ergotamine/caffeine (Rx)

Frequency Not Defined

Gastrointestinal: Nausea and vomiting; rectal or anal ulcer (from overuse of suppositories)

Neurological: Paresthesia, numbness, weakness, and vertigo

Allergic: Localized edema and itching

Cardiovascular

• Serious vasoconstrictive complications may occur including ischemia, cyanosis, absence of pulse, cold extremities, gangrene, precordial distress and pain, EKG changes, and muscle pains
• Most commonly occurs with long-term therapy at relatively high doses; also reported with short-term or normal doses
• Other cardiovascular adverse effects include transient tachycardia or bradycardia and hypertension

Contraindications

Potent CYP3A4 inhibitors owing to risk of acute ergot toxicity

Pregnancy

Peripheral vascular disease, coronary heart disease, hypertension, impaired hepatic or renal function, sepsis

Hypersensitivity to any of the ingredients

Cautions

Ergotism

• Although ergotism rarely develop even after long-term intermittent use of orally administered ergotamine, do not exceed dosage recommendations
• Ergotism manifested by intense arterial vasoconstriction, producing signs and symptoms of peripheral vascular ischemia
• Headache, intermittent claudication, muscle pains, numbness, or coldness and pallor of the digits may occur with chronic intoxication; if the condition is allowed to progress untreated, gangrene can result
• While most cases result from frank overdosage, some cases involve hypersensitivity
• There are few reports among patients taking doses within recommended limits or for brief periods
• Withdrawal symptoms (eg, rebound headache) upon discontinuation are rare; typically reported with long, indiscriminate use

Fibrotic complications

• Retroperitoneal and/or pleuropulmonary fibrosis reported
• Rare reports of fibrotic thickening of the aortic, mitral, tricuspid, and/or pulmonary valves with long-term, continuous use of ergotamine tartrate and caffeine
• Do not use for chronic daily administration

Drug interaction overview

• Ergotamine is a CYP3A substrate and inhibitor

• CYP3A inhibitors

  • Potent inhibitors: Contraindicated owing to risk for acute ergot toxicity (ergotism) characterized by vasospasm and ischemia of the extremities
  • Less potent inhibitors: Although not contraindicated, avoid if possible owing to risk for vasospasm

Pregnancy

Contraindicated; ergotamine elicits oxytocic effects

There are no studies on placental transfer or teratogenicity of the combination of ergotamine and caffeine

Labor and delivery

• Contraindicated in labor and delivery owing to ergotamine’s oxytocic effect, which is maximal in the third trimester

Animal studies

• Caffeine is known to cross the placenta and has been shown to be teratogenic in animals
• Ergotamine crosses the placenta in small amounts, although it does not appear to be embryotoxic in this quantity; however, prolonged vasoconstriction of uterine vessels and/or increased myometrial tone leading to reduced myometrial and placental blood flow may have contributed to fetal growth retardation observed in animals

Lactation

Ergot drugs are known to inhibit prolactin, but there are no reports of decreased lactation with ergotamine/caffeine

Ergotamine is excreted in breast milk and may cause symptoms of vomiting, diarrhea, weak pulse, and unstable blood pressure in nursing infants

Owing to the potential serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, considering the importance of the drug to the mother

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Ergotamine: Alpha-adrenergic blocking agent with direct stimulating effect on smooth muscle of peripheral and cranial blood vessels; also elicits serotonin antagonism

Caffeine: Cranial vasoconstrictor; added to further enhance vasoconstrictive effect without increasing ergotamine dosage

Absorption

Bioavailability: <5%

Peak plasma time: 2 hr (PO)

Distribution

Vd: 1.85 L/kg

Metabolism

Extensively metabolized in liver hepatic metabolism

Elimination

Half-life: 2-2.5 hr

Excretion: Feces (90%, mostly as metabolites)

Oral Administration

May take with or without food

Rectal Administration

Remove suppository from foil wrap

Lay on side and insert pointed end of suppository into rectum; remain on side to allow suppository to dissolve and absorb

Avoid handling unwrapped suppository for too long

If needed, may cut suppository lengthwise

Storage

Tablets

• Store at 20-25ºC (68-77ºF)
• Dispense in tight, light-resistant container

Suppositories

• Refrigerate at 2-8ºC (36-46ºF) in sealed foil