Azole antifungal (triazole; potent CYP3A4 and P-glycoprotein inhibitor)
Itraconazole is an antifungal used for fungal infections of the skin, nails and mouth and for deep fungal infections. It is effective, but interacts with many medicines and can affect the heart and liver, so it should be used under medical supervision.
Also known as: Sporanox, Itraconazol
Carbamazepine lowers Itraconazole levels (induction), increasing the risk of antifungal failure.
Itraconazole is a potent inhibitor of CYP3A4, the main pathway of carbamazepine metabolism; coadministration can raise carbamazepine concentrations and cause intoxication (nystagmus, ataxia, diplopia, sedation). Monitor carbamazepine plasma levels and reduce the dose if needed during antifungal treatment; consider a less inhibitory antifungal (e.g. low-dose fluconazole, with caution) when possible.
Itraconazole + carbamazepine: itraconazole inhibits CYP3A4 and may raise carbamazepine levels, with risk of toxicity. Monitor levels.
Carbamazepine induces CYP3A4, accelerating itraconazole metabolism and reducing its exposure.
Mycosis response; itraconazole levels (if available).
Worsening fungal infection.
Consider an alternative antifungal; if the combination is unavoidable, monitor clinical and mycological response.
DailyMed/FDA (NIH/NLM) — approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d555fa-787c-40fb-bb7d-b0d4f7318fd0 ; 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)
Rifampin (a CYP450 inducer) markedly reduces Itraconazole levels, risking antifungal treatment failure.
Itraconazole is metabolised by CYP3A4; rifampicin, a potent inducer, can reduce its concentrations and those of the active metabolite (hydroxy-itraconazole) to undetectable levels, with complete loss of antifungal effect. The combination is practically contraindicated; if unavoidable, consider an alternative antifungal (amphotericin B, echinocandins) or monitor itraconazole levels if available.
Itraconazole + rifampicin: rifampicin markedly reduces itraconazole levels (CYP3A4 induction), with antifungal failure. Practically contraindicated.
Enzymatic induction (CYP3A4/P-glycoprotein) by rifampin accelerates itraconazole elimination, reducing efficacy.
Clinical response to the antifungal; liver function tests.
Persistent or worsening fungal infection.
Avoid the combination. If both are needed, use an alternative antifungal and monitor clinical and mycological response.
DailyMed/FDA (NIH/NLM) — approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d555fa-787c-40fb-bb7d-b0d4f7318fd0 ; 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)
Antacids, H2-blockers, proton-pump inhibitors and sucralfate markedly reduce Itraconazole absorption.
Itraconazole capsules require an acidic gastric medium to dissolve and absorb the drug; antacids, by raising the pH, reduce itraconazole plasma concentrations and can compromise the treatment of systemic fungal infections or prophylaxis in immunocompromised patients. The itraconazole label recommends taking the capsules after a full meal (which promotes acidity) and separating from antacids by at least 2 hours. Alternatively, consider oral solution formulations of itraconazole (less pH-dependent) under medical guidance.
Antacids + itraconazole (capsules): absorption depends on acidic pH; antacids reduce it. Separate by at least 2 hours and, if possible, avoid the combination.
Itraconazole (capsule) absorption depends on gastric acidity; agents that raise gastric pH reduce absorption.
Clinical response; signs of antifungal failure.
Persistent or worsening fungal infection.
Give itraconazole at least 2 h before antacids/PPIs; consider the oral solution (less pH-dependent absorption).
DailyMed/FDA (NIH/NLM) — approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d555fa-787c-40fb-bb7d-b0d4f7318fd0 ; 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)
Itraconazole raises Amlodipine levels (CYP3A4 inhibition), with a risk of hypotension and oedema.
Amlodipine is metabolised by CYP3A4 and the label states that "co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction" (for example, with diltiazem — a moderate inhibitor — exposure increased by 60%). Itraconazole is a potent CYP3A4 inhibitor, so the combination raises amlodipine levels and its dose-dependent effects: hypotension, peripheral oedema, flushing, headache and dizziness, especially in the elderly. Monitor blood pressure and signs of relative overdose; if the combination is needed, consider starting with a lower amlodipine dose or reducing it, monitoring the patient in the first weeks.
Itraconazole + amlodipine: itraconazole inhibits CYP3A4 and raises amlodipine levels. Watch for hypotension, oedema and dizziness; consider a dose reduction.
CYP3A4 inhibition by itraconazole reduces amlodipine metabolism.
Blood pressure, peripheral oedema.
Symptomatic hypotension, significant oedema.
Monitor blood pressure and oedema; consider a reduced amlodipine dose.
DailyMed/FDA (NIH/NLM) — approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d555fa-787c-40fb-bb7d-b0d4f7318fd0 ; 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)
Itraconazole (CYP3A4 inhibitor) increases fentanyl concentrations, with risk of sedation and respiratory depression.
Fentanyl is metabolised by CYP3A4 and itraconazole is a potent inhibitor of this enzyme: the itraconazole label classifies fentanyl as "not recommended during and 2 weeks after treatment with itraconazole", and the fentanyl label warns that co-administration with CYP3A4 inhibitors (such as the azoles) "can result in a fatal overdose of fentanyl", with prolonged or delayed respiratory depression. Avoid the combination whenever possible; if unavoidable, reduce the fentanyl dose, closely monitor sedation and respiratory rate (especially in the first days and in patients with sleep apnoea, obesity or lung disease) and keep naloxone available.
Fentanyl + itraconazole: itraconazole inhibits CYP3A4 and raises fentanyl levels, with a risk of fatal respiratory depression. Avoid (not recommended during and 2 weeks after itraconazole).
Fentanyl is mainly metabolised by CYP3A4; itraconazole inhibits this enzyme and reduces opioid clearance.
Sedation, respiratory rate and signs of opioid toxicity.
Respiratory depression requires temporary withdrawal and support with naloxone.
Reduce the fentanyl dose and monitor closely; avoid the combination if possible.
DailyMed/FDA (NIH/NLM) — approved Fentanyl label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e15a7e9b-8025-49dd-9a6d-bafcccf1959f ; approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d555fa-787c-40fb-bb7d-b0d4f7318fd0 — with additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Itraconazole (a potent CYP3A4 inhibitor) raises Atorvastatin levels, increasing the risk of myopathy and rhabdomyolysis.
Itraconazole is a potent CYP3A4 inhibitor and can markedly raise atorvastatin concentrations (and the risk of myopathy/rhabdomyolysis), especially in prolonged antifungal courses or with renal impairment. The atorvastatin label recommends not exceeding 20 mg of atorvastatin per day during itraconazole treatment (an explicit limit in the label), with monitoring of muscle symptoms and CK. Instruct the patient to stop the statin in the presence of muscle pain, weakness or dark urine.
Atorvastatin + itraconazole: the azole inhibits CYP3A4 and can markedly raise statin levels. Stop the statin or reduce the dose.
CYP3A4 inhibition by itraconazole reduces first-pass atorvastatin metabolism, increasing its exposure.
Creatine kinase (CK), muscle symptoms (myalgia, weakness, dark urine).
Severe muscle pain, weakness, dark-coloured urine (rhabdomyolysis).
Prefer a non-CYP3A4 statin (pravastatin, rosuvastatin) or stop itraconazole; otherwise use the lowest atorvastatin dose with monitoring.
DailyMed/FDA (NIH/NLM) — approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d555fa-787c-40fb-bb7d-b0d4f7318fd0 ; 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)
Itraconazole can raise dutasteride blood levels. Use with caution and watch for side effects.
Itraconazole inhibits CYP3A4, the enzyme responsible for dutasteride elimination. Increased exposure and the drug long half-life justify caution; in long-term use, consider reducing dose frequency.
CYP3A4: itraconazole (strong inhibitor) raises dutasteride concentrations, with a potentially prolonged half-life; monitor tolerability.
CYP3A4 inhibition, reducing dutasteride elimination.
Dutasteride adverse effects.
Gynaecomastia, persistent sexual dysfunction.
Use with caution; watch for adverse effects; consider reducing dose frequency in long-term use.
DailyMed/FDA (NIH/NLM) — approved Dutasteride label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=947644ea-bc35-41df-8a7a-874360c90192 ; approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d555fa-787c-40fb-bb7d-b0d4f7318fd0 ; EMC-UK (MHRA) — approved Dutasteride SmPC: https://www.medicines.org.uk/emc/product/102479/smpc ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Itraconazole potentiates the anticoagulant effect of Warfarin, increasing the bleeding risk.
Itraconazole is a potent CYP3A4 inhibitor and also affects CYP2C9, enzymes involved in warfarin metabolism. The inhibition results in increased warfarin levels, INR elevation and bleeding risk — an interaction mentioned in approved labels. Whenever possible, choose an alternative antifungal with lower interaction potential; if itraconazole is unavoidable, reduce the warfarin dose, monitor the INR frequently at initiation and during treatment and watch for bleeding signs.
Itraconazole inhibits CYP3A4 (and CYP2C9) and can markedly raise the INR. Avoid if possible; if unavoidable, reduce warfarin and monitor the INR closely.
Metabolic inhibition (CYP2C9/CYP3A4) of warfarin by itraconazole, raising the INR.
INR, signs of bleeding (gums, bruising, melena).
Unexplained bleeding, haematuria, melena.
Monitor the INR frequently after starting/stopping itraconazole; adjust the warfarin dose.
DailyMed/FDA (NIH/NLM) — approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d555fa-787c-40fb-bb7d-b0d4f7318fd0 ; 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)
Itraconazole raises Digoxin concentrations, with a risk of digitalis toxicity.
Itraconazole is a potent P-glycoprotein inhibitor, reducing intestinal and renal digoxin excretion and raising its plasma concentrations — studies show 50–100% increases. The risk of digitalis toxicity (nausea, arrhythmias, visual disturbances) is significant. Monitor digoxin levels when itraconazole is started, reduce the digoxin dose if needed and watch the ECG and toxicity symptoms during and after antifungal treatment.
Itraconazole inhibits P-gp and can raise digoxin levels. Monitor digoxin levels and reduce the dose if needed.
P-glycoprotein inhibition by itraconazole reduces digoxin elimination.
Digoxin levels, ECG, gastrointestinal and visual symptoms.
Nausea, vomiting, arrhythmias, yellow/green vision.
Monitor digoxin levels and clinical signs; reduce the digoxin dose if needed (especially the elderly and renal impairment).
DailyMed/FDA (NIH/NLM) — approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d555fa-787c-40fb-bb7d-b0d4f7318fd0 ; 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)
Itraconazole plus Amiodarone carries a risk of QT prolongation and ventricular arrhythmias.
Itraconazole is a potent CYP3A4 inhibitor, the main pathway of amiodarone metabolism; coadministration can substantially raise amiodarone concentrations. As both prolong the QT interval, the risk of torsades de pointes and of amiodarone toxicity (pulmonary, hepatic, thyroid) increases. The combination should be avoided; if unavoidable, reduce the amiodarone dose, monitor the ECG and watch for adverse effects during antifungal treatment and after its discontinuation.
Itraconazole + amiodarone: itraconazole inhibits CYP3A4 and may raise amiodarone levels, with QT/arrhythmia risk. Avoid the combination.
Additive effect on cardiac repolarization; itraconazole may also raise amiodarone levels.
ECG (QT interval), electrolytes (K+, Mg2+), signs of arrhythmia.
Syncope, palpitations, torsades de pointes.
Use with caution; monitor ECG (QT) and electrolytes (K+, Mg2+); correct hypokalaemia before combining.
DailyMed/FDA (NIH/NLM) — approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d555fa-787c-40fb-bb7d-b0d4f7318fd0 ; approved Amiodarone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=51a88e8e-da02-4b97-9e7e-442fbffd908d
Omeprazole reduces Itraconazole absorption by raising gastric pH, compromising efficacy.
Itraconazole capsules require an acidic gastric medium to dissolve and absorb the drug; omeprazole, by raising the pH, reduces itraconazole plasma concentrations and can compromise antifungal treatment or prophylaxis. Separate administration (itraconazole with a meal and the PPI on an empty stomach) and, alternatively, use the itraconazole oral solution, which is less pH-dependent. Monitor the clinical response and, when available, the antifungal concentration.
Itraconazole (capsules) + omeprazole: absorption depends on acidic pH and is reduced by PPIs. Separate administration and consider the oral solution.
pH-dependent absorption: acid suppression reduces itraconazole dissolution in the stomach.
Clinical response to the antifungal.
Persistent fungal infection.
Separate dosing, switch omeprazole to a short-acting antacid outside the dosing window, or use another class.
DailyMed/FDA (NIH/NLM) — approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d555fa-787c-40fb-bb7d-b0d4f7318fd0 ; 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)
Itraconazole increases buprenorphine concentrations, potentiating sedation and respiratory depression.
Buprenorphine is metabolised by CYP3A4, and itraconazole (a potent CYP3A4 inhibitor) can raise its plasma concentrations: the itraconazole label lists buprenorphine (IV and sublingual) among the drugs with documented pharmacokinetic interaction with itraconazole, and the buprenorphine label warns that CYP3A4 inhibitors increase buprenorphine levels, recommending monitoring and, when the inhibitor is discontinued, considering dose adjustment. The combination (e.g. an opioid substitution patient starting an oral antifungal) requires vigilance for sedation, drowsiness, confusion and respiratory depression, especially at initiation; reduce the buprenorphine dose if needed.
Buprenorphine + itraconazole: itraconazole inhibits CYP3A4 and raises buprenorphine levels. Watch for sedation and respiratory depression.
Buprenorphine is metabolised by CYP3A4; inhibition by itraconazole reduces its metabolism.
Signs of opioid overdose: miosis, sedation, bradypnoea.
Persistent respiratory depression requires urgent assessment.
Use with caution; consider dose reduction and sedation monitoring.
DailyMed/FDA (NIH/NLM) — approved Buprenorphine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=713db2c6-0544-4633-b874-cfbeaf93db89 ; approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d555fa-787c-40fb-bb7d-b0d4f7318fd0 — with additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Itraconazole increases donepezil concentrations, with a risk of cholinergic effects.
Donepezil is metabolised by the CYP3A4 and CYP2D6 isoenzymes, and the donepezil label states that ketoconazole and quinidine, strong inhibitors of CYP3A4 and CYP2D6, respectively, inhibit donepezil metabolism in vitro (ketoconazole is from the same azole class as itraconazole, also a strong CYP3A4 inhibitor). Increased donepezil levels can potentiate the cholinergic effects (nausea, diarrhoea, vomiting, bradycardia, syncope — the label warns about vagotonic effects on the sinoatrial and atrioventricular nodes, with bradycardia or heart block). In elderly Alzheimer patients, monitor heart rate, gastrointestinal symptoms and signs of bradycardia/syncope when itraconazole is started; consider reducing the donepezil dose in susceptible patients.
Donepezil + itraconazole: itraconazole inhibits CYP3A4 and raises donepezil levels. Watch for cholinergic effects and bradycardia.
Donepezil is metabolised by CYP3A4 and CYP2D6; itraconazole inhibits CYP3A4 and raises the drug level.
Bradycardia, syncope, gastrointestinal complaints, agitation.
Symptomatic bradycardia or syncope require cardiology assessment.
Monitor cholinergic symptoms (nausea, bradycardia, diarrhoea); consider dose reduction.
DailyMed/FDA (NIH/NLM) — approved Donepezil label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=98e451e1-e4d7-4439-a675-c5457ba20975 ; approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d555fa-787c-40fb-bb7d-b0d4f7318fd0 — with additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Itraconazole raises Sildenafil concentrations, with a risk of hypotension and adverse effects.
Sildenafil is metabolised by CYP3A4, and the sildenafil label recommends "considering a starting dose of 25 mg in patients treated with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, saquinavir) or erythromycin"; the itraconazole label distinguishes the indications: for pulmonary hypertension, sildenafil is "not recommended during and 2 weeks after treatment with itraconazole", while for erectile dysfunction it recommends "monitoring for adverse reactions". Raised sildenafil levels potentiate the risk of hypotension, headache, flushing, dyspepsia and, rarely, priapism or visual disturbances. For erectile dysfunction, use the lowest effective dose (never exceeding 25 mg) and space the doses; for pulmonary hypertension, avoid the combination and seek an alternative.
Itraconazole + sildenafil: itraconazole inhibits CYP3A4 and raises sildenafil levels. Consider a 25 mg starting dose; PH: not recommended during and 2 weeks after itraconazole.
CYP3A4 inhibition — the main sildenafil metabolic pathway — increases its exposure.
Blood pressure, headache, flushing, palpitations.
Hypotension, syncope, priapism.
Limit the sildenafil dose (max 25 mg) during itraconazole therapy.
DailyMed/FDA (NIH/NLM) — approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d555fa-787c-40fb-bb7d-b0d4f7318fd0 ; approved Sildenafil label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=00ee09dd-2de0-4dc4-85f6-b51ed6eabd5b
Alcohol increases the risk of itraconazole hepatotoxicity.
Avoid alcohol during treatment.
DailyMed/FDA (NIH/NLM) — approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=68165d90-953c-e2f5-e053-2a91aa0ada25
Grapefruit reduces itraconazole absorption (capsules need an acid pH) and may decrease efficacy.
Avoid grapefruit juice; take capsules with food, but not with grapefruit.
DailyMed/FDA (NIH/NLM) — approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=68165d90-953c-e2f5-e053-2a91aa0ada25
Itraconazole is metabolised in the liver and may worsen liver disease; prolonged use is associated with hepatotoxicity.
Monitor transaminases; use with caution in liver disease.
DailyMed/FDA (NIH/NLM) — approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=68165d90-953c-e2f5-e053-2a91aa0ada25
Itraconazole has negative inotropic effects and is contraindicated in patients with heart failure or ventricular dysfunction.
Contraindicated in heart failure; assess cardiac function before treatment.
DailyMed/FDA (NIH/NLM) — approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=68165d90-953c-e2f5-e053-2a91aa0ada25
Itraconazole is teratogenic in animals; human data are limited and use in pregnancy should be avoided.
Contraindicated in pregnancy, except in severe fungal infection without an alternative.
Excreted into breast milk; avoid while breastfeeding.
Advise effective contraception during treatment and up to 2 months after stopping.
DailyMed/FDA (NIH/NLM) — approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=68165d90-953c-e2f5-e053-2a91aa0ada25
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Broad-spectrum triazole antifungal (dermatophytes, Candida, Aspergillus, blastomycosis, histoplasmosis). It accumulates extensively in tissues — concentrations 2 to 3 times higher than plasma in lung, kidney, liver and bone, and up to 4 times in skin; it persists in nails for up to 6 months after the end of treatment. Potent CYP3A4 inhibitor.
Inhibits the synthesis of ergosterol, a vital component of the fungal cell membrane, by blocking the cytochrome P450-dependent enzyme (14α-demethylase). The active metabolite hydroxy-itraconazole has antifungal activity comparable to the parent compound.
Rapidly absorbed after oral administration: peak plasma concentrations in 2 to 5 hours, absolute oral bioavailability of about 55% (capsules). Absorption is maximal when the capsules are taken immediately after a full meal and reduced with low gastric acidity (an acidic drink improves it).
Extensively metabolised in the liver (CYP3A4 is the main enzyme), with formation of the active metabolite hydroxy-itraconazole. It is excreted mainly as inactive metabolites: 35% in urine and 54% in faeces within the first week. Clearance decreases at high doses (saturable hepatic metabolism — non-linear pharmacokinetics).
The terminal half-life ranges from 16 to 28 hours after a single dose and increases to 34 to 42 hours with repeated dosing; plasma concentrations become almost undetectable 7 to 14 days after discontinuation.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
