- Drugs List
- Therapeutic Indications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
Oral formulation of ketoconazole.
Treatment of endogenous Cushing's syndrome in adults and adolescents above the age of 12 years.
Ketoconazole daily dose should be periodically adjusted on an individual basis with the aim to normalise urinary free cortisol and/or plasma cortisol levels.
The recommended dose at initiation is 400 to 600mg daily taken orally in two or three divided doses and this dose can be increased rapidly to 800 to 1200mg daily in 2 or 3 divided doses.
400mg daily to a maximal dose of 1200mg daily taken orally in 2 to 3 divided doses. In most publications the maintenance dose varied between 600 and 800mg daily.
A dose increase of 200mg daily every 7 to 28 days may be considered if urinary free cortisol and/or plasma cortisol levels are above the normal range, as long as the dose is tolerated by the patient.
Block-and-replace regimen: The maintenance dose of ketoconazole should be further increased by 200mg and concomitant corticosteroid replacement therapy should be added.
Children 12 years and older
(See Dosage; Adults)
Additional Dosage Information
The dose of ketoconazole should be decreased by at least 200mg daily or the treatment should be temporarily discontinued and/or a corticosteroid therapy should be added until the resolution of the event. Ketoconazole can be reintroduced thereafter at a lower dose.
In the case of an increase in liver enzymes of less than 3 x ULN, more frequent monitoring of liver function tests should be performed and the daily dose should be decreased by at least 200mg.
Children under 12 years
Hepatic enzymes above 2 times the upper limit of normal
Long QT syndrome
Torsade de pointes
Precautions and Warnings
Family history of long QT syndrome
Females of childbearing potential
Glucose-galactose malabsorption syndrome
History of hepatic impairment
History of torsade de pointes
Correct electrolyte disorders before treatment
Inflammatory/autoimmune disorder may occur after Cushing's remission
Advise ability to drive/operate machinery may be affected by side effects
Treatment to be initiated and supervised by a specialist
Monitor hepatic function prior to treatment
Perform ECG before treatment
Adrenal insufficiency suspected: Monitor cortisol and reduce/suspend dose
If adrenal insufficiency occurs, consider corticosteroid cover
Monitor cortisol levels every few days/weeks during treatment initiation
Monitor ECG within 1 week of initiation and then as clinically indicated
Monitor hepatic function every 4 weeks for 6 months, or as indicated
Monitor hepatic function weekly for 1 month after initiation
Monitor LFTs at same frequency as when initiating with any dose increase
Monitor serum electrolytes
Once effective dose is established, monitor cortisol every 3 to 6 months
Advise patient to report signs of hypocortisolism
Advise patients to report signs of hepatic damage (malaise, jaundice etc.)
Discontinue if hepatitis develops
Discontinue immediately following signs of acute hepatotoxicity
Discontinue if hepatic enzymes are equal to or greater than 3 x ULN
Advise patient not to take paracetamol during treatment
Advise patient not to take St John's wort concurrently
Advise patient to avoid antacids for at least 2 hours after dose
Advise patient to avoid alcohol during treatment
Female: Ensure adequate contraception during treatment
Block and replace regimen: Consider emergency card/glucocorticoid set
It is required before starting the treatment to measure liver enzymes (AST, ALAT, gammaGT and alkaline phosphatase) and bilirubin.
Patients should be informed about the risk of hepatotoxicity, including to stop treatment and to contact their doctor immediately if they feel unwell or in the event of symptoms such as anorexia, nausea, vomiting, fatigue, jaundice. abdominal pain or dark urine. If these occur, treatment should be stopped immediately and liver function tests should be performed.
In the case of an increase in liver enzymes of less than 3 times the upper limit of normal , more frequent monitoring of liver function tests should be performed and the daily dose should be decreased by at least 200mg.
Adrenal insufficiency can occur:
Under conditions of a relative cortisol deficiency due to an increased glucocorticoid demand (e.g. in case of stress, surgery, or infection).
In case of ketoconazole overtreatment in patients treated with a block-only regime.
In insufficient glucocorticoid replacement therapy in patients treated with a block-and-replace regimen.
Block and replace regimen
Patients treated with a block-and-replace regime should be taught to adjust their glucocorticoid replacement therapy dose under conditions of stress.
Absorption of ketoconazole is impaired with decreased gastric acidity.
In patients with achlorhydria, e.g. certain AIDS patients and those on acid secretion suppressors (such as H2-antagonists, proton pump inhibitors), it is advisable to administer ketoconazole with an acidic beverage e.g. cola, orange juice.
If acid secretion suppressors are added to or removed from the concomitant medication then ketoconazole dose should be adjusted according to cortisol levels.
Treatment of Infections
The CHMP has recommended that the use of oral ketoconazole to treat fungal infections should be suspended. The CHMP concluded that the risk of hepatotoxicity associated with oral ketoconazole is greater than the benefit in treating fungal infections. An alternative available treatment should be used.
Pregnancy and Lactation
Ketoconazole is contraindicated during pregnancy.
Use of ketoconazole during pregnancy is contraindicated by the manufacturer. Pre-clinical data show that ketoconazole crosses the placenta and is teratogenic.
Animal studies have shown teratogenic effects. There are insufficient data regarding the use of ketoconazole in pregnant women and as such a potential risk cannot be ruled out.
Schaefer reports the use of ketoconazole in several occasions in pregnancy with good maternal and fetal outcome (Schaefer 2015). Also, Schaefer reports some studies showing no evidence of an increased risk of malformation (Schaefer 2015).
Ketoconazole is contraindicated during breastfeeding.
The manufacturer suggests because ketoconazole is excreted in breast milk, patients should not breastfeed whilst being treated.
Briggs reports a case where the exposure to ketoconazole on a breastfeed infant did not appear to be clinically significant (Briggs 2015).
LactMed (2018) indicates that if oral ketoconazole is required by the mother, it may not be a reason to discontinue breastfeeding. Taking the dose just before the infant's longest sleep period or avoiding breastfeeding from 2 to 5 hours after the dose might decrease the infant's exposure to ketoconazole.
Abnormal liver function tests
Bulging fontanelles in infants
Decrease in plasma testosterone (transient)
Increases in hepatic enzymes
Raised intracranial pressure
Reduced platelet count
Transient adrenocortical insufficiency
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Last Full Review Date: April 2020.
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.
Summary of Product Characteristics: Ketoconazole HRA 200mg tablets. Laboratoire HRA Pharma. Revised August 2017.
US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Ketoconazole Available at: https://www.ncbi.nlm.nih.gov/books/NBK501922/
Last revised: 03 December 2018.
Last accessed: 25 February 2020.
European Medicines Agency (EMA).
Committee for Medicinal Products for Human Use (CHMP).
Available at: www.ema.europa.eu/en/medicines/human/referrals/ketoconazole-containing-medicines
Last accessed: 06 April 2020.
NICE Evidence Services Available at: www.nice.org.uk Last accessed: 25 February 2020.
The Norwegian Porphyria Centre (NAPOS).
Available at: https://www.drugs-porphyria.org
Last revised: October 2018
Last accessed: 25 February 2020.
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