Veterinarians are eager to get their hands on a new painkiller licensed for cats, but their enthusiasm is tempered by knowledge that some non-steroidal anti-inflammatory drugs, or NSAIDs, have a shaky safety record with feline patients.
     
The Food and Drug Administration (FDA) approved the oral NSAID robenacoxib, expected to hit the U.S. market within the next 10 months. European veterinarians have used the drug, labeled as Onsior and manufactured by Novartis Animal Health, in cats since late 2009 without much reported incident.

Many in the profession applaud the FDA’s decision to green-light Onsior because when it comes to feline analgesia, drug options are slim compared with the number of medications designed for use in humans or even canines. As a result, many drugs used to manage feline pain are prescribed and administered off-label.

Onsior tablets are indicated to control of postoperative pain and inflammation associated with orthopedic surgery, ovariohysterectomy and castration in cats weighing at least 5.5 pounds and 6 months old. Onsior comes in 6-mg tablets with the recommended dose of 1 mg/kg once daily for up to three days (with a maximum exposure of 2.4 mg/kg based on tablet size). A tablet can be given to cats on an empty stomach prior to surgery and again for the next two days following the procedure.

In Europe, the regulatory guidance for Onsior allows veterinarians to prescribe the drug for feline patients for up to six days. The drug is not licensed as a long-term analgesic to treat chronic pain.

“I certainly would be excited about the opportunity to have another tool to manage pain,” says Dr. Steven Bailey, a practitioner in Waterford, Mich., and member of the Veterinary Information Network (VIN), an online community for the profession. Practitioners shared their concerns and experiences with the drug in several VIN message-board discussions.
 
Dr. William Folger, a boarded feline specialist in Houston, already is trying to import the drug from Europe. So far, he's unsuccessful.

“We’re absolutely going to use it,” Folger says, acknowledging that he has been compensated to advise Novartis on the drug. “We’re going to use it for standard pre-surgical cases like neuters, declaws, dentals and spays.”

But dampening excitement surrounding the drug’s launch is an uneasiness that some practitioners feel when turning to NSAIDs for feline pain management. For reasons that aren’t clear, U.S. veterinarians have seen far more serious adverse reactions to the chemical meloxicam — the only other NSAID approved for use in cats in the United States — than practitioners do in other countries. Since the FDA approved meloxicam for use in cats in late 2004, the drug has been linked to cases of renal failure and death in the United States. Such reactions are rarely reported elsewhere.
     
When asked by VIN members how cats fared on Onsior in Europe, Dr. Juhana Honkavaara stated that he hasn’t noted problems at the University of Helsinki in Finland, where he is on the veterinary medical program’s faculty. Honkavaara added that he hasn’t had enough experience using Onsior in cats to determine whether it’s superior to Metacam in terms of safety or efficacy.  

“I only have a few cases where we have switched from another NSAID to robenacoxib (these were GI upsets) and were happy with the end result,” Honkavaara writes in a VIN discussion.

According to Novartis, multiple safety studies were conducted on Onsior in cats, including a 21-day, 42-day and six-month study at up to 10 times the daily dose approved for use. Some cats experienced mild and transient diarrhea, soft feces and vomiting, the company reports. At higher doses of Onsior, vomiting, neurologic signs, intestinal ulceration, increased liver enzymes and kidney damage were noted.

Bailey, in Michigan, wants to see Onsior on the U.S. market for up to a year before making a decision about whether to use it. With Buprenex, butorphanol, ketamine CRI and fentanyl patches in his pain-management arsenal, he vows not to incorporate Onsior until he hears of his colleagues’ experiences.

“You don't know how safe or effective a drug is until you start hearing about average veterinarians using it,” he says. “You can do your trial on 150 animals in a clinical setting and there could be no acute renal failure, and then you use it on 150,000 animals in the general population, and you can get very different results.”

He adds: “I would love to incorporate NSAIDs, but I don’t want to worry about additional kidney issues. We’ve seen problems with meloxicam. We seldom use it.”

Last September, the FDA responded to the reports of adverse reactions tied to Metacam by affixing a black box warning to the product’s label, the regulatory agency’s strongest safety alert.

Metacam’s U.S. product insert 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.”

Folger, once a major proponent of using Metacam, has abandoned the drug in the wake of the FDA's warning even though he's never seen an adverse reaction in a patient.

“I love the drug, I really do,” he says. “But it’s all about staying alive in practice right now. The label very plainly and unambiguously says don’t use this product in cats. What I’m saying is, if you have unintended consequences from Metacam, your practice is going to pay for it at a time when it’s all about staying alive in business. In this economy, none of us are enjoying a lot of growth this year.”

Some experts believe that in the case of meloxicam, the problem U.S. veterinarians have with the drug stems from a lack of education about how to safely dose the drug outside its labeled parameters. The FDA approves the use of Metacam as a single injection with dosing at 0.3 milligrams per kilogram bodyweight. It is indicated to control postoperative pain and inflammation associated with orthopedic surgery, ovariohysterectomy and castration when administered prior to surgery.

The FDA bars Metacam manufacturer Boehringer Ingelheim Vetmedica Inc. (BI) from giving widespread dosing instructions to practitioners on extra-label uses of the drug — it's considered “off-label promotion” — despite the fact that veterinarians use it outside of its labeled parameters, even sending it home with patients. In the countries that see vastly fewer reactions associated with Metacam in felines, the drug is more broadly licensed and mass education is taking place. Studies have supported meloxicam's safety as it pertains to the drug's low-dose, long-term use in cats. (Gunew M, Menrath V, Marshall R. Long-term safety, efficacy and palatability of oral meloxicam at 0.01–0.03 mg/kg for treatment of osteoarthritic pain in cats. J Feline Med Surg 2008; 10: 235–41.)

With a suspected fewer number of U.S. veterinarians now using Metacam (insiders report that sales are down since the black-box warning), practitioners wonder if they might turn to Onsior for long-term pain management.  

Veterinarians on VIN have expressed a need for an alternative to manage chronic pain in their arthritic feline patients. Dr. Nigel Swift, BVetMed, MRCVS, Dipl.ACVIM, works for BI and notes that both Metacam and Onsior are COX-2 selective, aiming to reduce the potential side effects of older, non-selective medications in the NSAID family.

“The veterinarian in me is happy to see that there is going to be more choice for clinicians trying to manage pain in our patients,” he says in a e-mail to the VIN News Service. “The scientist in me wants to make sure that clinicians make decisions based on facts.”

Swift notes that the medical community has spent a decade using Metacam, while Onsior has been on the market in Europe for little more than a year.

“I will stress the point that no medication, least of all NSAIDs, is without side effects, and the choice to use these medications is one made by a clinician knowing the patient and weighing up their benefits in relief of pain and discomfort, versus their potential side effects,” he says. “Careful patient assessment and monitoring, avoidance in cases of dehydration, hypotension or renal injury and careful accurate dosing are key to minimizing these adverse events.”

Folger believes that Metacam’s length of time on the market has worked only to hurt the drug’s safety reputation. Eventually, he suspects that veterinarians will prescribe Onsior off-label for extended use, though he does not expect the FDA to ever widen the drug’s labeled application.

The reason, Folger explains, rests with the fact that there is no universally accepted way to assess the impact of long-term NSAID use in cats. Efficacy cannot be properly evaluated because cats often conceal their pain as a protective mechanism, he says.

“Pain management scores in dogs and humans are very well established,” Folger says. “But there are no standards to grade pain in cats. Of course you can tell when cats are in really bad pain, but with mild to moderate long-standing degenerative joint disease, it’s hard to tell if a drug is working or benefiting the cat.“

Research published last year in Veterinary Journal illustrates Folger's point: The study found that 90 percent of adult cats of varying ages showed radiographic signs of osteoarthritis. Many were asymptomatic. (Slingerland LI, Hazewinkel HA, Meij BP, Picavet P, Voorhout G. Cross-sectional study of the prevalence and clinical features of osteoarthritis in 100 cats. Vet J. 2011 Mar;187(3):304-9.)

“Osteoarthritis in cats appears to be more prevalent than anyone had thought and may be a different pathopysiology than dogs,” says Dr. Mark Epstein, a boarded canine/feline practitioner in North Carolina and president of the International Academy of Pain Management. Like Folger, he also was paid to advise Novartis on Onsior. Since Metacam’s black box warning, he uses the drug sparingly and no longer sends it home with clients to manage their cats’ chronic pain.

“As a clinician, you’re stuck between trying to do what’s best for the patient and protecting the liability of the practice and doctors,” says Epstein, who reports never seeing a serious reaction to meloxicam in his patients. Now that there’s a black box on Metacam’s label, “we use it intermittently and selectively after fully informing the owner of the black label. It’s a much more limited basis,” he says.  

As far as Onsior is concerned, Epstein plans to follow the labeled dosing and indications until he gets comfortable using the drug. “I’m sure, given its pharmacologic action, there will be efforts made to explore off-label uses,” he predicts.  

The pharmacologic action Epstein speaks to stems from clinical evidence that robenacoxib clears quickly from the blood and does not concentrate in healthy tissues. Rather, it gravitates to inflamed areas, studies paid for by Novartis show.

“Based on the literature coming out of Europe, I’m excited about this,” Epstein says. “If Onsior does pharmacologically what it’s purported to do, it could be a game changer for non-steroidals in cats, in particular.”