Brand Names: Atopica®, Neoral®, Sandimmune®, and Optimmune® (Ophthalmic)   

Available in 0.2% ophthalmic ointment, 10 mg, 25 mg, 50 mg, and 100 mg  capsules and as oral liquid 

Background

There are many types of cells working in the service of the body's immune system. In the lymphocyte category, some lymphocytes make antibodies (B-cells), other lymphocytes seek and destroy foreign materials (Killer T-cells), and still, other lymphocytes regulate the other cells by either suppressing them or stimulating their activity as needed (T-suppressor cells and T-helper cells, respectively).  The regulatory T-cells produce chemical messages called interleukins that tell other lymphocytes what to do. Regulatory T-cells are of special interest because if they can be directed, the immune system itself can be directed.

Cyclosporine works by changing how different interleukins are made, and targets only parts of the immune system without affecting the entire immune system. It is one type of drug that can adjust the immune response instead of just suppressing it. Drugs like cyclosporine are now used for organ transplants, treating allergies, and managing other immune-related conditions.

How this Medication is Used

The following conditions have been treated successfully using cyclosporine:

• Keratoconjunctivitis sicca (dry eye) in dogs, where topical cyclosporine has been found effective in 85% of dry eye patients. (It should be noted that dry eye in cats usually stems from Herpes conjunctivitis rather than from immune-mediated tear gland destruction, and is thus usually made worse by immune suppressants such as cyclosporine.)
• Inflammatory bowel disease
• Feline eosinophilic granuloma complex
• Sebaceous adenitis
• Perianal fistulae
• Atopic dermatitis
• Immune-mediated hemolytic anemia
• Discoid lupus erythematosus (topical use)
• Feline asthma
• German Shepherd pannus 
• Kidney transplantation
• Pemphigus foliaceus

Administration and Absorption in Cats and Dogs

You may hear the term bioavailability when learning about medications; this means how much the medication can be absorbed and used in the body. Because cyclosporine bioavailability is not optimal in the best of circumstances, it is probably best to avoid generic forms as their bioavailability has not been tested in dogs or cats. 

There are two types of oral formulas available for this medication; emulsions and microemulsions. Microemulsion formulas provide better GI (gastrointestinal) absorption.

Giving this medication with or without food differs for dogs vs. cats:

• In dogs, absorption is better when given on an empty stomach.
• In cats, absorption is the same when given with or without food.

Blood Work - Monitoring

Therapeutic blood level monitoring, or checking to make sure enough medication is being absorbed to be effective for your pet, is often recommended with oral cyclosporine use. A blood cyclosporine level test is usually checked a day or two after starting the medication, and then every 2 to 4 weeks. Your veterinarian will let you know if treatment needs to be adjusted based on these levels.

In the case of allergic skin disease, however, the blood level of cyclosporine does not matter nearly as much as the skin tissue level of cyclosporine. The problem is that there is no way to measure a skin tissue level so monitoring is generally not performed in this situation. Pets with atopic dermatitis (allergic skin disease) typically begin with once-daily usage and then taper to a schedule more like every other day or less. A response may not be evident for six weeks after starting treatment but after a response is seen, the dosing interval is decreased to determine the minimum dose needed to control symptoms. As mentioned, blood testing is not needed because it is the skin cyclosporine level that is of relevance here and there is no way to measure that.

The Ketoconazole Trick

Because cyclosporine is a relatively expensive medication, a pharmacological "trick" is often used to get a higher blood level from a lower dose. This trick involves giving the antifungal medication ketoconazole with cyclosporine. Ketoconazole interferes with the liver enzymes responsive to the removal of cyclosporine from the body. A relatively low dose of ketoconazole may allow the cyclosporine dose to be cut in half.

Side Effects

The most common side effect seen with cyclosporine is upset stomach (appetite loss, vomiting, diarrhea, or all of these). Upset stomach occurs in one dog in three, but generally resolves within one week even if the medication is continued. Some options to mitigate the upset stomach side effect include:

• Beginning with a lower dose of cyclosporine and working up to the therapeutic dose over a couple of weeks.
• Giving cyclosporine with food at least for the first two weeks in canine patients.
• Freezing the capsules.
• Giving a dose of metoclopramide 30 minutes before the cyclosporine.

Dogs infected with the papillomavirus may develop large numbers of viral papillomas (warts) while on cyclosporine.

Dogs on cyclosporine may develop a thicker coat than usual and more shedding than usual can be expected.

Other side effects reported include heavy callusing on the footpads, red/swollen ear flaps, and proliferation of the gums. When cyclosporine was discontinued, these findings either resolved or improved. The gum proliferation can be mitigated by toothpaste containing azithromycin.

Interactions with Other Drugs

Aside from the ketoconazole relationship described above, the following other drugs can increase cyclosporine blood levels:

• amiodarone (a heart medicine),
• androgens such as testosterone,
• antifungals related to ketoconazole,
• calcium channel blockers such as amlodipine, and imipenem (an antibiotic),
• certain antibiotics (metronidazole, enrofloxacin, ciprofloxacin, chloramphenicol),
• allopurinol (used for certain bladder stones),
• amlodipine (used to lower blood pressure),
• clopidogrel (a blood thinner), 
  glipizide (used to control high blood sugar),
• the antacids omeprazole, cimetidine,
• and metoclopramide (a nausea medicine).

Medications that reduce cyclosporine blood levels include:

• azathioprine and cyclophosphamide (both immune suppressive medicines), 
• famotidine (an antacid), 
• griseofulvin (an antifungal), 
• sulfasalazine and trimethoprim (both antibiotics),
• and phenobarbital (used to control seizures).

Cyclosporine can increase blood levels of digoxin, a heart medication.

Cyclosporine may decrease blood levels of:

• trimethoprim-sulfa (an antibiotic), 
• omeprazole (an antacid),
• and phenobarbital (a seizure medication).

Concerns and Cautions

It takes 4 to 6 weeks to see a response to cyclosporine with atopic dermatitis cases.

Toxoplasmosis is a common infection in outdoor cats with the infectious organism encysting harmlessly long-term in muscle and can be reactivated with cyclosporine use. Toxoplasma antibody titers should be done in cats before using cyclosporine. It is also recommended to avoid feeding raw foods and prevent hunting activities of a cat on cyclosporine to reduce parasite risk.

Cyclosporine may not be suitable for cats positive for feline leukemia or feline immunodeficiency viruses.

Cyclosporine is processed by the liver, so it should be avoided in cats with liver issues unless needed to treat a condition where the immune system causes liver scarring.

Pre-treatment blood and urine testing is recommended before an oral cyclosporine trial (but, of course, such testing would be part of a patient's normal evaluation process for most of the diseases cyclosporine might be used for).

Vaccinations may not be effective when given to patients on cyclosporine, and live vaccines should be avoided if possible.

Cyclosporine should not be used in pregnant or nursing animals. Pregnant women should wear gloves when handling this medication.

Oral cyclosporine is best avoided in patients with a history of cancer.

Atopica® is labeled for dogs over 4 lbs. only and for cats over 3 lbs. in size and over 6 months of age.

Because of the expense of cyclosporine, it is tempting to seek low-cost alternatives. Only the brand name Atopica® and brand name Neoral® (and possibly human generic versions of Neoral®) are felt to be bioequivalent. These formulas are micronized, which enables the product to be properly absorbed. Other products, including compounded ones, are not similar.

As with any drug used long-term, blood tests are recommended twice a year with long-term cyclosporine use. Your veterinarian may also recommend blood pressure checks and other testing as necessary.

Cyclosporine is best given on an empty stomach (either 1 hour before a meal or 2 hours after a meal).

Oral cyclosporine is stored at room temperature but capsules can be frozen to reduce nausea side effects. Frozen capsules are good for 28 days after freezing. The oral liquid should be used within 2 months of opening the bottle. Do not refrigerate or freeze the oral liquid. 

If a dose is skipped on an every-other-day schedule, simply give the dose when it is remembered. Do not double up on the next dose, however, and do not dose more than once daily.