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Mitotane for Veterinary Use
by Barbara Forney, VMD
Mitotane is an adrenal cytotoxic drug that is derived from the insecticide DDT. It commonly is used to treat PDH in dogs. Mitotane causes severe, progressive, cellular necrosis of the zona fasiculata and the zona reticularis. To a much lesser degree it also may affect the zona glomerulosa. Mitotane also may inhibit adrenocortical function without causing cell death, although in this case the mechanism of action is not known. Mitotane is stored in body fat, metabolized by the liver and excreted in both bile and urine.
Cushing’s Disease is one of the most common endocrine disorders in dogs and within that group, 80-85% of the dogs have PDH, while the remaining 15% have a functional adrenal tumor. Mitotane is a commonly used treatment for PDH in dogs and approximately 80% of dogs with PDH will respond favorably to treatment. There are two different basic protocols for using mitotane in dogs with PDH. The traditional and more commonly used protocol has an induction period of about seven to 10 days followed by weekly treatments. The second protocol is a medical adrenalectomy using mitotane to destroy the adrenal cortex with the commitment to lifetime supplementation.
In the traditional protocol, about 25% of dogs will experience some adverse side effects during the induction phase. These usually occur when the plasma cortisol decreases too rapidly or is less than 1 microgram/dl. Small dogs, particularly those weighing less than 5kg, are more likely to experience adverse side effects. There are different schools of thought regarding the use of exogenous prednisone during the initial treatment. The rational for this practice is to reduce the possibility of side effects due to the rapid decline of endogenous steroid.
There is a great deal of individual variation in sensitivity to mitotane; owners will need to be educated to possible signs of hypoadrenocorticism. Dogs that are being treated for PDH will require medication and monitoring for the rest of their lives. Most dogs will require gradually increasing doses of mitotane in order to remain in remission. The oral absorption of mitotane is poor. It is enhanced by giving the drug with food, particularly food with a high fat or oil content. Some clinicians recommend coating the pill with vegetable oil before giving with a meal.
Trilostane is the drug of choice for dogs that either do not respond to or do not tolerate mitotane.
Although mitotane has been used in cats, it rarely is effective. The treatment of choice in cats is adrenalectomy and supplementation with mineralocorticoids and glucocorticoids.
Mitotane Side Effects
The likelihood of side effects may be decreased by dividing the daily dose and administering at eight to 12 hour intervals. The most common side effects include lethargy, gastritis, anorexia, vomiting and diarrhea. Although less common, hypoadrenalcorticism and an addisonian crisis also are potential side effects. In rare instances, dogs may experience central nervous system (CNS) signs, ataxia, weakness and seizures.
- Animals with diabetes mellitus may have rapidly changing insulin requirements during the induction period. They should be closely monitored until they are in stable remission.
- Mitotane should be used with additional caution in animals that have decreased kidney or liver function. They may require additional monitoring. Histologic changes to the liver have been reported in dogs given mitotane.
- Mitotane should not be given to dogs that are not eating well.
- Many clinicians dispense prednisone to the clients for use in an emergency. Clinical improvement should be seen within hours of the administration of prednisone.
- Hypoaldosteronism also may occur in some animals. If hyponatremia and hyperkalemia are found, supplementation with mineralocorticoids may be warranted.
- One might consider expanding pituitary microadenoma as a differential diagnosis in animals that persist with CNS signs after discontinuing mitotane.
- Clients should be instructed to wash their hands and/or to wear gloves when handling mitotane due to toxicity concerns.
- Mitotane will have additive effects when combined with other CNS depressant drugs.
- Due to the induction of hepatic microsomal enzymes, phenobarbital metabolism is affected by mitotane and, conversely, mitotane metabolism is affected by phenobarbital.
- Treatment of PDH with mitotane may change the insulin requirements in diabetic dogs.
- Spironolactone blocks the action of mitotane.
Mitotane has both a long half-life and is toxic to the adrenals. If recognized promptly, overdose should be treated aggressively with gut emptying protocols, activated charcoal and a cathartic. The patient should be followed closely and receive corticosteroids as necessary.
About the Author
Dr. Barbara Forney is a veterinary practitioner in Chester County, Pennsylvania. She has a master's degree in animal science from the University of Delaware and graduated from the University of Pennsylvania School of Veterinary Medicine in 1982.
She began to develop her interest in client education and medical writing in 1997. Recent publications include portions of The Pill Book Guide to Medication for Your Dog and Cat, and most recently Understanding Equine Medications published by the Bloodhorse.
Dr. Forney is an FEI veterinarian and an active member of the AAEP, AVMA, and AMWA.
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