Trilostane (Vetoryl)

Trilostane, marketed under the brand name Vetoryl, is the only FDA-approved medication for the treatment of hyperadrenocorticism (Cushing's disease) in dogs in the United States. This synthetic steroid analog works by inhibiting key enzymes involved in cortisol production in the adrenal glands, effectively reducing the excessive cortisol levels that characterize Cushing's disease. Since its approval for veterinary use, trilostane has become the most commonly prescribed medical treatment for canine Cushing's disease, offering effective control of clinical signs with a generally favorable safety profile when properly monitored.

The mechanism of action of trilostane involves competitive inhibition of the enzyme 3-beta-hydroxysteroid dehydrogenase (3β-HSD), which is essential for the synthesis of cortisol and other steroid hormones in the adrenal cortex. By blocking this enzyme, trilostane reduces the adrenal glands' ability to produce cortisol, thereby lowering circulating cortisol levels without destroying adrenal tissue. This mechanism is importantly reversible, meaning that if the medication is discontinued, the adrenal glands can resume normal cortisol production once the drug effect wears off. This reversibility provides a safety margin compared to adrenolytic medications that permanently destroy adrenal tissue.

Trilostane is formulated as capsules in multiple sizes designed specifically for veterinary use, allowing for precise dosing across the wide range of dog sizes. The medication is typically administered once daily with food to enhance absorption, though some dogs may require twice-daily dosing for optimal control. The capsules should be swallowed whole and not opened or crushed. Treatment with trilostane is intended as long-term or lifelong therapy, as Cushing's disease is a chronic condition requiring ongoing management to control clinical signs and prevent complications.

The safety profile of trilostane is generally favorable when the medication is used appropriately with regular veterinary monitoring. The most significant potential adverse effect is excessive suppression of cortisol production, which can cause signs of adrenal insufficiency. However, because trilostane's effect is reversible, discontinuing the medication allows cortisol levels to recover, typically within hours to days. Regular monitoring through ACTH stimulation testing and clinical assessment is essential for safe and effective therapy. When properly managed, most dogs with Cushing's disease experience significant improvement in quality of life with trilostane treatment.

The primary indication for trilostane in dogs is the treatment of hyperadrenocorticism, commonly known as Cushing's disease or Cushing's syndrome. This common endocrine disorder of middle-aged and older dogs results from chronic overproduction of cortisol, leading to a range of clinical signs that significantly impact quality of life. Trilostane is FDA-approved for treatment of both pituitary-dependent and adrenal-dependent hyperadrenocorticism in dogs, making it the only medication specifically approved for this use in the United States.

Pituitary-dependent hyperadrenocorticism (PDH) accounts for approximately 80 to 85 percent of canine Cushing's disease cases. In PDH, a tumor in the pituitary gland secretes excessive adrenocorticotropic hormone (ACTH), which overstimulates the adrenal glands to produce cortisol. Trilostane effectively controls PDH by limiting the adrenal glands' ability to respond to the excess ACTH stimulation, regardless of how much ACTH is being produced by the pituitary tumor. Most dogs with PDH show good clinical response to trilostane therapy.

Adrenal-dependent hyperadrenocorticism (ADH) results from tumors within the adrenal gland itself that autonomously produce cortisol without requiring ACTH stimulation. This form accounts for approximately 15 to 20 percent of Cushing's cases. While surgical removal of the adrenal tumor may be the preferred treatment when feasible, trilostane provides effective medical management for dogs with inoperable tumors or when surgery is not an option. The medication works equally well for suppressing cortisol production from adrenal tumors as from ACTH-stimulated hyperplasia.

The clinical signs of Cushing's disease that trilostane therapy aims to control include polyuria and polydipsia (increased urination and thirst), polyphagia (increased appetite), abdominal distension (pot-bellied appearance), bilateral symmetric alopecia (hair loss), thin skin, muscle weakness and atrophy, lethargy, panting, and recurrent skin or urinary tract infections. Without treatment, dogs with Cushing's disease are also at increased risk for serious complications including diabetes mellitus, hypertension, pancreatitis, and thromboembolism. Effective treatment with trilostane typically produces noticeable improvement in clinical signs within weeks to months.

The selection of trilostane as the treatment of choice for canine Cushing's disease is based on its efficacy, relative safety when properly monitored, FDA approval status, and reversible mechanism of action. Compared to mitotane, the older treatment option, trilostane offers the advantage of not permanently destroying adrenal tissue, allowing for dose adjustments and treatment discontinuation without irreversible consequences. The availability of multiple capsule sizes facilitates accurate dosing for dogs of various sizes. These factors have made trilostane the standard of care for medical management of canine Cushing's disease.

Dosing of trilostane requires individualization based on the patient's body weight, disease severity, and clinical response. The manufacturer's recommended starting dose is approximately 1 to 2 milligrams per kilogram of body weight once daily for dogs under 5 kilograms, 2 to 5 mg/kg once daily for dogs 5 to 20 kilograms, and lower per-kilogram doses for larger dogs. Many veterinarians use starting doses at the lower end of these ranges and adjust based on response. The veterinarian determines the specific starting dose and all subsequent adjustments based on the individual patient's needs and monitoring results.

The dosing schedule for trilostane is typically once daily administration in the morning with food. Giving the medication with a meal significantly enhances absorption and is essential for consistent therapeutic effect. Some dogs may require twice-daily dosing to maintain adequate cortisol suppression throughout the entire 24-hour period, particularly dogs that show good initial response but develop recurring signs of Cushing's disease in the hours before their next dose. The decision to switch to twice-daily dosing is made based on clinical response and monitoring test results.

Treatment duration with trilostane is generally lifelong, as Cushing's disease is a chronic condition that requires ongoing management. The medication does not cure the underlying disease but rather controls the excessive cortisol production that causes clinical signs. Discontinuing treatment allows cortisol levels to rise again, with return of clinical signs. Regular veterinary monitoring continues throughout the dog's life to ensure appropriate dosing and to detect any complications early. Dose adjustments are commonly needed over time as the disease or the dog's response changes.

Administration of trilostane capsules should occur at the same time each day, ideally in the morning with the dog's breakfast. Consistent timing helps maintain stable cortisol control and ensures that monitoring tests performed at specific intervals after dosing yield accurate results. Capsules should be given whole and should not be opened, crushed, or chewed. If a dog has difficulty swallowing capsules, the veterinarian can suggest administration techniques, but the capsule integrity should be maintained. Handlers should wash their hands after administration.

If a dose of trilostane is missed, the owner should give it as soon as remembered if it is still the same day and give it with food. If the dose is not remembered until the next day, the missed dose should be skipped, and the regular schedule resumed. Doses should never be doubled to make up for a missed dose. Occasional missed doses typically do not cause significant problems for dogs whose disease is well-controlled, but frequent missed doses can lead to recurrence of clinical signs. Owners should contact their veterinarian if multiple doses are missed.

Monitoring is a critical component of safe trilostane therapy. An ACTH stimulation test is typically performed 10 to 14 days after starting treatment or after any dose change to assess adrenal response. The test is performed 4 to 6 hours after trilostane administration to measure cortisol levels at the time of maximum drug effect. Based on the results and clinical response, the veterinarian determines whether the current dose is appropriate or needs adjustment. Once stable, monitoring frequency can be reduced to every 3 to 6 months, but regular assessment remains necessary throughout treatment.

Trilostane is generally well-tolerated in dogs when used at appropriate doses with proper monitoring, and most dogs experience significant improvement in quality of life on treatment. However, potential adverse effects can occur, and owners should be familiar with signs that warrant veterinary attention. Understanding these effects helps ensure prompt recognition and appropriate response if problems develop.

The most common side effects of trilostane relate to its intended therapeutic action of suppressing cortisol production. Some degree of cortisol reduction is the goal of therapy, but excessive suppression can cause signs of hypoadrenocorticism (Addison's disease-like syndrome). Mild signs of cortisol suppression may include decreased appetite, lethargy, and mild gastrointestinal upset. These effects often indicate that the dose may need reduction and typically resolve with dose adjustment. Owners should monitor for these changes, especially in the first few weeks of treatment or after dose increases.

Gastrointestinal side effects are among the most frequently reported adverse events in dogs receiving trilostane. These include decreased appetite, vomiting, and diarrhea. While mild gastrointestinal upset may simply reflect the dog's response to changing cortisol levels, persistent or severe symptoms require veterinary evaluation. Gastrointestinal signs can be an early indicator of excessive cortisol suppression, and the medication may need to be temporarily discontinued while the dog is assessed. Giving the medication with food as directed may help minimize gastrointestinal irritation.

More serious adverse effects can occur, though they are less common. Acute adrenal insufficiency or adrenal crisis represents the most serious potential complication, occurring when cortisol levels drop too low to support normal body functions. Signs include severe weakness, collapse, vomiting, diarrhea, and shock. This is a medical emergency requiring immediate veterinary treatment. Adrenal necrosis, a rare but potentially fatal complication involving destruction of adrenal tissue, has been reported in some dogs receiving trilostane. The mechanism is not fully understood, and this complication can occur unpredictably even in dogs that appeared stable on treatment.

Other reported adverse effects include skin reactions, neurological signs in dogs with large pituitary tumors, and changes in blood potassium levels. Any new or unexpected symptoms developing in a dog on trilostane therapy should prompt veterinary consultation. Regular monitoring helps detect problems before they become severe, and owners should maintain close communication with their veterinary team about any changes in their dog's condition. With appropriate monitoring and prompt attention to adverse effects, most dogs can be managed safely on trilostane therapy.

Trilostane is contraindicated in dogs with known hypersensitivity to trilostane or any components of the formulation. Dogs that have previously experienced severe adverse reactions to trilostane should not receive the medication again without careful consideration of the risks and benefits. Alternative treatments should be explored for dogs that cannot tolerate trilostane.

Dogs with primary hepatic disease or renal insufficiency should receive trilostane with caution, as these conditions may affect drug metabolism and excretion. While not absolute contraindications, liver or kidney dysfunction may require dose modifications and more frequent monitoring. The veterinarian will evaluate the overall health status and determine whether trilostane therapy is appropriate for dogs with concurrent organ dysfunction.

Pregnancy is a contraindication for trilostane use, as the medication can potentially affect fetal development through its effects on steroid hormone synthesis. Trilostane should not be used in pregnant dogs, and female dogs receiving trilostane should not be bred. The medication should also be used with caution in lactating dogs due to potential effects on nursing puppies. If a dog becomes pregnant while on trilostane, immediate veterinary consultation is necessary.

Dogs intended for breeding should not receive trilostane, as the medication affects steroid hormone production that is essential for reproduction. Males may experience reduced fertility, and females may have disrupted reproductive cycles. The medication should be discontinued well in advance of any planned breeding, with veterinary guidance on appropriate timing. Given that Cushing's disease primarily affects older dogs past breeding age, this contraindication is relevant mainly for younger dogs or those in breeding programs where the condition has been diagnosed.

Dogs with certain concurrent conditions require careful evaluation before starting trilostane. Those with diabetes mellitus may experience significant changes in insulin requirements as cortisol levels change during treatment, requiring intensive glucose monitoring. Dogs with pre-existing hypoadrenocorticism should not receive trilostane, as further suppression of adrenal function could be dangerous. Very debilitated or critically ill dogs may not be appropriate candidates for initiating Cushing's disease treatment until their condition stabilizes.

Thorough disclosure of all medications, supplements, and treatments the dog is receiving is essential before starting trilostane therapy. Drug interactions can affect both the efficacy and safety of treatment, and managing Cushing's disease requires understanding all factors that might influence the patient's response. This includes prescription medications, over-the-counter products, supplements, and any concurrent treatments.

Interactions with medications that affect adrenal function or potassium levels are particularly important to consider. Potassium-sparing diuretics such as spironolactone can potentially interact with trilostane's effects on adrenal steroid production. ACE inhibitors, commonly used for cardiac conditions, can affect potassium levels and aldosterone, warranting monitoring when used concurrently with trilostane. Ketoconazole and other azole antifungals have their own cortisol-suppressing properties, and concurrent use could potentially cause excessive adrenal suppression.

Medications affecting liver enzymes can potentially influence trilostane metabolism. Phenobarbital and other drugs that induce hepatic enzymes may increase trilostane metabolism, potentially affecting its efficacy. Conversely, drugs that inhibit liver enzymes might increase trilostane levels and effects. When dogs on trilostane need additional medications that affect liver metabolism, the veterinarian may need to adjust the trilostane dose or increase monitoring frequency.

The interaction between trilostane and insulin in diabetic dogs deserves special attention. Cortisol has significant effects on blood glucose regulation, and as trilostane lowers cortisol levels, insulin requirements typically decrease. Diabetic dogs starting trilostane therapy need intensive blood glucose monitoring and often require substantial insulin dose reductions to prevent hypoglycemia. The veterinarian will coordinate management of both conditions, and owners of diabetic dogs should be prepared for more frequent monitoring and adjustments during the initial treatment period.

Monitoring for drug interactions involves regular clinical assessment and laboratory monitoring throughout trilostane therapy. Any new medications should be discussed with the veterinarian before starting them, and the veterinary team should be informed if new treatments are prescribed by other healthcare providers. Signs of potential interactions include unexpected changes in clinical status, abnormal laboratory results, or poor disease control despite appropriate trilostane dosing. Coordinated management of all the dog's health conditions through a single veterinary team helps minimize the risk of problematic interactions.

General precautions for trilostane therapy emphasize the importance of accurate diagnosis and appropriate monitoring. Cushing's disease should be definitively diagnosed through appropriate testing before initiating trilostane, as treating dogs without the condition could cause adrenal insufficiency. Diagnostic testing typically includes ACTH stimulation tests, low-dose dexamethasone suppression tests, and imaging studies to characterize the underlying cause. Once treatment begins, regular monitoring is not optional but rather an essential component of safe therapy.

Handler safety precautions are important when working with trilostane. Pregnant women or women who may become pregnant should not handle the medication, as trilostane can affect steroid hormone synthesis and potentially harm a developing fetus. Handlers should wear disposable gloves when administering the medication and should wash hands thoroughly afterward. Capsules should not be opened, crushed, or broken, as this could release the contents and increase exposure risk. If accidental exposure occurs, the affected area should be washed immediately.

Monitoring requirements during trilostane therapy are extensive, particularly during the initial treatment period. ACTH stimulation testing is typically performed at 10 to 14 days, 30 days, and 90 days after starting treatment, then every 3 to 6 months once stable. The timing of testing relative to drug administration is important, with tests typically performed 4 to 6 hours post-dose to measure cortisol at the time of maximum trilostane effect. Clinical monitoring for signs of both inadequate treatment and excessive suppression should be ongoing between veterinary visits.

Special populations requiring additional precaution include dogs with large pituitary tumors, who may experience tumor growth or neurological complications during treatment. While trilostane itself does not promote tumor growth, removing the negative feedback from high cortisol levels may allow pituitary tumors to enlarge. Dogs with macroadenomas should be monitored for neurological signs. Senior dogs and those with concurrent health conditions may need more individualized monitoring schedules and dose adjustments based on their overall health status.

Owner education is a crucial component of safe trilostane therapy. Owners must understand the importance of consistent administration with food, the signs of both inadequate treatment and excessive cortisol suppression, and the need for regular monitoring appointments. They should know when to contact the veterinarian urgently, such as when signs of adrenal insufficiency develop. Written instructions and emergency contact information help ensure owners can respond appropriately if problems arise. The success of trilostane therapy depends significantly on owner compliance and communication with the veterinary team.

Proper storage of trilostane maintains the medication's stability and effectiveness while protecting household members from unnecessary exposure. Capsules should be stored at controlled room temperature, between 68 and 77 degrees Fahrenheit (20 to 25 degrees Celsius), protected from light and moisture. The medication should be kept in its original container with the child-resistant cap tightly secured. Storage locations should be away from heat sources, direct sunlight, and areas of high humidity such as bathrooms or kitchens.

Specific handling requirements for trilostane reflect safety considerations for both the medication and handlers. Capsules should remain intact and should not be opened, crushed, or broken. Handling should be minimized, and disposable gloves are recommended, particularly for individuals who handle the medication regularly. Pregnant women, women who may become pregnant, and nursing mothers should not handle trilostane capsules at all. If alternative caregivers are needed for medication administration, this should be arranged before starting treatment. Hands should be washed thoroughly with soap and water after handling the medication even when gloves are used.

Safety and disposal considerations for trilostane protect household members, other animals, and the environment. The medication should be stored securely where children and pets cannot access it. In multi-pet households, medications for each animal should be clearly labeled and stored separately to prevent confusion. Any capsules that are dropped or become damaged should be handled with gloves and disposed of properly rather than administered. Expired or unused trilostane should be disposed of through pharmacy take-back programs or according to local guidelines for pharmaceutical disposal. The medication should not be flushed down toilets or drains or placed in household trash unless specifically directed by disposal guidelines.

Most dogs respond similarly to trilostane regardless of breed, with dosing determined primarily by body weight and individual response rather than breed-specific factors. The medication's mechanism of enzyme inhibition works consistently across breeds, though individual variation in drug metabolism and disease presentation exists. The principles of treatment and monitoring apply broadly to all dogs with Cushing's disease.

Certain breeds have documented higher prevalence of hyperadrenocorticism, representing a larger proportion of patients receiving trilostane therapy. Breeds with elevated Cushing's disease rates include Poodles (particularly Miniature and Toy varieties), Dachshunds, Beagles, Boxers, Boston Terriers, Yorkshire Terriers, Staffordshire Bull Terriers, and German Shepherds. While breed predisposition affects the likelihood of diagnosis, it does not typically alter how individual dogs respond to trilostane or require breed-specific dosing modifications.

Size considerations are important for accurate trilostane dosing given the wide range of dog sizes and the availability of multiple capsule strengths. Trilostane capsules come in 5, 10, 30, 60, and 120 milligram sizes, allowing for dosing precision across the spectrum from small toy breeds to giant breeds. Very small dogs may require the lowest capsule strengths, while large and giant breeds may need multiple capsules or the highest available strengths. The veterinarian selects the appropriate capsule size or combination to achieve the desired dose based on the individual patient's weight and needs.

Age-related considerations are particularly relevant for trilostane therapy because Cushing's disease primarily affects middle-aged and older dogs. Most affected dogs are over 6 years of age at diagnosis, with the condition being uncommon in young animals. Senior dogs may have concurrent age-related conditions that affect their overall treatment plan and prognosis. Hepatic and renal function should be assessed before starting treatment, as these organs decline with age and affect drug handling. The presence of concurrent conditions such as diabetes, heart disease, or kidney disease influences monitoring schedules and may require coordination of treatment for multiple conditions. Despite these considerations, age alone is not a contraindication to trilostane therapy, and many geriatric dogs benefit significantly from Cushing's disease treatment.

Mitotane (Lysodren) represents the primary alternative medical treatment for canine Cushing's disease. Unlike trilostane's reversible enzyme inhibition, mitotane works by selectively destroying portions of the adrenal cortex, permanently reducing the glands' capacity to produce cortisol. This cytotoxic mechanism means mitotane's effects are not readily reversible, which can be either advantageous or problematic depending on the clinical situation. Mitotane may be considered for dogs that do not respond adequately to trilostane, cannot tolerate it, or in specific clinical scenarios where the veterinarian determines it may be preferable. The choice between trilostane and mitotane involves weighing efficacy, safety profiles, monitoring requirements, and individual patient factors.

Surgical treatment options exist for certain dogs with Cushing's disease. Adrenalectomy, surgical removal of an affected adrenal gland, can provide definitive treatment for adrenal-dependent Cushing's disease when the tumor is amenable to surgical excision. This approach requires specialized surgical expertise and carries significant perioperative risks but can be curative for appropriate candidates. Hypophysectomy, surgical removal of pituitary tumors causing pituitary-dependent Cushing's disease, is performed at specialized centers but is not widely available. Radiation therapy for pituitary tumors is another option available at some referral centers. For most dogs, medical management with trilostane remains the primary treatment approach.

Complementary approaches to managing dogs with Cushing's disease support overall health and address complications of the condition. Dietary management may help control weight gain and metabolic abnormalities associated with excess cortisol. Treatment of concurrent conditions such as diabetes mellitus, urinary tract infections, or hypertension is essential for comprehensive care. Some dogs require medications for specific complications during the initial treatment period while trilostane takes effect. Regular monitoring and follow-up care are critical regardless of which primary treatment is used. Owners should work closely with their veterinary team to optimize all aspects of their dog's care, and any changes to Cushing's disease treatment should only be made under professional guidance.