Cyclosporine

(for veterinary information only)

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, there are "B-cells" which produce antibodies and "T-cells" which are further categorized as "T-suppressor cells," " T-helper cells," and "killer T-cells." When T-cells are stimulated, they may help stimulate other T or B-cells, may suppress other T or B-cells, or may regulate the killer T-cells which then migrate through the body seeking cells which should not be there (cancer cells, viral infected cells, cells left behind by biting insects or predators). The biochemicals secreted by T-cells as messages to one another are called "interleukins." There are as many types of interleukins are there are types of messages to send between immune cells.

Cyclosporine, sometimes referred to as "cyclsporin A," is an immunosuppressive agent produced by the soil fungus Beauveria nivia. It initially attracted the interest of the medical community in the management of organ transplant patients, as its mechanism of immune suppression is unique. Unlike other medications of immune suppression which act by killing cells of the immune system, cyclosporine acts by interfering with helper T-lymphocyte interleukin production. Without interleukins, T-cells cannot communicate with one another and ultimately killer T cells are not armed and sent out to destroy the donated organ.

The veterinary profession came to become most interested in cyclosporine when it was found to relieve the symptoms and discomfort associated with "Dry Eye" (keratoconjunctivitis sicca). Dry Eye (also called "KCS") is a common problem in smaller breed dogs when tear production is lost due to immune-mediated inflammation in the tear glands. A commercial eye ointment was quickly marketed (Optimmune®) and found effective in approximately 85% of KCS patients. Cyclosporine has since been found effective in numerous inflammatory conditions of the canine cornea with effects confined to the eye and minimal absorption into the body.

Cyclosporine has been used in more serious immune-mediated diseases (see below) but the most recent application of cyclosporine involves the treatment of atopic dermatitis(itchy skin due to airborne allergens). Dogs with this type of allergy are very itchy and completely depend on medications for symptomatic relief. Previously corticosteroids such as prednisone, dexamethasone, and triamcinolone have been used to control itching but long term use has been problematic due to side effects. The release of oral cyclosporine for this use may spare many dogs some unpleasant hormonal side effects.

HOW THIS MEDICATION IS USED

The following conditions have been treated successfully using cyclosporine:

When cyclosporine is used orally, two different formulations are available: emulsion and microemulsion. It is probably best not to use formulations other than the microemulsion as they provide the best absorption from the GI tract. Absorption from the GI tract is an issue with cyclosporine and even microemulsification provides only 23-45% bioavailability, better absorption occurring on an empty stomach. Because bioavailability is not optimal in the best of circumstances, it is probably best to avoid generic cyclosporines as their bioavailability has not been tested in dogs or cats.

Cyclosporine is generally given once or twice daily depending on the disease being treated. Dogs with atopic dermatitis begin with once daily usage and then taper to a schedule more like every other day or less. Because the dose one swallows orally does not reliably produce a predictable blood level, therapeutic blood level monitoring is often recommended with oral cyclosporine use. A blood cyclosporine level is usually checked a day or two into therapy and then every 2-4 weeks. The lowest blood level of the day should be 100-500 ng/ml in dogs and 250-1,000 ng/ml in cats, though this in some part depends on the laboratory running the test. In using cyclosporine for the treatment of atopic dermatitis, blood levels are generally not monitored because it is the concentration of drug in the patient's skin (not the blood) which is pertinent and there is no way to measure skin levels of cyclosporine.

Because cyclosporine is a relatively expensive medication, a pharmacological "trick" is often employed get a higher blood level from a lower dose. This trick involves concurrent use of the antifungal ketoconazole. Ketoconazole interferes with the liver enzymes responsive for 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. Alternatively the drug administration frequency can be dropped until the GI issues resolve and then brought back up to the more usual dose.

Dogs infected with the papilloma virus may develop large numbers of 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.

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, imipenem (an antibiotic), erythromycin (an antibiotic), and metoclopramide (a nausea medicine).

Cyclosporine can increase blood levels of digoxin.

Cyclosporine may decrease blood levels of trimethoprim-sulfa (an antibiotic), omeprazole (an antacid), or phenobarbital (a seizure medication).

CONCERNS AND CAUTIONS

It takes 4-6 weeks to see a response to cyclosporine in the treatment of atopic dermatitis.

Toxoplasmosis is a common infection in outdoor cats with the infectious organism encysting harmlessly long term in muscle. This infection can be reactivated with cyclosporine use. Toxoplasma antibody titers should be performed in cats prior to cyclosporine use. It is also recommended to avoid feeding raw foods and to curtail the hunting activities of a cat taking cyclosporine (to reduce the risk of parasitism).

Cyclosporine is removed from the body by the liver and is best avoided in patients with liver disease, unless it is needed to treat an immune-mediated scarring process. A pre-treatment blood and urine database are 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 "take" when given to patients on cyclosporine. It has also been recommended that modified live vaccines not be given to patients on cyclosporine lest an active infection of the disease vaccinated against be induced. This has never actually happened but is theoretically possible.

Cyclosporine should not be used in pregnancy or lactation.

As with any drug used long term, blood panels are recommended twice a year with long term cyclosporine use. In humans, cyclosporine has induced high blood pressure so many veterinarians recommend that a pet's blood pressure be checked at the time of basic blood testing.

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

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

Atopica, the Novartis product, is labeled for dogs over 4 lbs only. Use in cats or in smaller dogs or dogs under age 6 months is considered "off label" and has not been approved by the FDA.

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

Page last updated: 1/19/2012