Mitotane

Adrenocorticolytic agent Antineoplastic and adrenal suppressant

Dosage & Administration Guidelines

Species Route Dose Frequency Duration & Clinical Notes
Dog PO Induction: 25-50 mg/kg/day divided q12h or q24h; Maintenance: 25-50 mg/kg/week divided into 2-3 doses Induction: daily; Maintenance: 2-3 times per week Duration: Induction: 7-14 days (until cortisol response to ACTH is normal); Maintenance: lifelong
Notes: Administer with food to enhance absorption. Monitor ACTH stimulation test every 1-2 weeks during induction, then every 3-6 months. Adjust dose based on clinical response and cortisol levels.
Cat PO 25-50 mg/kg/day divided q12h or q24h Daily Duration: Induction: 7-14 days; Maintenance: as needed
Notes: Limited efficacy; use with caution. Monitor for adverse effects. Alternative treatments (e.g., trilostane) are preferred.

Clinical Indications & Species Uses

General Indications
  • Treatment of hyperadrenocorticism (Cushing's syndrome) in dogs
Dog (Canine)
  • Pituitary-dependent hyperadrenocorticism (PDH)
  • Adrenal-dependent hyperadrenocorticism (functional adrenal tumor)
  • Adrenocortical carcinoma (palliative treatment)
Cat (Feline)
  • Adrenocortical tumors (rarely used)

Pharmacology & Mechanism of Action

Drug Class: Adrenocorticolytic agent | Pharmacological Group: Antineoplastic and adrenal suppressant

Mechanism of Action: Mitotane is an isomer of DDT that is selectively toxic to the zona fasciculata and zona reticularis of the adrenal cortex. It inhibits adrenal steroidogenesis by blocking 11β-hydroxylation and cholesterol side-chain cleavage, leading to decreased production of cortisol, corticosterone, and aldosterone. It also causes mitochondrial damage and necrosis of adrenocortical cells, resulting in atrophy of the adrenal cortex. In functional adrenocortical tumors, it reduces tumor mass and hormone secretion.

Pharmacodynamics: Mitotane produces a dose-dependent suppression of adrenocortical function. At low doses, it inhibits cortisol synthesis without causing cell death, while at higher doses it induces adrenocortical necrosis. The drug also alters peripheral metabolism of steroids, increasing the conversion of cortisol to 6β-hydroxycortisol. Clinical effects are seen within days to weeks, with maximal adrenocortical suppression occurring after several weeks of continuous therapy. In dogs with pituitary-dependent hyperadrenocorticism, mitotane reduces cortisol secretion and improves clinical signs such as polyuria, polydipsia, and alopecia.

⚡ Pharmacokinetics Summary

Absorption: Mitotane is well absorbed after oral administration, but absorption is variable and enhanced when given with food, particularly fatty meals. Peak plasma concentrations occur within 3-5 hours.
Distribution: Mitotane is highly lipophilic and accumulates in adipose tissue and the adrenal cortex. It crosses the blood-brain barrier and is distributed widely throughout the body. It is extensively bound to plasma proteins (approximately 85%).
Metabolism: Mitotane is metabolized in the liver to two major metabolites: o,p'-DDA (dichlorodiphenylacetic acid) and o,p'-DDE (dichlorodiphenyldichloroethylene). The metabolites are less active than the parent compound. Metabolism is hepatic, involving cytochrome P450 enzymes.
Excretion: Mitotane and its metabolites are excreted primarily in the bile and feces, with a small amount excreted in urine. The drug has a long elimination half-life due to extensive tissue accumulation and enterohepatic recirculation.
Half-Life: Dogs: approximately 18-24 hours for the parent drug, but metabolites may persist for weeks. In humans, half-life is 18-159 days.
Bioavailability: Oral bioavailability is variable, estimated at 40-60% in dogs, and is increased when administered with food.
Protein Binding: Approximately 85% bound to plasma proteins.

Available Formulations & Strengths

Oral Tablet 500 mg (PO)

Contraindications & Clinical Warnings

Contraindications:
  • Hypersensitivity to mitotane or any component
  • Hepatic insufficiency (severe)
  • Renal insufficiency (severe)
  • Pregnancy or lactation (teratogenic potential)
  • Concurrent use with spironolactone (may reduce efficacy)
Warnings & Clinical Precautions:
  • Use with caution in animals with diabetes mellitus, as cortisol suppression may alter insulin requirements.
  • May cause adrenal insufficiency; monitor for signs of hypocortisolism (weakness, lethargy, anorexia, vomiting, diarrhea).
  • Induction therapy requires close monitoring with ACTH stimulation tests to avoid overtreatment.
  • Mitotane is a potential carcinogen; handle with care.
  • Use with caution in debilitated or geriatric animals.
  • May cause CNS depression; avoid use in animals with seizure disorders.
  • Safety in breeding animals has not been established.

Adverse Effects & Reactions

Common:

  • Anorexia
  • Vomiting
  • Diarrhea
  • Lethargy
  • Weakness
  • Ataxia
  • Depression

Serious / Severe:

  • Adrenal necrosis leading to hypoadrenocorticism (Addisonian crisis)
  • Hepatotoxicity
  • Pancreatitis
  • Bone marrow suppression
  • Neurologic signs (seizures, disorientation)

Rare:

  • Hyperglycemia
  • Hypoalbuminemia
  • Gastrointestinal ulceration
  • Skin reactions

Key Drug Interactions

Interacting Drug / Class Clinical Effect & Mechanism Severity
Spironolactone May reduce mitotane's adrenocorticolytic effect; avoid concurrent use. High
Corticosteroids (e.g., prednisone) May mask signs of adrenal insufficiency; use with caution. Moderate
Warfarin and other anticoagulants Mitotane may increase anticoagulant effect; monitor coagulation parameters. Moderate
Phenytoin May alter metabolism of both drugs; monitor therapeutic levels. Moderate
Insulin or oral hypoglycemics Cortisol suppression may affect glucose homeostasis; adjust insulin doses as needed. Moderate

Overdose & Toxicity Management

Signs of Toxicity:

  • Severe vomiting
  • Diarrhea
  • Anorexia
  • Lethargy
  • Ataxia
  • Tremors
  • Seizures
  • Adrenal crisis (hypotension, collapse, electrolyte imbalances)

Emergency Treatment Protocol: Induce emesis if recent ingestion and animal is conscious. Administer activated charcoal to reduce absorption. Provide supportive care: IV fluids, electrolyte replacement, and glucocorticoid supplementation (e.g., prednisone) to manage adrenal insufficiency. Monitor for hepatic and neurologic toxicity. Symptomatic and supportive treatment is essential.

Food Animal Withdrawal Times

Not approved for use in food animals; no withdrawal times established. Use in food-producing animals is prohibited.

Storage, Handling & Regulatory Information

Storage Temperature: Store at controlled room temperature 20-25°C (68-77°F)

Handling & Special Conditions: Keep container tightly closed. Protect from moisture.

Dispensing Status: Prescription Required (Rx Only)

Approval Status: Not FDA-approved for veterinary use; approved for human use (Lysodren) for adrenocortical carcinoma.

Extra-Label (Off-Label) Use: In the US, mitotane is not FDA-approved for veterinary use but is used extra-label in dogs and cats under AMDUCA. Extra-label use requires a valid veterinarian-client-patient relationship and appropriate withdrawal times for food animals (none established).

Clinical Pearls & Practice Notes

💡 Clinical Insights: Mitotane is a potent adrenocorticolytic agent primarily used in dogs for the treatment of pituitary-dependent hyperadrenocorticism (Cushing's disease). It is also used for functional adrenal tumors. Therapy is divided into an induction phase and a maintenance phase. During induction, the drug is given daily until the ACTH stimulation test shows normal cortisol levels, typically within 7-14 days. Then, maintenance dosing is initiated at a reduced frequency (e.g., twice weekly). Close monitoring is essential to avoid overtreatment, which can lead to hypoadrenocorticism. If signs of Addison's disease occur, discontinue mitotane and administer glucocorticoids. Mitotane should be given with food to enhance absorption. It is not recommended for cats due to poor efficacy and high risk of adverse effects. Alternative treatments such as trilostane are often preferred. Due to its potential toxicity, mitotane should be handled with care, and owners should be educated on the signs of adrenal insufficiency. Regular monitoring of electrolytes, liver enzymes, and cortisol levels is recommended.

References & Literature

  • 📚 Plumb's Veterinary Drug Handbook
  • 📚 Papich Veterinary Pharmacology and Therapeutics
  • 📚 Compendium of Veterinary Products (CVP)