Systemic antimycotics. Imidazole derivatives
ATC code: J02AB02 (Ketoconazole)
Brand names
Nizoral, Ketoconazole
Inhibits the fungal cytochrome P450 enzyme 14α-demethylase. This disrupts ergosterol synthesis, the main component of fungal cell membranes, leading to membrane permeability and cell death. Ketoconazole also inhibits human cytochrome P450, particularly CYP3A4, which explains drug interactions and systemic adverse effects. It suppresses steroid synthesis via inhibition of 11β-hydroxylase and 17α-hydroxylase, which underlies its off-label use in Cushing syndrome.
First line
Topical ketoconazole 2% shampoo or 2% cream is first-line therapy for seborrheic dermatitis and related dandruff. The 2015 Cochrane review confirmed shampoo efficacy versus placebo for remission of dandruff and pruritus. Shampoo is used twice weekly in the active phase, then once weekly for maintenance. Systemic absorption from topical use is minimal with no hepatotoxic risk.
Topical form is acceptable in pregnancy and breastfeeding – systemic absorption through intact skin is negligible. For pronounced facial inflammation, short courses combined with topical calcineurin inhibitors may be considered.
Second line
Ketoconazole is used off-label in endogenous Cushing syndrome to suppress cortisol synthesis when surgery is not feasible or is incomplete. The effect appears in 1–4 weeks at 400–1200 mg daily. In Europe, Ketoconazole HRA has been registered for this indication since 2014; in the US, use is off-label. Therapy requires lifelong ALT, AST and ALP monitoring and regular cortisol assessment.
Off-label use is only appropriate with involvement of an endocrinologist experienced in Cushing syndrome. The decision is made by a multidisciplinary team.
Second line
Systemic ketoconazole is used only in severe systemic mycoses when alternative azoles (fluconazole, itraconazole, voriconazole) and echinocandins are contraindicated, unavailable or ineffective. After the 2013 review, it lost its first-line indications due to the risk of fulminant hepatic failure. The in 2013 recommended withdrawal of oral formulations for fungal infections. International guidelines consider it a salvage option after other agents have been exhausted.
Not used for superficial mycoses or onychomycosis due to an unacceptable risk-benefit ratio. ALT, AST and ALP monitoring is mandatory before initiation and every 2 weeks during the first 2 months.
The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.
Not recommended
Oral ketoconazole is not used for superficial mycoses of skin, nails or mucosa. In 2013 the and withdrew these indications because of fulminant hepatic failure risk. The benefit-risk ratio is unfavorable for cutaneous and nail fungal infections: terbinafine is preferred for onychomycosis, itraconazole for extensive dermatomycoses, fluconazole for mucosal candidiasis. The topical form (shampoo, cream) retains its indications and does not carry systemic risk.
If a clinician proposes oral ketoconazole tablets for nail fungus or thrush, this conflicts with international practice and the Russian regulatory position. The patient may reasonably discuss alternatives or seek a second opinion.
24 pairs found. Sorted from critical to minor.
Mechanism
Ketoconazole strongly inhibits both CYP3A4 and P-glycoprotein – the clearance routes of apixaban. Apixaban plasma levels roughly double. The lists the combination as an absolute contraindication.
Symptoms
Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage, gross haematuria with renal colic, spontaneous retroperitoneal haematomas. Symptoms may appear within days of co-prescription.
Management
The combination is not prescribed. Alternative antifungals: terbinafine or echinocandins. During ketoconazole therapy, replace apixaban with a parenteral anticoagulant.
Sources
Mechanism
Colchicine is cleared via CYP3A4 and P-glycoprotein. Ketoconazole strongly inhibits both. Colchicine plasma levels rise several-fold. Colcrys carries a boxed warning for fatal toxicity.
Symptoms
Profuse diarrhoea, vomiting, abdominal pain – first signs of toxicity. Pancytopenia (drop in leukocytes, erythrocytes, platelets), muscle weakness, peripheral neuropathy, hepatic and renal injury follow. Fatal cases have been reported.
Management
For patients with renal or hepatic impairment, the combination is not prescribed. With preserved function, use colchicine 0.3 mg every other day, no more than 5 days. Alternative antifungals: terbinafine or echinocandins.
Mechanism
Ketoconazole is a strong CYP3A4 inhibitor, the main dronedarone clearance route. Dronedarone plasma levels rise 17-fold. Multaq Section 4.3 specifically lists strong CYP3A4 inhibitors.
Symptoms
QT prolongation on ECG. Clinically: dizziness, syncope, palpitations. Severe cases progress to polymorphic ventricular tachycardia (torsades de pointes) with risk of ventricular fibrillation and sudden cardiac death. Risk rises with hypokalaemia and hypomagnesaemia.
Management
The combination is not prescribed. Alternative antifungals: echinocandins (micafungin, caspofungin) or fluconazole for candidiasis (weaker CYP3A4 effect). Alternative antiarrhythmic: amiodarone or catheter ablation.
Mechanism
Ketoconazole is a potent inhibitor of hepatic CYP3A4 and the P-glycoprotein transporter. Rivaroxaban uses both for clearance. Rivaroxaban plasma levels rise 2.6-fold. The lists the combination as an absolute contraindication.
Symptoms
Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage, gross haematuria with renal colic, spontaneous retroperitoneal haematomas. Symptoms may appear within days of co-prescription.
Management
The combination is not prescribed. Alternative antifungals: terbinafine (no CYP3A4 use) for dermatophytosis, echinocandins for systemic mycoses. If a short ketoconazole course is required, switch rivaroxaban to a parenteral anticoagulant temporarily.
Sources
Mechanism
Simvastatin clearance is 98% via hepatic CYP3A4. Ketoconazole is one of the strongest CYP3A4 inhibitors. Simvastatin plasma levels rise 10-fold or more. The lists the combination as an absolute contraindication.
Symptoms
Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Severe cases progress to rhabdomyolysis with acute kidney injury. Symptoms appear within 1–2 weeks of co-prescription.
Management
The combination is not prescribed. Hold simvastatin during ketoconazole therapy or switch to pravastatin or rosuvastatin (no CYP3A4 use). Alternative antifungals: terbinafine or echinocandins.
Mechanism
Ketoconazole strongly blocks CYP3A4 – the main alprazolam metabolic route. Alprazolam plasma levels rise 3- to 4-fold. Particularly dangerous in older patients: deep sedation and fall risk.
Symptoms
Deep sedation, drowsiness, marked ataxia, cognitive impairment. In older patients: fall and fracture risk. Symptoms appear within 1–2 days.
Management
Avoid the combination. Alternative antifungals: terbinafine (no CYP3A4 effect) for dermatophytosis or echinocandins for systemic mycoses. Alternative benzodiazepines without CYP3A4 dependence: lorazepam, oxazepam.
Mechanism
Ketoconazole strongly blocks CYP3A4 – the N-deethylation pathway of amiodarone. Amiodarone and its active metabolite (N-desethyl-amiodarone) levels rise; QT effect intensifies.
Symptoms
QT prolongation on ECG. Clinically: dizziness, syncope, palpitations. Severe cases progress to polymorphic ventricular tachycardia (torsades de pointes) with risk of ventricular fibrillation and sudden cardiac death. Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.
Management
Avoid the combination. Alternative antifungals: terbinafine (no CYP3A4 effect) for dermatophytosis or echinocandins for systemic mycoses.
Mechanism
Ketoconazole is a strong CYP3A4 inhibitor – the main amlodipine metabolic route. Amlodipine plasma levels rise 2- to 3-fold; symptomatic hypotension and acute kidney injury risk.
Symptoms
Blood pressure drop: postural dizziness, syncope. Ankle oedema (typical of amlodipine), facial flushing, reflex tachycardia are possible.
Management
Avoid the combination. Alternative antifungals: terbinafine for dermatophytosis or echinocandins for systemic mycoses. If ketoconazole is needed, halve amlodipine.
Mechanism
Ketoconazole strongly inhibits CYP3A4 – the main atorvastatin metabolic route. Atorvastatin plasma levels rise 3- to 4-fold. Lipitor 2017 advises avoiding concomitant use.
Symptoms
Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Severe cases progress to rhabdomyolysis with acute kidney injury. Symptoms appear within 1–4 weeks of co-administration.
Management
During ketoconazole therapy, hold atorvastatin or switch to pravastatin/rosuvastatin (no CYP3A4 dependence). Alternative antifungals: terbinafine for dermatophytosis or echinocandins for systemic mycoses.
Mechanism
Ketoconazole strongly blocks CYP3A4 – the main budesonide metabolic route. Systemic budesonide exposure (oral or inhaled) rises 6- to 12-fold. High Cushing's syndrome risk with prolonged combination.
Symptoms
Moon face, central obesity, abdominal striae, hypertension, hyperglycaemia. With prolonged combination and abrupt withdrawal: adrenal insufficiency risk.
Management
The combination is not prescribed. Alternative antifungals: terbinafine for dermatophytosis or echinocandins for systemic mycoses. Alternative inhaled corticosteroid: fluticasone/mometasone (less CYP3A4-dependent).
Sources
Mechanism
Ketoconazole is a potent CYP3A4 and P-glycoprotein inhibitor – two main cyclosporine clearance routes. Cyclosporine plasma levels rise 2- to 3-fold; nephrotoxicity and neurotoxicity risk.
Symptoms
Acute nephrotoxicity: rising creatinine, hypertension, tremor, headache. In transplant patients: accelerated graft function decline.
Management
If unavoidable, reduce cyclosporine by 50–66% and check trough (C0) daily. Alternative antifungals: terbinafine for dermatophytosis or echinocandins for systemic mycoses.
Mechanism
Ketoconazole is a potent CYP3A4 inhibitor. Effect on citalopram is moderate (CYP3A4 is a minor route), but ketoconazole itself prolongs QT, so additive torsades de pointes risk persists.
Symptoms
QT prolongation on ECG. Clinically: dizziness, syncope, palpitations. Severe cases progress to polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.
Management
Avoid the combination. Alternative antifungals: terbinafine for dermatophytosis or echinocandins for systemic mycoses. If ketoconazole is needed: ECG before start and at day 3 of therapy.
Mechanism
Ketoconazole strongly blocks P-glycoprotein, the main transporter of dabigatran. Dabigatran plasma levels double, especially in renal impairment.
Symptoms
Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.
Management
The combination is not prescribed. Alternative antifungals: terbinafine (no P-glycoprotein use) for dermatophytosis, or echinocandins for systemic mycoses.
Mechanism
Ketoconazole is a potent CYP3A4 inhibitor – the main haloperidol metabolic route. Haloperidol plasma levels rise 2- to 3-fold. Ketoconazole itself prolongs QT; effects add up.
Symptoms
QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.
Management
Avoid the combination. Alternative antifungals: terbinafine or echinocandins. Alternative antipsychotics: olanzapine or aripiprazole.
Mechanism
Ketoconazole strongly blocks CYP3A4 – the main methylprednisolone metabolic route. Methylprednisolone plasma levels rise 2- to 3-fold. Risk of iatrogenic Cushing's syndrome and adrenal insufficiency on withdrawal.
Symptoms
Moon face, central obesity, abdominal striae, hypertension, hyperglycaemia (Cushing's syndrome). With prolonged combination and abrupt withdrawal: adrenal insufficiency risk with hypotension and weakness.
Management
Avoid the combination. Alternative antifungals: terbinafine for dermatophytosis or echinocandins for systemic mycoses. If ketoconazole is needed, halve the methylprednisolone dose.
Mechanism
Ketoconazole is a potent CYP3A4 inhibitor – the main quetiapine metabolic route. Quetiapine plasma levels rise 6- to 7-fold. Marked sedation, orthostatic hypotension, QT prolongation emerge.
Symptoms
Deep sedation, orthostatic hypotension with syncope, tachycardia, QT prolongation on ECG. Older patients: fall risk.
Management
During ketoconazole therapy, reduce quetiapine 4- to 6-fold and monitor ECG and blood pressure. Alternative antifungals: terbinafine or echinocandins. Alternative antipsychotics without CYP3A4 dependence: olanzapine or aripiprazole.
Mechanism
Dual mechanism. Rifampicin strongly induces CYP3A4, which partly metabolises ketoconazole. Ketoconazole plasma levels fall by 50–80%; antifungal efficacy is lost.
Symptoms
Recurrence of mycosis symptoms: ongoing fever, skin or mucosal lesions; in immunocompromised patients, risk of systemic mycosis progression.
Management
The combination is not prescribed. Alternative antifungal during anti-TB therapy: echinocandins (micafungin, caspofungin; resistant to CYP3A4 induction) or terbinafine for dermatophytosis.
Mechanism
Dual potent CYP3A4 inhibition. Ketoconazole plasma levels may rise 3-fold. Hepatotoxicity and adrenal cortex suppression intensify.
Symptoms
Nausea, rising liver enzymes (ALT, AST). Prolonged use: adrenal insufficiency risk with hypotension, hypoglycaemia, hyponatraemia. Cardiac symptoms from QT prolongation.
Management
Avoid the combination. Alternative antifungals on ritonavir: terbinafine for dermatophytosis or echinocandins for systemic mycoses.
Mechanism
Ketoconazole strongly blocks CYP3A4 – the main sildenafil metabolic route. Sildenafil plasma levels rise 4- to 8-fold. The hypotensive effect surges; priapism and ischaemic optic neuropathy risks rise.
Symptoms
Sudden blood pressure drop: dizziness, syncope. Priapism – painful erection lasting more than 4 hours. Visual disturbances, tinnitus. Symptoms appear within hours of co-administration.
Management
Avoid the combination. Alternative antifungals: terbinafine for dermatophytosis or echinocandins for systemic mycoses. If ketoconazole is needed, cap sildenafil at 25 mg and one dose per 24 hours.
Mechanism
Ketoconazole is the most potent CYP3A4 inhibitor available – the main tacrolimus metabolic route. Tacrolimus plasma levels rise 3- to 5-fold. The narrow therapeutic window makes any rise clinically dangerous.
Symptoms
Acute nephrotoxicity: rising creatinine and falling glomerular filtration rate. Tremor, headache, hypertension, hyperglycaemia, hyperkalaemia. In transplant patients: accelerated graft function decline.
Management
Avoid the combination. Alternative antifungals: terbinafine for dermatophytosis or echinocandins for systemic mycoses. If unavoidable, reduce tacrolimus 2- to 3-fold and check trough (C0) levels daily.
Mechanism
Ketoconazole is a potent CYP3A4 inhibitor – the main tamsulosin metabolic route. Tamsulosin plasma levels rise 2- to 3-fold; orthostatic hypotension and syncope emerge.
Symptoms
Sudden blood pressure drop on standing, syncope, dizziness. Older patients: fall and fracture risk.
Management
Avoid the combination. Alternative antifungals: terbinafine for dermatophytosis or echinocandins for systemic mycoses. Alternative for benign prostatic hyperplasia: a 5α-reductase inhibitor (finasteride, dutasteride).
Mechanism
Ketoconazole blocks CYP3A4 (one of the amitriptyline metabolic routes). TCA plasma levels may rise.
Symptoms
Worsening anticholinergic symptoms, drowsiness, tachycardia. Older patients: delirium and fall risk.
Management
For short ketoconazole courses, reduce amitriptyline by 25% temporarily. Alternative antifungals without CYP3A4 effect: terbinafine for dermatophytosis or echinocandins for systemic mycoses.
Mechanism
Additive QT prolongation.
Symptoms
QT prolongation on ECG. Dizziness, syncope, palpitations. Rarely: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.
Management
Avoid the combination. Alternative antifungals: terbinafine for dermatophytosis or echinocandins for systemic mycoses. Alternative antibiotics: a cephalosporin or doxycycline (no QT effect).
Mechanism
Escitalopram is metabolised mainly by CYP2C19 and partly by CYP3A4. Ketoconazole is a strong CYP3A4 inhibitor; escitalopram AUC rises modestly (20–40%) without major clinical effect. Additive QT risk is moderate.
Symptoms
QT prolongation on ECG. Dizziness, syncope, palpitations. Rarely: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease. Typical escitalopram side effects may appear: nausea, insomnia, decreased libido.
Management
For short systemic ketoconazole courses (7–14 days), cap escitalopram at 10 mg/day. Topical ketoconazole (shampoo, cream) does not interact. For long-term systemic therapy (e.g. invasive mycosis), antidepressant alternative: sertraline (minimal CYP3A4 interaction).
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Boxed warning
FDA boxed warning: systemic ketoconazole causes severe hepatotoxicity, including fulminant hepatic failure with death or need for transplantation. The drug is not used for superficial fungal infections. A separate boxed warning addresses clinically significant drug interactions and QT prolongation.
FDA category C. Animal studies show embryotoxicity and teratogenicity at high systemic doses. Human data are insufficient. Systemic forms are not used during pregnancy; alternative azoles or echinocandins are preferred. Topical formulations (shampoo) are acceptable.
Systemic forms are not used while breastfeeding – ketoconazole transfers into breast milk. Topical use of shampoo or cream on areas not in contact with the infant is safe.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
Ketoconazole is evaluated for the following indications with varying evidence strength: Seborrheic dermatitis (evidence tier A), Refractory systemic mycoses (evidence tier B), Cushing syndrome (evidence tier B). See the full indication matrix with dosing and citations above on this page.
Common side effects of Ketoconazole (≥ 1 in 100): Nausea, vomiting, abdominal discomfort, Rash, pruritus, Headache, dizziness, ALT/AST increase within 2× ULN. See the Safety section for uncommon and serious reactions.
FDA category C. FDA category C. Animal studies show embryotoxicity and teratogenicity at high systemic doses. Human data are insufficient. Systemic forms are not used during pregnancy; alternative azoles or echinocandins are preferred. Topical formulations (shampoo) are acceptable.
Systemic forms are not used while breastfeeding – ketoconazole transfers into breast milk. Topical use of shampoo or cream on areas not in contact with the infant is safe.
Ketoconazole is contraindicated in: Acute or chronic liver disease; ALT or AST > 2× ULN before therapy initiation; QT prolongation or history of ventricular arrhythmia; Co-administration with QT-prolonging drugs: cisapride, pimozide, quinidine, dofetilide; Co-administration with simvastatin, lovastatin, triazolam, oral midazolam, ergot alkaloids. Full list in the Safety section.
FDA boxed warning: systemic ketoconazole causes severe hepatotoxicity, including fulminant hepatic failure with death or need for transplantation. The drug is not used for superficial fungal infections. A separate boxed warning addresses clinically significant drug interactions and QT prolongation.
the FDA restricted these indications in 2013; terbinafine and itraconazole are used for onychomycosis.
systemic absorption of the shampoo is minimal, with no hepatotoxic risk. Topical and systemic forms are different safety categories.
fulminant hepatic failure occurs in approximately 1 in 15 000 patients, which prompted FDA and EMA restrictions.