When Ronda Archangelo’s dog Mimi died after being treated with a gabapentin solution that contained xylitol, she wondered how such a tragic mistake could have happened. When she asked her veterinarian for answers, it became clear that her veterinarian was unaware that the gabapentin solution she prescribed for Mimi’s seizure disorder had xylitol in it. And the more seizures Mimi had, the more gabapentin was she was told to give her. It wasn’t until later that she discovered that one of the symptoms of xylitol toxicity in dogs is seizures.
Still, Ms. Archangelo wondered how a prescription with xylitol could have been filled when the pharmacists knew the prescription was ordered by a veterinarian, and the drug was for a dog. She asked Walgreens, the pharmacy that filled the fatal prescription if there was some kind of retail prescription software alert system to prevent these kinds of errors from happening. They told her there wasn’t. Then she asked if their pharmacists had access to a veterinary drug reference or a veterinary drug formulary, one which would have provided their pharmacists with the information that human gabapentin products can contain xylitol. They told her they didn’t have one.
And then they told her they did.
The National Association of Boards of Pharmacy’s Model Pharmacy Act/Rules states that “each pharmacy shall have ready access to references, to include at least one current reference […] such as Plumb’s Veterinary Drug Handbook.” But not every state requires that a pharmacy must have a veterinary drug reference on hand.
The American Veterinary Medical Association said the Act/Rule “is a model for the states, and ultimately, it is up to each state to determine the requirements for resident pharmacists.” So, depending on which state you live in, your pharmacist may or may not be using a veterinary drug reference.
And if they are, it’s just possible that they’re using the wrong one.
WALGREENS & THE WRONG VETERINARY MANUAL
When Ms. Archangelo contacted her local Walgreens, they told her they didn’t have a veterinary drug reference manual on hand to verify if they were dispensing a human medication with dangerous side effects on animals.
However, when Walgreens corporate offices spoke to her, they reassured her that all their pharmacists have access to Merck’s Veterinary Manual online. Truthfully, anyone can have access to the Manual online. But, unfortunately, what Walgreen’s corporate didn’t realize is that had Ms. Archangelo’s pharmacist referenced the Manual, it wouldn’t have saved Mimi’s life because there is a mistake in it. A big one.
THE MISTAKE(S) IN THE MERCK VETERINARY MANUAL
The Manual wouldn’t have helped Walgreens’ pharmacists, because there is no warning that liquid solutions of gabapentin contain xylitol. The information regarding gabapentin in the Manual reads:
This synthetic analogue of the inhibitory neurotransmitter γ-amino butyric acid (GABA) inhibits seizure activity via multiple mechanisms, […] Higher dosages (30–60 mg/kg, PO, tid-qid) may be necessary but can produce sedation and ataxia. If excessive sedation occurs, a lower dose should be used initially and gradually increased. Therapeutic monitoring is not usually necessary with this drug. No drug interactions have been reported.*
(*The FDA has warned of serious respiratory problems with the use of gabapentin. “Animal studies have shown that gabapentinoids can cause respiratory depression alone and in combination with opioids,” a message the Manual failed to include.)
In a table from the Manual for gabapentin’s use in dogs, there should be a warning of the risk of hepatic injury and/or failure and death with liquid solutions that contain xylitol, but there isn’t.
|Drug||Dosage/Frequency||Half-life||Time to Steady State||Therapeutic Level||Adverse Effects/Comments|
|Gabapentin||Dogs: 10 mg/kg, PO, tid; up to 30–60 mg/kg, tid||3–4 hr||<24>||4–16 mg/La (70–120 μmol/L)||Sedation, dizziness, ataxia, fatigue, diarrhea, reduce dose with renal dysfunction.|
Yet, the Merck Veterinary Manual warns, explicitly, about the dangers of xylitol, that the ingestion of xylitol can result in the development of hepatic injury and/or failure, and that “dogs with signs of liver injury died or were euthanized despite aggressive veterinary intervention.” Despite this, the editors of the Manual categorize xylitol only as a potential Food Hazard without realizing that it would be useful to list it as a Toxicity from Human Drugs as well.
However, after hearing of the story, Micheal Moses, the Executive Editor of Merck’s Veterinary Manual, wrote and said, “We will be adjusting our content soon to address this issue.” When the topic is updated, it will be listed on their home page and their various social media channels.
A PHARMACISTS BURDEN
While it’s possible for a pharmacist to have an encyclopedic knowledge of every pharmaceutical drug known to man, it is unlikely. And yet, pharmacists who fill prescriptions for animal patients, are expected to do just that if their pharmacy does not have a veterinary drug reference on hand.
Or worse, the only drug reference they have on hand is the Merck Veterinary Manual.
And as more and more pet parents get their pet’s medication at places other than their veterinarian’s offices, they rely on pharmacists who, because of overwork and increased pressure to perform, are making mistakes – and a lot more often than anyone ever knew. An explosive investigation by the New York Times about pharmacies describes an industry in chaos.
A DRUG MAKERS PROMISE
Yet, amid the chaos and heartache, Acella Pharmaceuticals, the maker of the gabapentin solution product that was given to Mimi, is pledging to work with the U.S. Food and Drug Administration (FDA) to allow the company to revise the labeling of its gabapentin solution. After hearing about Mimi’s death, Harold Deas, Jr., the Chief Executive Officer of Acella, wrote to Ms. Archangelo expressing his deep sorrow that her dog died as a result of a drug his company manufactured. Mr. Deas explained that their label is approved by the FDA for use in humans only. But, he’s made a promise to try to change that.
“We are not permitted by the FDA to unilaterally change our label without their permission. However, as dog lovers ourselves, we at Acella do not want to see anther dog be given our liquid Gabapentin product due to a mistake by a veterinarian or pharmacist. While we cannot be sure that the FDA will allow the change, we will ask the FDA to permit us to add a warning to our product label to note that our product contains xylitol and should not be administered to dogs. This process will take time, but if it will help prevent these types of mistakes in the future, it is certainly worth the effort on our end.”
If the FDA approves of Acella’s request to include a warning that a drug intended for humans might pose a risk to dogs because it contains xylitol is a move that could pave the way for other pharmaceutical companies to have a warning on a human drug label that their product contains xylitol and should not be administered to dogs.
HUMAN DRUGS v. ANIMAL DRUGS
One of the main reasons why fewer drugs exist in veterinary medicine is that FDA’s new drug approval process is very costly and time consuming for pharmaceutical companies, with little return on investment for animal drug products when compared to the return on investment associated with human drug products, creating a relative disincentive for companies to put resources toward creating new veterinary drugs.
It is for this reason that veterinarians often dip into the vast pool of drugs developed and approved for use in humans. Under the extralabel drug use provisions, veterinarians are allowed – under certain circumstances – to treat animal disease with FDA-approved drugs intended for humans. Unfortunately, in Mimi’s case, her veterinarian was not aware that the liquid solution of gabapentin she prescribed for her was sweetened with xylitol.
THE NEEDLE IN THE HAYSTACK
A search in the U. S. National Library of Medicine’s drug database, it found 427 gabapentin drugs, but not one of them is approved for use in animals, and of them, only six are in a liquid form. And of those, only one of them does not contain xylitol. They are, as listed:
Acella Pharmaceuticals, LLC gabapentin oral solution contains xylitol as an inactive ingredient (Updated November 6, 2019);
Amneal Pharmaceuticals LLC gabapentin oral solution does not contain xylitol (updated December 27, 2019);
Atlantic Biologicals Corp. gabapentin oral solution contains xylitol as an inactive ingredient (updated February 20, 2020);
Hi-Tech Pharmacal Co., Inc. gabapentin oral solution contains xylitol as an inactive ingredient (updated March 9, 2018);
Lohxa gabapentin oral solution contains xylitol as an inactive ingredient (updated December 19, 2019);
Parke-Davis Div of Pfizer Inc. gabapentin oral solution contains xylitol as an inactive ingredient (updated January 16, 2020).
THE REGULATORY QUAGMIRE
One of the most alarming problems is that when something goes wrong is sometimes reports aren’t made. And when they are drugmakers are not required to report an adverse event if it involves a human drug that was used to treat an animal. And veterinarians are not required to report adverse events with animal or human drugs to the drugmaker or the FDA.
Yet, should a drug maker receive a report from a healthcare professional or consumer about an adverse event involving a human patient that was administered a human drug, the company is required to send the report to the FDA as specified by regulations 21 CFR 314.80.
Likewise, if manufacturers of FDA-approved animal drugs receive adverse event reports from a veterinarian or a pet parent, the manufacturer is required to comply with the regulations in 21 CFR 514.80 for reporting of all serious, unexpected adverse experiences to the FDA/CVM.
THE BLACK HOLE
But, if veterinarians are reluctant to come forward and pet parents aren’t aware that they should tell drugmakers and the FDA if their pet has suffered because of a drug a veterinarian prescribed, then it leaves a gap, a divide where terrible things happen, and nobody knows about it. Where deaths, like Mimi’s, slip under the radar.
Considering this incomprehensible regulatory quagmire, it explains why a spokeswoman for the CVM said Ms. Archangelo’s report about Mimi’s death was the only report the agency has ever received regarding gabapentin and xylitol toxicity. “That said, we believe that adverse events are underreported as a whole, in both food and drugs.”
LIFE ALTERING CHANGES
Yet, with just one report to the FDA, the one Ms. Archangelo made regarding Mimi’s death, the agency has promised to update their webpage, Paws Off Xylitol; It’s Dangerous for Dogs, and their video, Xylitol and Dogs, A Deadly Combination, to include the risk of xylitol in human medications. And Acella Pharmaceuticals is going to ask the FDA to permit them to add a warning to their product label to note that their product contains xylitol and should not be administered to dogs. And the Executive Editor of the Merck Veterinary Manual has promised to update their publication and their online content to include the danger that liquid gabapentin could pose if formulated using xylitol.
These are enormous steps, changes that will affect the lives of dogs and pet parents for years to come. But, sadly, it took the death of a precious and beloved dog named Mimi to affect these changes and bring nationwide attention to a devastating problem within the government, the veterinary, and the pharmaceutical industries.
CRITICAL INFORMATION LACKING
The FDA/CVM encourages animal owners to voluntarily report adverse drug experiences and product defects associated with – including human – drugs administered to animals. The reason is obvious: Voluntary reporting can help FDA identify unknown risks for approved medical products. Reported adverse drug experiences to the FDA/CVM is the primary means by which they obtain information regarding potential problems with the safety and efficacy of drugs as well as potential product/manufacturing problems. And without reports from veterinarians and pet parents, the agency can do little to protect pets.
HOW TO MAKE A REPORT TO THE FDA
Therefore, if you have a problem with an animal drug or a human drug that was prescribed by your vet, you should submit FORM FDA 1932a, “Veterinary Adverse Experience, Lack of Effectiveness or Product Defect Report.” You can use this form to report adverse drug experiences for any animal drug (approved or not approved by the FDA) or animal device. Unapproved animal drugs include compounded drug products and human drugs prescribed by veterinarians.
Or reporting can be done through the FDA’s online reporting portal. (Note that submissions for animal drug products through MedWatch will be accepted and directed to the correct center or office.) For directions and advice on how to report an animal drug side effects and product, problems are available on the FDA website, where you can find out more about reporting adverse drug experiences for animal drugs, including human drugs (approved or not approved by the FDA). Unapproved animal drugs include compounded drug products and human drugs. And if you have any questions about adverse drug event reporting, you can write to the CVM by email at AskCVM@fda.hhs.gov, or by calling them at 1-888-FDA-VETS (1-888-332-8387).
NOTE: This article is a continuation of an earlier story How a Lethal Ingredient in Human Medicine Prescribed by Vets Is Poisoning and Killing Dogs.
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