Maxidex Eye Drops use in dogs - safe or just ineffective if stored below recommended temperatures?

Question

Our dog had a red/bloodshot eye and we were prescribed Maxidex (dexamethasone) eye drops for our dog.

The first two times we used them they were stored at room temperature (bottle just store below 25°C and NOT TO FREEZE); however, we then seen our vet on a unrelated incidence and he said we should store them in the fridge.

So we put them in the fridge and used them about 5 more times as she was having one drop twice a day. I was then reading about them online and noted that some documents stated to NOT store them in the fridge (the leaflet we got never mentioned this, just said not to freeze).

I have a temperature gauge in my fridge and I placed it right next to the bottle to see what temperature it ended up being stored at, and according to that it got down to about 0°C - 1°C.

After reading this I stopped giving it to her as her eye was looking better anyway.

Because of this I was curious if now we had given it to her after being in the fridge if it was just going to be ineffective or if it would be harmful in some way, so I emailed the company.

They didn't seem to want to get into specifics but told me that:

The TGA-Approved Consumer Medicine Information1 for Maxidex® eye drops has stated under Storage

Keep Maxidex in a cool dry place where the temperature stays below *25°C.

Do not freeze Maxidex. Do not store Maxidex or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills.

As previously stated, Maxidex® eye drops can be refrigerated as long as the temperature inside the refrigerator does not drop below +2°C. 2

Storing Maxidex® eye drops outside the registered storage conditions may affect the quality of the product. Novartis can't recommend the use of Maxidex® eye drops stored outside registered storage conditions.

Please speak to your pharmacist or veterinarian if you have any further questions about the storage and use of Maxidex® for your dog.

Novartis recommends the use and store of its products only in accordance with the Consumer Medicines Information (copy available at http://www.novartis.com.au/products/consumer.shtml or from your pharmacist, doctor or our company).

So all they seemed to want to tell me is that storing them outside these temperatures may affect the quality of the product; but didn't seem to want to tell me if it would just make the product ineffective or possibly harmful?

Does anyone know how, when doing so, in that it seemingly was stored at 0°C - 1°C, which is slightly below the stated storage guidelines indicated above would make the product, would affect the product?

Edit: If you see the "2" referenced next to the +2°C statement, this refers to this:

Clinical data pertaining to reference 2 is unpublished and the confidential property of Novartis. Novartis is providing this information in good faith due to the lack of data of this type in the published literature.

At first I thought this was saying that their reasoning for the +2°C was confidential, but I think it's saying that this finding of +2°C is only referenced in confidential data, but I also assume that this confidential data contains the reason why.

Also, I assume it's not a great concern, but since I am asking the primary question, the first two times I also forgot to shake the bottle when it states to "SHAKE BEFORE USE", hopefully that doesn't prevent another potential problem?

Here is the CMI.

Another document I found states to store it between 8°C and 27°C.

Lastly, here is a full PI.

Answer 1

I am not a medical professional and this answer is not medical advice nor a substitute for medical advice.

At first, it could be helpful to estimate whether the eye drops could even have frozen in the temperature inside your fridge. Pure water freezes at 0 °C, but any dissolved impurities will generally lower the freezing point (for example, saturating water with salt lowers the freezing point from 0 °C to around -19 °C). What I would do - I would get some transparent, small container - like a vial or a disposable jug from pharmacy intended to hold urine samples - then I would drop a few drops of this medicine to it, close the vial and put it in the fridge to see whether the medicine freezes in this temperature. Afterwards, I would dispose of the vial/jug together with the drops in that bin at pharmacy where it is intended to throw away expired medicines.

Generally overheating medications is much worse that overcooling them. Lowering the temperature tends to slow down the rate of chemical reactions (including decomposition), while increasing temperature accelerates that rate. However, this simple relation doesn't take into account that the process of phase change in freezing/thawing could potentially change physical properties of the medicine.

According to this chemical data sheet of dexamethasone and other sources, it is practically insoluble in water (water solubility of 89 mg/L according to one of the figures in the data sheet). It makes sense because dexamethasone is a steroid and steroids are generally hydrophobic (insoluble in water, soluble in non-polar solvents like fats).

According to this source, the ingredients of Maxidex are:

The active ingredient in Maxidex Eye Drops is dexamethasone 1 mg in 1 mL.

Maxidex Eye Drops also contain:

• benzalkonium chloride as a preservative;
• dibasic anhydrous sodium phosphate;
• polysorbate 80 (Tween 80);
• disodium edetate;
• sodium chloride;
• hypromellose;
• citric acid monohydrate and/or sodium hydroxide use to adjust pH;
• purified water.

Polysorbate 80 and hypromellose are both emulsifiers, also known as emulgators, which means they are added to stabilize the mixture of immiscible substances - this, together with the instruction of shaking before use, strongly suggests that these eye drops are indeed an emulsion, probably dexamethasone and water in this case.

The problem is that many emulsions are not freeze-thaw stable. With some exceptions, emulsions are thermodynamically unstable and have a natural tendency to separate over time. For example, it requires a lot of energy input - in the form of vigorous stirring and shaking the container - to mix oil with water, but without any stabilizer such mixture quickly separates into two completely distinct layers. Stabilizer's function is to greatly slow down this process of separation. However, subjecting an emulsion to freezing-thawing cycle causes stress at the interface of immiscible phases and thus could facilitate aggregation of the dispersed particles into larger units.

If the suspended phase aggregates and separates from the solution as larger clumps, then it is a valid concern; it would change the physical properties of the medicine into something different that the producers intended. For example, the fact of separation would make it so that the concentration of the active substance will no longer be uniform in the liquid. It could be a problem because the safety and effectiveness of the treatment depends on using the specified dosage - but if the solution in not uniform in terms of concentration anymore, you risk dosing too little or too much; theoretically the first couple of drops could contain no dexamethasone whatsoever, then the next couple of drops could contain a few times more that you'd expect.

In the topic of shaking the eye drops before use - it is done to further make sure that the mixture is as uniform as possible. As said before, emulsions "want" to separate and do it slowly over time, so it is especially important if the drops have been sitting immobile for a long time (a few months?) on the shelf before use. However, I think we could certainly assume that during the recent time you were buying the drops and transporting them home, they have been moved around and at least somewhat shaken. It is definitely better to remember doing it manually next time, I don't think it was anything bad or catastrophic that you forgot the first two times - it just was not optimal.

Nonetheless, if you are still concerned about not shaking before use, here is my next idea about testing for yourself - you could leave the bottle of these drops to sit on a shelf undisturbed for, let's say, a week; then without shaking apply a few drops on some surface (I suggest some flat, transparent piece of glass) in one place, then vigorously shake the bottle for at least a minute and apply a few drops again in a different place on the surface - and then observe whether there is any noticeable difference in the appearance of these two samples (one more cloudy than another, one having different color, etc.), preferably using some bright light source to see more details.