WVC 2017: Mirtazapine for Appetite Stimulation in Cats

UPDATE (JULY 10, 2018)—Mirataz, an FDA-approved transdermal ointment for the management of weight loss in cats, is now available for purchase to veterinarians in the United States. Developed by California-based Kindred Biosciences, this new ointment contains mirtazapine—a tetracyclic compound originally developed as an antidepressant for humans. Research on the use of mirtazapine in cats discovered its benefit as an appetite stimulant for felines experiencing unintended weight loss.

According to market research conducted by KindredBio, US veterinarians see as many as 9 million cats each year with unintended weight loss due to various conditions—making weight loss a leading cause of feline veterinary visits.

Read the complete update.

Jessica Quimby, DVM, ACVIM, PhD, has a long-standing interest in chronic kidney disease in cats. Obviously, one of the issues in managing this disease is ensuring that patients eat. At the 2017 Western Veterinary Conference in Las Vegas, Nevada, Dr. Quimby spoke about the popularity and success of pharmacologic appetite stimulation with mirtazapine, provided tips to lessen side effects, and offered insight into research findings and the future of this drug.

From Human to Veterinary Medicine

Originally developed as a human antidepressant medication, mirtazapine is a tetracyclic compound whose mechanism of action is largely unknown. Although successful as a human antidepressant, the drug has the unwanted yet significant and common side effect of appetite stimulation, which decreased its popularity as an antidepressant in people. However, because of that and its concurrent anti-nausea effect, the drug found a new niche in treating human cancer patients.

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Mirtazapine’s introduction to veterinary medicine came via a physician who gave it to his dog as an appetite stimulant. Encouraged by that report, further work on 24 dogs and 17 cats yielded good to robust responses within 30 minutes in 25 of the test subjects. Cats displayed more side effects than did dogs, most notably pronounced vocalizations. An anecdotal dose of one-quarter of a 15-mg tablet every 72 hours was prescribed for cats based on the knowledge that the drug was glucuronidated in the liver and excreted through the kidneys.

Research Findings

The benefit of the drug was evident, but the side effect of what Dr. Quimby called the “kitty crazies” was detrimental. The most common side effects noted by the ASPCA Poison Control include vocalization, agitation, vomiting, ataxia, restlessness, trembling, and hypersalivation.¹ Researchers like Dr. Quimby wondered whether the same positive results could be achieved and the side effects mitigated if the drug were given at a lower dose. Furthermore, so far, the test subjects had all been young, healthy cats, yet the drug was wanted for use in older, chronically ill cats. Would there be a difference in onset, duration, and excretion of the drug in those patients? Finally, would the accepted every-3-day dosing in cats give the best results with the fewest side effects?

Results of a 2011 study led by Dr. Quimby² suggested that the active appetite-stimulating effects of mirtazapine in young, healthy cats occur at a dose of one-eighth of a tablet (1.88 mg) versus the traditional higher dose of one-quarter of a tablet (3.75 mg). In their blinded trial, cats receiving mirtazapine consumed significantly more food than cats receiving placebo. However, there was no significant difference in appetite stimulation or calorie ingestion between cats given either dose. Fewer side effects were reported in the lower-dose group. What’s more, the half-life of the drug was 15.9 hours at the higher dose and 9.2 hours at the lower dose. Pharmacokinetics in the cat appear nonlinear, and metabolism may be slower at higher doses. In that same study, Dr. Quimby and her team compared the drug’s action in normal young cats versus healthy old cats. Results for both groups showed equally useful appetite-stimulation effects at the lower dose and more side effects at the higher dose. As with humans, clearance of the drug is affected by disease state. The human data show that with moderate kidney disease, clearance is decreased by 33%. That rises to 50% in severe kidney disease. In patients with liver disease, one can expect a 33% reduction in clearance. The half-life of mirtazapine increased to 15 hours in cats with chronic renal failure. Research is currently under way to determine the effects of feline liver disease on drug clearance.

In a placebo-controlled, double-masked clinical trial of 16 cats with chronic kidney disease and no comorbidities, cats were given either mirtazapine dosed at 1.87 mg every other day or a placebo for 3 weeks.³ The cats were then "washed out" for 4 days and placed in the other group for an additional 3 weeks. The owners kept daily logs, and cats were routinely examined, weighed, and body condition scored. Eleven cats completed the study. Of those, 91% of mirtazapine cats gained weight and 71% had improved body condition scores, while 82% of cats lost weight when taking the placebo. There was a significant (P = .002) increase in appetite in the cats treated with mirtazapine.

Dosing

Veterinarians should be careful about mirtazapine toxicity. It does occur—and is most often due to a misunderstanding about dividing the pill. Dr. Quimby suggests dispensing exact of doses of mirtazapine to reduce accidental administration of a full tablet (15 mg) and resultant toxicity.

Dr. Quimby expressed enthusiasm for transdermal mirtazapine administration. Citing a 2016 study published in the Journal of Feline Medicine and Surgery,⁴ she noted that even though drug concentration in the compounded preparation can vary up to 10% and that drug absorption is reduced when administered through the skin instead of orally, transdermal delivery results in easier administration and more constant blood concentration. That steady blood level appears to reduce side effects. With proper compounding, transdermal application achieves sufficient serum concentration and stimulates appetite in healthy cats. As with other transdermal medications, the strength needs to be a higher to achieve the same blood levels. A 7.5-mg transdermal dose has been shown to be effective, but studies are under way to determine if a lower dose will be equally effective. Dr. Quimby reminded the audience how essential it is to wipe off the previous dose from the inner pinna before giving the next one to avoid drug accumulation.

Summary

In conclusion, mirtazapine works as an appetite stimulant in cats. Current dosing recommendations for mirtazapine in young, healthy cats is 1.88 mg/day. In older cats and those with chronic kidney or liver disease, 1.88 mg can be given every 48 hours. This dose, while effective, results in fewer undesirable side effects than the traditional 3.75-mg dose. Transdermal preparations are easier to administer and work well when compounded correctly. We look forward to commercially available transdermal preparations in the future.

Dr. Thompson is a small animal veterinarian, animal health executive, editor, and writer. She has held numerous positions with oversight responsibilities for editorial and business direction, including for Veterinary Learning Systems (publisher of Veterinary Technician and Compendium), Vetstreet.com, HealthyPet, and NAVC.

References:

• Ferguson LE, Mclean MK, Bates JA, Quimby JM. Mirtazapine toxicity in cats: retrospective study of 84 cases (2006-2011). J Feline Med Surg. 2015;Jul 30;pii. 1098612X15599026. [Epub ahead of print]
• Quimby JM, Gustafson DL, Lunn KF. The pharmacokinetics of mirtazapine in cats with chronic kidney disease and in age-matched control cats. J Vet Intern Med. 2011;25(5):985-989.
• Quimby JM, Lunn KF. Mirtazapine as an appetite stimulant and anti-emetic in cats with chronic kidney disease: a masked placebo-controlled crossover clinical trial. Vet J. 2013;197(3):651-655.
• Benson KK, Zajic LB, Morgan P, et al. Drug exposure and clinical effect of transdermal mirtazapine in healthy young cats: a pilot study. J Fel Med Surg. 2016;Sept 9:pii: 1098612X16667168.