MEDIHALER ERGOTAMINE
Clinical safety rating: avoid
Strong CYP3A4 inhibitors (eg clarithromycin) are contraindicated due to risk of ergotism Contraindicated in coronary artery disease and uncontrolled hypertension.
Ergotamine is a serotonin (5-HT1B/1D) receptor agonist with additional affinity for 5-HT2, dopamine D2, and alpha-adrenergic receptors. It causes vasoconstriction of cranial blood vessels and inhibits neurogenic inflammation.
| Metabolism | Hepatic, primarily via CYP3A4. Undergoes first-pass metabolism. |
| Excretion | Ergotamine is extensively metabolized in the liver. Approximately 90% of the dose is excreted as metabolites in the bile/feces, with less than 3% excreted unchanged in urine. |
| Half-life | The terminal elimination half-life is approximately 2 hours for the initial phase, followed by a prolonged terminal phase of 21-30 hours due to slow release from tissue binding sites. This long terminal half-life contributes to the risk of accumulation and toxicity with frequent dosing. |
| Protein binding | Protein binding: 90-95%, primarily to albumin and possibly to alpha-1-acid glycoprotein. |
| Volume of Distribution | Volume of distribution: approximately 1.9 L/kg (range 1.4-2.4 L/kg). This large Vd indicates extensive tissue distribution, including accumulation in peripheral tissues such as the lungs and liver, which explains the prolonged terminal half-life and risk of toxicity. |
| Bioavailability | Bioavailability via inhalation: approximately 25-40% (compared to IM route). Oral bioavailability is very low (<5%) due to extensive first-pass metabolism; thus, oral forms are not used. The inhalation route bypasses first-pass hepatic metabolism, providing higher systemic availability than oral. |
| Onset of Action | Inhalation via Medihaler: onset within 5-10 minutes for relief of migraine headache. |
| Duration of Action | Duration of action is 4-6 hours for relief of acute migraine. However, the drug's prolonged elimination half-life and tissue binding lead to potential cumulative effects with repeated use; clinical effect may be prolonged but with increased risk of ergotism. |
| Molecular Weight | 581.67 Da |
One inhalation (0.36 mg ergotamine) at onset of migraine; may repeat after 5 minutes if needed, up to 6 inhalations per attack and 15 per week.
| Dosage form | AEROSOL, METERED |
| Renal impairment | Contraindicated in severe renal impairment (GFR <30 mL/min). No specific dose adjustment for mild to moderate impairment; use with caution. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh C). Avoid use in moderate impairment (Child-Pugh B); no data for mild impairment (use with caution). |
| Pediatric use | Not recommended for use in children due to risk of toxicity and lack of safety data. |
| Geriatric use | Use with caution due to increased susceptibility to vasospasm and peripheral vascular disease; start with lower dose (e.g., 1 inhalation) and monitor for adverse effects. |
| 1st trimester | Contraindicated: Ergotamine is oxytocic and can cause uterine contractions; associated with fetal harm and spontaneous abortion. |
| 2nd trimester | Contraindicated: Risk of uterotonic effects and fetal hypoxia; not recommended. |
| 3rd trimester | Contraindicated: Can induce premature labor and fetal distress due to vasoconstriction and oxytocic effects. |
Clinical note
Strong CYP3A4 inhibitors (eg clarithromycin) are contraindicated due to risk of ergotism Contraindicated in coronary artery disease and uncontrolled hypertension.
| FDA category | Contraindicated |
| Placental transfer | Ergotamine crosses the placenta readily; can cause fetal vasoconstriction and hypoxia. |
| Breastfeeding |
■ FDA Black Box Warning
Serious and/or life-threatening peripheral ischemia and vasospasm have been associated with ergotamine when coadministered with potent CYP3A4 inhibitors (including protease inhibitors, macrolide antibiotics, and azole antifungals). Concomitant use is contraindicated.
| Common Effects | Nausea |
| Serious Effects |
Hypersensitivity to ergot alkaloidsCoronary artery diseasePeripheral vascular diseaseHypertension (severe or uncontrolled)SepsisHepatic or renal impairmentPregnancyBreastfeedingConcurrent use of potent CYP3A4 inhibitors (e.g., macrolides, protease inhibitors)
| Precautions | Vasospastic reactions: may cause prolonged vasoconstriction leading to ischemia or gangrene, Risk of ergotism: chronic use or overdose may lead to severe vasoconstriction and ischemia, Cardiac effects: may cause angina, myocardial infarction, or coronary vasospasm, Fibrotic complications: retroperitoneal, pleural, or cardiac valve fibrosis with long-term use, Cerebrovascular effects: may cause cerebral ischemia or stroke, Rebound headache: overuse may lead to medication-overuse headache |
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| Ergotamine is excreted into breast milk in small amounts but may cause ergotism in infants (vomiting, diarrhea, convulsions). Due to potential toxicity, breastfeeding is not recommended during use. Discontinue nursing or drug. |
| Lactation Rating | L5 (Contraindicated) or 'Avoid' |
| Teratogenic Risk | Ergotamine is contraindicated in pregnancy. First trimester: Increased risk of congenital malformations, including vascular disruption defects (e.g., limb reduction, gastroschisis). Second and third trimesters: Uterine hypertonicity, placental insufficiency, fetal distress, and increased risk of preterm labor and low birth weight. Ergotamine crosses the placenta. Category X. |
| Fetal Monitoring | Monitor maternal blood pressure (risk of hypertension), uterine activity (signs of hypertonicity or tetanic contractions), and fetal heart rate patterns (non-stress test/bioimpedance) for distress. Assess for signs of ergotism (nausea, vomiting, vasospasm, paresthesia). |
| Fertility Effects | Ergotamine may impair fertility in females by disrupting ovulatory function due to its dopamine agonist activity, potentially causing hyperprolactinemia. In males, no specific data; however, ergot alkaloids may affect fertility via vascular effects on reproductive organs. Use is not recommended for individuals seeking conception. |
| Food/Dietary | Avoid grapefruit and grapefruit juice during treatment as they inhibit CYP3A4 and increase ergotamine levels. Limit caffeine intake; excessive caffeine may worsen vasoconstriction. No other significant food interactions. |
| Clinical Pearls | Ergotamine is contraindicated in patients with coronary artery disease, peripheral vascular disease, hypertension, or sepsis due to risk of vasospasm. Avoid concurrent use with strong CYP3A4 inhibitors (e.g., macrolides, protease inhibitors) as it increases risk of ergotism. Do not exceed recommended dosing (maximum 6 mg per attack, 10 mg per week) to avoid toxicity. Use with caution in patients with hepatic or renal impairment. |
| Patient Advice | Use only at the first sign of a migraine attack for best results. · Do not use more than prescribed: maximum 2 inhalations per attack and 5 inhalations per week. · Seek emergency care if you experience symptoms of ergotism: severe muscle pain, coldness, numbness, or color changes in fingers or toes. · Avoid smoking or using nicotine products as they increase vasoconstriction risk. · Do not take with other ergot medications or triptans within 24 hours. · Report chest pain, irregular heartbeat, or shortness of breath immediately. |