Azole antifungal (imidazole; potent CYP3A4 inhibitor)
Ketoconazole is an antifungal (azole) used orally for deep or severe fungal infections that have not responded to other treatments. It strongly blocks the elimination of many medicines, so the risk of serious interactions is high and close medical supervision is required.
Also known as: Nizoral, Cetoconazol
Rifampin (a CYP450 inducer) markedly reduces Ketoconazole levels, risking antifungal treatment failure.
The interaction is bidirectional: rifampicin induces CYP3A4 and markedly reduces ketoconazole concentrations (loss of antifungal effect), while ketoconazole inhibits CYP3A4 and can raise rifampicin levels, with risk of hepatotoxicity. The combination should be avoided; if unavoidable, monitor the antifungal response and liver function, considering antifungal alternatives not dependent on CYP3A4 (e.g. amphotericin B, echinocandins).
Ketoconazole + rifampicin: rifampicin lowers ketoconazole levels (antifungal failure) and ketoconazole raises rifampicin levels. Avoid the combination.
Enzymatic induction (CYP3A4/P-glycoprotein) by rifampin accelerates ketoconazole elimination and reduces its efficacy.
Clinical response to the antifungal; ketoconazole levels (if available); liver function tests.
Persistent or worsening fungal infection, recurrent fever.
Avoid the combination. If both are required, use an alternative antifungal and monitor clinical and mycological response.
DailyMed/FDA (NIH/NLM) — approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 ; approved Rifampin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b389b1a3-672f-47e3-916c-4a9c044b211b — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Fexofenadine + ketoconazole: increased fexofenadine exposure.
Fexofenadine is a P-glycoprotein (P-gp) substrate, and ketoconazole, by inhibiting this transporter, can raise fexofenadine concentrations. Although fexofenadine is a non-sedating antihistamine, high levels can cause drowsiness, headache or dizziness in susceptible patients. The interaction is generally mild; monitor symptoms and consider adjusting the antihistamine dose during antifungal treatment.
Ketoconazole + fexofenadine: the azole can raise fexofenadine levels (P-gp inhibition), with possible drowsiness. Monitor.
Ketoconazole interferes with intestinal fexofenadine transport (P-gp/OATP).
Antihistamine adverse effects.
Drowsiness, dizziness, nausea.
Watch for adverse effects; no relevant clinical impact for most patients.
DailyMed (FDA) — approved Fexofenadine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=dd0da52b-fc82-4ec9-854c-0d7c52e926fb ; approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Ketoconazole (a potent CYP3A4 inhibitor) raises Atorvastatin levels, increasing the risk of myopathy and rhabdomyolysis.
Ketoconazole is a potent inhibitor of CYP3A4, the main enzyme that metabolises atorvastatin; co-administration markedly raises statin concentrations and the risk of myopathy, including rhabdomyolysis, especially at high doses or in patients with renal or hepatic dysfunction. The atorvastatin label recommends considering the risk/benefit of concomitant use with other azole antifungals (including ketoconazole) and monitoring all patients for signs of myopathy, particularly at initiation and during titration; no specific dose limit is given for ketoconazole (unlike itraconazole, 20 mg). Instruct the patient to stop the statin in the presence of muscle pain, weakness or dark urine.
Atorvastatin + ketoconazole: the azole inhibits CYP3A4 and can raise statin levels, with a risk of myopathy/rhabdomyolysis. Stop the statin or reduce the dose.
CYP3A4 inhibition by ketoconazole reduces first-pass metabolism of atorvastatin, increasing its systemic exposure.
Creatine kinase (CK), muscle symptoms (myalgia, weakness, dark urine).
Severe muscle pain, weakness, dark-coloured urine (sign of rhabdomyolysis).
Prefer a statin not metabolized by CYP3A4 (e.g., pravastatin, rosuvastatin) or discontinue ketoconazole during therapy. If unavoidable, use the lowest atorvastatin dose with monitoring.
DailyMed/FDA (NIH/NLM) — approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 ; approved Atorvastatin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=86841382-4229-4e03-958e-3ac22639efd4 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Ketoconazole raises Digoxin concentrations, with a risk of digitalis toxicity.
Ketoconazole is a potent inhibitor of P-glycoprotein and CYP3A4, the two systems that eliminate digoxin. The inhibition increases oral bioavailability and reduces digoxin clearance, raising its concentrations and the risk of digitalis toxicity. Monitor digoxin levels when ketoconazole is started or adjusted, reduce the digoxin dose if needed and watch for toxicity symptoms (nausea, bradycardia, arrhythmias, visual disturbances), especially in prolonged treatment.
Ketoconazole inhibits P-glycoprotein and can raise digoxin levels. Monitor digoxin levels and toxicity signs.
P-glycoprotein inhibition by ketoconazole reduces digoxin elimination and increases its bioavailability.
Digoxin levels, ECG (bradycardia, arrhythmias), gastrointestinal and visual symptoms.
Nausea, vomiting, arrhythmias, yellow/green vision (xanthopsia).
Monitor digoxin levels and clinical signs; reduce the digoxin dose if needed. Watch closely in the elderly and in renal impairment.
DailyMed/FDA (NIH/NLM) — approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 ; approved Digoxin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5886e233-b2da-4acb-be05-9bf40fb8e7f4 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Carbamazepine lowers ketoconazole levels (induction) while ketoconazole can raise carbamazepine; reciprocal effects.
Carbamazepine is metabolised by CYP3A4; ketoconazole is a potent inhibitor of this enzyme and can raise carbamazepine concentrations, with risk of intoxication (nystagmus, ataxia, diplopia, sedation and, in severe cases, arrhythmias and seizures). Monitor carbamazepine plasma levels, reduce the dose if needed and watch for toxicity signs while the antifungal lasts.
Ketoconazole + carbamazepine: ketoconazole inhibits CYP3A4 and may raise carbamazepine levels, with risk of toxicity (nystagmus, ataxia, sedation). Monitor levels.
Carbamazepine induces ketoconazole metabolism; ketoconazole inhibits CYP3A4, reducing carbamazepine metabolism.
Carbamazepine concentration, toxicity symptoms (diplopia, nystagmus, ataxia), mycosis response.
Diplopia, nystagmus, ataxia, drowsiness; or worsening fungal infection.
Monitor carbamazepine levels and antifungal response; adjust doses; consider a non-CYP3A4-inducing alternative.
DailyMed/FDA (NIH/NLM) — approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 ; approved Carbamazepine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f3d91cd-a959-4e07-a51b-8a4e9ba9ece2 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Omeprazole (proton-pump inhibitor) reduces Ketoconazole absorption by raising gastric pH.
Ketoconazole (tablet) is a weak base whose dissolution and oral absorption depend strongly on acidic gastric pH. Omeprazole, by suppressing acid secretion, reduces ketoconazole plasma concentrations in a clinically significant way, potentially compromising the treatment of systemic fungal infections. The ketoconazole label and the Portuguese Prontuário Terapêutico recommend avoiding the combination or, if unavoidable, considering alternative formulations and monitoring the clinical response to the antifungal.
Omeprazole + ketoconazole: ketoconazole absorption depends on acidic pH and is drastically reduced by PPIs. Avoid the combination.
pH-dependent absorption: acid suppression reduces ketoconazole dissolution in the stomach.
Clinical response to the antifungal.
Persistent fungal infection.
Separate dosing (ketoconazole 2 h before omeprazole) or prefer a non-pH-dependent azole.
DailyMed/FDA (NIH/NLM) — approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 ; approved Omeprazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=37291cab-e350-d8e3-e063-6294a90a9cb1 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Antacids, H2-blockers, proton-pump inhibitors and sucralfate markedly reduce Ketoconazole absorption, compromising efficacy.
Ketoconazole (tablet) is an azole antifungal whose oral absorption is strongly dependent on an acidic gastric pH — the drug is a weak base that only dissolves well in an acidic medium. Antacids, by raising the pH, can reduce ketoconazole plasma concentrations in a clinically significant way, compromising the treatment of systemic fungal infections. The ketoconazole label and the Portuguese Prontuário Terapêutico recommend avoiding the combination or separating administration by at least 2 hours (ideally more), and considering monitoring the clinical response to the antifungal.
Antacids + ketoconazole: ketoconazole tablet absorption depends on acidic pH; antacids reduce it dramatically. Avoid simultaneous administration and separate by at least 2 hours.
Ketoconazole absorption depends on gastric acidity; agents that raise gastric pH reduce its dissolution and absorption.
Clinical response; signs of antifungal failure; temporal separation of doses.
Worsening or persistent fungal infection.
Give ketoconazole at least 2 h before antacids/PPIs; otherwise use fluconazole/voriconazole (less pH-dependent).
DailyMed/FDA (NIH/NLM) — approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 ; approved Antacids label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c72f0736-ee20-45b4-baf0-b80f1e3fa9cb — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Combining Alprazolam with Ketoconazole increases Alprazolam concentrations, with a risk of excessive sedation.
Alprazolam is metabolised by CYP3A4, and ketoconazole is a potent inhibitor of this enzyme, potentially raising benzodiazepine concentrations and effects markedly (sedation, drowsiness, ataxia, respiratory depression), especially in the elderly. The ketoconazole label considers co-administration with alprazolam (like oral midazolam and triazolam) contraindicated, because the elevated concentrations can potentiate and prolong hypnotic and sedative effects. Do not combine; consider an alternative benzodiazepine or anxiolytic not metabolised by CYP3A4.
Alprazolam + ketoconazole: the azole inhibits CYP3A4 and can greatly raise alprazolam levels, with sedation and respiratory depression. Contraindicated (ketoconazole label).
Ketoconazole, a CYP3A4 inhibitor, reduces Alprazolam metabolism, raising its levels.
Marked sedation, confusion or respiratory depression require immediate intervention.
Marked sedation or respiratory depression require immediate intervention.
Reduce the Alprazolam dose or avoid the combination; monitor sedation.
DailyMed/FDA (NIH/NLM) — approved Alprazolam label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0cf8b567-201b-44fa-8fd3-c74023aff44f ; approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Loratadine + ketoconazole: possible increased loratadine concentrations.
Loratadine is metabolised by CYP3A4, and ketoconazole can raise its concentrations. Unlike first-generation antihistamines, loratadine is not associated with significant QT prolongation, even at high levels; the interaction manifests mainly as drowsiness or mild sedation in susceptible patients. Monitor symptoms, use the lowest effective dose and consider an alternative antihistamine if sedation is troublesome.
Ketoconazole + loratadine: the azole raises loratadine levels (CYP3A4), without relevant QT prolongation. Monitor drowsiness.
Ketoconazole (CYP3A4 and P-gp inhibitor) reduces loratadine clearance.
Sedative effects and ECG if risk factors present.
Syncope, palpitations, marked drowsiness.
Watch for drowsiness; trials showed no relevant QTc prolongation.
DailyMed (FDA) — approved Loratadine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=569a35be-d653-181c-e063-6294a90a6eb9 ; approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Desloratadine + ketoconazole: possible increased desloratadine concentrations.
Ketoconazole, by inhibiting CYP3A4, can raise desloratadine concentrations; however, desloratadine and its active metabolite have a wide safety margin and the combination is not associated with significant QT prolongation (unlike the old terfenadine/astemizole). In practice, the interaction is generally well tolerated; monitor drowsiness or sedation in susceptible patients and use the lowest effective antihistamine dose during antifungal treatment.
Ketoconazole + desloratadine: the azole raises desloratadine levels (CYP3A4), usually without relevant QT prolongation. Monitor drowsiness.
Ketoconazole inhibits CYP3A4, raising desloratadine levels.
Symptoms of antihistamine excess.
Drowsiness, palpitations, dizziness.
Watch for sedation and adverse effects.
DailyMed (FDA) — approved Desloratadine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2a90b899-7746-43dc-ac8a-e754428eb30c ; approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Ketoconazole can raise tadalafil blood levels (ketoconazole 400 mg/day can quadruple exposure), with a higher risk of side effects.
Tadalafil is mainly metabolised by CYP3A4. Ketoconazole (200 mg/day) increased tadalafil exposure (AUC) 2-fold; at 400 mg/day, 4-fold. This increases adverse reactions (headache, dyspepsia, myalgia, flushing, nasal congestion). Other strong CYP3A4 inhibitors (ritonavir, itraconazole, clarithromycin) are expected to have a similar effect.
CYP3A4: ketoconazole (strong inhibitor) increased tadalafil AUC 2–4-fold. Adjust the dose: as-needed tadalafil max. 10 mg every 72 h; daily use max. 2.5 mg.
CYP3A4 inhibition by ketoconazole, reducing tadalafil clearance.
Tadalafil adverse effects (headache, flushing, myalgia, dyspepsia).
Severe headache, symptomatic hypotension, priapism.
Adjust the dose per the label (as-needed: max. 10 mg/72 h; daily: max. 2.5 mg) and watch for adverse effects.
DailyMed/FDA (NIH/NLM) — approved Tadalafil label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bcd8f8ab-81a2-4891-83db-24a0b0e25895 ; approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Ketoconazole greatly raises vardenafil blood levels (up to 10-fold), with a high risk of side effects. The combination should be avoided, especially in men over 75.
Vardenafil is metabolised by CYP3A4. Ketoconazole (200 mg) increased vardenafil AUC about 10-fold and Cmax 4-fold. Concomitant use with ketoconazole or itraconazole (oral) should be avoided; it is contraindicated in men over 75. It increases the risk of headache, flushing, dyspepsia, nasal congestion and hypotension.
CYP3A4: ketoconazole increased vardenafil AUC ~10-fold. Avoid the combination; if unavoidable, max vardenafil 2.5 mg/24 h (or 5 mg with ketoconazole 200 mg); contraindicated over 75 years.
CYP3A4 inhibition, reducing vardenafil clearance.
Vardenafil adverse effects and hypotension symptoms.
Severe headache, symptomatic hypotension, priapism.
Avoid the combination; if unavoidable, reduce the vardenafil dose per the label.
DailyMed/FDA (NIH/NLM) — approved Vardenafil label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2782efed-6198-47b9-81ac-3e255e2ab7f6 ; approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 ; EMC-UK (MHRA) — approved Vardenafil SmPC: https://www.medicines.org.uk/emc/product/11394/smpc ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Ketoconazole raises tamsulosin blood levels (up to ~2.8-fold), with a higher risk of hypotension and dizziness.
Tamsulosin is metabolised by CYP3A4 and CYP2D6. Ketoconazole (400 mg/day) increased tamsulosin Cmax 2.2-fold and AUC 2.8-fold. Combining with strong CYP3A4 inhibitors should be avoided in CYP2D6 poor metabolisers and used with caution in others, due to the risk of hypotension and adverse effects.
CYP3A4: ketoconazole increased tamsulosin AUC ~2.8-fold. Do not use with strong CYP3A4 inhibitors in CYP2D6 poor metabolisers; use with caution in others.
CYP3A4 inhibition, reducing tamsulosin clearance.
Orthostatic blood pressure and tamsulosin adverse effects.
Dizziness, symptomatic hypotension, syncope.
Avoid the combination in CYP2D6 poor metabolisers; in others, use with caution and watch for hypotension.
DailyMed/FDA (NIH/NLM) — approved Tamsulosin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5ed219aa-cf65-457f-8570-d26b48edb240 ; approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 ; EMC-UK (MHRA) — approved Tamsulosin SmPC: https://www.medicines.org.uk/emc/product/102038/smpc ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Ketoconazole can raise doxazosin blood levels, with a higher risk of hypotension. Use with caution.
Doxazosin is metabolised by CYP3A4. Strong inhibitors of this enzyme (ketoconazole, itraconazole, clarithromycin, indinavir, ritonavir, saquinavir) raise plasma concentrations and the risk of postural hypotension.
CYP3A4: doxazosin is a CYP3A4 substrate; strong inhibitors (ketoconazole, itraconazole, clarithromycin) increase exposure and the risk of hypotension.
CYP3A4 inhibition, reducing doxazosin clearance.
Orthostatic blood pressure.
Dizziness on standing, symptomatic hypotension, syncope.
Use with caution and monitor blood pressure, especially at initiation.
DailyMed/FDA (NIH/NLM) — approved Doxazosin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5e1f5e49-2da1-43ab-9795-228a8bcc5a82 ; approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 ; EMC-UK (MHRA) — approved Doxazosin SmPC: https://www.medicines.org.uk/emc/product/102410/smpc ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Ketoconazole (or other strong CYP3A4 inhibitors) can raise dutasteride blood levels. Use with caution and watch for side effects.
Dutasteride is eliminated mainly by hepatic metabolism (CYP3A4/3A5). Potent inhibitors of this enzyme raise serum concentrations; in population studies, moderate inhibitors (verapamil, diltiazem) increased concentrations 1.6–1.8-fold. The long half-life may be further prolonged, taking more than 6 months to reach a new steady state.
CYP3A4: dutasteride is eliminated by CYP3A4/3A5 metabolism; strong inhibitors (ketoconazole, itraconazole, ritonavir) raise serum concentrations. In long-term use, consider reducing dose frequency.
CYP3A4/3A5 inhibition, reducing dutasteride elimination.
Dutasteride adverse effects (decreased libido, erectile dysfunction, ejaculation disorders, gynaecomastia).
Gynaecomastia, persistent sexual dysfunction.
Use with caution; in long-term use with strong inhibitors, consider reducing dose frequency; watch for adverse effects.
DailyMed/FDA (NIH/NLM) — approved Dutasteride label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=947644ea-bc35-41df-8a7a-874360c90192 ; approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 ; EMC-UK (MHRA) — approved Dutasteride SmPC: https://www.medicines.org.uk/emc/product/102479/smpc ; PubMed — https://pubmed.ncbi.nlm.nih.gov/31835695/ ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Ketoconazole may slightly raise finasteride blood levels, but the clinical impact is considered of little significance.
Finasteride is mainly metabolised by CYP3A4 but does not significantly affect this system. CYP3A4 inhibitors and inducers may alter its plasma concentrations; however, based on established safety margins, they are unlikely to be clinically significant.
CYP3A4: finasteride is metabolised by CYP3A4, but the label states that any increase from inhibitors is unlikely to be clinically significant (wide safety margins).
Finasteride CYP3A4 metabolism, with clinical impact unlikely.
No specific monitoring.
No specific red flags.
No special precaution needed; maintain usual surveillance.
DailyMed/FDA (NIH/NLM) — approved Finasteride label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=350b2bdb-84a1-4465-b0ad-175b8f720400 ; approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 ; EMC-UK (MHRA) — approved Finasteride SmPC: https://www.medicines.org.uk/emc/product/100132/smpc ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Ketoconazole can increase estradiol levels and its side effects. Watch for signs such as nausea, breast tenderness or swelling.
The approved estradiol label (DailyMed) lists ketoconazole among the CYP3A4 inhibitors that increase plasma oestrogen concentrations. Systemic ketoconazole is now restricted, but the combination can occur with highly absorbed topical antifungals or in older regimens. Signs of oestrogen excess should be watched during treatment.
Ketoconazole (a potent CYP3A4 inhibitor) increases oestrogen concentrations; monitor dose-dependent effects during the combination.
CYP3A4 inhibition, reducing oestrogen metabolism.
Symptoms of oestrogen excess.
Breast pain, oedema, irregular bleeding.
Watch for adverse effects during the antifungal; adjust the estradiol dose if needed.
DailyMed/FDA (NIH/NLM) — approved Estradiol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5718f042-e8c0-b721-e063-6294a90a5bef ; approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Ketoconazole potentiates the anticoagulant effect of Warfarin, increasing the bleeding risk.
Ketoconazole is a potent inhibitor of several cytochrome P450 isoenzymes, including CYP2C9 (which metabolises active S-warfarin) and CYP3A4 (which metabolises R-warfarin). The inhibition results in increased warfarin levels, INR elevation and significant bleeding risk — the ketoconazole and warfarin labels both mention this interaction. Whenever possible the combination should be avoided (alternative antifungals with fewer interactions exist); if unavoidable, reduce the warfarin dose, monitor the INR frequently at initiation and watch for bleeding signs.
Ketoconazole inhibits CYP2C9 and CYP3A4 and can markedly raise the INR. Avoid if possible; if unavoidable, reduce warfarin and monitor the INR closely.
CYP2C9 (and CYP3A4) inhibition by ketoconazole reduces warfarin metabolism and raises the INR.
INR, signs of bleeding (gums, bruising, melena).
Unexplained bleeding, haematuria, melena, intracranial haemorrhage.
Monitor the INR more frequently after starting/stopping ketoconazole; adjust the warfarin dose accordingly.
DailyMed/FDA (NIH/NLM) — approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Ketoconazole plus Amiodarone carries a risk of QT prolongation and ventricular arrhythmias.
Amiodarone is metabolised by CYP3A4 and CYP2C8; ketoconazole is a potent CYP3A4 inhibitor and reduces amiodarone clearance, potentially doubling its concentrations. Since both also prolong the QT interval, the risk of torsades de pointes and of toxicity (pulmonary, hepatic, thyroid, neuropathy) increases. The combination should be avoided; if unavoidable, reduce the amiodarone dose, monitor the ECG and plasma levels (if available) and watch for adverse effects.
Ketoconazole + amiodarone: ketoconazole inhibits CYP3A4 and may raise amiodarone levels, increasing the QT/arrhythmia risk. Avoid the combination.
Additive effect on cardiac repolarization; ketoconazole may also raise amiodarone levels via metabolic inhibition.
ECG (QT interval), electrolytes (K+, Mg2+), signs of arrhythmia/palpitations.
Syncope, palpitations, torsades de pointes.
Use with caution; monitor ECG (QT interval) and electrolytes (K+, Mg2+); correct hypokalaemia before combining.
DailyMed/FDA (NIH/NLM) — approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 ; approved Amiodarone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=51a88e8e-da02-4b97-9e7e-442fbffd908d
Ketoconazole raises Amlodipine levels (CYP3A4 inhibition), with a risk of hypotension and oedema.
Amlodipine is a CYP3A4 substrate, and ketoconazole, by inhibiting this enzyme, can raise its concentrations and potentiate the vasodilator effects (hypotension, peripheral oedema, flushing, headache). In most patients the interaction is managed by monitoring blood pressure and signs of oedema; if symptoms arise, consider reducing the amlodipine dose or using an antihypertensive less dependent on CYP3A4 during the antifungal.
Amlodipine + ketoconazole: CYP3A4 inhibition raising amlodipine levels. Monitor hypotension and oedema.
CYP3A4 inhibition by ketoconazole reduces first-pass amlodipine metabolism.
Blood pressure, peripheral oedema, headache, flushing.
Symptomatic hypotension, significant oedema.
Monitor blood pressure and oedema; consider reducing the amlodipine dose if adverse effects occur.
DailyMed/FDA (NIH/NLM) — approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 ; approved Amlodipine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=58a67272-c4c7-4e2c-85a5-9d39034d12c3 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Combining Nevirapine with Ketoconazole alters the concentrations of both: it raises Nevirapine and lowers Ketoconazole.
Nevirapine, a non-nucleoside reverse transcriptase inhibitor, induces CYP3A4 and lowers ketoconazole concentrations, potentially compromising antifungal treatment; conversely, ketoconazole inhibits CYP3A4 and can raise nevirapine levels, with a higher risk of adverse effects (notably hepatotoxicity and skin rash). The nevirapine label states that ketoconazole and nevirapine should not be administered concomitantly (reduced ketoconazole may compromise antifungal efficacy) and that increased nevirapine exposure warrants close monitoring for adverse effects. If the combination is unavoidable, monitor the clinical response to the fungal infection and liver function/rash.
Ketoconazole + nevirapine: nevirapine lowers ketoconazole levels and the azole raises nevirapine levels. The label advises against the combination; monitor response and liver function.
Nevirapine (an enzyme inducer) lowers Ketoconazole concentrations; Ketoconazole (a CYP3A4 inhibitor) raises Nevirapine concentrations.
Monitor liver function and antifungal efficacy; signs of Nevirapine toxicity (skin rash, hepatitis).
Antifungal failure or raised transaminases require reassessment of the regimen.
Avoid the combination whenever possible; if needed, monitor the therapeutic response and adverse effects of both.
DailyMed/FDA (NIH/NLM) — approved Nevirapine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fbd628db-4076-4fe0-8323-9cc33ae92e42 ; approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Ketoconazole raises Sildenafil concentrations, with a risk of hypotension and intensified adverse effects.
Sildenafil is a CYP3A4 substrate, and ketoconazole, a potent inhibitor of this enzyme, can markedly raise its concentrations, potentiating vasodilation (hypotension, headache, flushing, nasal congestion) and the risk of priapism. The sildenafil label recommends considering a starting dose of 25 mg in patients treated with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole). Alert the patient to alarm signs (priapism, chest pain) and avoid the simultaneous use of nitrates.
Ketoconazole + sildenafil: the azole greatly raises sildenafil levels (CYP3A4), with a risk of hypotension, priapism and toxicity. Consider a starting dose of 25 mg.
CYP3A4 inhibition — the main sildenafil metabolic pathway — increases its plasma exposure.
Blood pressure, headache, facial flushing, palpitations.
Severe hypotension, syncope, chest pain, priapism.
Limit the sildenafil dose (max 25 mg) during ketoconazole therapy; avoid use in unstable cardiovascular disease.
DailyMed/FDA (NIH/NLM) — approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 ; approved Sildenafil label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=00ee09dd-2de0-4dc4-85f6-b51ed6eabd5b
Alcohol increases the risk of liver injury during ketoconazole treatment.
Avoid alcohol during treatment.
DailyMed/FDA (NIH/NLM) — approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0
Grapefruit raises ketoconazole concentrations (CYP3A4 inhibition), increasing the risk of hepatotoxicity and QT prolongation.
Avoid grapefruit juice during treatment.
DailyMed/FDA (NIH/NLM) — approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0
Ketoconazole prolongs the QT and increases the risk of ventricular arrhythmias, especially with other QT-prolonging drugs.
Avoid in QT prolongation or with QT-prolonging drugs; monitor ECG and electrolytes.
DailyMed/FDA (NIH/NLM) — approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0
Ketoconazole can cause severe hepatotoxicity and is contraindicated in acute or chronic liver disease.
Contraindicated in liver disease; assess liver function before and during treatment.
DailyMed/FDA (NIH/NLM) — approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0
Oral ketoconazole is teratogenic in animals and should not be used in pregnancy (topical use has minimal exposure).
Contraindicated orally in pregnancy; prefer an alternative antifungal.
Excreted into breast milk; avoid while breastfeeding.
Advise effective contraception during oral treatment.
DailyMed/FDA (NIH/NLM) — approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Oral azole antifungal for severe systemic fungal infections (blastomycosis, coccidioidomycosis, histoplasmosis, paracoccidioidomycosis) when no alternative exists. Potent CYP3A4 and P-glycoprotein inhibitor; prolongs the QT interval and can suppress adrenal corticosteroid secretion at doses ≥400 mg.
Blocks the synthesis of ergosterol, an essential component of the fungal cell membrane, by inhibiting the cytochrome P450-dependent enzyme lanosterol 14α-demethylase, which converts lanosterol into ergosterol. Ergosterol depletion weakens the structure and function of the fungal cell membrane.
Weak dibasic agent: requires gastric acidity for dissolution and absorption. Peak plasma concentrations (~3.5 mcg/mL after 200 mg with a meal) occur in 1 to 2 hours. Antacids and acid-suppressing drugs greatly reduce absorption (with omeprazole, bioavailability falls to 17%); an acidic drink (e.g. cola) improves absorption.
After gastrointestinal absorption it is converted into several inactive metabolites; CYP3A4 is the major enzyme involved (oxidation and degradation of the imidazole and piperazine rings). About 13% of the dose is excreted in the urine (2–4% unchanged); the main route is biliary, with about 57% excreted in the faeces.
Biphasic elimination: a half-life of 2 hours during the first 10 hours and 8 hours thereafter.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
