Prescriber Highlights -
- Adrenal cytoxic agent used for medical treatment of
- Caution: pregnancy, diabetes, and preexisting renal or hepatic
- Adverse Effects: Lethargy, ataxia, wekness, anorexia, vomiting,
liver changes possible.
- Relapses are not uncommon
- All dogs receiving mitotane therapy should receive additional
supplementation if undergoing a stress (e.g., surgery, trauma, acute
- Monitoring is mandatorty
- Avoid human exposure
- Drug interactions
Mitotane, also commonly known in veterinary medicine as
structuarally related to the infamous insecticide, chlorophenothane (DDT). It
occurs as a
white, crystalline powder with slightly aromatic odor. It is practically
insoluble in water
and soluble in alcohol.
While mitotane is considered an adrenal cytotoxic agent,
can also inhibit adrenocortical function without causing cell destruction.
the exact mechan-
nisms of action for these are not clearly understood.
In dogs with pituitary-dependent hyperadrenocorticism (PDH),
mitotane has been dem-
onstrated to cause severe, progressive necrosis of the zona fasciculata and
These effects occur quite rapidly (usually within 5-10 days of starting
therapy). It has been
stated that mitotane spares the zona glomerulosa and therefore aldosterone
synthesis is un-
affected. This is only partially true, as the zona glomerulosa may also be
affected by mi-
totane therapy, but it is uncommon for clinically significant effects on
tion to be noted with therapy.
Inveterinary medicine, mitotane is used primarily for the
treatment of pituitary-dependent hyperadrenocorticism (PDH), principally in the
has also been used for the palliative treatment of adrenal carcinorma in humans
Mitotane is contraindicated in patients known to be hy-
persensitive to it. Patients with concurrent diabetes mellitus may have rapidly
insulin requirements during the initial treatment period. these animals should
monitored until they are clinically stable.
Dogs with preexisting renal or hepatic disease should receive
the drug with caution and
with more intense monitoring.
some clinicians recommend giving prednisolone at 0.2
mg/kg/day during the initial
treatment period (0.4 mg/kg/day to diabetic dogs) to reduce the potential for
from acute endogenous steroid withdrawal. Other clinicians have argued that
administering steroids masks the clinical markers that signify when the endpoint
apy has been reached and must be withdrawn 2-3 days before ACTH stimulation
be done. Since in adequately observed patients, adverse effects requiring
therapy may only be necessary in 5% of patients, the benefits of routine
administration may not be warranted.
For medical treatment of
pituitary-dependent hyperadrenocorticism (bilateral adrenal
hyperplasia): NOTE: The information
provided below (in :a and b:) is a synopsis of the
authors' treatment protocols. It is
strongly recommended to refer to the original refer-
ences and read the entire discussion
before instituting therapy for the first time.
Initiate therapy at home (preferably on a Saturday): 50 mg/kg divided twice a
day, PO with food. Do not give glucocorticoids, but owner should have a small
supply of prednisolone. Give until one of the following occurs: Polydipsic dogs
consume less tha 60 ml/kg/day of water; dogs with excellent appetite takes 10-
30 minutes longer than before mitotane therapy to consume meals (feed two
small meals twice daily ); dog comits, is listless, or has diarrhea. Beginning
3rd day of therapy, contact owner daily to monitor the situation and encourage.
If dog develops GI upset 3-4 days after starting therapy, evaluate and either
temporarily halt therapy or divide dosage further.
after 8-9 days after therapy initiated, the dog should be evaluated and history
and physical repeated, ACTH response test, BUN, serum sodium potassium
redone. If the dog has responded clinically, stop mitotane until ACTH response
test can be evaluated. If the response test yields normal or high cortisol
mitotane is continued (generally for 3-7days). Repeat ACTH response test
every 7-10 days until a low post-ACTH cortisol level is obtained. Most dogs
respond during 7-10 days and nearly all respond by the 16th day of ther-
Maintenance therapy: Dogs who have responded to mitotane within 10 days of
initiation receive 25 mg/kg every 7 days. Recheck ACTH response every 1-3
months. Those taking longer than 10 days to respnd, receive 50 mg/kg weekly.
If ACTH-stimulated cortisol levels begin to increase, mitotane dosage should be
increased. Dogs with recurrent signs and symptoms of PDH or post ACTH cor-
tisol values of >5 micrograms/dl, should undergo daily therapy as outlined
above. These animals should also be evaluated for other conditions (e.g., renal
disease, diabetes mellitus). Should anorexia and listlessness be seen with low
plasma cortisol levels, reduce dosage. (Feldman 1989) Note: A more recent ref-
ference by the same author with similar recommendations is (Feldman 200)
b) 40-50 mg/kg/day
with food until serum cortisol reaches the normal resting
range (usually takes 7-10 days). Once adrenal reserve is appropriately reduced,
continue at 50 mg/kg/week in 2-3 divided dosages. See full reference for more
specific details regarding dosage adjustments and monitoring of therapy.
causing complete destruction of the adrenal cortex as an alternative
to the traditional mitotane treatment: Mitotane at 75-100 mg/kg per day for 25
consecutive days, given 3-4 doses per day with food. Lifelong prednisone at
0.1-0.5 mg/kg PO twice daily initially and mineralocorticoid therapy is begun at
25-day protocol. Relapse is common and periodic ACTH stimulation testing is
necessary. May be considerably more expensive than traditional therapy be-
cause of the expense associated with treating Addisonian dogs.
d) For total
adrenal ablation for managment of Cushing's: Mitotane 100
mg/kg/day divided bid for 30 days. Supplement cortisone acetate 2 mg/kg/day
daily are begun on day 1 of mitotane therapy. Diet is supplemented with 1-5
grams of sodium chloride per day. One week after induction phase with mito-
tane, cortisone acetate is reduced to 1 mg/kg/day. Electrolytes and ACTH
stimulation test are performed at end of induction, every 6 months, and at any
time animal demonstrates signs compatible with either hypo- or hyperdreno-
corticism. This form of management requires close patient monitoring and life-
long daily therapy. Close attention during stress and non-adrenal illnesses re-