Adult: As tab: Initially, 400-600 mg daily, may be increased by 200 mg daily every 7-28 days according to the urinary free cortisol and/or plasma cortisol levels. Maintenance dose range: 400-800 mg daily. Max: 1,200 mg daily. All daily doses are given in 2 or 3 divided doses. Dose reduction or discontinuation may be required based on the patient's adrenal and liver function. Treatment recommendations may vary between countries and individual products (refer to specific product or local official guidelines). Child: ≥12 years As tab: Same as adult dose.
Adult: For the treatment of cases in patients who have failed or are intolerant to other therapies, and the potential benefits of oral ketoconazole outweigh the potential risks: As tab: 200 mg once daily, may be increased to 400 mg once daily if clinical response is insufficient. Continue treatment until the active fungal infection has subsided; some infections require treatment duration of up to 6 months. Treatment recommendations may vary between countries and individual products (refer to specific product or local official guidelines). Child: For the treatment of cases in patients who have failed or are intolerant to other therapies, and the potential benefits of oral ketoconazole outweigh the potential risks: >2 years As tab: 3.3-6.6 mg/kg once daily. Duration of treatment varies according to patient, pathogen and disease-specific factors. Treatment recommendations may vary between countries and individual products (refer to specific product or local official guidelines).
Topical/Cutaneous Pityriasis versicolor
Adult: As 2% cream: Apply a sufficient amount onto the affected and immediate surrounding area(s) once daily for 2-3 weeks. Continue treatment until a few days after symptoms have resolved. Reconsider the diagnosis if no clinical improvement is noted after the treatment period. As 2% shampoo: Treatment: Apply a sufficient amount on wet hair and scalp once daily for a Max of 5 days. Alternatively, apply on damp hair and the surrounding area(s) as a single application. Prophylaxis: Apply a sufficient amount on wet hair and scalp once daily for a Max of 3 days before exposure to sunlight. Gently massage the shampoo, leave on for 3-5 minutes, then rinse thoroughly. Dosage and treatment recommendations may vary between countries and individual products (refer to specific product or local official guidelines).
Adult: As 2% cream: Apply a sufficient amount onto the affected and immediate surrounding area(s) 1-2 times daily. Usual treatment duration: 2-3 weeks (candidal infection); 2-4 weeks (tinea cruris); 3-4 weeks (tinea corporis); 4-6 weeks (tinea pedis). Continue treatment until a few days after symptoms have resolved. Reconsider the diagnosis if no clinical improvement is noted after the treatment period. Dosage and treatment duration recommendations may vary between countries and individual products (refer to specific product or local official guidelines).
Topical/Cutaneous Seborrhoeic dermatitis
Adult: As 2% cream: Apply a sufficient amount onto the affected area(s) 1-2 times daily for 2-4 weeks. Continue treatment until a few days after symptoms have resolved. Reconsider the diagnosis if no clinical improvement is noted after the treatment period. As 2% shampoo: Treatment: Apply a sufficient amount on wet hair and scalp 2 times weekly for 2-4 weeks. Prophylaxis: Apply a sufficient amount on wet hair and scalp once every 1-2 weeks. Gently massage the shampoo, leave on for 3-5 minutes, then rinse thoroughly. Dosage and treatment recommendations may vary between countries and individual products (refer to specific product or local official guidelines).
Topical/Cutaneous Dandruff
Adult: As 1% shampoo: Apply a sufficient amount on wet hair and scalp, lather and rinse thoroughly. Repeat use every 3 or 4 days for up to 8 weeks or as directed. Thereafter, use only as necessary to control dandruff. As 2% shampoo: Treatment: Apply a sufficient amount on wet hair and scalp 2 times weekly for 2-4 weeks. Prophylaxis: Apply a sufficient amount on wet hair and scalp once every 1-2 weeks. Gently massage the shampoo, leave on for 3-5 minutes, then rinse thoroughly. Dosage and treatment recommendations may vary between countries and individual products (refer to specific product or local official guidelines). Child: ≥12 years As 1% shampoo: Same as adult dose.
Hepatic Impairment
Oral:
Contraindicated.
Administration
Should be taken with food.
Contraindications
Hypersensitivity. Oral: Fungal meningitis (when used for systemic fungal infections); congenital or documented acquired QTc prolongation, pre-treatment liver enzymes >2 times the ULN (when used for Cushing's syndrome). Acute or chronic hepatic impairment. Pregnancy and lactation. Concomitant use with CYP3A4 metabolised HMG-CoA reductase inhibitors (e.g. simvastatin, lovastatin), ergot alkaloids (e.g. ergotamine, ergometrine), methadone, disopyramide, quinidine, dofetilide, dronedarone, pimozide, sertindole, ranolazine, cisapride, mizolastine, halofantrine, saquinavir/ritonavir, alprazolam, triazolam, oral midazolam, eplerenone, dabigatran, felodipine, nisoldipine, irinotecan, lurasidone, quetiapine, everolimus, sirolimus, paritaprevir/ombitasvir and tolvaptan. Concurrent use with telithromycin, clarithromycin, colchicine, fesoterodine and solifenacin (particularly in patients with renal impairment).
Special Precautions
Oral: Patient with actual or borderline adrenal insufficiency, prolonged periods of physiological stress (e.g. major surgery, intensive care, infection); acute porphyria. Administer ketoconazole with an acidic beverage (e.g. cola) to prevent reduced absorption due to high gastric content pH in patients with achlorhydria. When used for systemic fungal infections: Ketoconazole tab must be used only when other effective antifungal therapy is not available or tolerated and the potential benefits outweigh the potential risks; not indicated for the treatment of cutaneous dermatophyte infections, onychomycosis or Candida infections. Children. Pregnancy and lactation (topical).
Adverse Reactions
Significant: Oral: QT prolongation, adrenal suppression, hypersensitivity reactions (e.g. anaphylaxis, urticaria); decreased testosterone concentrations in men (manifested as reversible gynaecomastia, oligospermia and impotence). Gastrointestinal disorders: Nausea, vomiting, diarrhoea, abdominal pain, dyspepsia, flatulence, dry mouth. General disorders and administration site conditions: Asthenia, fatigue; application site burning sensation, erythema, irritation and pruritus (topical). Hepatobiliary disorders: Jaundice, hepatitis. Investigations: Abnormal LFTs, decreased platelet count. Metabolism and nutrition disorders: Alcohol intolerance, anorexia. Musculoskeletal and connective tissue disorders: Myalgia, arthralgia. Nervous system disorders: Headache, dizziness, somnolence, paraesthesia. Psychiatric disorders: Insomnia, nervousness. Reproductive system and breast disorders: Menstrual disorder, erectile dysfunction. Skin and subcutaneous tissue disorders: Pruritus, rash, alopecia, photosensitivity, dermatitis, dry skin; dry hair, hair discolouration, abnormal hair texture (shampoo). Potentially Fatal: Oral: Serious hepatotoxicity, including hepatic failure or cases that may require liver transplantation.
Oral: This drug may cause dizziness and somnolence, if affected, do not drive or operate machinery. Women of childbearing potential must use proven birth control methods during therapy. Topical: Avoid contact with eyes and other mucous membrane. Do not use the shampoo on a broken or inflamed scalp.
Monitoring Parameters
Oral: Assess for signs and symptoms of hepatotoxicity and adrenal insufficiency. For systemic fungal infections: Closely monitor LFTs at baseline and then weekly (particularly for serum ALT levels) during treatment; prothrombin time and INR prior to therapy initiation; adrenal function as clinically necessary. For Cushing's syndrome: Obtain LFTs at baseline, weekly for the 1st month after starting the treatment, then monthly for the next 6 months; in case of dose increases after the 1st 6 months of therapy, monitor LFTs weekly for 1 month. Monitor adrenal function (e.g. plasma free cortisol, urinary free cortisol) 1 week following initiation of therapy, then periodically thereafter; when cortisol levels are normalised or close to target and the effective dose is established, monitor cortisol every 3-6 months. Perform ECG before starting therapy, 1 week after initiation of treatment, and as clinically indicated thereafter.
Overdosage
Symptoms: Signs of adrenal insufficiency. Management: Symptomatic and supportive treatment. May administer activated charcoal or perform gastric lavage within the 1st hour after ingestion. In case of adrenal insufficiency, administer hydrocortisone with saline and glucose infusions. Closely monitor blood pressure and fluid or electrolyte balance for a few days.
Drug Interactions
May reduce absorption with agents that increase gastric pH (e.g. antacids, histamine 2 [H2]-receptor antagonists, PPIs); administer these agents at least 2 hours after taking ketoconazole and preferably with an acidic beverage (e.g. cola). Significantly reduced bioavailability with potent CYP3A4 inducers (e.g. rifampicin, rifabutin, carbamazepine, phenytoin, isoniazid, nevirapine, mitotane). May increase bioavailability with potent CYP3A4 inhibitors (e.g. ritonavir, ritonavir-boosted darunavir and fosamprenavir). May increase the plasma concentrations of buprenorphine (IV and sublingual), alfentanil, fentanyl, oxycodone, digoxin, apixaban, warfarin, cilostazol, repaglinide, saxagliptin, praziquantel, isavuconazole, eletriptan, dasatinib, lapatinib, docetaxel, vinca alkaloids (e.g. vincristine, vinblastine), haloperidol, midazolam (IV), buspirone, aripiprazole, nadolol, verapamil, aliskiren, bosentan, aprepitant, ciclosporin, dexamethasone, fluticasone, methylprednisone, salmeterol, vardenafil, sildenafil, tolterodine, cinacalcet and ebastine. Potentially Fatal: Increased risk of QT prolongation and ventricular dysrhythmias (including torsades de pointes) with methadone, disopyramide, quinidine, dofetilide, dronedarone, pimozide, sertindole, ranolazine, cisapride, mizolastine, halofantrine, saquinavir/ritonavir and pasireotide. May result in prolonged or increased sedation and respiratory depression with alprazolam, triazolam or oral midazolam. Increased risk of skeletal muscle toxicity including rhabdomyolysis with CYP3A4 metabolised HMG-CoA reductase inhibitors (e.g. lovastatin, simvastatin). May increase the risk of ergotism and vasospastic events with ergot alkaloids (e.g. ergometrine, ergotamine). Increased risk of hyperkalaemia and hypotension with eplerenone. May increase the risk of bleeding with dabigatran. Increased risk of oedema and CHF with felodipine and nisoldipine. May increase the plasma concentrations and risk of serious adverse effects of irinotecan, lurasidone, quetiapine, everolimus, sirolimus, paritaprevir/ombitasvir and tolvaptan. Increased risk of serious adverse effects with colchicine, fesoterodine and solifenacin (in patients with renal impairment). May increase the risk of hepatotoxicity and QT prolongation with telithromycin and clarithromycin (in patients with severe renal impairment). May increase the risk of liver damage with paracetamol.
Food Interaction
Oral: May result in a disulfiram-like reaction with alcohol. Absorption increases with decreasing stomach pH.
Action
Description: Mechanism of Action: Ketoconazole, a synthetic imidazole derivative, is an antifungal agent and a potent cortisol and aldosterone synthesis inhibitor. It alters the fungal CYP450-dependent enzyme lanosterol 14α-demethylase activity, thereby inhibiting ergosterol biosynthesis and consequently weakening the function and structure of the fungal cell membrane. It also inhibits several CYP450 enzymes in the adrenal glands primarily the activity of 17α-hydroxylase, 11-hydroxylation steps, and the cholesterol side-chain cleavage enzyme at high doses. Additionally, ketoconazole is a potent androgen synthesis inhibitor by blocking the C17-20 lyase activity in the adrenal and Leydig cells. Pharmacokinetics: Absorption: Variably absorbed from the gastrointestinal tract; minimally absorbed (topical). Oral: Absorption increases with decreasing stomach pH. Bioavailability: Decreases as gastric pH increases. Time to peak plasma concentration: Approx 1-2 hours. Distribution: Oral: Widely distributed in the tissues, including saliva, sebum, cerumen, bile, faeces, urine, inflamed joint fluid, tendons, skin and soft tissues, and testes. Poorly penetrates the blood-brain barrier and CSF (negligible amounts). Enters breast milk. Plasma protein binding: Approx 99%, mainly to albumin. Metabolism: Oral: Metabolised in the liver via oxidation, degradation of the imidazole and piperazine rings, oxidative-O-dealkylation and aromatic hydroxylation by CYP3A4 to form inactive metabolites. Excretion: Oral: 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 Compound Summary for CID 456201, (+)-Ketoconazole. https://pubchem.ncbi.nlm.nih.gov/compound/Xolegel. Accessed June 26, 2024.
Storage
Tab: Store between 20-25°C. Protect from moisture. Cream/Shampoo: Store between 15-30°C.
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
Aetos Kenazor Cream 2% w/w (Aetos Pharma Sdn Bhd). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 03/06/2024.Anon. Ketoconazole (Systemic). AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 03/06/2024.Anon. Ketoconazole (Topical). AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 03/06/2024.Brayfield A, Cadart C (eds). Ketoconazole. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 03/06/2024.Hovid-Ketoconazole Tablet 200 mg (Hovid Bhd.). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 03/06/2024.Joint Formulary Committee. Ketoconazole. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 03/06/2024.Ketoconazole (Systemic). UpToDate Lexidrug, Lexi-Drugs Multinational Online. Waltham, MA. UpToDate, Inc. https://online.lexi.com. Accessed 03/06/2024.Ketoconazole (Topical). UpToDate Lexidrug, Lexi-Drugs Multinational Online. Waltham, MA. UpToDate, Inc. https://online.lexi.com. Accessed 03/06/2024.Ketoconazole 2% Cream (Tasman Pharma Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 03/06/2024.Ketoconazole 2% w/w Shampoo (Pinewood Laboratories Limited trading as Pinewood Healthcare). MHRA. https://products.mhra.gov.uk. Accessed 03/06/2024.Ketoconazole HRA 200 mg Tablets (HRA Pharma Rare Diseases). MHRA. https://products.mhra.gov.uk. Accessed 03/06/2024.Ketoconazole Shampoo, Suspension 2% (Padagis Israel Pharmaceuticals Ltd). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 03/06/2024.Ketoconazole Tablet (Taro Pharmaceuticals U.S.A., Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 03/06/2024.Nizoral 2% Cream (Thornton & Ross Ltd.). MHRA. https://products.mhra.gov.uk. Accessed 03/06/2024.Nizoral Shampoo 1% (Kramer Laboratories). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 03/06/2024.
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