Drug reference
An imidazole derivative which acts as a potent inhibitor of cortisol and aldosterone synthesis by inhibiting the activity of 17a-hydroxylase, 11-hydroxylation steps and at higher doses the cholesterol side-chain cleavage enzyme. It also inhibits the activity of adrenal C17-20 lyase enzymes resulting in androgen synthesis inhibition, and may have a direct effect on corticotropic tumour cells in patients with Cushing’s disease.
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Endogenous Cushing’s syndrome (specialist use only) ▶BY MOUTH ▶Adult: Initially 400–600 mg daily in 2–3 divided doses, increased to 800–1200 mg daily; maintenance 400–800 mg daily in 2–3 divided doses, for dose titrations in patients with established dose, adjustments in adrenal insufficiency, or concomitant corticosteroid replacement therapy, consult product literature; maximum 1200 mg per day
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DUE TO INTERACTIONS ▶Manufacturer advises max. dose 200 mg daily with concurrent use of cobicistat.
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Acquired QTc prolongation. Acute porphyrias p. 1120. avoid concomitant use of hepatotoxic drugs. congenital QTc prolongation
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Pre-treatment liver enzymes should not exceed 2 times the normal upper limit. risk of adrenal insufficiency
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CHMP ADVICE: KETOCONAZOLE (JULY 2013) The CHMP has recommended that the marketing authorisation for 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. Doctors should review patients who are being treated with oral ketoconazole for fungal infections, with a view to stopping treatment or choosing an alternative treatment. Patients with a prescription of oral ketoconazole for fungal infections should be referred back to their doctors. Oral ketoconazole for Cushing’s syndrome and topical products containing ketoconazole are not affected by this advice.
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→Appendix 1: antifungals, azoles
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▶Common or very common Adrenal insufficiency. diarrhoea. gastrointestinal discomfort. nausea. skin reactions. vomiting ▶Uncommon Allergic conditions. alopecia. angioedema. asthenia. dizziness. drowsiness. headache. thrombocytopenia ▶Rare or very rare Fever. hepatic disorders. taste altered ▶Frequency not known Alcohol intolerance. appetite abnormal. arthralgia. azoospermia. dry mouth. epistaxis. flatulence. fontanelle bulging. gynaecomastia. hot flush. insomnia. intracranial pressure increased. malaise. menstrual disorder. myalgia. nervousness. papilloedema. paraesthesia. peripheral oedema. photophobia. photosensitivity reaction. tongue discolouration SIDE-EFFECTS, FURTHER INFORMATION Potentially life- threatening hepatotoxicity reported rarely with oral use. Manufacturer advises reduce dose if hepatic enzymes increased to less than 3 times the upper limit of normal— consult product literature; discontinue permanently if hepatic enzymes at least 3 times the upper limit of normal.
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Effective contraception must be used in women of child-bearing potential.
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Manufacturer advises avoid—teratogenic in animal studies.
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Manufacturer advises avoid—present in breast milk.
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Manufacturer advises avoid.
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▶Monitor ECG before and one week after initiation, and then as clinically indicated thereafter. ▶Adrenal insufficiency Monitor adrenal function within one week of initiation, then regularly thereafter. When cortisol levels are normalised or close to target and effective dose established, monitor every 3–6 months as there is a risk of autoimmune disease development or exacerbation after normalisation of cortisol levels. If symptoms suggestive of adrenal insufficiency such as fatigue, anorexia, nausea, vomiting, hypotension, hyponatraemia, hyperkalaemia, and/or hypoglycaemia occur, measure cortisol levels and discontinue treatment temporarily (can be resumed thereafter at lower dose) or reduce dose and if necessary, initiate corticosteroid substitution. ▶Hepatotoxicity Monitor liver function before initiation of treatment, then weekly for 1 month after initiation, then monthly for 6 months—more frequently if dose adjusted or abnormal liver function detected.
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There can be variation in the licensing of different medicines containing the same drug. Forms available from special-order manufacturers include: oral suspension Tablet CAUTIONARY AND ADVISORY LABELS 2, 5, 21 A ▶Ketoconazole (non-proprietary) Ketoconazole 200 mg Ketoconazole 200mg tablets | 60 tablet P £480.00 DT = £480.00
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Patients or their carers should be told how to recognise signs of liver disorder, and advised to discontinue treatment and seek prompt medical attention if symptoms such as anorexia, nausea, vomiting, fatigue, jaundice, abdominal pain, or dark urine develop. Patients or their carers should also be told how to recognise signs of adrenal insufficiency. Driving and skilled tasks Dizziness and somnolence may affect the performance of skilled tasks (e.g. driving).
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Initially 400–600 mg daily in 2–3 divided doses,
First-line fragment. Read the complete Indications and Dose section above.
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