Dihydroergotamine × Voriconazole

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.

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.

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).