ERGOTAMINE TARTRATE AND CAFFEINE
Clinical safety rating: avoid
Contraindicated (not allowed)
Ergotamine is a partial agonist/antagonist at serotonin (5-HT), dopamine, and alpha-adrenergic receptors, causing vasoconstriction of cranial blood vessels. Caffeine enhances ergotamine absorption and has additive vasoconstrictive effects.
| Metabolism | Ergotamine is extensively metabolized by CYP3A4. Caffeine is metabolized primarily by CYP1A2. |
| Excretion | Ergotamine is primarily excreted in bile and feces as metabolites, with approximately 90% of a dose eliminated via the biliary-fecal route and less than 4% excreted unchanged in urine. Caffeine is extensively metabolized in the liver and its metabolites are excreted renally, with only about 1% excreted unchanged. |
| Half-life | Ergotamine has a terminal elimination half-life of approximately 2 hours (range 1.5–2.5 hours) for the alpha phase, but a longer terminal half-life of 12–24 hours due to slow tissue release; this contributes to its prolonged duration of action and risk of accumulation with frequent dosing. |
| Protein binding | Ergotamine is approximately 90% bound to plasma proteins, primarily to albumin and alpha-1 acid glycoprotein. Caffeine is about 35% bound, mainly to albumin. |
| Volume of Distribution | Ergotamine has a large volume of distribution, approximately 2–3 L/kg (range 1.5–4 L/kg), indicating extensive tissue distribution and binding to tissues, including the brain. Caffeine has a Vd of about 0.5–0.7 L/kg. |
| Bioavailability | Oral: bioavailability of ergotamine is low and erratic due to extensive first-pass metabolism, typically <5% (range 0–5%). Sublingual: bioavailability is slightly higher but still low, around 1–3%. Rectal: bioavailability is approximately 2–5%, somewhat more consistent than oral. Caffeine is well absorbed orally with bioavailability near 100%. |
| Onset of Action | Oral: onset of action typically occurs within 30–60 minutes. Sublingual: onset within 15–30 minutes. Rectal: onset within 15–30 minutes. Inhalation (not currently available in the US): onset within 5–10 minutes. |
| Duration of Action | Duration of action is typically 6–12 hours after oral or rectal administration, but may be longer due to slow tissue redistribution; clinical effects on migraine can persist up to 24 hours. |
| Molecular Weight | 581.67 Da (ergotamine tartrate) + 194.19 Da (caffeine) as free bases; salt form ergotamine tartrate MW ~1317; typical monographs list combined salt form MW ~611.5 for ergotamine tartrate component. |
Oral: 2 mg ergotamine tartrate and 200 mg caffeine at onset of migraine, then 1 mg ergotamine tartrate and 100 mg caffeine every 30 minutes as needed; maximum 6 mg ergotamine tartrate and 600 mg caffeine per day or 10 mg ergotamine tartrate and 1000 mg caffeine per week. Rectal: 2 mg ergotamine tartrate and 200 mg caffeine as a single suppository at onset; repeat once after 1 hour if needed; maximum 4 mg ergotamine tartrate and 400 mg caffeine per day or 8 mg ergotamine tartrate and 800 mg caffeine per week.
| Dosage form | TABLET |
| Renal impairment | No specific dose adjustments available; contraindicated in severe renal impairment (CrCl < 20 mL/min) due to risk of accumulation. |
| Liver impairment | Contraindicated in hepatic impairment (Child-Pugh class B or C). Use with caution in mild impairment (Child-Pugh class A); reduce initial dose by 50% and closely monitor for adverse effects. |
| Pediatric use | Not recommended for patients younger than 12 years due to lack of safety and efficacy data. For adolescents aged 12-17 years: 1 mg ergotamine tartrate and 100 mg caffeine orally at onset, repeat every 30 minutes if needed; maximum 3 mg ergotamine tartrate and 300 mg caffeine per day; or rectal suppository (1 mg ergotamine tartrate/100 mg caffeine) at onset, repeat once after 1 hour; maximum 2 mg ergotamine tartrate and 200 mg caffeine per day. |
| Geriatric use |
| 1st trimester | Contraindicated: Ergot alkaloids are oxytocic and may cause uterine hypertonicity, fetal distress, and higher risk of spontaneous abortion. |
| 2nd trimester | Contraindicated: Ergot alkaloids continue to pose risk of uterine hypertonicity and decreased placental blood flow. |
| 3rd trimester | Contraindicated: Ergot alkaloids can induce labor and cause severe neonatal adverse effects (e.g., respiratory depression, hypotonia, seizures) due to oxytocic and vasoconstrictive properties. |
Clinical note
Strong CYP3A4 inhibitors (eg clarithromycin) are contraindicated due to risk of ergotism Contraindicated in coronary artery disease and uncontrolled hypertension.
| Placental transfer | Ergot alkaloids cross the placenta readily, as evidenced by its ability to cause uterine contractions and fetal harm. Direct measurement confirms significant transfer. |
| Breastfeeding | Ergot alkaloids are excreted into breast milk and may cause ergotism in infants (vomiting, diarrhea, poor feeding, convulsions). Caffeine also appears in milk. Discontinue nursing or avoid drug; use only if potential benefit outweighs severe risk. |
■ FDA Black Box Warning
Serious or life-threatening peripheral ischemia and cerebral ischemia have been associated with ergotamine use, especially with prolonged use or overdose. Concomitant use with potent CYP3A4 inhibitors (e.g., macrolide antibiotics, protease inhibitors) increases risk.
| Common Effects | Nausea |
| Serious Effects |
Hypersensitivity to ergot alkaloids or caffeinePeripheral vascular diseaseCoronary artery diseaseHypertensionImpaired hepatic or renal functionSepsisPregnancyBreastfeeding
| Precautions | Risk of ergotism (ischemia, gangrene) with prolonged use or high doses, May cause vasospastic reactions, including coronary vasospasm, Overuse can lead to medication-overuse headache, Avoid concomitant use with vasoconstrictors or ergot-like drugs, May cause nausea, vomiting, and paresthesias |
| Food/Dietary |
Loading safety data…
| Use with caution due to increased risk of peripheral vascular disease, coronary artery disease, and reduced hepatic/renal function. Initiate at lowest effective dose (e.g., 1 mg ergotamine tartrate and 100 mg caffeine orally) and monitor for signs of ischemia. Avoid in patients over 65 with uncontrolled hypertension or vascular risk. |
| Lactation Rating | L5 - Contraindicated |
| Teratogenic Risk | Pregnancy Category X. Ergotamine is contraindicated in all trimesters due to potent uterotonic effects and vasoconstriction, which can cause fetal hypoxia, growth retardation, and spontaneous abortion. Caffeine may be associated with low birth weight and preterm delivery at high doses. There are no adequate studies in pregnant women. |
| Fetal Monitoring | Monitor for signs of ergotism (numbness, tingling, muscle pain, claudication), blood pressure (vasoconstriction may cause hypertension), fetal heart rate (if inadvertent use), and uterine activity due to oxytocic potential. |
| Fertility Effects | May impair fertility due to ergotamine's dopamine agonist effects, which can increase prolactin levels and disrupt ovulation. Caffeine in high doses may also adversely affect fertility. |
| Avoid grapefruit juice; it inhibits CYP3A4, increasing ergotamine absorption and risk of toxicity. Caffeine-containing foods (coffee, tea, cola) may be consumed in moderation but excessive caffeine intake may exacerbate adverse effects. |
| Clinical Pearls | Ergotamine tartrate is a serotonin 5-HT1B/1D receptor agonist and alpha-adrenergic blocker. Caffeine enhances ergotamine absorption and adds vasoconstriction. Contraindicated in coronary artery disease, uncontrolled hypertension, peripheral vascular disease, sepsis, and within 24 hours of triptans. Risk of ergotism with excessive use. Limit acute use to ≤6 mg/attack and ≤10 mg/week. Avoid prolonged daily use to prevent rebound headache. |
| Patient Advice | Take at the first sign of migraine headache; do not use for prevention. · Do not exceed one dose per 24 hours; maximum 2 tablets per attack and 5 tablets per week. · Seek emergency care if symptoms of ergotism (cold/blue extremities, muscle pain, numbness, tingling) occur. · Avoid concurrent use with triptans or other ergot alkaloids within 24 hours. · Not for use during pregnancy or breastfeeding; use reliable contraception. · Do not consume grapefruit juice as it may increase ergotamine levels. · Report chest pain, palpitations, or severe abdominal pain immediately. |