Adult: In patients who have failed or who are intolerant to other therapies: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis: 200 mg once daily, may increase to 400 mg once daily if clinical response is not obtained. Continue treatment until fungal infection is resolved. Child: >2 years 3.3-6.6 mg/kg once daily. Continue treatment until fungal infection is resolved.
Oral Cushing's syndrome
Adult: Initially, 400-600 mg daily, may be increased by 200 mg daily increments every 7-28 days if tolerated, according to patient’s urinary free or plasma cortisol levels. Maintenance dose range: 600-800 mg daily. Max: 1,200 mg daily. All doses are given in 2 or 3 divided doses. Dose reduction or discontinuation may be required based on patient adrenal and liver function (refer to detailed product guideline). Child: ≥12 years Same as adult dose.
Topical/Cutaneous Pityriasis versicolor
Adult: As 2% cream: Apply onto affected and immediate surrounding area 1-2 times daily for 2-3 weeks. Continue treatment until a few days after symptoms have resolved. As 2% shampoo: Treatment: Apply on wet scalp once daily for Max 5 days. Prophylaxis: Apply on wet scalp once daily for Max 3 days before exposure to sunlight.
Adult: As 2% cream: Apply onto affected and immediate surrounding area 1-2 times daily. Duration of treatment: Yeast infections: 2-3 weeks; tinea cruris: 2-4 weeks; tinea corporis: 3-4 weeks; tinea pedis: 4-6 weeks. Continue treatment until a few days after symptoms have resolved.
Topical/Cutaneous Seborrhoeic dermatitis
Adult: As 2% cream: Apply onto affected area 1-2 times daily for 2-4 weeks. Maintenance treatment: Apply once weekly on affected area. Continue treatment until a few days after symptoms have resolved. As 2% shampoo: Treatment: Apply on wet scalp twice weekly for 2-4 weeks. Prophylaxis: Apply on wet scalp once every 1-2 weeks. Leave for 3-5 minutes then rinse thoroughly. As 2% foam: Apply on the affected area bid for 4 weeks.
Topical/Cutaneous Dandruff
Adult: As 2% shampoo: Treatment: Apply on wet scalp twice weekly for 2-4 weeks. Prophylaxis: Apply on wet scalp once every 1-2 weeks. Leave for 3-5 minutes then rinse thoroughly.
Oral: This drug may cause dizziness and somnolence, if affected, do not drive or operate machinery. Topical: Avoid use of shampoo within 48 hours of applying hair dye, straightening or waving preparations. Avoid exposure to open flame or other source of ignition during or after application. Avoid contact with eyes and other mucous membrane.
Monitoring Parameters
Monitor LFT, bilirubin, adrenal function and QTc interval at baseline and at frequent intervals during therapy; serum Ca and phosphorus periodically (long-term use). Assess signs and symptoms of hepatotoxicity and hypocortisolism.
Overdosage
Symptoms: Oral: Signs of adrenal insufficiency e.g. severe nausea, vomiting, anorexia, weakness, severe fatigue. Management: Symptomatic and supportive treatment. May perform gastric lavage within the 1st hour after ingestion. May consider activated charcoal. In cases of adrenal insufficiency, administer hydrocortisone with saline and glucose infusions.
Drug Interactions
Increased risk of hyperkalaemia and hypotension with eplerenone. Increased risk of hepatotoxicity and QTc interval prolongation with telithromycin and clarithromycin Increased risk of oedema and CHF with felodipine and nisoldipine. Increased risk of liver damage with paracetamol. May reduce absorption with antacids, antimuscarinics, PPIs, H2-receptor antagonists. May decrease plasma concentration with CYP3A4 inducers (e.g. rifampicin, rifabutin, carbamazepine, phenytoin, isoniazid, nevirapine, mitotane). May increase serum level with CYP3A4 inhibitors (e.g. ritonavir-boosted darunavir and fosamprenavir). May increase plasma concentrations of buprenorphine, alfentanil, fentanyl, oxycodone, digoxin, apixaban, warfarin, cilostazol, repaglinide, praziquantel, saxaliptin, isavuconazole, eletriptan, buspirone, aripiprazole, reboxitine, risperidone, midazolam (IV), maraviroc, indinavir, nadolol, verapamil, aliskiren, bosentan, domperidone, naloxegol, ciclosporin, budesonide, dexamethasone, fluticasone, sildenafil, vardenafil, cinacalcet, ibrutinib, busulfan, docetaxel, vinca alkaloids (e.g. vincristine, vinblastine). May increase risk of QTc interval prolongation with haloperidol, salmeterol, ebastine, pasireotide and tolterodine. Potentially Fatal: Increased risk of QT prolongation and ventricular tachyarrhythmia (including torsade de pointes) with dronedarone, disopyramide, quinidine, dofetilide, methadone, cisapride, pimozide, sertindole, ranolazine, mizolastine, halofantrine and saquinavir/ritonavir. May increase risk of myopathy including rhabdomyolysis with HMG-CoA reductase inhibitors (e.g. lovastatin, simvastatin). May potentiate or prolong sedation and respiratory depression with oral midazolam, triazolam and alprazolam. Increased risk of bleeding with dabigatran. May increase risk of ergotism and vasospastic events with ergot alkaloids (e.g. ergometrine, ergotamine). May increase plasma concentrations of irinotecan, lurasidone, quetiapine, everolimus, sirolimus, tolvaptan, paritaprevir/ombitasvir; colchicine, fesoterodine and solifenacin (patient with renal impairment). Increase risk of adverse effect with colchicine.
Food Interaction
May result to disulfiram-like reaction with alcohol. May decrease serum concentration with St. John’s wort. May increase absorption with acidic beverages (e.g. non-diet cola) when co-administered with drugs that reduce gastric acidity (e.g. antacids).
Action
Description: Ketoconazole, an imidazole antifungal agent, inhibits fungal CYP450 activity, thereby decreasing ergosterol biosynthesis and inhibiting fungal cell membrane formation. It also inhibits some fungal enzymes resulting in the accumulation of toxic concentrations of hydrogen peroxide. Ketoconazole is also a potent cortisol and aldosterone synthesis inhibitor due to its ability to block several CYP450 enzymes in the adrenal glands. Pharmacokinetics: Absorption: Variably absorbed from the gastrointestinal tract. Bioavailability: Decreases as gastric pH increases. Time to peak plasma concentration: Approx 1-2 hours. Distribution: Widely distributed into tissues including inflamed joint fluid, tendons, saliva, sebum, cerumen, bile, faeces, urine, testes, skin and soft tissues; poorly penetrates the blood-brain barrier and CSF (negligible amounts). Crosses placenta and enters breast milk. Plasma protein binding: Approx 99%, mainly to albumin. Metabolism: Extensively metabolised in the liver via oxidation, oxidative-O-dealkylation and aromatic hydroxylation by CYP3A4 isoenzyme to its inactive metabolites. Excretion: Mainly via faeces (57%); urine (13%, 2-4% as unchanged drug). Elimination half-life: 2 hours (initial); 8 hours (terminal).
Chemical Structure
Ketoconazole Source: National Center for Biotechnology Information. PubChem Database. Xolegel, CID=456201, https://pubchem.ncbi.nlm.nih.gov/compound/Xolegel (accessed on Jan. 21, 2020)
Storage
Tab: Store between 20-25°C. Cream, shampoo: Store below 25°C. Protect from light. Foam: Store between 20-25°C. Protect from heat and direct sunlight.
J02AB02 - ketoconazole ; Belongs to the class of imidazole derivatives. Used in the systemic treatment of mycotic infections. D01AC08 - ketoconazole ; Belongs to the class of imidazole and triazole derivatives. Used in the topical treatment of fungal infection.
References
Anon. Ketoconazole (Systemic). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 11/06/2019.Anon. Ketoconazole (Topical). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 11/06/2019.Buckingham R (ed). Ketoconazole. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 13/06/2019.Daktarin Gold 2% Cream (McNeil Products Limited). MHRA. https://products.mhra.gov.uk/. Accessed 13/06/2019.Dandrazol 2% Shampoo (Transdermal Limited). MHRA. https://products.mhra.gov.uk/. Accessed 11/06/2019.Douglas Pharmaceuticals Ltd. Sebizole 2% w/w Shampoo data sheet 08 March 2018. Medsafe. http://www.medsafe.govt.nz/. Accessed 13/06/2019.Extina Aerosol, Foam (Mylan Pharmaceuticals Inc). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 11/06/2019.Ketoconazole HRA Recommended For Approval in Cushing's Syndrome. European Medicines Agency [online]. Accessed 04/07/2019.Ketoconazole Tablet (Mylan Pharmaceuticals Inc). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 11/06/2019.Oral Ketoconazole: Do Not Prescribe or Use for Fungal Infections - Risk of Liver Injury Outweighs Benefits. Medicines & Healthcare products Regulatory Agency. https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency. Accessed 13/06/2019.
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