Ergotamine

Mechanism

Both drugs constrict arteries. Almotriptan stimulates serotonin receptors in cranial vessels and constricts them. Like other triptans, it can very rarely cause coronary artery spasm. Ergotamine constricts blood vessels and can cause myocardial ischaemia, or rarely infarction, even in people with no known heart disease. Vasospasm after ergot drugs can be prolonged. In a study of 12 healthy volunteers, oral almotriptan with ergotamine caused no extra vasospasm, but the vasoconstrictor effects may in theory add up.

Symptoms

Coronary artery spasm causes chest pain, pressure or tightness, sometimes severe and spreading to the throat, neck or jaw, and can lead to myocardial infarction. Vasospasm from ergotamine causes numbness and tingling in the fingers and toes, headache and pain over the heart. With severe spasm, the limbs turn blue and their pulses disappear. Spasm of the intestinal arteries causes abdominal pain with bloody diarrhoea. Sudden vision loss and stroke have been reported after triptans. Both drugs can raise blood pressure.

Management

The almotriptan documents of the Spanish Agency of Medicines and Medical Devices (AEMPS) and the US Food and Drug Administration (FDA) contraindicate the combination. The Spanish summary of product characteristics (SmPC) for ergotamine with caffeine contraindicates all triptans (AEMPS). After ergotamine, wait at least 24 hours before taking almotriptan (almotriptan SmPC, AEMPS, and label, FDA). After almotriptan, the Spanish SmPC allows ergotamine after 6 hours, while the US label requires the same 24 hours (almotriptan label, FDA). If ergotamine has not stopped the attack, do not add a triptan for the same attack (ergotamine with caffeine SmPC, AEMPS). If chest pain or tightness appears after an almotriptan dose, withhold further doses and assess the patient for cardiac ischaemia (almotriptan SmPC, AEMPS). Stop ergotamine at once if numbness or tingling in the fingers, pain over the heart or other signs of vasospasm appear (ergotamine with caffeine SmPC, AEMPS). If abdominal pain with blood in the stool, white fingers or vision loss follow a dose, assess arterial blood flow (almotriptan label, FDA). Taking ergotamine, triptans or both on 10 or more days a month can cause medication overuse headache, with more frequent attacks (almotriptan label, FDA).

Mechanism

CYP3A4 inhibition – fatal ergotism. Fatal cases reported.

Symptoms

Limb ischaemia, stroke.

Management

Combination contraindicated.

Mechanism

Clarithromycin inhibits CYP3A4. Ergotamine is metabolised exclusively by CYP3A4; concentration rises 10+ fold. Fatal ergotism: digital ischaemia, MI, stroke. FDA boxed warning.

Symptoms

Within 1–3 days: digital numbness, pallor, limb pain; in severe cases gangrene. Fatal cases reported.

Management

Combination contraindicated. For migraine in a clarithromycin patient – switch ergotamine to triptan after course completion, or use paracetamol for acute attack.

Mechanism

Cobicistat is a strong CYP3A4 inhibitor. EMA Tybost Section 4.3 strict contraindication with ergot alkaloids.

Symptoms

Fatal ergotism.

Management

Combination contraindicated.

Mechanism

CYP3A4 inhibition – fatal ergotism.

Symptoms

Limb ischaemia, stroke.

Management

Combination contraindicated.

Mechanism

Both drugs constrict arteries. Eletriptan stimulates serotonin receptors in the vessel wall, and drugs of this group can cause coronary artery spasm. Ergotamine constricts blood vessels and can cause myocardial ischaemia, or rarely infarction, even in people with no known heart disease. Vasospasm after ergot drugs can be prolonged. In clinical trials, oral ergotamine with caffeine given 1 and 2 hours after eletriptan raised blood pressure only slightly. Still, the effects of the two drugs added up, as their pharmacology predicts.

Symptoms

Coronary artery spasm causes chest pain, pressure or tightness, sometimes severe and spreading to the throat, neck or jaw, and can lead to myocardial infarction. Serious arrhythmias such as ventricular tachycardia and ventricular fibrillation have been reported within a few hours of taking drugs of this group. Vasospasm from ergotamine causes numbness and tingling in the fingers and toes, headache and pain over the heart. With severe spasm, the limbs turn blue and their pulses disappear. Spasm of the intestinal arteries causes abdominal pain with bloody diarrhoea, and spasm of the finger arteries causes Raynaud's syndrome. In rare cases, blood pressure rises to a hypertensive crisis.

Management

The eletriptan documents of the Spanish Agency of Medicines and Medical Devices (AEMPS) and the US Food and Drug Administration (FDA) contraindicate the combination. The Spanish summary of product characteristics (SmPC) for ergotamine with caffeine contraindicates all triptans (AEMPS). Keep at least 24 hours between the two drugs, in either order (eletriptan SmPC, AEMPS, and label, FDA). If ergotamine has not stopped the attack, do not add a triptan for the same attack (ergotamine with caffeine SmPC, AEMPS). If chest pain or tightness suggesting cardiac ischaemia appears after an eletriptan dose, give no further doses and evaluate the heart (eletriptan SmPC, AEMPS). Stop ergotamine at once if numbness or tingling in the fingers, pain over the heart or other signs of vasospasm appear (ergotamine with caffeine SmPC, AEMPS). Stop eletriptan if arrhythmias occur, and monitor blood pressure during treatment (eletriptan label, FDA). If abdominal pain with blood in the stool or white fingers appear, rule out vasospasm before the next eletriptan dose (eletriptan label, FDA). Taking ergotamine, triptans or both on 10 or more days a month can cause medication overuse headache, with more frequent attacks (eletriptan label, FDA).

Mechanism

Erythromycin is a CYP3A4 inhibitor. Ergotamine rises 5–10 fold, fatal ergotism. FDA Ergomar Section 4.

Symptoms

Digital ischaemia, MI within 1–5 days.

Management

Combination contraindicated.

Mechanism

Frovatriptan constricts cranial vessels through serotonin receptors. Ergotamine also constricts arteries, and the effects of the two drugs add up. The Spanish frovatriptan summary of product characteristics (SmPC) warns of high blood pressure and coronary artery spasm when both drugs are taken for the same migraine attack. Ergotamine on its own can cause myocardial ischaemia, or rarely infarction, even in people with no known heart disease. Vasospasm after ergot drugs can be prolonged. The risk comes from the effect on vessels, not from drug levels. With ergotamine, the area under the curve and peak concentration of frovatriptan actually fell, by about 25%.

Symptoms

Coronary artery spasm causes chest pain, pressure or tightness, sometimes severe and spreading to the throat, neck or jaw, and can lead to myocardial infarction. Serious arrhythmias such as ventricular tachycardia and ventricular fibrillation have been reported within a few hours of taking drugs of this group. Vasospasm from ergotamine causes numbness and tingling in the fingers and toes, headache and pain over the heart. With severe spasm, the limbs turn blue and their pulses disappear. Spasm of other arteries causes Raynaud's syndrome and bowel ischaemia with abdominal pain and bloody diarrhoea. Splenic infarction has also been reported. In rare cases, blood pressure rises to a hypertensive crisis.

Management

The frovatriptan documents of the Spanish Agency of Medicines and Medical Devices (AEMPS) and the US Food and Drug Administration (FDA) contraindicate the combination. The Spanish summary of product characteristics (SmPC) for ergotamine with caffeine contraindicates all triptans (AEMPS). Keep at least 24 hours between the two drugs, in either order (frovatriptan SmPC, AEMPS, and label, FDA). If ergotamine has not stopped the attack, do not add a triptan for the same attack (ergotamine with caffeine SmPC, AEMPS). If chest pain or tightness suggesting cardiac ischaemia appears after a frovatriptan dose, give no further doses and examine the patient further (frovatriptan SmPC, AEMPS). Stop ergotamine at once if numbness or tingling in the fingers, pain over the heart or other signs of vasospasm appear (ergotamine with caffeine SmPC, AEMPS). Stop frovatriptan if arrhythmias occur, and monitor blood pressure during treatment (frovatriptan label, FDA). If abdominal pain with blood in the stool or white fingers appear, rule out vasospasm before the patient takes frovatriptan again (frovatriptan label, FDA). Taking ergotamine, triptans or both on 10 or more days a month can cause medication overuse headache, with more frequent attacks (frovatriptan label, FDA).

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

Ketoconazole is a strong CYP3A4 inhibitor. Ergotamine rises 15-fold, fatal ergotism.

Symptoms

Limb ischaemia within 24 hours.

Management

Combination contraindicated.

Mechanism

Posaconazole is a strong CYP3A4 inhibitor. EMA Noxafil Section 4.3 strict contraindication.

Symptoms

Fatal ergotism.

Management

Combination contraindicated.

Mechanism

Ritonavir is the strongest CYP3A4 inhibitor. Fatal ergotism. FDA Ergomar Section 4.

Symptoms

Digital ischaemia, MI, stroke.

Management

Combination contraindicated.

Mechanism

Both drugs are 5-HT1B/1D vasoconstrictors. Additive effect on coronary and peripheral arteries. FDA requires at least 24-hour separation.

Symptoms

Myocardial ischaemia, stroke, digital ischaemia within hours.

Management

Combination contraindicated. At least 24 hours between ergotamine and any triptan.

Mechanism

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

Symptoms

Fatal ergotism.

Management

Combination contraindicated.