Itraconazole

Mechanism

The liver breaks down alprazolam mainly through the enzyme CYP3A4, and itraconazole and its main metabolite hydroxy-itraconazole strongly inhibit this enzyme. In a study with alprazolam 0.8 mg, itraconazole raised the alprazolam area under the curve (AUC) 2.8-fold, while peak concentration did not change. More alprazolam stays in the blood, and its sedative effect becomes stronger and may last longer. The inhibition reaches full strength only when itraconazole reaches steady state, after about 15 days with the capsules. After itraconazole is stopped, it takes 7–14 days to leave the blood.

Symptoms

Too much alprazolam shows as drowsiness, slurred speech, poor coordination, confusion, lethargy, low muscle tone and low blood pressure. Severe poisoning can bring respiratory depression and, rarely, coma. The risk is higher if the person also takes alcohol or other drugs that depress the nervous system.

Management

The combination is contraindicated. The alprazolam label forbids use with strong inhibitors of the enzyme CYP3A4 and names itraconazole (alprazolam label, US Food and Drug Administration, FDA). The Spanish alprazolam label does not recommend it with itraconazole or other azole antifungals (alprazolam label, Spanish Agency of Medicines and Medical Devices, AEMPS). The itraconazole documents are milder: they list alprazolam among drugs to use with caution, with close monitoring and a lower dose if needed (itraconazole labels, AEMPS and FDA). After itraconazole is stopped, it takes 7–14 days to leave the blood, and longer in liver cirrhosis. Take this into account when starting alprazolam after a course of itraconazole (itraconazole label, AEMPS). If the two have been taken together, watch for drowsiness, slurred speech, poor coordination, low blood pressure and slowed breathing (alprazolam and itraconazole labels, AEMPS). Alcohol is not recommended with alprazolam because it adds to the sedation (alprazolam label, AEMPS). In a serious overdose, support breathing and circulation. Flumazenil, a benzodiazepine receptor antagonist, may help (alprazolam label, AEMPS).

Mechanism

Itraconazole is the strongest CYP3A4 inhibitor. Cabergoline rises 5-7 fold. Valvulopathy and pulmonary fibrosis risk.

Symptoms

Dyspnoea, cardiac murmurs, edema.

Management

Combination contraindicated.

Mechanism

Itraconazole is the strongest CYP3A4 inhibitor. Cisapride rises 10+ fold. Fatal torsades.

Symptoms

Torsades de pointes.

Management

Combination contraindicated.

Mechanism

Strongest CYP3A4 inhibitor – dihydroergotamine rises 20+ fold.

Symptoms

Fatal ergotism.

Management

Combination contraindicated.

Mechanism

The liver breaks down dronedarone mainly through the enzyme CYP3A4, and itraconazole strongly inhibits this enzyme (labels of both drugs). No study has looked at this pair directly. According to the itraconazole label, itraconazole is likely to raise dronedarone levels. The dronedarone label reports a 17-fold rise in dronedarone levels with ketoconazole 200 mg a day, another strong inhibitor of the enzyme. The QT interval gets longer as dronedarone concentration rises. The itraconazole labels explain the contraindication for such drugs by the risk of ventricular tachyarrhythmias, including life-threatening torsade de pointes. Beyond the kinetics, both drugs carry a risk for the heart muscle. Itraconazole has a negative inotropic effect and has been linked to congestive heart failure. Dronedarone reduces myocardial contractility and is contraindicated in current or past heart failure (labels of both drugs).

Symptoms

The main risk is ventricular arrhythmia from a prolonged QT interval, up to life-threatening torsade de pointes: palpitations, skipped beats, dizziness, fainting. Both drugs list a slow heart rate (bradycardia) among their adverse effects. Both can cause new heart failure or make it worse. Signs include increasing shortness of breath, rapid weight gain and swelling of the legs.

Management

The combination is contraindicated in the labels of both drugs: dronedarone (European Medicines Agency, EMA, and US Food and Drug Administration, FDA) and itraconazole (Spanish Agency of Medicines and Medical Devices, AEMPS, and FDA). Do not give dronedarone during itraconazole treatment or for 2 weeks after itraconazole is stopped (itraconazole labels, AEMPS and FDA). After itraconazole is stopped, its plasma levels take 7–14 days to become almost undetectable, and even longer in liver cirrhosis or with other inhibitors of the enzyme CYP3A4 (itraconazole label, AEMPS). If itraconazole has been started during dronedarone treatment, stop dronedarone: the label requires stopping it whenever any contraindicated condition develops (dronedarone label, EMA). Correct potassium and magnesium before starting dronedarone and keep them in the normal range during treatment (dronedarone labels, EMA and FDA). Monitor the electrocardiogram (ECG) during dronedarone treatment and stop dronedarone if the QTc interval (QT corrected for heart rate) reaches 500 milliseconds or more (dronedarone label, EMA). If signs of heart failure appear, stop itraconazole (itraconazole labels, AEMPS and FDA) and dronedarone (dronedarone label, EMA).

Mechanism

The liver breaks down eletriptan mainly through the enzyme CYP3A4, and itraconazole strongly inhibits this enzyme. No study has looked at this pair directly, but according to the itraconazole label, itraconazole is likely to raise eletriptan concentrations. The closest guide is data on other strong CYP3A4 inhibitors. Ketoconazole 400 mg raised the eletriptan area under the curve (AUC) 5.9-fold and lengthened its half-life from 4.8 to 8.3 hours. Erythromycin 1000 mg raised the AUC 3.6-fold. After itraconazole is stopped, its plasma levels take 7–14 days to become almost undetectable. Like other triptans, eletriptan can cause coronary artery spasm. In clinical trials, doses of 60 mg or more caused short-lived rises in blood pressure.

Symptoms

Tightness, pain or pressure in the chest, throat, neck and jaw is common after eletriptan. It is usually not cardiac but can be a sign of coronary artery spasm. Myocardial infarction, ventricular tachycardia and ventricular fibrillation have been reported within a few hours of triptan use, sometimes in people without known heart disease. Rarely, blood pressure rises sharply, even to a hypertensive crisis. Spasm of other arteries can cause Raynaud's syndrome or bowel ischaemia with abdominal pain and bloody diarrhoea. Stroke and brain haemorrhage have occurred after triptans.

Management

The combination is contraindicated (eletriptan label, US Food and Drug Administration, FDA). The eletriptan summary of product characteristics (SmPC) says not to use eletriptan with itraconazole or other strong inhibitors of the enzyme CYP3A4 (Spanish Agency of Medicines and Medical Devices, AEMPS). The itraconazole SmPC also lists eletriptan as not recommended: avoid it during itraconazole treatment and for 2 weeks after stopping itraconazole (itraconazole SmPC, AEMPS). The FDA eletriptan label requires a gap of at least 72 hours after a strong inhibitor. Yet after itraconazole is stopped, its plasma levels take 7–14 days to become almost undetectable, and even longer in liver cirrhosis or with other CYP3A4 inhibitors (itraconazole SmPC, AEMPS). If eletriptan has been taken during itraconazole treatment and chest pain or tightness suggesting cardiac ischaemia appears, give no further doses and evaluate the heart (eletriptan SmPC, AEMPS). Stop eletriptan if arrhythmias occur and monitor blood pressure during treatment (eletriptan label, FDA). If signs of spasm in other arteries appear, such as abdominal pain with blood in the stool or white, cold fingers, rule out vasospasm before the next dose (eletriptan label, FDA).

Mechanism

According to the Inspra summary of product characteristics (SmPC) from the Spanish Agency of Medicines and Medical Devices (AEMPS), eplerenone is cleared mainly through the enzyme CYP3A4 (section 5.2). Itraconazole strongly inhibits this enzyme (Sporanox SmPC, AEMPS, section 4.5). The pair has not been studied directly, but the itraconazole SmPC expects eplerenone levels to rise (section 4.5). The closest guide is ketoconazole, another strong CYP3A4 inhibitor. At 200 mg twice daily, it raised the eplerenone area under the curve (AUC) by 441%, or 5.4-fold (Inspra SmPC, AEMPS, section 4.5; Inspra prescribing information, US Food and Drug Administration, FDA, section 12.3). Eplerenone blocks mineralocorticoid receptors, so excess drug increases potassium retention and lowers blood pressure further. The SmPC names hypotension and hyperkalaemia as the most likely signs of overdose (Inspra SmPC, AEMPS, section 4.9). Itraconazole leaves the blood slowly. After it is stopped, its plasma levels take 7–14 days to become almost undetectable, depending on dose and treatment length (Sporanox SmPC, AEMPS, section 4.5). Itraconazole itself has a negative inotropic effect and has been linked to cases of congestive heart failure (Sporanox SmPC, AEMPS, section 4.4).

Symptoms

The main danger is hyperkalaemia. The eplerenone label of the US Food and Drug Administration (FDA) says the risk is higher even with moderate inhibitors of the enzyme CYP3A4. The same label lists itraconazole among the strong ones (sections 4 and 5.1). High potassium causes muscle weakness, bradycardia and arrhythmias up to cardiac arrest, with peaked T waves and a widened QRS complex on the electrocardiogram (ECG). Low blood pressure causes dizziness and fainting, especially on standing (Inspra summary of product characteristics, SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS, sections 4.8 and 4.9). The risk of hyperkalaemia is higher in older people, in reduced kidney function or diabetes, and with concurrent angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (Inspra SmPC, AEMPS, section 4.4). Itraconazole has been linked to cases of congestive heart failure (Sporanox SmPC, AEMPS, section 4.4). Signs include shortness of breath, swelling of the feet, ankles or legs, sudden weight gain, increased tiredness, coughing up white or pink mucus, a fast heartbeat and waking up at night more than usual (Sporanox label, FDA, Medication Guide).

Management

The labels of both drugs contraindicate the combination. The Inspra summary of product characteristics (SmPC) and prescribing information bar eplerenone with strong inhibitors of the enzyme CYP3A4 and name itraconazole in that list (Inspra SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS, sections 4.3 and 4.5; Inspra prescribing information, US Food and Drug Administration, FDA, section 4). The itraconazole labels list eplerenone among contraindicated drugs (AEMPS, sections 4.3 and 4.5; FDA, Contraindications). The ban also covers the two weeks after itraconazole is stopped (Sporanox SmPC, AEMPS, section 4.5; FDA, Drug Interactions table). In Spain, eplerenone is indicated only for heart failure (Inspra SmPC, AEMPS, section 4.1). In heart failure, itraconazole is given only for life-threatening or other serious infections and is stopped if signs of heart failure appear (Sporanox SmPC, AEMPS, sections 4.3 and 4.4). If a systemic azole is needed, note that the eplerenone SmPC classes fluconazole as a weak-to-moderate CYP3A4 inhibitor and limits eplerenone to 25 mg daily with it (Inspra SmPC, AEMPS, sections 4.2 and 4.5; FDA, sections 2.4 and 7.1). Ketoconazole, like itraconazole, is contraindicated. If the two drugs have already been taken together, stop one of them and check potassium and creatinine at once. The eplerenone labels require a potassium check at any dose change, and a potassium and creatinine check within 3–7 days of adding even a moderate CYP3A4 inhibitor (Inspra SmPC, AEMPS, section 4.4; FDA, section 2.3). Stop eplerenone if serum potassium reaches 6.0 mmol/L or higher (Inspra SmPC, AEMPS, section 4.2).

Mechanism

Itraconazole is the strongest CYP3A4 inhibitor. Ergotamine rises 20+ fold, fatal ergotism with gangrene. FDA Ergomar Section 4.

Symptoms

Digital ischaemia, gangrene, stroke within hours.

Management

Combination contraindicated.

Mechanism

Strong CYP3A4 inhibitor – everolimus rises 9-fold. EMA Certican Section 4.3 strict contraindication.

Symptoms

Acute immunosuppression, pneumonitis.

Management

Combination contraindicated.

Mechanism

In the liver and gut, a single enzyme, CYP3A4 (cytochrome P450 3A4), breaks down ivabradine, and itraconazole strongly inhibits this enzyme (ivabradine and itraconazole summaries of product characteristics, SmPCs). When the two are taken together, ivabradine levels in the blood rise, and high levels can lead to excessive bradycardia (ivabradine SmPC, European Medicines Agency, EMA). The documents give no figures for itraconazole itself. Ketoconazole, another azole antifungal, raised mean ivabradine plasma exposure 7- to 8-fold at 200 mg once daily (ivabradine SmPC, EMA). Itraconazole keeps acting after the last dose. Its plasma levels take 7–14 days to become almost undetectable, and even longer in liver cirrhosis or with other CYP3A4 inhibitors (itraconazole SmPC). A second risk concerns the heart itself. Itraconazole has a negative inotropic effect and has been linked to cases of congestive heart failure, while ivabradine is also used in chronic heart failure (itraconazole and ivabradine SmPCs).

Symptoms

Excessive bradycardia shows as a resting heart rate below 50 beats per minute, dizziness, fatigue and low blood pressure (ivabradine summary of product characteristics, European Medicines Agency, EMA). Sinus arrest and heart block can occur (Corlanor label, US Food and Drug Administration, FDA). Marked bradycardia raises the risk of QT interval prolongation and severe ventricular arrhythmia, including torsade de pointes (Corlanor label, FDA). Signs of congestive heart failure during itraconazole treatment: shortness of breath, swelling of the feet, ankles or legs, sudden weight gain, increased tiredness, coughing up white or pink mucus, fast heartbeat, waking up at night more than usual (Sporanox label, FDA).

Management

The combination is contraindicated on both sides. The ivabradine summary of product characteristics (SmPC) lists itraconazole among the strong inhibitors of the enzyme CYP3A4 (cytochrome P450 3A4) that must not be taken with ivabradine (European Medicines Agency, EMA, sections 4.3 and 4.5). The itraconazole SmPC lists ivabradine among contraindicated drugs (Spanish Agency of Medicines and Medical Devices, AEMPS, 4.3 and 4.5). The US labels of both drugs also contraindicate the combination (US Food and Drug Administration, FDA). So during itraconazole treatment, pause ivabradine or choose another antifungal (this follows from the contraindication in both labels). When choosing another antifungal, note that strong CYP3A4 inhibitors are contraindicated with ivabradine (ivabradine label, FDA, 4). With moderate inhibitors, start ivabradine only at 2.5 mg twice daily, with a resting heart rate above 70 beats per minute and heart rate monitoring (ivabradine SmPC, EMA, 4.5), or avoid these inhibitors altogether (ivabradine label, FDA, 7.1). The ban covers the whole itraconazole course and two weeks after its last dose (itraconazole SmPC, AEMPS, 4.5, and FDA label). Restart ivabradine no earlier than that, and only if the resting heart rate is at least 70 beats per minute on several measurements, an electrocardiogram (ECG) or 24-hour monitoring (ivabradine SmPC, EMA, 4.3 and 4.4). Ivabradine is also used in chronic heart failure (ivabradine SmPC, EMA, 4.1). Itraconazole is contraindicated in current or past heart failure, except in life-threatening or other serious infections. Stop it if signs of heart failure appear during treatment (itraconazole SmPC, AEMPS, 4.3 and 4.4). If the drugs have already been taken together, stop one of them and monitor the heart rate and ECG. With a resting heart rate below 50 beats per minute or symptoms of bradycardia, reduce the ivabradine dose, and if bradycardia persists, stop ivabradine (ivabradine SmPC, EMA, 4.2 and 4.4). Treat severe bradycardia in a specialised unit. If it compromises the circulation, give intravenous beta-stimulants such as isoprenaline, and use temporary cardiac pacing if that is not enough (ivabradine SmPC, EMA, 4.9).

Mechanism

Strong CYP3A4 inhibitor – lovastatin rises 20+ fold. FDA contraindication.

Symptoms

Myalgia, weakness, dark urine, rising CK within 5-10 days.

Management

Combination contraindicated.

Mechanism

Itraconazole is the strongest clinical CYP3A4 inhibitor. Pimozide concentration rises 10+ fold; torsades de pointes risk is maximal. FDA Orap Section 4 strict contraindication.

Symptoms

QT prolongation by day 3, syncope, torsades de pointes.

Management

Combination contraindicated. Alternative antifungal: terbinafine for superficial infections. For systemic infections, hold pimozide one week before itraconazole and resume 2 weeks after.

Mechanism

Itraconazole is the strongest CYP3A4 inhibitor in clinical use. Simvastatin is a sensitive substrate; its concentration rises 10–20 fold. Risk of rhabdomyolysis with acute kidney injury is the highest among statin–azole combinations.

Symptoms

Rhabdomyolysis within 3–7 days: myalgia, weakness, dark urine. CK above 50× ULN, oliguria.

Management

Combination contraindicated. Stop simvastatin one week before starting itraconazole and resume 2 weeks after the last dose. Alternative: pravastatin or rosuvastatin.

Mechanism

Strong CYP3A4 inhibitor – ticagrelor rises 5-7 fold. FDA Section 4.3.

Symptoms

Bleeding.

Management

Combination contraindicated.

Mechanism

Itraconazole inhibits CYP3A4 and P-gp. Vincristine rises 5+ fold – fatal neurotoxicity with motor deficit and autonomic neuropathy.

Symptoms

Severe peripheral neuropathy, paralytic ileus, autonomic disorders.

Management

Combination contraindicated. Alternative antifungal – micafungin or caspofungin.

Mechanism

Itraconazole inhibits CYP3A4 and P-glycoprotein. Atorvastatin concentration rises 3–4 fold. FDA does not contraindicate the combination outright but caps atorvastatin at 20 mg/day and requires CK monitoring.

Symptoms

Myalgia and weakness within 1–3 weeks; CK above 5× ULN.

Management

Cap atorvastatin at 20 mg/day. For short itraconazole courses (up to 14 days) the safer option is to hold atorvastatin altogether.

Mechanism

Strong CYP3A4 inhibitor. Cyclosporine rises 5+ fold.

Symptoms

Nephrotoxicity.

Management

Reduce cyclosporine by 75%.

Mechanism

Strong CYP3A4 inhibitor. Methadone rises 2-3 fold.

Symptoms

Sedation, respiratory depression, QT prolongation.

Management

Reduce methadone by 25%, ECG monitoring.

Mechanism

Itraconazole is a strong inhibitor of CYP3A4 and P-glycoprotein, and sirolimus is cleared through both. The pair has not been studied directly: the itraconazole SmPC says a rise in sirolimus levels is likely and does not recommend the combination. The sirolimus SmPC and the FDA label also advise against strong CYP3A4 inhibitors and name itraconazole. No label lists the pair as a contraindication.

Symptoms

Acute nephrotoxicity, hepatotoxicity, cytopenia.

Management

Avoid the combination during itraconazole therapy and for 2 weeks after it, as the itraconazole SmPC and the FDA label state. For a fungal infection in a patient on sirolimus, the FDA sirolimus label advises an antifungal with lower interaction potential. If itraconazole is still needed, measure sirolimus blood levels more often and reduce or pause the dose according to the result.

Mechanism

Itraconazole is a strong CYP3A4 inhibitor. Tacrolimus rises 5+ fold – severe nephrotoxicity.

Symptoms

Rising creatinine, hypertension, tremor within 3-7 days.

Management

Reduce tacrolimus by 75% with frequent blood level monitoring. If possible, switch itraconazole to an echinocandin.

Mechanism

The doxycycline and itraconazole labels do not mention each other and describe no shared interaction mechanism. Itraconazole is a strong inhibitor of the CYP3A4 enzyme, but doxycycline is not cleared through it: only hepatic enzyme inducers (carbamazepine, phenytoin, barbiturates, rifampicin, chronic alcohol use) speed up its metabolism, and it is excreted through the gut and the kidney. The only common ground is the liver. Both drugs are potentially hepatotoxic: itraconazole has very rare reports of serious hepatotoxicity, including fatal acute liver failure, mostly in patients with pre-existing liver disease or taking other hepatotoxic drugs, and the doxycycline label asks for caution with potentially hepatotoxic drugs.

Symptoms

The documents expect no change in the concentration of either drug and describe no added adverse effects from an interaction. The liver is what to watch: loss of appetite, nausea, vomiting, fatigue, abdominal pain or dark urine are signs of hepatitis that the itraconazole label asks patients to report at once. During long doxycycline courses, liver tests, blood counts and kidney function are checked as well.

Management

The combination is acceptable and doses stay unchanged: neither the doxycycline label nor the itraconazole label (AEMPS and FDA) names this pair. Caution concerns the liver. Potentially hepatotoxic drugs are used with caution in patients taking doxycycline (doxycycline label, 4.5), and liver function monitoring is considered in patients taking itraconazole, above all with prior liver disease or hepatotoxicity from other drugs (itraconazole label, 4.4). Patients are told to report signs of hepatitis right away: loss of appetite, nausea, vomiting, fatigue, abdominal pain or dark urine (itraconazole label, 4.4). On long doxycycline courses, blood counts and kidney and liver function are checked periodically (doxycycline label, 4.4; FDA doxycycline label, 5.11).

Mechanism

The liver breaks down meloxicam mainly through the enzyme CYP2C9, with a smaller contribution from the enzyme CYP3A4. Itraconazole strongly inhibits CYP3A4, yet it lowers meloxicam levels. In a study with meloxicam 15 mg, peak concentration fell by 64% and the area under the curve by 37%. The labels do not explain why. The risk of the combination is that meloxicam may work less well.

Symptoms

Meloxicam may relieve pain and inflammation less well. In osteoarthritis flares, rheumatoid arthritis or ankylosing spondylitis, pain and stiffness in the joints or spine return or get worse. Meloxicam levels fall with this pair, so the labels describe no meloxicam overdose from it.

Management

Use meloxicam cautiously alongside itraconazole. Check whether its effect has weakened and adjust the dose if needed (itraconazole label, Spanish Agency of Medicines and Medical Devices, AEMPS). A higher meloxicam dose may be necessary (itraconazole label, US Food and Drug Administration, FDA). The meloxicam dose limit stays the same: no more than 15 mg a day, and no more than 7.5 mg a day in patients on dialysis with severe kidney failure (meloxicam label, AEMPS). Give meloxicam at the lowest effective dose for the shortest time, and regularly review whether it is still needed and how well it works (meloxicam label, AEMPS). If the meloxicam dose was raised during the itraconazole course, review it in the same way after itraconazole is stopped. Itraconazole takes 7–14 days to leave the blood (itraconazole label, AEMPS).