather why would they care to modify their existing drug info sheet? What would motivate them strongly enough to do this?
I'm not basing my opinion on greed or ignorance as much as on human emotional inertia. From the manufacturer's perspective, those documents are a done deal. They contain whatever content they contain as a result of the process that created them.
Insulin is probably considered to be an extremely well understood "drug" at this point in time. Each year that passes further hardens the implicit assumption that these documents are perfectly fine with their current content. Any request to modify them now ... and I expect they would have to ask for permission/approval ... just invites closer scrutiny than if they just continue to use them as they are.
Why would they want to go down that road? How does it benefit them? What would make opening that door compelling for them?
Again, I would be very interested in whatever additional information you might come up with. I would suggest you do try to ask the insulin manufacturers. You will probably just get a boilerplate response that has been sanitized by their legal staff, but if you are really that interested it can't hurt to try, no?
-iJohn
"Don't cover the sensor and transmitter with Iv3000 because it interferes with the radio signal to the pump."
The thing which especially irritates me about statements like that is that it is true in a very narrow & technically misleading sense.
Yes, there would be some attenuation of the radio signal resulting from passing through the physical barrier of the IV3000 film. It would be so slight that I'm not sure the degree of attenuation could even be reliably measured, but it would happen.
And it would also (obviously) be irrelevant unless there is something truly bizarre about IV3000 tape & radio waves that I am completely unaware of.
My moment came a few weeks back & was slightly different. But still unexpected, absurd & frustrating. I was still using the old Sof-sensor (aka Harpoon) at the time. I called when the sensor went wonky somewhere after the 3'rd day. I was told that the Harpoons are only supposed to last 3 days, not 6 ... in the US.
I referred to the Medtronic document announcing that the company supported "up to 6 day sensor usage" which I found a while back on the Medtronic ANZ (Australasia) web site. The customer rep told me that those sensors "could" be different than the US sensors. Yeah. Sure. As if. <sigh />
Still, in hindsight, who the heck actually knows? It is currently true for the Enlite sensors. A slightly different, "enhanced" version of the Enlite is currently sold outside the US than inside the US.
I had previously assumed that by this point in time Medtronic would have consolidated its world wide stock of Sof-sensors and they would all be the same product. But maybe there are some slight changes that they never bothered to take through the US regulatory process because they were so focused on the Enlite.
This required lack of transparency in the drug industry, which I expect is supposedly there to protect us, is maddening. It's not just that the companies won't talk to us. They can actually rather smugly point out that they are required to keep us clueless so that we are not hoodwinked. Arrrgh!
-iJohn
John, the only important phrase above is "sanitized by their legal staff". This is spot-on, and is not the manufacturers fault. They face a labrynthine maze of landmines dealing with this sort of thing.
And yes, any change, at all, must be approved be the FDA.
I am not offering judgement on whether or not all this restriction is good/bad. Just pointing out to people that it's not eeeeeevil Big Pharma being sneaky, greedy, and dishonest.
As I said in a previous post, we all need look no farther than the mirror for why it is this way.
I found this: http://www.consumermedsafety.org/insulin-safety-center/item/420
Itās interesting because it says opened insulin vials can be stored in a fridge but opened pens should not (with no explanation of why).
And thereās this: http://iddt.org/about/living-with-diabetes/looking-after-your-insulin-and-injection-devices/storing-insulin
It emphasizes that āIn use cartridges should be kept at room temperature and SHOULD NOT be kept in the refrigerator,ā but again gives no explanation as to why.
Our friends at the FDA donāt seem to talk about refrigerating (or not) opened insulin: http://www.fda.gov/Drugs/EmergencyPreparedness/ucm085213.htm
Yet another place where this is not stated: http://www.bd.com/us/diabetes/page.aspx?cat=7001&id=7247
And the ADA seems to have the same take: http://www.diabetes.org/living-with-diabetes/treatment-and-care/medication/insulin/insulin-storage-and-syringe-safety.html
someone asked recently what the max temp for insulin is. I found this from Norvo Nordisk
Permitted Exposure Times For Various Temperature Ranges
Insulin preparations should not be exposed to temperatures between:
-20 to ā10 degees C for more than 15 minutes
-10 to ā5 degrees C for more than 30 minutes
-5 to +2 degrees C for more than 2 hours
8 to 15 degrees C for more than 96 hours
15 to 30 degrees C for more than 48 hours
30 to 40 degrees C for more than 6 hours
Insulin should never be stored above 40 degrees C.
Something seems to be wrong with these ranges:
"8 to 15 degrees C for more than 96 hours"
but 7 C is the ideal temperature of a fridge
15 to 30 degrees C for more than 48 hours
but 22 C (room temperature) is good for 30 days plus
I Googled insulin permitted exposure times various temperature ranges. One of the hits was to a page on a website I hadn't looked at before, http://iddt.org/. Since I'm not familiar with the website, I can't vouch for it. But I did find the info there interesting so I'll excerpt & reference it below.
On the page about Storing Insulin the table of exposures times is clarified as supposedly showing "permitted temperature and exposure times that will not reduce the efficacy of the insulin, PROVIDED it is then returned to the refrigerator". It also carries the additional caveat that the table is for "single exposures only and repeated exposures to higher temperatures will gradually reduce the efficacy of the insulin".
They say that 28 days is the time insulin can be stored at room temperature. But they also include the quote below which they attribute to Eli Lilly.
Our Humulin range has regulatory approval for in-use out of the fridge for 28 days. We have also performed our own in-house studies, however these were also completed after 28 days. Therefore, we do not have any data on in-use of Humulin vials after 28 days and thus, although we have no information to suggest that there is any problem with in-use vials stored in the fridge after 28 days, without data to support this we currently can only recommend in-use for 28 days.
My obviously biased paraphrase of this quote is, "Officially, we just don't have a clue what happens after 28 days so, good luck with that!".
There is also an earlier quote in the same piece attributed to Novo Nordisk Pharmaceuticals Ltd.
Our unopened insulins are stable until the expiry date if stored in a refrigerator. Once open vialled insulin is stable for up to 3 months in the refrigerator and 6 weeks at 25 degrees C. Insulin in cartridges is stable for up to 4 weeks once opened if stored at 25 degrees C; we do not recommend that in use cartridges are stored in the refrigerator. Brief exposure to temperature extremes need not necessarily reduce its efficacy. Our guidelines are quite cautious and are a guide so that people can be aware that should these restrictions be exceeded there is a strong likelihood that their insulin may be damaged and they should consider discarding it.
I found it interesting that supposedly vialed insulin is safe for up to 6 weeks if stored at no more than 25 degrees C (77 F). I think it illustrates how murky and uncertain this topic is. The larger your sample size and the more stable the conditions the more confidence you can have in your assertions. Or, viewed from the other direction, it's harder to predict exactly what is going to happen for one person using insulin under varying conditions. Welcome to physics actual.
The above is only an excerpt from the website. I haven't read the material in detail and can't claim to know much about what else is on the site. However, I also wanted to include the points below which are listed on a page titled "Facts" (about insulin).
- Insulin is a powder that is mixed in solution and once in solution it breaks down slowly into insulin transformation products [ITPs].
- There is a slow rate of breakdown or transformation when insulin is stored in the refrigerator at 4 degrees C.
- This breakdown is accelerated by exposure to light, heat and agitation or regular shaking.
- Increasing the purity of insulin reduces its stability.
The last item, that higher purity insulin is less stable, was a surprise to me. I had always assumed the opposite. I am so ashamed & embarrassed. Oh, well!
-iJohn
Many of the sites I looked at made a clear distinction between using vials and insulin cartridges (such as those in pens). The info on vials indicates they can be returned to the fridge after opening, but the cartridges often emphasized (in caps) that they should NOT be returned to the fridge after opening. But I havenāt yet seen an explanation as to why this is the case.
I emailed Novo Nordisk and just got their reply today. It says I need to call them. Iāll do so and report back here what I learn, if anything.
Many of the sites I looked at made a clear distinction between using vials and insulin cartridges (such as those in pens).
Thanks for clarifying "cartridges". I have only used syringes or Medtronic pumps and was not completely sure what they were referring to.
Possibly this relates to the concern Holger raised earlier that "temperature changes might increase the likelihood for air bubbles to form". I'm not sure how much of a problem that might be for insulin pens in actual day to day use, however, I do know that it does happen.
It is the reason why I try to always fill my pump reservoirs at least a few hours to a day ahead of actually using them. It gives time for the insulin to rise to room temperature & for the air to come out of solution and form bubbles. That way I can eliminate the bubbles when I prime my infusion set tubing from the new reservoir.
I emailed Novo Nordisk and just got their reply today. It says I need to call them.
Thanks for following up.
-iJohn
You do realize that "champagne" bubble in your tubing is of zero consequence do you not? It takes inches of air in one's tubing to create the loss of ONE UNIT. This is right up there with people freaking out if they see some air in an IV when in the hospital or surgery center. Except for babies, lots of air in IV lines is NO DANGER.
Why not simply leave your insulin at room temp? Fill your reservoir, prime, and enjoy?
I just got done speaking with a nurse at Novo Nordisk about this. She said the insulin in vials is exactly the same as the insulin in cartridges. The reason that they and other insulin manufacters recommend not to refrigerated opened pens of insulin is not because of the insulin but because of the pen delivery mechanism specs. Apparently the studies done on the pens in use were done at room temperature. So they have to recommend their use at such temperatures.
That now makes total sense to me. Probably, then, it would be fine to store the pens in the fridge. I myself have seen no difference in the function of the pens, refrigerated after opened or not. The manufacturers just canāt sanction it, per se.
My wife and I have stored dozens of "in use" pens of various formulations without issue. The one thing I WILL mention, is don't leave a tip installed for long or it will 1) allow air in and 2) tend to occlude totally.
It takes inches of air in one's tubing to create the loss of ONE UNIT.
Yes, that's about right. Usually there is an inch or two of air that I need to make sure I've "primed past".
As to why do I do it? It makes me happy.
Champagne bubbles I ignore. Visible gaps of air in the tubing I don't. If nothing else, it's one more question I don't want to have to wonder about when things go wonky on me.
-iJohn
Glad you aren't concerned with the champagne bubbles. :) I seldom see anything worse than them, but that's because I'm really adept at quickly removing bubbles when changing sets. I used to go on at length to explain in great detail how to do that, but in my old age I'm too lazy to type much. sorry! :) I tend to write just short missives.