Voriconazole

Mechanism

Voriconazole strongly inhibits the liver enzyme CYP3A4, and this enzyme breaks down dihydroergotamine. The combination has not been studied, but voriconazole is likely to raise dihydroergotamine blood levels and can cause ergotism (poisoning by ergot alkaloids). Higher dihydroergotamine levels raise the risk of vasospasm leading to ischaemia of the brain and limbs. Serious and life-threatening ischaemia has been reported when dihydroergotamine was combined with strong CYP3A4 inhibitors, including antifungals.

Symptoms

With excess dihydroergotamine, the arms and legs become numb, tingling and painful. The fingers and toes turn cold, pale or bluish, and pulses in the arms and legs weaken or disappear. Leg ischaemia causes cramping and pain in the legs or hips, heaviness or tightness in the leg muscles, burning or aching pain in the feet at rest, and a cold feeling or colour change in one or both legs. Brain ischaemia causes slurred speech and sudden weakness. Severe poisoning can bring nausea, vomiting, abdominal pain, respiratory depression, a rise and then usually a fall in blood pressure, confusion, delirium, seizures and coma. Persistent vasospasm in people with poor circulation can lead to gangrene or death.

Management

The voriconazole documents contraindicate the combination: the summary of product characteristics (SmPC) of the European Medicines Agency (EMA, sections 4.3 and 4.5), the SmPC of the Spanish Agency of Medicines and Medical Devices (AEMPS, section 4.3) and the label of the US Food and Drug Administration (FDA, sections 4 and 7). Dihydroergotamine is contraindicated with strong inhibitors of the enzyme CYP3A4 (dihydroergotamine labels, FDA). Voriconazole is a strong inhibitor of this enzyme (voriconazole SmPC, EMA, and label, FDA). If the two drugs have been taken together and signs of vasospasm appear, stop dihydroergotamine at once and get emergency medical help (dihydroergotamine labels, FDA). Such signs include numb, cold, pale or bluish fingers, cramping and pain in the legs, slurred speech or sudden weakness. For overdose, stop dihydroergotamine, give general supportive care with monitoring of vital signs, and observe the patient for at least 24 hours or while symptoms persist (dihydroergotamine label, FDA).

Mechanism

The liver breaks down dronedarone mainly through the enzyme CYP3A4, and voriconazole strongly inhibits this enzyme (labels of both drugs). The labels give no study of this exact pair. The dronedarone label reports a 17-fold rise in dronedarone levels with ketoconazole 200 mg a day, another strong inhibitor of the enzyme. For this reason, it contraindicates voriconazole and other strong inhibitors. The QT interval gets longer as dronedarone concentration rises, and voriconazole prolongs the QT interval on its own. Dronedarone itself moderately inhibits CYP3A4, and the liver clears voriconazole partly through this enzyme. The documents give no figures for the rise in voriconazole levels.

Symptoms

The main risk of the pair is arrhythmia from a prolonged QT interval, up to torsade de pointes: palpitations, skipped beats, dizziness, fainting. As dronedarone levels rise, the QT and PR intervals on the electrocardiogram (ECG) get longer. A slow pulse is common with dronedarone even without other drugs. With voriconazole, rare cases of torsade de pointes have occurred in people with risk factors such as cardiomyopathy, low potassium, past cardiotoxic chemotherapy or other drugs taken at the same time.

Management

The combination is contraindicated (dronedarone labels, European Medicines Agency, EMA, and US Food and Drug Administration, FDA). Both labels name voriconazole among the strong inhibitors of the enzyme CYP3A4. Stop a strong CYP3A4 inhibitor before starting dronedarone (dronedarone label, FDA). If voriconazole has been started during dronedarone treatment, stop dronedarone: the label requires stopping it whenever any contraindicated condition develops (dronedarone label, EMA). After stopping 400 mg twice daily, dronedarone and its metabolite are fully cleared from plasma within 2 weeks (dronedarone label, EMA). The documents set no specific interval before starting voriconazole. Correct potassium and magnesium before starting dronedarone and keep them in the normal range during treatment (dronedarone labels, EMA and FDA). Correct low potassium, magnesium and calcium before and during voriconazole treatment (voriconazole 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). In dronedarone overdose, monitor heart rhythm and blood pressure and give supportive treatment. There is no specific antidote (dronedarone labels, EMA and FDA).

Mechanism

Voriconazole is a strong CYP3A4 inhibitor. Ergotamine rises 10+ fold. EMA Vfend Section 4.3.

Symptoms

Fatal ergotism.

Management

Combination contraindicated.

Mechanism

Strong CYP3A4 inhibitor. Lovastatin rises 10+ fold.

Symptoms

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

Management

Combination contraindicated.

Mechanism

Voriconazole is a strong CYP3A4 inhibitor and itself a QT prolonger. Double torsades risk. FDA Orap Section 4.

Symptoms

QTc above 500 ms by day 2–3, syncope, torsades de pointes.

Management

Combination contraindicated. For invasive mycosis in a pimozide patient, hold pimozide during the voriconazole course and resume 7 days after.

Mechanism

The interaction runs both ways. Voriconazole inhibits CYP3A4, the liver enzyme that breaks down rifabutin. With voriconazole 400 mg twice daily, the rifabutin area under the curve (AUC) rose by 331% and peak concentration by 195%. Rifabutin in turn speeds up voriconazole metabolism: at the usual 200 mg twice daily, voriconazole AUC fell by 78% and peak concentration by 69%. At 350 mg twice daily, voriconazole peak concentration was close to the usual level (4% lower), but AUC stayed 32% lower than with 200 mg without rifabutin. At 400 mg twice daily, voriconazole peak concentration and AUC almost doubled.

Symptoms

Excess rifabutin can show as uveitis: eye pain and redness, photophobia, blurred vision. Neutrophil and, less often, platelet counts fall, which can lead to fever, infections or bruising. Too little voriconazole shows as a fungal infection that does not respond to treatment: fever persists and lesions in the lungs or other organs do not regress.

Management

The combination is contraindicated in the US labels of both voriconazole and rifabutin (US Food and Drug Administration, FDA). In Europe it is not contraindicated, but avoid it unless the benefit outweighs the risk (voriconazole SmPC, European Medicines Agency, EMA; rifabutin ficha técnica, Spanish Agency of Medicines, AEMPS). If there is no alternative to rifabutin, raise the voriconazole maintenance dose: orally from 200 to 350 mg twice daily (from 100 to 200 mg twice daily in patients under 40 kg), or intravenously to 5 mg/kg twice daily (voriconazole SmPC, EMA). Throughout co-administration, closely monitor the full blood count and adverse effects of rifabutin, especially uveitis (voriconazole SmPC, EMA). If uveitis is suspected, refer the patient to an ophthalmologist and stop rifabutin if needed (rifabutin ficha técnica, AEMPS).

Mechanism

Voriconazole is a strong CYP3A4 inhibitor, the main enzyme for sirolimus. Sirolimus levels rise 11-fold causing severe toxicity: nephrotoxicity, hepatotoxicity, cytopenias, thrombotic microangiopathy. FDA Vfend Section 4.3 – strict contraindication.

Symptoms

Within 3–7 days – rising creatinine and transaminases, thrombocytopenia, oedema, haematuria.

Management

Combination contraindicated. For severe aspergillosis in a transplant patient, switch sirolimus to tacrolimus with a 50% dose reduction and blood-level monitoring. Alternative antifungal: isavuconazole with weaker CYP3A4 inhibition.

Mechanism

Strong CYP3A4 inhibitor. FDA Section 4.3.

Symptoms

Bleeding.

Management

Combination contraindicated.

Mechanism

Strong CYP3A4 inhibitor. Fatal neurotoxicity.

Symptoms

Severe neuropathy.

Management

Combination contraindicated.

Mechanism

Voriconazole inhibits CYP3A4. Atorvastatin rises 3-4 fold.

Symptoms

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

Management

Cap atorvastatin at 20 mg/day.

Mechanism

Voriconazole inhibits CYP3A4. Cyclosporine rises 1.7-fold.

Symptoms

Nephrotoxicity.

Management

Halve cyclosporine dose.

Mechanism

Voriconazole strongly inhibits CYP3A4, the enzyme that clears everolimus. The pair has not been studied directly, but ketoconazole, an inhibitor of the same strength, raises everolimus AUC 15-fold.

Symptoms

Immunosuppression, nephrotoxicity.

Management

Both labels advise against the pair (AEMPS, FDA): there are no data to set an everolimus dose. For antifungal treatment, choose a drug that does not inhibit CYP3A4 this strongly. If voriconazole cannot be avoided, measure everolimus trough levels and adjust the dose to them.

Mechanism

Ritonavir is a strong CYP3A4 inhibitor, but it also induces CYP2C19 and CYP2C9, the main enzymes that clear voriconazole. Induction wins, and voriconazole exposure falls. With ritonavir 400 mg twice daily, voriconazole AUC drops by 82% and Cmax by 66%; with 100 mg twice daily, by 39% and 24% (Vfend SmPC, EMA). Voriconazole inhibits CYP3A4, but this barely affects ritonavir: its exposure is unchanged with the high dose and falls by 13% (AUC) with the low dose.

Symptoms

The main risk is loss of antifungal effect: invasive aspergillosis, candidiasis or another fungal infection treated with voriconazole fails to respond or progresses. The voriconazole and ritonavir labels (EMA and FDA) warn of a possible loss of effect. On the ritonavir side there is little to see: its concentration changes little, and the labels describe no added ritonavir toxicity.

Management

Do not combine voriconazole with ritonavir at 400 mg twice daily or higher, the dose at which ritonavir is an antiretroviral in its own right: both labels list this as a contraindication (Vfend SmPC, EMA, section 4.3; Norvir SmPC, EMA, section 4.3; Vfend and Norvir prescribing information, FDA, sections 4 and 7). Also avoid voriconazole with ritonavir 100 mg twice daily, the booster dose for another protease inhibitor, unless an assessment of benefit and risk for the patient justifies voriconazole (Vfend SmPC, EMA, sections 4.4 and 4.5; Norvir SmPC, EMA, section 4.5). The labels give no voriconazole dose adjustment for this case. When keeping both drugs, expect voriconazole exposure to fall by about 39% (Vfend SmPC, EMA) and watch the response of the fungal infection. When ritonavir is used as a booster, look up the contraindications of the boosted protease inhibitor in its own label (Norvir SmPC, EMA, section 4.3).

Mechanism

Voriconazole inhibits CYP3A4. Tacrolimus concentration rises 3-fold with risk of nephrotoxicity and neurotoxicity (tremor, headache, paresthesia). FDA requires reducing tacrolimus to one third of baseline and frequent blood-level monitoring.

Symptoms

Rising creatinine, tremor, headache, paresthesia, hypertension within 7 days. Tacrolimus trough above target range.

Management

Reduce tacrolimus to one third of baseline. Check trough after 2 days, then weekly. Up-titrate after voriconazole withdrawal.