Expired doxycycline - what exactly breaks down?

A question for pharmacologists: How exactly do doxycycline hyclate tablets break down after the expiration date?

I have nearly an entire bottle (was for my cats) that expires this month. All the online drug references say to throw doxycycline out when it reaches the expiration date, but they don’t say what happens. The only cite I could find was this one for tetracycline where a Darwin award contestant developed Fanconi syndrome after taking 4g(!) of tetracycline over a 48hr period – pills that she had let get wet and then dried out, then kept these deteriorated pills in a cardboard box for a year before using them again! :smack:

Here it says doxycycline hyclate is normally stable and doesn’t break down. My vet tells me that generally, most antibiotics in tablet form are pretty stable.

So which is it dopers? Stable or “OMG, we’re all gonna die!”?

The problem with drugs after there expiration date is that no one actually knows what happens to them. Expiration dates are normally set by what’s called advanced stability testing, where they simulate how long a drug will last In the lab. But they can only use that for a maximum of 3 years. So, no one knows exactly what will happen. It could be safe, or it could do nothing, or it could be toxic. No one knows… However, it is an antibiotic which shouldn’t be used except under a doctor’s recommendations, so I would just suggest tossing it.

Perhaps if you searched for “outdated tetracycline” or “tetracycline renal problems” you’d get some more information on the whole expired doxy issue- but most of the random Medical sites I saw just seem to point out that expired tetracycline is toxic to the kidneys.

As to how it actually breaks down, I can’t really answer that question- but if you are asking is there a known side effect of outdated tetracyclines- then yes, renal impairment, necrosis, and failure are all possible with outdated tetracyclines.

Wiki on Fanconi, drugs.com on Tetracycline, tetracycline precautions, and one more on the side effects of Doxycycline All of these point out that yes, Outdated Tetracyclines seem to be bad for your kidneys.

And one quote to boot, since it was the best summary I could find on expired Doxy:


Sorry I couldn’t answer your initial question, but I hope I can at least help you reaffirm that yes, outdated Doxy/Tetracyclines can do some bad things (and ergo, must probably break down or at least have something unique about them that this medication is quite explicitly labeled with causing a certain specific set of problems once it’s expired).

You can make some guesses based on the structure. I’m not sure how they’re tracking stability in those tests–I’d expect something like HPLC–and they may not care what it breaks down into, though with regulatory agencies these days knowledge of degradation products is becoming more important. I don’t see anything that jumps out at me with doxycycline. Perhaps reactions with the amide on the end or dehydration with all those alcohols.

Yeah. I did do that. Which is how I ended up with the above cite for the one case study of that Darwin award contestant. Which is why I was asking for more cites. Unfortunately, you found exactly what I found (with the exception of the original case study).

All the online drug references (including Merck) seem to base their cautions about all expired tetracycline drugs on that one single case study – hardly a rigorous analysis. If that’s the case, then it may be that doxycycline hyclate is actually stable in tablet form (like my vet infers) and the expiration date is more precaution than anything else.

In case you don’t know, the doxycycline breakdown products in the body are much, much safer for the kidneys that other tetracyclines, hence the usage in my CRF cats.

Hmm, how much break down and over what time frame (best guess)?

According to this abstract, the major degradation products (and that’s the keyword for a search, by the way) of doxycycline are metacycline and 6-epidoxycyline, neither of which appears to be all that toxic. The abstract also lists some time frames.

Awesome! I knew dopers would come through.

And yeah, that was the one term I DIDN’T use. But it looks like my vet was right (again) and I don’t have too much to worry about by using doxy tablets a little past their expiration date.

Stability is usually tested by HPLC, but in some products GC or even UV is used (very rare, but I have seen it). Near-IR is being developed as well, but I never saw it in action. The HPLC method used is the one used for the lot release Assay and Impurities testing, done when the drug lot is manufactured and prior to shipping to customers.

The degradation products are absolutely known by the FDA/HPFBI/etc and by the manufacturing company because it is part of the initial work done in pre-formulation and formulation development (which establishes the dosage form to be used; tablet, capsule, gelcap, cream, injectable, suppository, etc. and the ingredient recipe used). The Active Pharmaceutical Ingredient (the pure drug) is systematically exposed to light, heat, acids, bases, water, and each potential dosage form ingredient individually and “forced” to degrade - each degradation product is identified by various means.

Short-term accelerated stability is part of this: the drug and prototype dosage forms are stored in different conditions (in my experience, typically 45C/75% relative humidity, 30C/60% RH, 25C/60% or Ambient RH and 5C/Ambient RH) and a 3 or 6 month (sometimes longer, but I’m not sure about that) stability study is done where the drug is tested through its entire release testing protocol to see whether it is degrading. This helps establish an expiry date and the recommended storage conditions for the drug - this is where instructions to keep some things in your fridge comes from, for example. Sometimes several studies are done, in order to make corrections to the recipe.

Long-term stability is an actual 3 year study at the ideal storage conditions, with backups at 5C/Ambient (IME), and the drug is evaluated at defined intervals during that time. This often gets done around the same time as clinical trials (multi-tasking pharma companies to save money!)

Once the product is approved and on the market, a certain number of lots of the drug manufactured every single year is stored for 3 years at ideal conditions: the same testing protocol applies and if there are any problems, then expect a product recall to be initiated.

Thisis a WHO monograph for doxycycline hyclate. The drug would never make it out the door of the manufacturing company with more than 2% metacycline or 6-epidoxycycline, and no more than 0.5% other impurities/degradation products (with respect to the API). Your cite lists metacycline and 6-epidoxycycline at approx 28, 14 and 18% after 90 days in different dosage forms.

I would not take the tablets in your cite.

As I’ve said before on these boards: drugs are not time bombs. They do not become degraded (risk of undermedicating the illness), toxic, or otherwise useless/dangerous a day or two after the expiration date, but logically, at some future point in time, they do degrade significantly. There’s just no way to know when the transition happens. The law does not require pharmaceutical companies to show that their products are safe indefinitely - they only require them to show that the drug remains stable/unchanged within set limits for a certain amount of time, reflected in the expiration date. There is no data after that; no one knows what happens because no one needs to know.

Taking expired drugs is a risk and there is no data to help you decide how big that risk is.

Here is another article describing 3 patients with reversible Fanconi syndrome after using expired tetracycline.

I just want to reinforce this. mnemosyne is an expert when it comes to the testing side of pharmaceuticals. The problem with taking a drug after the expiration date is that no one actually knows what happens to the drug. After that date, no one knows what happens for sure, they only have guesses. Also, the products of the drugs are different when they are tested in vivo (in the body) vs. in vitro (outside the body).

So, you need to be careful when it comes to the drugs you take…

Also, Doxycycline is an older antibiotic, and is actually pretty cheap. Doxycycline is on Wallmart’s (and Kroger’s, and everyone elses who matches) $4 prescription list. So, is it really worth the risk to take something expired when you can get new meds for so cheap?

Heck, $4 for a 5-day prescription (for example) is still a decent profit margin (taking in to account only percent cost of drug, notwithstanding that it presumably takes the pharmacist the same amount of time and expertise to deal with dirt-cheap antibiotics as with a gorillacillin). At my old job, when I knew the price of most drugs, we would sell a 500-count bottle of doxycycline for about $60, or 12 cents per pill, and that was with whatever markup the clinic charged (usually about 100% for drugs). Absorption must not be as good in horses as in people, since a 500 kg horse gets 5 g, or 50 pills, of doxy BID, whereas a 50 kg person gets 100-200 mg SID to BID.

I don’t disagree with you. Still, I wanted to point out (and correct me if I’m wrong) that toxicity from outdated tetracycline may be unique, i.e. outdated meds may sometimes lose their effectiveness, but only outdated tetracyclines pose a health hazard.

I’m not a doctor or a toxicologist. Heck, I’m not even a chemist anymore (and I wouldn’t call myself an expert, but thank you, Hirka T’Bawa …I just did a heck of a lot of stability analytical testing and got a general sense of how it worked and why it was being done).

I don’t know that only tetracyclines can become toxic when degraded. There are thousands of drugs out there, all of which have degradation products, and I have to believe that more than a couple are going to have degradation products which might qualify as toxic (and I’m not even sure what that means, from a scientific perspective).

Is anything with some level of pharmaceutical action on the human being considered to be toxic? My understanding is that a lot of the impurity and degradation products of drugs have such action, and can often be the source of unwanted side effects. Some are eventually researched as drugs themselves. Some degradation products are carcinogenic, or mutagenic or teratogenic… these are, IMHO, toxic and undesired. That’s why you have testing criteria of No More Than 0.5%, or even 0.2% and 0.1% in some cases, even if the active ingredient is still at 99.4% with an assay criteria of 100.0% +/- 2.0%.

Besides all that, so many drugs are being taken for chronic and serious illnesses - why would you want to undermedicate that? I want my drugs to work as promised, not only halfway, and with a minimum of side effects.

IANAMD, but Aspirin breaks down to acetic acid and salicylic acid. I understand salicylic acid is a lot more irritating to the gut than acetylsalicylic acid (Aspirin). So in the sense that you increase your chances of getting (at least) a gut ache by taking expired Aspirin, it poses a bit of a health hazard.

The toxicity of expired tetracycline may not be unique, but it is extraordinary. Most drugs degrade into compounds that are not significantly more toxic than the parent compound, and some are equally effective. One compound I worked with was actually allowed to degrade by nearly 7% during clinical testing, because the daughter compound had been pharm/tox tested up to 15%.

Mnemosyne, the abstract is a bit less than crystal clear, but I believe the high numbers in the study I cited were for materials stored at high temperature; the stability for materials at 25˚C was normal. My point in citing the study was not to claim that expired doxycycline is safe, but to answer one of the OP’s questions: “How does doxycycline break down?” The other question, “How does expired doxycycline cause nephrotoxicity?” was not addressed by this study, and indeed does not appear to have been answered definitively. If I had to guess, I’d say that all tetracyclines are nephrotoxic in susceptible populations, or in sufficient amounts, and many degradation products are especially so.

Nametag, who has run a few stability studies in his time

My thoughts and discussion on Toxicity, spoiler-ed so as not to Hijack from the Doxy Talk, because it might be a bit lighter or unrelated to the main issues in the OP.

Toxicology: Basically in summary, Toxicology is the study of all chemicals- because as the Toxicologist giving us our lecture loved to quote: “Dose alone makes a poison” (basically the concept that ANY chemical in high enough concentrations or doses could cause harmful effects).

Toxinsvs. Poisons though are another issue. Toxins are naturally produced, while artificially created things or inorganic substances are usually classified in another way (some say Toxicantsbut again this is all just nitpicking more for those in the field IMHO). And don’t even get into the whole Poisondiscussion either w/ Toxins vs. Venom.

But to go back to your quote- technically in Toxicology, the principle concept would be that EVERY chemical can exhibit toxic effects (also known as side effects, or basically even more simplified “effects are are not desired” [though with some medications, the secondary effects for a drug may be a desired effect for some people, and a side effect for another group).
That said, it would be said that every chemical could have undesired effects on the human body- it just depends on the dose- 500mg of Tylenol is great, but 5g of Tylenol makes it Toxic. And it’s the Toxicologist’s tasks to deal with it, basically coming down to Symptom managements a lot of the time for the lesser known/famous chemicals. Monitor Vitals, manage the ABC’s and keep the patient going until you can get the materials out of them safely, while managing any of the “toxic side effects” that pop up.

So in that sense “every chemical’s degradation product” can be classified as “toxic” but it’s the dosage that the doc’s gonna care about. I thought it was sort of a nitpicky detail in class, but it makes sense, and it was one he kept repeating, so I assume it must mean more for the Toxicologist than to the everyday person. Like Vitamin C is great for us, it’s good to get 100% the daily values, but when you start taking several times MORE than the daily levels, you’ll get things like an upset stomach and GI irritation- an unwanted side effect of Vitamin C toxicity, basically.

So I suppose from a ‘scientific perspective’, it’s not very useful to say if something is simply toxic or not- though it is useful to know WHAT the toxic effects are (as then the ToxDoc knows what to prepare for, and what he can try to do to relieve the problems as they come along), but for them it’s not so much the “is it toxic or not” but rather a question of “HOW MUCH until it becomes Toxic” as the main question. [/spoiler]

Not quite related to what the current discussion is about, but I just wanted to share a bit more from my understandings on the topic from the few lectures I had on Toxicology. It’s a really cool and fascinating subject to me, and I apologize if the above was probably a bit soft or vague. Blame me for that.

And for what it’s worth- yeah, all my Board review books like to point out “Expired Tetracycline= Renal problems” so it IS a concept it seems they want Medical students to be aware of at least- though there isn’t much more in depth than that in the review materials (such as First Aid, and Kaplan Studies and such). But expired tetracycline is “special” in that it is known to have a certain specific correlation to a specific known toxic effect.

According to this older study, doxycycline tends to pass through the kidneys mostly undegraded in rats and dogs (nothing about cats though). It probably does the same in humans. This cite (top google link) says it appears to be chelated in the intestines in humans.

Shouldn’t all expired drugs be taken to a pharmacist or similar professional for proper disposal? Just in case someone picks them up from your rubbish or to prevent the police from getting the wrong idea.

Doxycycline becomes more potent when it expire and can cause fatal kidney failure.