Apoquel Q&A: Will oclacitinib revolutionize the treatment of allergic dermatitis?

Getty Images/Charles MannFor a couple of years, we have waited with anticipation for a new proposed drug for itching that was being developed by Zoetis. First in the laboratory, then in clinical trials, and then finally through the FDA approval process, oclacitinib (Apoquel-Zoetis) became available in limited supply. Since allergy season is upon us and as a veterinary dermatologist, I am fielding questions daily about Apoquel, and I thought I would report my experience with the drug as someone who has been prescribing it for the past two years to about 500 patients. 

Its mechanism of action, dosing, side effects and laboratory monitoring will be discussed based on Zoetis' data, the North American Veterinary Dermatology Forum's Apoquel roundtable in April 2015 and anecdotal information that I and other veterinary dermatologists have run across in our use of the drug. I hope that sorting out this information and bringing it to you as a practitioner will help you in your efforts to treat your pruritic patients safely and effectively.

What is a Janus kinase (JAK) inhibitor? 

JAKs were discovered in the late 1980s by an Australian chemist who isolated two kinase molecules. He named the two “JAK's” (“just another kinase”). As a group, JAKs are found to be important in white and red blood cell formation, immunity, inflammation and growth and development, as well as sentinels in the body to protect against tumor formation. Four JAKs are currently known-JAK1, JAK2, JAK3 and TYK2. 

Oclacitinib is a selective inhibitor of JAK1 and JAK3 enzymes-proteins important in signaling a pathway that results in itching and inflammation. By inhibiting these enzymes, cytokines that result in inflammation and itching active in allergy are halted, particularly interleukin-31 (IL-31). JAK2 is an enzyme involved in manufacturing red and white blood cells (hematopoiesis), and oclacitinib has little effect on those cytokines. 

Other JAK inhibitors available in people include tofacitinib (Xeljanz-Pfizer), which is used to treat rheumatoid arthritis, and ruxolitinib. Six others are currently in clinical trials. Oclacitinib is not a corticosteroid or antihistamine.

When do I use Apoquel? 

According to Zoetis, Apoquel is FDA-approved for canine allergic dermatitis, including flea allergy dermatitis, food allergy, atopic dermatitis and contact dermatitis. As a veterinary dermatologist, I have seen the most success with its use in atopic dermatitis. In the 2015 American College of Veterinary Dermatology (ACVD) roundtable on Apoquel, participants varied as to whether it was helpful in food allergy-some found it to be successful while others did not. In Zoetis studies, Apoquel inhibited IL-31 (a cytokine responsible for pruritus in dogs) faster than oral prednisolone and injectable dexamethasone and controlled itching and skin condition comparable to glucocorticoids in flea-allergic dogs.1

In the clinical trial of allergic dermatitis in dogs, treatment success was found in 67% of treated dogs with Apoquel vs. 29% of dogs treated with placebo after one week of treatment. In dogs with atopic dermatitis, 66% of dogs treated with Apoquel vs. 4% of placebo-treated dogs were treated successfully.2

In my experience, oclacitinib has been very helpful in my atopic patients that were nonresponsive or had a limited response to the previously available treatments for atopy-injectable immunotherapy, sublingual immunotherapy, modified cyclosporine or glucocorticoids. My feeling is that if an atopic patient is not under control with any of the first three of the above therapies that have been available for several years and if it appears corticosteroids will be needed long-term, oclacitinib is a plausible alternative to long-term corticosteroids or if corticosteroids are contraindicated such as in cases of diabetes or pancreatitis. 

We are all aware of what long-term corticosteroids do to the body, and even though oclacitinib has not been available “long-term,” iatrogenic Cushing's disease is crippling in many ways to the patient and if it can be avoided, it should be. Remember that a diagnosis of atopy is one of rule-outs. Before any medication is prescribed, particularly a new one such as oclacitinib, the correct diagnosis needs to be determined. Some patients referred to me had been prescribed oclacitinib just because they had a “skin condition.” Some of these patients had demodicosis or neoplasia and had no place being prescribed this drug. So when prescribing oclacitinib (or any newly FDA-approved drug), be sure you are using it for the prescribed disease-just because it helps with pruritus doesn't mean you don't have to rule out such conditions as ectoparasites, food allergy, demodicosis and bacterial pyoderma.

How is Apoquel dosed? 

The labeled dose of Apoquel is 0.4 to 0.6 mg/kg twice a day for up to 14 days and then once a day. Because it is quick-acting, most dogs respond within 24 hours. It is rapidly absorbed, reaching peak plasma concentrations within one hour. The benefit is that it's quick-acting, but it also has a short duration of action, and very seldom can you go to every-other-day dosing for your patients. About 30 percent of patients will flare with dermatologic signs when moving to once-a-day dosing. Those patients after a few days will either have their clinical signs settle down, or the dose will have to be increased. If given the once-a-day dose divided twice a day, some dogs will improve. It can be given with or without food.

What do I need to watch for when using Apoquel? 

The major metabolic clearance route is metabolism via renal and biliary elimination. It has minimal effect on cytochrome P-450 enzymes, meaning little interference with azoles such as ketoconazole. In clinical studies, the most common side effects included vomiting and diarrhea. Other side effects reported included lethargy, anorexia, skin irritation or infection, and ear irritation or infection.3

According to the manufacturer, “Apoquel may increase the susceptibility to infection and demodicosis and may exacerbate neoplastic conditions.”3 What's important about that statement is if a client calls because the dog is getting worse while receiving Apoquel with either pruritus or lesions, you need to get the dog in for an examination to determine if the Apoquel is causing or promoting a pyoderma or demodicosis. Many clients will call wanting to increase the dose because it helped so much at first, but before doing that, check the patient for pyoderma or demodicosis. In the Target Animal Safety Study performed by the manufacturer, dogs over 12 months of age were given Apoquel at one, three and five times the labeled dose twice daily for six weeks and then once daily for 20 weeks with no cases of demodicosis reported in those dogs.4

Also have the owner call you if any new skin “lumps” or areas of hair loss occur so that you can rule out the above-mentioned infections. My colleagues at the 2015 ACVD roundtable on Apoquel have seen the development of demodicosis as a side effect. I have not, but I have had to discontinue Apoquel in several patients because serious bacterial pyoderma developed while they were receiving it. I have found that it can exacerbate otitis, and, in some cases, the drug has to be temporarily discontinued to start the dog on corticosteroids for the otitis or interdigital pyoderma (Figure 1). 

Figure 1. Interdigital pyoderma that developed while this dog was receiving Apoquel. (Photo courtesy of Dr. Alice Jeromin)

Other anecdotal adverse effects seen by me or my ACVD colleagues include viral papillomas (especially in young dogs such as German shepherd mixes going to doggie daycare) (Figure 2), reactive aggressive behavior that stopped when Apoquel was discontinued, grand mal seizures in three patients, leucopenia (several roundtable participants mentioned this; some patients' complete blood counts went back to normal even when the drug was not discontinued), weight gain/polyphagia (I have had three patients gain 10 to 20 percent of their body weight), elevated alanine transaminase and alkaline phosphatase activities, histiocytomas, elevated creatinine concentrations, and skin tumors. 

Figure 2. Viral papillomas resolving after discontinuation of Apoquel. (Photo courtesy of Dr. Alice Jeromin)

In the original studies, the manufacturer reported 12%  (34/283) of dogs developing “non-specified dermal lumps” within 112 days.4 There has appeared to be no exacerbation of diabetes, pancreatitis or cardiac disease when Apoquel is used in these patients. It should not be used in dogs less than 1 year of age. Vaccines can be given while an animal is receiving Apoquel, and the manufacturer reports no interference with skin testing.5

In another study, the mean length of time on the study was 401 days (15 to 672 days) with 247 dogs enrolled in the study.6 Owners saw a positive impact on the dogs' quality of life in more than 91% of cases. Adverse effects included urinary tract infection or cystitis, vomiting, otitis, pyoderma and diarrhea with no changes in complete blood count or serum profile results. 

What laboratory parameters should I monitor? 

The consensus from the 2015 ACVD roundtable on Apoquel was that a baseline complete blood count, serum chemistry profile and urinalysis should be performed before starting the drug, again in 30 to 60 days, and then, depending on the patient's age, every six to 12 months thereafter. Zoetis recommends monitoring for the “development of infections, including demodicosis, and neoplasia.”3 Again, it is important for the owner to communicate any worsening of the dog's condition, development of any skin “lumps” or areas of hair loss, or any problems that arise while the dog is receiving the medication that were not formerly present. Apoquel should not be combined with other immunosuppressives such as modified cyclosporine or corticosteroids, if possible. 

Can oclacitinib be used in cats? 

The drug is not FDA-approved in cats. Unpublished research by Zoetis of a cat with cutaneous mastocytosis responded to oclacitinib (1 mg/kg once a day). Another study used oclacitinib in experimentally induced feline asthma with success.7 Another report used 1 to 1.5 mg/kg once a day with success in one case of feline idiopathic ulcerative dermatosis.8 Studies show that IL-31 is responsible for pruritus in cats and oclacitinib blocks the IL-31-induced itch.9

My experience along with my colleagues' when Apoquel is used for atopy in cats is that some respond, while others do not. Doses include 0.7 mg/kg twice a day and 1 mg/kg twice a day, with no long-term studies performed and vomiting and diarrhea occurring in some patients. It appears that cats more rapidly metabolize oclacitinib.

What about compounded oclacitinib? 

Because of the unavailability of the drug, some of us have received advertisements of compounded oclacitinib. I am a pharmacist, and compounding medications is not my favorite option unless the compounding pharmacy can guarantee stability, compatibility of ingredients and sterility-seldom, if ever, are these factors even addressed. None of the compounded forms of oclacitinib have undergone any testing for effectiveness or safety. So none of the FDA-approved permission for compounding of this drug has been satisfied. Technically, compounded oclacitinib is classified by the FDA as adulterated or misbranded, and it is against the law to dispense as its safety and effectiveness cannot be guaranteed. 

My personal thoughts about Apoquel

First, as mentioned above, please be sure of the disease you are recommending it for-dogs with serious pyodermas, demodicosis or neoplasia should not receive Apoquel. I have had many clients call it a “miracle drug” and, in fact, it has been for many of my 500 patients currently receiving it (Figures 3 and 4). Those patients were nonresponders to modified cyclosporine, sublingual immunotherapy or injectable immunotherapy. If other current patients are well-controlled on one of those three therapies but their owners want to switch to Apoquel because they've heard it's a miracle drug, I discourage it. If the pets are well-controlled on a therapy that we know the long-term effects of, why change? 

Figures 3 and 4. A patient, Bear, before receiving Apoquel and after. (Photo courtesy of Dr. Alice Jeromin)

As much as I am using Apoquel and monitoring my patients carefully, I am still concerned about the long-term use and adverse effects down the road. Today, everyone wants a “quick fix” and Apoquel does work quickly without the damaging effects seen with corticosteroids-and I like that. From Zoetis communication: “While we do not have long-term data on safety in a large number of dogs, we are fortunate to have the data from the CT study which we believe validates our interpretation of the very good safety profile of Apoquel and which is more than we had for Atopica when it was launched.”10

References

1. Fleck TJ, Humphrey WH, Galvan BA, et al. Comparison of the onset of anti-pruritic activity of the JAK inhibitor oclacitinib to prednisolone and dexamethasone in an IL-31 canine model of pruritus, in Proceedings. North American Veterinary Dermatology Forum, Louisville, Kentucky, 2013.

2. Cosgrove SB, Wren JB, Cleaver DM, et al. Efficacy and safety of oclacitinib compared to placebo for the control of atopic dermatitis in client-owned dogs. Vet Dermatol 2013;24(5):479-e114.

3. Apoquel package insert, Zoetis, February, 2013.

4. Freedom on information study: Original new animal drug application. NADA 141-345. Control of pruritus associated with allergic dermatitis and control of atopic dermatitis in dogs at least 12 months of age. May 14, 2013.

5. Clear V, Petersen A, Rosser Jr EJ, et al. Investigation of the effects of 30 day administration of oclacitinib (Apoquel) on intradermal and allergen-specific IgE serology testing in atopic dogs, in Proceedings. North American Veterinary Dermatology Forum, Nashville, Tennessee, 2015. 

6. Cosgrove SV, Cleaver DM, King VL, et al. Long-term compassionate use of oclacitinib in dogs with atopic and allergic skin disease: safety, efficacy and quality of life. Vet Dermatol 2015;26(3):171-179.

7. Chang CH, Dodam JR, Cohn LA, et al. An experimental Janus kinase (JAK) inhibitor suppresses eosinophilic airway inflammation in feline asthma, in Proceedings. American College of Veterinary Internal Medicine Forum, 2013.

8. Loft K, Simon B. Feline idiopathic ulcerative dermatosis treated successfully with oclacitinib, in Proceedings. North American Veterinary Dermatology Forum, Nashville, Tennessee, 2015.

9. Fleck T, Aleo M, Galvan B, et al. Oclacitinib reduces itch in a novel IL-31 induced pruritus model in the cat (abst). Vet Pharm Therapeutics 2013.

10. Hillier A. Zoetis, Florham Park, New Jersey: Personal communication, Feb. 5, 2014.

Suggested reading 

Apoquel roundtable. North American Veterinary Dermatology Forum. Nashville, Tennessee, 2015.

Data on file. Apoquel First to Know. Global. 2013. Zoetis.

Clark JD, Flanagan ME, Telliez JB, Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem 2014;57(12):5023-5038.

Hines R. Should I be giving my allergic dog Apoquel to stop its itching and scratching? 2nd chance info. Accessed: March 2015. Available at: http://www.2ndchance.info/Apoquel.htm.

Aleo M, Galvan B, Fleck T, et al. Effects of oclacitinib and prednisolone on skin test sensitivity, in Proceedings. North American Veterinary Dermatology Forum, Louisville, Kentucky, 2013.

Cosgrove S, Wren J, Cleaver D, et al. Efficacy and speed of onset of oclacitinib for the control of pruritus and associated skin lesions in dogs with canine allergic dermatitis, in Proceedings. North American Veterinary Dermatology Forum, Louisville, Kentucky, 2013.

Gadeyne C, Little P, King VL, et al. Efficacy and safety of oclacitinib compared to prednisolone for the control of pruritus and clinical signs associated with allergic dermatitis in client-owned dogs in Australia. Vet Dermatol 2014;25(6):512-e86. 

Little P, Davis K, King V, et al. Efficacy and safety of oclacitinib compared to ciclosporin for the control of atopic dermatitis in client-owned dogs, in Proceedings. North American Veterinary Dermatology Forum, Phoenix, Arizona, 2014. 

Dr. Alice Jeromin is a pharmacist and veterinary dermatologist in private practice in Cleveland. She is a graduate of The Ohio State University College of Veterinary Medicine and an adjunct professor at Case Western Reserve University's College of Medicine.