Ketoconazole for Cushing’s disease
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What is ketoconazole for Cushing’s disease?
Cushing’s disease and other forms of Cushing’s syndrome are characterized by the presence of excessive levels of a hormone called cortisol.
Ketoconazole is an antifungal agent that may be used to reduce cortisol levels and ease Cushing’s symptoms. While it’s approved in Europe for that purpose, the medication is not officially authorized — but is sometimes used off-label — in the U.S. to treat Cushing’s.
Brand names and formulations
In Europe, ketoconazole is approved to treat Cushing’s disease and other forms of endogenous Cushing’s syndrome in patients 12 and older. The therapy, marketed in the form of oral tablets by HRA Pharma Rare Diseases, is sold under the brand name Ketoconazole HRA.
Formulations of ketoconazole that are applied topically, such as in creams and shampoos, are also available and used to treat some fungal infections. However, these formulations are not used for Cushing’s.
In the U.S., ketoconazole is approved to treat some types of fungal infections. Oral and topical formulations of the medication sold under the brand name Nizoral have been discontinued in the U.S. Some oral and topical generics are still available, as is a shampoo formulation sold over-the-counter under the name Nizoral Anti-Dandruff.
Therapy Snapshot
| Treatment Name: | Ketoconazole |
| Administration: | Oral tablets |
| Clinical testing: | Observational study ongoing to collect real-world data |
How does ketoconazole work in Cushing’s disease?
Cushing’s disease is caused by a tumor in the pituitary gland, located at the base of the brain. The pituitary tumor releases signaling molecules that prompt the adrenal glands sitting atop the kidneys to make excessive amounts of a hormone called cortisol. Excessive cortisol levels ultimately lead to the typical symptoms of Cushing’s, which may include weight gain and skin changes.
First-line treatment is surgery to remove the disease-driving tumor, but when surgery isn’t effective or an option, cortisol-lowering medications may be used to help control the disease.
Ketoconazole blocks the activity of several enzymes required for cortisol production in the adrenal glands, including 21-hydroxylase, 17-alpha-hydroxylase, and 11-beta-hydroxylase. By doing so, the therapy can lower cortisol levels, thereby helping to ease Cushing’s symptoms.
How is ketoconazole administered in Cushing’s disease?
Ketoconazole is available in round tablets, each containing 200 mg of the active ingredient.
In Europe, the approved dosing schedule is to start at a daily dose of 400-600 mg, divided in two or three doses across the entire day. The total daily dose can then be increased up to 800-1,200 mg, with adjustments based on tolerability and on how well cortisol levels are controlled. Similar dosing schedules are used for off-label treatment.
Medications that reduce the acidity of the stomach should not be taken for at least two hours after a patient takes ketoconazole, as the tablet is not absorbed as well if the stomach isn’t acidic.
Because ketoconazole poses an increased risk of liver toxicity, it is contraindicated, or not recommended, for people with acute or chronic liver disease. The medication should never be given to patients whose liver enzyme levels are two times higher than the upper limit of normal. If liver enzyme levels increase during treatment, the dose may be adjusted or the treatment discontinued.
In the U.S., generic tablet formulations of ketoconazole carry a boxed warning noting that using the medication with certain other drugs may increase the risk of QTc prolongation — a type of abnormal heart rhythm in which the interval between the heart contracting and relaxing is longer than normal — which may be life-threatening. Therefore, ketoconazole is not to be taken along with these drugs and routine monitoring of QTc interval is recommended while on the medication.
Ketoconazole in Cushing’s clinical trials
The safety and efficacy of ketoconazole for different forms of Cushing’s syndrome has been described across several retrospective studies and case reports involving more than 800 patients. In these studies, ketoconazole was found to normalize urine cortisol levels in 43% to 80% of the patients.
In a French retrospective study involving 200 Cushing’s disease patients, standalone treatment with ketoconazole normalized urine cortisol levels for 78 participants (49.3%) at the last follow-up visit. A total of 37 (23.4%) saw their urine cortisol levels drop by at least 50%, even though they were still above the normal range. In 43 (27.2%), urine cortisol levels remained unchanged.
More than half of the patients (55.2%) also experienced improvements in clinical signs of Cushing’s at the last follow-up visit. Improvements in high blood pressure were observed in 40% of the patients at the last visit, and in diabetes in 59% of the patients.
Studies in children and adolescents
Data about ketoconazole treatment in children and adolescents with endogenous Cushing’s are available for a relatively small number of patients. However, findings indicate that in most of these younger patients, ketoconazole normalized urine cortisol levels and blood pressure, and led to other clinical improvements, including weight loss and growth rate recovery. Ketoconazole doses used in children 12 and older were similar to those used in adults.
Ongoing trials
HRA Pharma, whose subsidiary HRA Pharma Rare Diseases markets ketoconazole, is sponsoring the KetoPASS observational study (NCT04872920) to collect more data on people with Cushing’s who are treated with ketoconazole in real-world clinical practice.
The main goal of the study is to gather more information about ketoconazole’s safety profile, particularly the risk of liver toxicity and heart rhythm abnormalities.
The study is also assessing whether real-world use of ketoconazole includes all the monitoring that’s recommended for people on the medication. Data on the therapy’s effectiveness, including its ability to control cortisol levels and its effects on quality of life, will be evaluated as well.
Common side effects of ketoconazole
The most common side effects of ketoconazole include:
- adrenal insufficiency
- digestive problems like nausea, vomiting, abdominal pain, and diarrhea
- rash and itching
- elevations in liver enzymes, indicating liver damage.
Adrenal insufficiency
In people with Cushing’s, ketoconazole is used to suppress the production of cortisol in the adrenal glands, but the therapy can sometimes decrease adrenal activity too much, leading to a condition called adrenal insufficiency. Patients should be monitored and educated about the signs and symptoms of adrenal insufficiency, which may include weakness, fatigue, nausea, vomiting, and low blood pressure. If such signs and symptoms occur, patients should contact their doctor immediately.
If adrenal insufficiency occurs, it may be necessary to pause ketoconazole treatment, decrease the therapy’s dose, and/or resort to treatment with corticosteroids (medications that mimic the effects of cortisol in the body).
Liver damage
Ketoconazole can cause liver damage, which can be serious. The therapy should never be given to patients who have liver impairment or signs of liver disease. The health of the liver should be monitored before starting treatment and regularly monitored thereafter.
If liver enzyme levels approach three times the upper limit of normal during treatment, ketoconazole’s dose should be reduced by at least 200 mg. If increments in liver enzyme levels exceed three times the upper limit of normal, treatment with ketoconazole should be stopped immediately and not resumed due to the serious risk of liver toxicity.
Heart rhythm abnormalities
Ketoconazole can cause an alteration in heart rhythm called QTc prolongation. It’s recommended that heart function be checked before starting treatment and then again a week after starting ketoconazole, with additional checkups conducted as clinically indicated thereafter.
Drug interactions
Ketoconazole can interact with several common medications and lead to potentially life-threatening adverse reactions. Some of these include statins (cholesterol-lowering medicines), benzodiazepines (a class of therapies for anxiety, seizures, and insomnia), and medications that can alter heart rhythm. Ketoconazole should also be used with caution in patients taking certain medications, particularly antiviral agents, that may increase the concentration of ketoconazole in the body.
It’s recommended that patients taking ketoconazole abstain from consuming alcohol because the combination can lead to symptoms such as rash, redness, swelling, nausea, and headache.
Patients should talk to their healthcare team about all medical and recreational drugs they are taking before starting on ketoconazole.
Allergic reactions
Ketoconazole should not be given to anyone with a known allergy against it, or to any imidazole antifungal medications.
Use in pregnancy and breastfeeding
Data on the use of ketoconazole in pregnant women is limited, but studies done in animals suggest that the therapy is toxic for a developing fetus. Ketoconazole should be avoided during pregnancy, and patients who have the potential to get pregnant should use effective forms of contraception while on the medication.
Because ketoconazole can pass into breast milk, patients should not breastfeed while on treatment.
Cushing’s Disease News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
FAQs about Ketoconazole
Ketoconazole is not approved by the U.S. Food and Drug Administration for Cushing’s disease, and it’s not known if or when the regulatory agency may approve the medication for this indication. In Europe, the therapy is approved for Cushing’s disease and other forms of endogenous Cushing’s syndrome in adults and children, 12 and older. In the U.S., it’s sometimes used off-label for that purpose.
Cushing’s disease symptoms are caused by the excessive levels of a hormone called cortisol. Ketoconazole can block the production of cortisol, thereby lowering its levels and helping to ease symptoms.
It’s recommended that people taking ketoconazole abstain from drinking alcohol as combining the two has reportedly led to patients experiencing flushing, rash, swelling, nausea, and headache.
Studies evaluating the effects of ketoconazole on Cushing’s patients vary widely in terms of treatment duration and dosing regimens. Data from five studies involving more than 250 patients showed that at a median follow-up of 7.5 months, a median 50% of the patients saw their cortisol levels normalize, meaning that some individuals may see the results of treatment within a few months. Cortisol normalization was most frequently seen when ketoconazole was administered at a dose between 600 and 800 mg per day.
The most common side effects of ketoconazole include adrenal insufficiency, rash, itching, liver damage, and digestive problems such as nausea, vomiting, abdominal pain, and diarrhea. Patients should discuss any unexpected effects of treatment with their healthcare team.
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