From the Guidelines
Ketoconazole is associated with a significant risk of developing Cushing's syndrome-like side effects, but it can be used to treat Cushing's syndrome, particularly when surgery is not an option or has been unsuccessful, with a typical starting dose of 400-1200 mg/day PO, dosing BID. When initiating treatment, it is essential to:
- Monitor cortisol levels regularly
- Adjust dosage based on clinical response and cortisol levels
- Watch for side effects, especially liver toxicity, GI disturbances, and gynecomastia, as reported in studies 1, 2 Ketoconazole works by inhibiting steroidogenesis, specifically blocking the enzymes involved in cortisol production, which reduces excessive cortisol levels characteristic of Cushing's syndrome. Important considerations:
- Perform baseline liver function tests and monitor regularly, as hepatotoxicity is a significant concern, seen in 10-20% of patients 2
- Avoid in patients with pre-existing liver disease
- Be aware of potential drug interactions, especially with medications metabolized by CYP3A4, as careful review of the patient’s medication list for potentially problematic interactions is essential 2
- Inform patients about potential side effects, including nausea, vomiting, and skin rashes, which are common, seen in 5-20% of patients 2 While effective, ketoconazole is generally considered a second-line treatment due to its potential for hepatotoxicity, and close monitoring and follow-up are essential for safe and effective use in managing Cushing's syndrome, with studies showing UFC normalization in 64.3% of patients, but up to 23% of initially responsive patients losing biochemical control and escaping 2
From the FDA Drug Label
Adrenal Insufficiency Ketoconazole tablets decrease adrenal corticosteroid secretion at doses of 400 mg and higher. Ketoconazole has been used in high doses for the treatment of advanced prostate cancer and for Cushing’s syndrome when other treatment options have failed.
Ketoconazole is associated with adrenal insufficiency, which is a condition that can be related to Cushing's syndrome. However, the use of ketoconazole for Cushing's syndrome is not approved by the FDA.
- The FDA label does mention that ketoconazole has been used for Cushing's syndrome, but this is not an approved use.
- Adrenal insufficiency is a possible side effect of ketoconazole, especially at high doses 3. It is essential to note that while ketoconazole may be used off-label for Cushing's syndrome, its safety and efficacy for this indication are not established 4.
From the Research
Association between Ketoconazole and Cushing's Syndrome
- Ketoconazole has been used to treat Cushing's syndrome, with studies showing its effectiveness in reducing cortisol levels 5, 6, 7, 8, 9.
- The drug works by inhibiting steroid hormone synthesis, which can help control hypercortisolism in patients with Cushing's syndrome 5, 6, 7, 8, 9.
Efficacy of Ketoconazole in Cushing's Syndrome
- Studies have shown that ketoconazole can decrease urinary cortisol levels and improve clinical symptoms in patients with Cushing's syndrome 5, 6, 7, 8, 9.
- A retrospective multicenter study found that 49.3% of patients had normal urinary free cortisol levels after treatment with ketoconazole, while 25.6% had at least a 50% decrease in levels 9.
Side Effects of Ketoconazole
- Common side effects of ketoconazole include liver toxicity, gastrointestinal symptoms, and worsening of gynaecomastia 5, 7, 9.
- A study found that 20.5% of patients stopped treatment due to poor tolerance, while 13.5% and 2.5% of patients experienced mild and major increases in liver enzymes, respectively 9.
Long-term Effects of Ketoconazole
- Long-term treatment with ketoconazole has been shown to be effective in controlling hypercortisolism in patients with Cushing's syndrome 6, 8, 9.
- A study found that ketoconazole was effective in the long-term treatment of residual or recurrent Cushing's disease, with follow-up periods ranging from 65 to 86 months 6.