Trilostane

Overview

Trilostane blocks adrenal synthesis of glucocorticoids by competitively and reversibly inhibiting the adrenocortical enzyme 3-beta-hydroxysteroid dehydrogenase, with relatively minor effects on mineralocorticoid production.

It is used for the treatment of pituitary- and adrenal-dependent hyperadrenocorticism in dogs and has also been reported to be useful in cats with hyperadrenocorticism. In dogs, it has additionally been used for the management of alopecia X syndrome.

Indications

Trilostane is used for the management of hyperadrenocorticism in dogs and cats. In dogs, it is also used for the treatment of alopecia X syndrome.

• Canine hyperadrenocorticism: Treatment of pituitary-dependent hyperadrenocorticism, and of adrenal-dependent hyperadrenocorticism when surgery is not an option.
• Feline hyperadrenocorticism: Reportedly useful for the treatment of hyperadrenocorticism; clinical signs improve but do not fully resolve, and regulation of concurrent diabetes mellitus often improves.
• Alopecia X syndrome (dogs): Used for the management of canine alopecia X syndrome.

Dosage (Reference)

Dog

Trilostane should be administered with food. Treatment should be monitored regularly, and dosage adjustments may be required based on clinical response and cortisol monitoring.

Cat

Trilostane is administered orally for the treatment of hyperadrenocorticism.

Warnings & Precautions

Trilostane should be used with appropriate clinical and hormonal monitoring throughout treatment, as dosage adjustments may be required and adrenal insufficiency may occur.

• Renal or hepatic insufficiency: Contraindicated in patients with renal or hepatic insufficiency.
• Treatment monitoring: Monitor treatment after 10 days, 4 weeks, 12 weeks, and then every 3–4 months using clinical signs together with an ACTH stimulation test or a pre-pill cortisol measurement.
• Pregnancy and breeding: Contraindicated in pregnant animals. Trilostane reduces progesterone synthesis and has caused teratogenic effects and early pregnancy loss in laboratory animals; safe use has not been evaluated in male dogs intended for breeding.
• Hypersensitivity: Contraindicated in animals that have shown hypersensitivity to trilostane.
• Risk at any dose: Hypoadrenocorticism can develop at any dose and at any time during treatment and does not appear to be dose-dependent.
• Stress and surgery: During periods of stress such as boarding or surgery, treated animals may require short-term supplementation with exogenous corticosteroids.
• Sex hormone-driven disease: Trilostane augments sex hormone accumulation, so another adrenal drug is usually preferred where adrenal hyperplasia is driven by sex hormones.
• Handling the capsules: Do not empty the capsule contents and do not attempt to divide the capsules. Wash your hands after handling this medicine.

Drug Interactions

Concurrent use of trilostane with other drugs that suppress adrenal function should be avoided due to the potential for additive adrenal suppression.

• Mitotane: Do not administer concurrently, as both drugs suppress adrenal function; wait at least 1 month after discontinuing mitotane before starting trilostane.
• Itraconazole: Concurrent administration should be avoided because itraconazole also suppresses adrenal function.
• Ketoconazole: May potentiate the effects of trilostane and lead to hypoadrenocorticism; concurrent use is not recommended.
• ACE inhibitors: May increase the risk of hyperkalemia; monitor serum potassium when the two are used together.
• Potassium-sparing diuretics and supplements: Hyperkalemia is also a risk with spironolactone, with potassium supplements and with high-potassium foods.

Side Effects & Overdose

Side Effects

Trilostane is generally well tolerated, but adverse effects associated with adrenal suppression and mild biochemical changes may occur during treatment.

• Gastrointestinal effects: In dogs, vomiting, diarrhea, lethargy and reduced appetite may occur during the first few days of treatment. They are usually mild and self-limiting, but the same signs can be the first indication of hypoadrenocorticism and should not be attributed to drug intolerance alone.
• Serum biochemical changes: Mild increases in serum potassium, bilirubin, and calcium have been reported. Trilostane may also decrease aldosterone in some dogs, in which case dehydration, weakness, hyponatremia and hyperkalemia are possible.
• Hypoadrenocorticism: Clinical hypoadrenocorticism may develop during treatment and may cause collapse or a hypoadrenocortical crisis.
• Adrenal necrosis: Reported in dogs, and it can be irreversible; affected dogs must then be managed for hypoadrenocorticism with glucocorticoid and mineralocorticoid supplementation, and death has occurred.
• Adrenal hyperplasia: Has been observed with prolonged treatment, although its clinical significance is unknown.
• Prolonged adrenal suppression: Hypocortisolemia usually resolves within 48–72 hours of stopping the drug, but suppression lasting weeks to months, and occasionally permanent suppression, can occur.
• Cats: Reported adverse effects in cats include lethargy, anorexia, dulled mentation, weight loss and pancreatitis.
• Red cell parameters: A statistically significant fall in red blood cell parameters occurred in treated dogs in the field studies, although values remained within the normal range; consider monitoring a CBC in dogs with underlying anemia.

Overdose

• Death occurred in 50% of healthy beagles administered 20.1 to 33.5 mg/kg PO twice daily for 90 days.
• If clinical signs of hypoadrenocorticism are present, treatment with corticosteroids, mineralocorticoids, and IV fluids may be required; blood pressure, hydration status, and electrolyte balance should be monitored.
• Because the drug’s effects are relatively short, monitoring of patients without complications should only be required for a few days after ingestion.
• Accidental ingestion: After a single unintended ingestion, dogs are likely to experience mild, self-limiting signs; the most frequently reported are vomiting, lethargy and diarrhea. In a review of 403 cases, fewer than 1% required veterinary treatment for trilostane toxicosis.
• Client instructions: Advise owners to stop the drug and contact the practice immediately if vomiting, diarrhea, lethargy, reduced appetite, weakness or collapse are seen.

Key Notes

• Use of the licensed product is recommended. In one evaluation, 38% of compounded batches were outside the acceptance criteria for content, ranging from 39% to 152% of the stated label, and 20% failed dissolution.
• Do not handle trilostane if pregnant or trying to conceive.
• Pharmacokinetics: Oral absorption is rapid but erratic, with peak concentrations 1.5 to 2 hours after dosing. The hepatic metabolite ketotrilostane is active and several times more potent than trilostane itself.
• Duration of action: Trilostane is short-acting, with a peak effect at about 4 hours and a duration of 8 to 10 hours, so 24-hour cortisol suppression often does not occur.
• Adrenal tumors: In dogs with an adrenal tumor, trilostane controls the clinical signs but does not shrink the tumor and the adrenal glands may enlarge during treatment; the use is palliative.
• Expected course: In pituitary-dependent disease, median survival with medical treatment (mitotane or trilostane) is about 2 years and at least 10% of dogs survive 4 years; polyuria, polydipsia and polyphagia improve in 70% to 80% of dogs.
• Timing of cortisol samples: For each patient, keep the timing of trilostane administration and of ACTH stimulation testing consistent when monitoring therapy. Pre-trilostane and 3-hour post-trilostane cortisol have been reported to correlate better with owner-assessed clinical control than the post-ACTH cortisol, although no cortisol result correlated well enough with the clinical score to be used on its own.
• Storage: Store capsules at room temperature, 25°C (77°F), with excursions permitted between 15°C and 30°C (59°F–86°F).
• Licensed status: Trilostane is approved for use in dogs and is a prescription-only medicine. It must not be used in animals that produce food.