A sobering new warning affixed to meloxicam (Metacam) has incited a groundswell of confusion and distress among veterinarians who rely on the non-steroidal anti-inflammatory drug, or NSAID, to ease discomfort in feline patients.
Adding to the mix is a widely distributed consensus paper on analgesia by the American Association of Feline Practitioners (AAFP) and the International Society of Feline Medicine (ISFM) that, when it comes to meloxicam, appears out-of-step with directives laid out by the U.S. Food and Drug Administration’s Center for Veterinary Medicine (FDA-CVM).
Last month, the feline use of Metacam received the FDA’s strongest safety alert known as a “black box warning,” named for the unmistakable black border surrounding a cautionary statement on a drug’s insert or packaging. The product insert for Metacam now reads: “Repeated use of meloxicam in cats has been associated with acute renal failure and death. Do not administer additional doses of injectable or oral meloxicam to cats.”
Such stern words of caution come on the heels of ISFM-AAFP guidelines that characterize NSAIDs as “an important class of drug in feline medicine” and — contrary to the advice of U.S. regulators — explores treating cats suffering from long-term chronic pain with meloxicam.
Meloxicam is the only NSAID licensed by the FDA to treat pain in cats. The FDA approves the use of Metacam as a single injection with dosing at 0.3 milligrams per kilogram bodyweight. It is indicated for the control of postoperative pain and inflammation associated with orthopedic surgery, ovariohysterectomy and castration when administered prior to surgery.
The label instructs U.S. veterinarians to administer meloxicam in concentrations three times the strength used by practitioners in Europe and Australia, where it’s more broadly licensed. Why? Much has to do with how the drug is regulated. Metacam is licensed as a one-off in America and the recommended dose reflects that; it's designed for 24-hour pain relief.
By contrast, veterinarians in other countries where Metacam is approved are instructed to follow up with additional doses of the drug, eliminating the need for such a potent punch. What's more, Metacam sold overseas also comes in canine and feline versions, the latter representing a lower concentration to make it easier for veterinarians to accurately dose small patients.
Some believe that these differences feed a paradox whereby U.S. practitioners are seeing far more problems with the drug than their colleagues in other countries. Yet no one has a definitive explanation. As a result, the black box warning has raised the hackles of practitioners who swear by the drug’s safety and efficacy to alleviate pain and inflammation in cats. Others fear the continued use of the drug outside its FDA-approved parameters might increase their liability in some circumstances.
Practitioners are so concerned, that talks about the warning on the Veterinary Information Network (VIN), an online community for the profession, have attracted more than 8,500 visitors to date. Veterinarians have expressed everything from concern and outrage to confusion. While some who’ve witnessed or had bad experiences using the drug support the amped-up warning, most are more concerned about the ramifications of continuing to use the drug off-label when it carries a black box that advises against it.
One veterinarian who spoke on condition of anonymity with the VIN News Service stated that the new warning has changed her prescribing habits: “Obviously I'm not going to be sending it home anymore since there's a large black warning on the box. Before it was just off-label, which to me is different than using a drug when the company explicitly tells you not to. That's a shame for the cats.”
In the United States, the Metacam product insert for the oral suspension has always stated, under contraindications, “Do not use Metacam oral suspension in cats." The FDA-CVM did not respond to VIN News Service questions about what triggered the black box warning. Public regulatory data does not show a spike in reported adverse events associated with meloxicam in feline patients.
Metacam manufacturer Boehringer Ingelheim Vetmedica Inc. (BI) foreshadowed the warning in a “Dear Doctor” letter to veterinarians dated Sept. 17. In an interview, company officials acknowledged seeing a consistent number of adverse events tied to the off-label use of the drug, many associated with inappropriate dosing. That prompted BI to agree to use a black box to highlight contraindications associated with Metacam.
Since the change, practitioners on VIN have expressed angst concerning a lack of alternatives in feline analgesia beyond buprenorphine, which many hesitate to send home with clients because it is an expensive narcotic regulated as a controlled substance.
A VIN member who declined to be identified summed it up this way: “Just what are we supposed to use for our cats that are in pain that will not break their owners’ pocketbooks and is not an opiate that we have to dispense as a controlled substance? The cats are in pain."
By contrast, Dr. Laura Collins, a VIN member and practitioner in Cranbury, N.J., considers meloxicam to be hazardous, referencing the scores of reports from owners damning the drug on the Internet.
“I understand idiosyncratic reactions,” writes Collins in another VIN discussion. “But it bothers me that when I search Metacam and acute renal failure in cats and get 86 hits. I’ve reviewed most of them, and many of them did not have the higher dose, were not hypotensive and did have normal kidney values pre-op. We can all critique more miniscule details, but the bottom line is these are responsible vets who did everything they could for their patient, followed the much touted new pain-management guidelines and ended up with dead or nearly dead cats.”
Dr. Gary White, a VIN member and practitioner in California, agrees. He stopped using meloxicam in cats years ago after watching an associate’s patient die upon receiving it.
“I don’t need to kill two animals to learn a lesson,” he says. “Everything here leaves with pain relief, whether it’s buprenorphine, fentanyl, Adequan or gabapentin. We generally use corticosteroids to treat inflammation. Meloxicam is not an option for cats in this practice.”
Buprenorphine, fentanyl, Adequan or gabapentin are not licensed for use in cats though the drugs have not been associated with a high degree of controversy in feline medicine.
The FDA’s Cumulative Adverse Drug Experiences Reports, or ADEs, cite 2,088 reported adverse events tied to oral meloxicam in dogs with 260 reports indicating adverse reactions associated with the drug’s parenteral administration. Concerning cats, more than 1,100 reported reactions have been tied to the drug’s oral use and 358 events linked to its parenteral administration.
In all product use categories tied to meloxicam, death was listed as one of the adverse events. Those numbers are believed to date back to 2003 and 2004, when the FDA gave the drug a green light for use in canine and feline patients, respectively.
Comparing those numbers with adverse events tied to other painkillers can be difficult. The popular anesthetic ketamine, for example, has incited more than 5,000 reports of adverse reactions in cats logged by the FDA, but regulators have collected reports on the drug for more than two decades. To put the new FDA action into context, virtually every NSAID painkiller including aspirin, ibuprofen and naproxen carries a black box warning concerning safety. Yet no other NSAID in the veterinary market apart from meloxicam has been affixed with such a cautionary statement. According to BI officials, this is the first time the company has added a black box to a pet product label.
The move seems appropriate to veterinarians like Dr. Michele Gaspar, a boarded feline specialist in Chicago and VIN consultant who never prescribes meloxicam to treat patients. In response to a growing number of reports of meloxicam-linked reactions posted to VIN discussions, Gaspar and Dr. Holly Hansen, working at another Chicago-area animal hospital, conducted an online survey of veterinarians on VIN last year.
The results, representing roughly a dozen complete cases where a cat had responded adversely to meloxicam, revealed that veterinarians administer the drug off-label in unique dosages and, in some instances, monitor patients inadequately. According to the report, each of the patients received meloxicam alongside anesthesia for a range of elective procedures apart from one case of urethral obstruction.
Veterinarians, trained to use drugs off-label, have been known to administer Metacam in varying strengths and prescribe it as a long-term analgesic. That makes it tough to determine what percentage of adverse events associated with Metacam is due to the drug's misuse apart from something more idiosyncratic.
Gaspar suggests moving away from the drug for most cases. “Rather than seeing this as some blow to feline analgesia or feline management, let’s start taking a look outside the box and look beyond the pill, the liquid or the elixir,” Gaspar says. “In addition to buprenorphine, fentanyl patches and gabapentin, I would like to see more clinicians be open and learn to use other modalities like acupuncture and chiropractic, especially for musculoskeletal pain. Everybody has their line in the sand about what they believe is good medicine.”
It appears veterinarians overseas and in Canada do not have to make such tough decisions with regards to NSAIDs and meloxicam, in particular.
The drug is licensed in Canada for use in cats as a single injection with dosing ranging from 0.1 milligrams per kilograms to 0.2 milligrams per kilogram. Canadian veterinarians also have access to two other feline-licensed NSAIDs, including Merial's Anafen (ketoprofen) and Vetoquinol's Tolfedine (tolfenamic acid).
Meloxicam has been available for use in Europe in injectable and oral suspension forms since the early 1990s, prescribed and licensed for its anti-inflammatory benefits in mostly canine patients. In June 2007, a new oral form was licensed for long-term management of chronic pain in cats in Australia, Europe and New Zealand. In the United Kingdom, for example, the licensed indication for Metacam reads: “Chronic musculo-skeletal disorders: Initial treatment is a single oral dose of 0.1 mg meloxicam/kg body weight on the first day. Treatment is to be continued once daily by oral administration (at 24-hour intervals) at a maintenance dose of 0.05 mg meloxicam/kg body weight.”
Dr. Richard Malik, world renowned in feline medicine and a researcher at Australia’s University of Sydney, reports having prescribed Metacam safely for more than a decade. "I only use it orally and only in cats that are eating,” he says. “With these provisos I have only good things to say. I don’t use it by injection and don’t give it on the day of surgery. Most problems I am aware of are related to people who give it by injection or combined with dehydration or hypovolemia.” He adds: “I think the drug, if used wisely, is of great benefit to cats.”
Dr. Margie Scherk, a boarded feline specialist in Vancouver, Canada and VIN consultant, considers the FDA’s language of its black box warning to be “ridiculously strong.” The problems that U.S. practitioners are having with the drug have more to do with lax protocols than the NSAID, she says.
“We've gotten terrible at doing histories and proper physical exams,” Scherk says. “No drug is 100-percent safe under all circumstances.”
That doesn’t explain why U.S. practitioners seem to have more negative results with meloxicam than veterinarians in other countries. The European Medicine Authority, a regulatory body equivalent to the FDA, classifies adverse events tied to Metacam’s use in dogs and cats as “very rare.”
Scherk speculates that North American cats are fatter than their European counterparts, so U.S. veterinarians might be improperly calculating the dosages based on weight rather than lean mass.
But Dr. Nigel Swift, BVetMed, MRCVS, Dipl.ACVIM, believes the problem has more to do with education. As a veterinarian working with manufacturer BI, he explains that the FDA bars drug companies from giving widespread dosing instructions to practitioners on off-label indications, even when it's acknowledged that veterinarians are using it in that fashion. “It’s considered off-label promotion,” he says.
So a veterinarian seeking direction on how to safely prescribe the drug orally to cats would have to seek out BI Vetmedica veterinarians to get one-on-one guidance. That’s in sharp contrast to the widespread education that’s presented in countries where the drug is broadly licensed.
“We and the FDA acknowledge that there's extra label use of this product,” Swift says. “The vast majority of adverse events (in America) are associated with inappropriate dosing of the drug; there's a lot of inaccurate dosing. We know that a lot of the adverse events reported in cats are people inappropriately using the 1.5 mg/ml suspension meant for dogs, which is more difficult to accurately dose for small patients.
“If this was a licensed product and we were seeing adverse events associated with the 1.5 mg/ml suspension, we could go out to vets and do a big campaign and talk to them about appropriate use. Right now, we can't do that and so the best way to protect cats from inappropriate use is to highlight the product safety information.”
That’s where the ISFM-AAFP guidance might prove useful, experts tied to the document say. Though BI is listed in the work as having provided an educational grant to fund the independent panel of experts and clinicians who authored the document on NSAIDs, those close to the report insist that the drug company had no involvement with the guideline's formulation.
Published in the July issue of the Journal of Feline Medicine and Surgery, the work aims “to provide practical information for veterinarians to encourage appropriate NSAID therapy whenever cats will benefit from the use of these drugs.” With 108 NSAID-related reports referenced throughout 17 pages, “Long-term use of NSAIDs in cats” goes way beyond Metacam.
Where meloxicam is concerned, the report includes a dosing chart that gives parenteral and oral recommendations for the drug’s use alongside other medications in its class. Incidentally, the report’s panel of international experts finds it “encouraging” that studies show meloxicam’s long-term use in cats with chronic kidney disease can even be safe.
Dr. Andy Sparkes, an international heavyweight in feline medicine and lead author of the ISFM-AAFP guidelines, admits to seeing extremely rare cases of acute kidney failure as a result of NSAID misuse in cats. But in his personal experience, vomiting and gastrointestinal irritation are far more common adverse events.
The ability to titrate a dose on a long-term basis to try to avoid any adverse events while still providing good therapy is an important principle, he says, adding: “It happens that meloxicam is the only drug with a true long-term license in cats (in some geographies) at present, but that will undoubtedly change in the future.”
In the United States, the market could expand sooner rather than later. When it comes to NSAIDs, Novartis Animal Health — maker of the popular non-steroidal Deramaxx — is rumored to have a feline-specific version in the development stages.