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Is Atopica® Safe ? - Should I Give Atopica To My Dog ?
Cyclosporine=Cyclosporin=Ciclosporin=Cyclosporin A

 

Ron Hines DVM PhD

What about my cat ?

One of the greatest consternations dog owners have is a persistently itchy, uncomfortable pet. Their skin just wasn’t designed to hold up to hours of licking, chewing and scratching. In that situation, it doesn’t take long for your dog's coat to look moth-eaten and thin. More importantly, your pet’s natural skin barriers against bacteria and fungi infections are soon breached. When that occurs, dogs develop a typical musty seborrheic skin odor, sores and scabs. It is the itch that comes first – the bacteria, fungi and yeast are just opportunistic freeloaders. (ref1, ref2)

When dog owners and their veterinarians are lucky, the problem is due to fleas. Vets and owners have terrific ways to eliminate fleas these days. But more likely than not, when fleas are not the problem - or only part of the problem - your pet has developed multiple allergies (aka atopic skin disease).

If you are truly fortunate, those allergies will be due to ingredients in your dog’s diet. But contrary to what specialty dog food diet companies would have you believe, the vast majority of itchy dogs itch ( (pruritis)for reasons that have have nothing to do with what they are eating. And when food allergies are involved, they are likely to be only a small part of the pet’s general allergic condition. When food ingredients are the trigger for allergies or sensitivities, the primary target is the intestine (diarrhea), not the skin. The much most common form of allergic skin disease in dogs is due to allergies to the ordinary contaminants in your pet’s environment – contaminants that are nearly impossible to eliminate. That said, dogs with tendencies toward multiple environmental allergies almost always itch violently after being bitten by a flea.

When we humans develop allergies to environmental contaminants, things like pollen, mold, dust mites and the like, the primary target is our respiratory system. We sneeze, our eyes water, our nose is congested, we sniffle. That is because most of the histamines and other mediators that produce inflammation are released by the mast cells present in our respiratory system. (ref1, ref2) But dogs are different. When they have allergies, these same inflammatory chemicals are released primarily in their skin. That is what causes them to itch. (ref1, ref2)

When veterinarians are faced with allergic/atopic pets, the first things they often dispense are soothing medicated shampoos and lotions. Itching is a self-perpetuating habit. If your pet’s problem was a one-time thing, if it is relatively minor or if it is seasonal , perhaps those products, along with some oral antihistamines, will take care of the problem.

But with the passage of time, itching problems that are related to true allergy tend to return and become worse. Or itch problems that were once seasonal inconveniences become an all-the-time problem. In those cases, your veterinarian might suggest blood-based allergy testing (ref) or one of the many prescription low-antigen diets most vets keep in the back room. Occasionally, that approach is successful - but more often, it is not.

Perhaps your veterinarian might have then dispensed an oral corticosteroids or given a corticosteroids injection to your pet. That probably did produced a dramatic improvement ! Your dog stopped itching – for a while. But it may have also peed more, ate more and gained weight. Your veterinarian was probably reluctant to repeat that therapy, telling you about the serious side effects of prolonged corticosteroid use. You probably already knew that anyway. But it is so terribly difficult to live with an itchy dog. Your dog is family and you know how uncomfortable it must feel. So you might have talked your vet into repeating the steroid treatment now and then.

Veterinarians all know that the effects of corticosteroids like prednisone against allergic itching is dramatic. These drugs mimic the effects of the natural corticosteroids produced every day by your dog’s adrenal glands. Corticosteroids inhibit your dog's mast cells from releasing histamine - even when the things in your dog's environment that it is allergic to are present. (ref) Besides weight gain, prolonged corticosteroid use can lead to decreased strength of the binding protein (collagen) that hold the body together. Prolonged use thins the skin, increased blood glucose and circulating lipids (fats) that negatively affect your pet’s pancreas and liver. And those are only a few of the undesirable things that long-term corticosteroid used can cause. Increased susceptibility to infection is another. So you can see why most veterinarians try so hard to give their clients alternative options.

 

 

It is not that corticosteroids are evil. There are very important uses for them in our dogs and cats. Dogs with many forms of lupus (autoimmune disease) have very few alternative medicines to help them. Corticosteroids can also be life saving during episodes of anaphylaxis (shock). When they are included in the topical products your veterinarian dispenses for itching, they are often in a less absorbable form that is likely to cause fewer systemic (whole body) side effects (eg clobetasone). (ref) When corticosteroids are in the drops your veterinarian prescribes for ear infections, they sooth and decrease inflammation and self trauma long enough for the antibiotics in the products to have time to work.

What is Atopica® ?

The lack of good options for the long-term control of canine allergic dermatitis or atopy led Novartis Pharmaceutical Co (now an Elanco product [ref]) to apply for an FDA permit to market cyclosporin for canine itching under the trade name, Atopica. Their request was approved in August, 2003. You can read the package insert here.

Cyclosporin is a compound that occurs naturally in a particular fungus. Sandoz found the fungus growing in soil samples from Wisconsin and Norway. They were looking for new antibiotics. Fungi often produce novel antibiotics (eg penicillin) to defend themselves. Sandoz found that cyclosporin did have weak antibiotic properties; but not enough to pursue the drug for that use. However, they noticed that the drug was also immunosupressive in laboratory rodents. Because of that, it has since become useful in treating a wide variety of autoimmune diseases in people (due to an out of control immune system) and in fighting the body's rejection of transplanted organs (kidneys, liver, heart & bone marrow transplants) through the drug's ability to limit the effectiveness of the body's immune system. (chiefly by inhibiting T-lymphocytes)

How Does Atopica Work ?

The body’s allergic process is extremely complicated. All allergy is an immune system mistake. Sentry cells in the system have mistaken something harmless in the environment for something dangerous to the body. The system consists of many different cells, transmitter chemicals and processes; but here is my simplified explanation:

Allergies are caused by unnecessary antibodies - antibodies your dog produces against compounds in its environment (like mold, house, dust mites or pollen) that would ordinarily be ignored. Your dog itches because those antibodies cause mast cells in its skin to release histamines. Those histamines produce inflammation that irritates the nerve endings in your dog’s skin. Mildly irritated nerve endings itch - severely irritated nerve endings are painful. It does not cause the skin damage, hair loss and skin infections that you observe – the dog does that to itself by scratching.

Cyclosporin (Atopica) interferes with this extremely complex process. It prevents a certain specific group of lymphocytes (immune system cells) the helper T- lymphocytes , from transmitting chemical messages (calcineurin / interleukins) that result in histamine release from your dog's skin mast cells. Without released histamine, your pet does not itch. You can think of helper T-lymphocytes as the policemen of the body – always looking for intruders and blowing their whistle when they find them.

Will Atopica Stop My Dog From Itching And Scratching ?

Yes.

Atopica is usually just as effective as corticosteroids in reducing inflammation and stopping itch.

Atopica is sold in four-size capsules that should be given to dogs with an empty stomach. Veterinarians generally dispense the medication for daily use until substantial improvement in itching is noticed (about 3-6 weeks). When that happens, the dose frequency is reduced to every second day. If that is sufficient in stabilizing your pet, your veterinarian may try to give Atopica even less frequently – perhaps every 3-4 days.

Not all dogs absorb Atopica or maintain blood levels of the drug equally well. Some veterinarians will follow these levels with periodic blood tests and adjust their dose schedule accordingly. (ref) Others vets do not believe that blood levels accurately predict concentration of the medication in the skin itself and make their adjustments based on the positive response they see (less itching, improved skin). I am in the second group.

Does Atopica Have Less Long Term Side Effects Than Corticosteroids Like Prednisone ?

No.

Although there are dogs, like people, who handle one medication better than another, the potential long-term side effects of Atopica are at least as severe as those of corticosteroids. They are just different side effects. These side effects might take longer to occur and they might not be as readily apparent to you at first. You can read about some of those serious side effects when they occur in humans here. When given to cats subsequent to a kidney transplant, the odds of them developing cancer increased by 18.3%. (ref)

It is not at all clear that you pet will do any better long-term on Atopic than it would on a wisely-thought-out program of intermittent corticosteroid (prednisone, etc.) use combined with less severe options that include topical products, nutritional management and physical intervention. (ref) Cyclosporin can also be hard on the kidneys. (ref) However, dogs receiving cyclosporin are considerably less likely to gain weight than those receiving corticosteroids. Veterinarians and dog owners have quite a few options in dealing with overweight dogs. (ref) But we have nothing that will heal damaged kidneys. (ref)

Can You Tell Me More About These Specific “Dangers” You Mentioned ?

The Potential Immediate Side Effects

The majority of dogs that receive a proper Atopica dose do not experience any noticeable side effects. About 30% do experience vomiting, loss of appetite, GI upsets or diarrhea. When your pet begins the drug, if you start the first week at a lower than label-suggested dose you can often avoid those issues. If not, immediate side effects, when they occur, often lessen or disappear after the dog has been on the medication for a week or two.

Since most dogs seem to handle the drug just fine, owners are usually quite satisfied with their pet’s lack of itching and the lack of the weight gain and frequent urination that often accompanies corticosteroid use.

Atopica can, on occasion, cause inflammation of skin and gums So some dogs develop thickened, swollen gums (epulis, gingival hyperplasia). (ref) Others develop reddened or tender ear flaps and some develop thickened foot pads (calluses, epidermal hyperplasia, hyperkeratosis).
Some dogs appear to shed more hair while on cyclosporin.

The Potential Long-term Side Effects Of Atopica

Veterinarians like myself have no problem telling you what the immediate side effects of Atopica are. When they occur they are quite obvious. It is harder for us to tell you what the long-term consequences of keeping your pet on this drug might be. That is because it is very difficult to prove that any new health issue your pet experiences is do to the cyclosporin and not some other health issue. I mentioned that allergies are faulty decisions made by your dog's immune system. Immune systems prone to one judgment error might be prone to another without Atopica playing a part.

However, the same cyclosporin (Neoral), produced by Novartis (Sandoz) has been used in humans since 1983. There is a larger body of information on its long-term side effects in people and there is no reason to believe that these documented side effects would be very different in dogs. That is why many of my reference links and warnings are based on human studies, not dog studies that have yet to be performed.

I explained earlier that Atopica works by disrupting the activity of your pet’s immune system. That, unfortunately, is a double-edged sword. The same helper T-cell policemen that I told you about earlier – the ones whose activities are disrupted by Atopica, are the officers that patrol your pet’s body for invading bacteria, and other pathogens. More concerning to me, these are the same policemen cells that keep a lookout for abnormal body cells – the ones that later give rise to cancer. Atopica is not at all selective as to which helper T-cell job or activity it blocks. It blocks them all. None of the drugs in the cyclosporin/Atopica class generate cancer. But they all weaken the portions of the immune system that are responsible for nipping cancers in the bud. We and our dogs all give rise to occasional mutant (precancerous) cells. Most biologists believe that a vibrant (strong) immune systems usually detect and destroy these mutated cells before a tumor can form. (ref)

Potential Effects On Your Pet’s Kidneys

A second potential problem with Atopica is that the calcineurin messenger compounds (rptref) that it blocks are also found in your pet’s kidneys. So Atopica has the potential to damage kidneys as well. You can read about that here , here and here.

Potential Effects On Your Pet’s Liver

Cyclosporin appears to also have the potential to injure the liver. The liver is a very vascular (blood-filled) organ and cyclosporin damages microcirculation in many organs. (ref1, ref2)

Ear Infections

An increase in the number of ear infections (otitis externa) appears to occur in dogs receiving cyclosporin/Atopica. It is hard to sort out why that might be. Most dogs with chronic skin allergies already have associated ear problems. It could be that rather than causing the problem, cyclosporin only weakens the pet’s natural immune defenses that are keeping those infections at bay. Whether the swollen ear flaps sometimes seen with the drug's use are due it its effect on skin or reactivated ear infections and increased ear scratching is unknown.

Increased Number Of Tumors

I already mentioned that cyclosporin is known to increase the incidence of cancer in humans. (ref1, ref2) As dogs age, they too develop abnormal, precancerous cells throughout their bodies – we all do. We all rely on those immune system policemen cells to locate those precancerous cells and destroy them through a process called apoptosis. (ref) Dogs and humans receiving cyclosporin are not as effective in doing that. (ref) Novartis acknowledges that dogs on Atopica run a greater risk of developing cancers. They explain that as the drugs ability to “exacerbate sub-clinical neoplastic conditions". But they give no explanation as to how they came to the convenient conclusion that no really new tumors were formed.

Leukemias and lymphomas are lymphocyte tumors. They increase in frequency in humans receiving cyclosporin. There are reports that lymphomas increase in frequency in dogs receiving cyclosporin as well. Novartis reported to the FDA that the lymph nodes of dogs receiving Atopica became enlarged in 2.3% of the dogs receiving the drug for 28 days. Lymph node enlargement (lymphadenopathy), when not related to infection, is often a prelude to lymphoma.

Effect On Blood Capillaries

Some of the potential side effects of cyclosporin are due to its ability to cause injury to the lining of small blood vessels found throughout your pet's body. (ref) That is sometimes referred to as its potential for "vasculotoxicity".

Increased Susceptibility To Infections In General


Dogs and humans receiving cyclosporin appear to have reduced ability to fight infections of all kinds. That includes bacterial and fungal skin infections and urinary tract infections.

Dogs and cats can have infections and parasites that you and your veterinarian are not aware of - but that are being kept under control by the pet's healthy immune system. If you weaken that system with medications like cyclosporin/Atopica, the animal's body can loose its ability to keep the situation under control. Toxoplasma is one of those parasites, you can read about what happened to two cats when they were given cyclosporin here. You can read another 2011 report of the worrisome number of side effects associated with the use of this drug in cats here.

Neurotoxicity

Some dogs receiving Atopica appear weaker than usual – particularly in their hind legs. It is very hard to judge the causes of generalized weakness in pets. Sometimes a dog just not feeling well can be misinterpreted as weakness. But cyclosporin is known to occasionally produce muscular weakness and nerve dysfunction in human beings, perhaps in our pets as well. (ref)

Potential Effects On The Pancreas

Cyclosporin also has the capacity to lower your dog’s ability to produce insulin , and in doing so, interfere with blood sugar metabolism. (ref)

Increased Number Of Warts (papillomas)

Veterinarians have noticed that some dogs receiving Atopica grow more warts. Warts on dogs are benign skin tumors caused by a virus (ref) (canine papilloma virus). (ref) Some believe that this same virus might even be involved in the other skin thickening and inflammation problems occasionally seen in dogs receiving cyclosporin (ref)

What Should I Do ?

As you probably already guessed, I am not a fan of this drug. I see few, if any, advantages in giving your dog Atopica/cyclosporin over giving it periodic and carefully monitored corticosteroids. Both offer equal relief. They just differ in their major negative side effects. Those side effects can be substantial when giving either drug.

My suggestion in 2019 is that you explore giving your dog Cytopoint® rather than Atopica or corticosteroids. Cytopoint interrupts the itch cycle in a more focused and precise way than either Atopica or corticosteroids. So far, my feedback from dog owners that use Cytopoint have been generally good. (ref)

Can I Use Less Expensive Generic Drugs Similar To Atopica ?

Naturally, Novartis/Elanco does not like that idea. You can contrast their statements with those of the FDA here , and you can read about Teva’s generic equivalent here. There is no published data that I know of comparing the two products. But many pet owners seem equally satisfied with the results they obtain from the generic and the name-brand forms; and many people who have had kidney transplants trust their lives to the same generic cyclosporin.

Are There Dogs In Which Atopica Should Be Used With Considerably More Caution Than Others ?

Atopica should be used with caution in all dogs. But since the drug is removed from your pet’s body by its liver, dogs with liver disease should not receive it. Nor would I use Atopica in dogs with even the slightest evidence of kidney disease, heart disease, certain blood disorders or potentially malignant cancers. Those are my personal feelings. I am, by nature, cautious. There are many veterinarians whose approach would be different than mine.

What Should My Veterinarian Monitor While My Pet is Taking Atopica ?

Your veterinarian needs to run blood tests before dispensing Atopica to be sure your pet does not have any hidden kidney, liver or heart problems or evidence of early cancer.
Then your veterinarian needs to monitor your pet’s kidneys, liver and heart while it is on the medication. You need to be aware that negative effects of cyclosporin sometimes appear in humans long after the drug was discontinued. I would suggest that blood tests be run one month and two months after the first dose to screen for acute problems and twice a year thereafter.

Checking for the potential of cancer is much harder. Novartis hints that when cancer occurs in pets taking Atopica, it only speeds the growth of cancers that are already present. That is not based on any scientific information I am aware of. Veterinarians do not have screening tests, short of biopsies from every organ, that might detect early cancer. About the best we can do is monitor your pet’s superficial lymph node size, and check its blood for the presence of any abnormal cells (Pre-leukemic syndrome). That only directly detects tumors of the lymphatic system and blood. Periodic x-rays or ultrasound examinations might also be helpful in select cases.

Since kidney damage is the most frequent serious side effect in humans taking cyclosporin, it would be wise to periodically have your dog's urine and blood checked to keep tabs on its kidney function. I do not believe that making decisions based on the pet's blood BUN and creatinine levels while on the medication are sufficient. By the time those values rise, the pet’s kidneys are already severely damaged. The tests that pick up ongoing kidney damage earliest are the urine protein:creatinine ratio and the urine microalbuminuria test. You can read about them here. These are the same monitoring tests suggested for humans taking cyclosporin. SDMA results are too erratic to be of much help.