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Ergotamine and Caffeine

Pronunciation

(er GOT a meen & KAF een)

Index Terms

  • Caffeine and Ergotamine
  • Ergotamine Tartrate and Caffeine
  • Ergotamine Tartrate/Caffeine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suppository, rectal:

Migergot: Ergotamine tartrate 2 mg and caffeine 100 mg (12s)

Tablet, oral:

Cafergot: Ergotamine tartrate 1 mg and caffeine 100 mg

Generic: Ergotamine tartrate 1 mg and caffeine 100 mg

Brand Names: U.S.

  • Cafergot
  • Migergot

Pharmacologic Category

  • Antimigraine Agent
  • Central Nervous System Stimulant
  • Ergot Derivative

Pharmacology

Has partial agonist and/or antagonist activity against tryptaminergic, dopaminergic and alpha-adrenergic receptors depending upon their site; is a highly active uterine stimulant; it causes constriction of peripheral and cranial blood vessels and produces depression of central vasomotor centers

Absorption

Ergotamine: Oral, rectal: Erratic (Perrin, 1985)

Metabolism

Ergotamine: Extensively hepatic, including high first-pass metabolism (Perrin, 1985)

Excretion

Ergotamine: Feces (90%, primarily as metabolites) (Perrin, 1985)

Time to Peak

Serum: Ergotamine: 2 hours (Perrin, 1985)

Half-Life Elimination

2 to 2.5 hours (Perrin, 1985)

Use: Labeled Indications

Vascular headache: Prevention or treatment of vascular headaches, such as migraine, migraine variants, or so-called “histaminic cephalalgia”

Contraindications

Hypersensitivity to ergotamine, caffeine, or any component of the formulation; peripheral vascular disease; hepatic or renal impairment; coronary heart disease; hypertension; sepsis; concomitant use of ergot alkaloids with strong inhibitors of CYP3A4 (includes HIV and HCV protease inhibitors, cobicistat, azole antifungals, and some macrolide antibiotics); pregnancy

Dosing: Adult

Vascular headache:

Oral: Note: Each tablet contains ergotamine 1 mg and caffeine 100 mg: Ergotamine 2 mg and caffeine 200 mg (2 tablets) at onset of attack; then ergotamine 1 mg and caffeine 100 mg (1 tablet) every 30 minutes as needed

Maximum dose: Ergotamine 6 mg and caffeine 600 mg (6 tablets) per attack; do not exceed ergotamine 10 mg and caffeine 1,000 mg (10 tablets) per week

Rectal: Ergotamine 2 mg and caffeine 100 mg (1 suppository) at first sign of an attack; follow with second dose after 1 hour, if needed

Maximum dose: Ergotamine 4 mg and caffeine 200 mg (2 suppositories) per attack; do not exceed ergotamine 10 mg and caffeine 500 mg (5 suppositories) per week

Dosing: Renal Impairment

Use is contraindicated.

Dosing: Hepatic Impairment

Use is contraindicated.

Administration

Oral: Administer with or without food.

Rectal: Suppository: Remove foil from rectal suppository and insert pointed end first. Avoid handling unwrapped suppository for too long.

Storage

Suppositories: Store refrigerated at 2°C to 8°C (36°F to 46°F) in sealed foil.

Tablet: Store at 20°C to 25°C (68°F to 77°F). Protect from light.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Acebrophylline: May enhance the stimulatory effect of CNS Stimulants. Avoid combination

Adenosine: Caffeine and Caffeine Containing Products may diminish the therapeutic effect of Adenosine. Management: Monitor for decreased effect of adenosine if patient is receiving caffeine. Discontinue caffeine in advance of scheduled diagnostic use of adenosine whenever possible. Consider therapy modification

Alpha-/Beta-Agonists: Ergot Derivatives may enhance the hypertensive effect of Alpha-/Beta-Agonists. Ergot Derivatives may enhance the vasoconstricting effect of Alpha-/Beta-Agonists. Avoid combination

Alpha1-Agonists: Ergot Derivatives may enhance the hypertensive effect of Alpha1-Agonists. Ergot Derivatives may enhance the vasoconstricting effect of Alpha1-Agonists. Avoid combination

Analgesics (Opioid): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antihepaciviral Combination Products: May increase the serum concentration of Ergot Derivatives. Avoid combination

Anti-Parkinson Agents (Monoamine Oxidase Inhibitor): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity if selegiline, rasagiline, or safinamide is combined with a serotonin modulator. Use of transdermal selegiline with serotonin modulators is contraindicated. Consider therapy modification

Antipsychotic Agents: Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

AtoMOXetine: May enhance the hypertensive effect of Sympathomimetics. AtoMOXetine may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Beta-Blockers: May enhance the vasoconstricting effect of Ergot Derivatives. Consider therapy modification

Boceprevir: May increase the serum concentration of Ergotamine. Avoid combination

Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Exceptions: Cannabidiol. Monitor therapy

Ciprofloxacin (Systemic): May increase the serum concentration of Caffeine. Monitor therapy

Clarithromycin: May increase the serum concentration of Ergotamine. Avoid combination

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Monitor therapy

Cobicistat: May increase the serum concentration of Ergotamine. Avoid combination

Cocaine: May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Crizotinib: May increase the serum concentration of Ergotamine. Avoid combination

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Monitor therapy

CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Doxofylline: Caffeine and Caffeine Containing Products may enhance the adverse/toxic effect of Doxofylline. Avoid combination

Enzalutamide: May decrease the serum concentration of Ergotamine. Avoid combination

Formoterol: Caffeine and Caffeine Containing Products may enhance the adverse/toxic effect of Formoterol. Caffeine and Caffeine Containing Products may enhance the hypokalemic effect of Formoterol. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Indacaterol: Caffeine and Caffeine Containing Products may enhance the adverse/toxic effect of Indacaterol. Caffeine and Caffeine Containing Products may enhance the hypokalemic effect of Indacaterol. Monitor therapy

Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Itraconazole: May increase the serum concentration of Ergotamine. Avoid combination

Ketoconazole (Systemic): May increase the serum concentration of Ergotamine. Avoid combination

Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Reduce initial doses of sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid. Specific dose adjustment recommendations are not presently available. Consider therapy modification

Linezolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Management: Due to a risk of serotonin syndrome/serotonin toxicity, discontinue serotonin modulators 2 weeks prior to the administration of linezolid. If urgent initiation of linezolid is needed, discontinue serotonin modulators immediately and monitor closely. Consider therapy modification

Lithium: Caffeine and Caffeine Containing Products may decrease the serum concentration of Lithium. Monitor therapy

Lorcaserin: May enhance the adverse/toxic effect of Ergot Derivatives. Specifically, use of these drugs together may increase the risk of developing valvular heart disease. Lorcaserin may enhance the serotonergic effect of Ergot Derivatives. This could result in serotonin syndrome. Avoid combination

Macrolide Antibiotics: May increase the serum concentration of Ergot Derivatives. Cabergoline and Clarithromycin may interact, see specific monograph for full details. Exceptions: Azithromycin (Systemic); Fidaxomicin; Spiramycin. Consider therapy modification

Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination

Methylphenidate: May enhance the adverse/toxic effect of Serotonin Modulators. Specifically, the risk of serotonin syndrome or serotonin toxicity may be increased. Monitor therapy

Metoclopramide: Serotonin Modulators may enhance the adverse/toxic effect of Metoclopramide. This may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Monitor therapy

MiFEPRIStone: May increase the serum concentration of Ergotamine. Management: Avoid ergotamine during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Nitroglycerin: Ergot Derivatives may diminish the vasodilatory effect of Nitroglycerin. This is of particular concern in patients being treated for angina. Nitroglycerin may increase the serum concentration of Ergot Derivatives. Avoid combination

Norfloxacin: May increase the serum concentration of Caffeine and Caffeine Containing Products. Monitor therapy

Obeticholic Acid: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Olodaterol: Caffeine and Caffeine Containing Products may enhance the adverse/toxic effect of Olodaterol. Caffeine and Caffeine Containing Products may enhance the hypokalemic effect of Olodaterol. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Peginterferon Alfa-2b: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy

Posaconazole: May increase the serum concentration of Ergotamine. Avoid combination

Protease Inhibitors: May increase the serum concentration of Ergot Derivatives. Avoid combination

Reboxetine: May enhance the hypertensive effect of Ergot Derivatives. Monitor therapy

Regadenoson: Caffeine and Caffeine Containing Products may diminish the vasodilatory effect of Regadenoson. Management: Avoiding using caffeine or other methylxanthine containing products (e.g., theophylline) for at least 12 hours prior to the administration of regadenoson. Consider therapy modification

Roxithromycin: May increase the serum concentration of Ergot Derivatives. Avoid combination

Serotonin 5-HT1D Receptor Agonists: Ergot Derivatives may enhance the vasoconstricting effect of Serotonin 5-HT1D Receptor Agonists. Serotonin 5-HT1D Receptor Agonists may enhance the vasoconstricting effect of Ergot Derivatives. Avoid combination

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Stiripentol: May increase the serum concentration of Caffeine and Caffeine Containing Products. Avoid combination

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Monitor therapy

Tedizolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Telaprevir: May increase the serum concentration of Ergotamine. Avoid combination

Teriflunomide: May decrease the serum concentration of Caffeine and Caffeine Containing Products. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

TraMADol: Serotonin Modulators may enhance the adverse/toxic effect of TraMADol. The risk of seizures may be increased. TraMADol may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Vemurafenib: May increase the serum concentration of CYP1A2 Substrates. Management: Consider alternatives to such combinations whenever possible, particularly if the CYP1A2 substrate has a relatively narrow therapeutic index. Consider therapy modification

Voriconazole: May increase the serum concentration of Ergotamine. Avoid combination

Adverse Reactions

Frequency not defined.

Cardiovascular: Bradycardia, cold extremities, ECG changes, edema, hypertension, ischemia, tachycardia, valvular sclerosis, vasospasm

Central nervous system: Numbness, paresthesia, precordial pain, vertigo

Dermatologic: Gangrene of skin or other tissue, pruritus

Gastrointestinal: Anal fissure (with overuse of suppository), nausea, rectal ulcer (with overuse of suppository), vomiting

Genitourinary: Retroperitoneal fibrosis

Neuromuscular & skeletal: Myalgia, weakness

Respiratory: Cyanosis, pleuropulmonary fibrosis

ALERT: U.S. Boxed Warning

Concurrent drug therapy:

Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of ergotamine/caffeine with potent CYP 3A4 inhibitors including protease inhibitors and macrolide antibiotics. Because CYP 3A4 inhibition elevates the serum levels of ergotamine/caffeine, the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities is increased. Hence, concomitant use of these medications is contraindicated.

Warnings/Precautions

Concerns related to adverse effects:

• Cardiac valvular fibrosis: Ergot alkaloids have been associated (rarely) with fibrotic valve thickening (eg, aortic, mitral, tricuspid); usually associated with long-term, chronic use.

• Cardiovascular effects: Vasospasm or vasoconstriction can occur, possibly resulting in cyanosis, decreased cerebral blood flow, bradycardia or tachycardia, asystole, and hypertension; sustained vasoconstriction may also lead to intermittent claudication, precordial distress, and pain. Do not use in any patient at risk or predisposed to vascular effects of ergot alkaloids.

• Ergotism: Ergot alkaloid use may result in ergotism (intense vasoconstriction) resulting in peripheral vascular ischemia and possible gangrene. Ergotism is usually associated with overdosage or prolonged chronic use; do not exceed dosing guidelines and avoid prolonged administration.

• Pleural/retroperitoneal fibrosis: Rare cases of pleural and/or retroperitoneal fibrosis have been reported with prolonged daily administration.

Concurrent drug therapy issues:

• CYP3A4 inhibitors: [U.S. Boxed Warning]: Ergot alkaloids are contraindicated with potent inhibitors of CYP3A4 (includes protease inhibitors and some macrolide antibiotics). Serum levels of ergotamines may be elevated, leading to increased risk of vasospasm leading to cerebral ischemia and/or ischemia of extremities. Serious and/or life-threatening peripheral ischemia has been associated with concomitant use.

• Drug-drug interactions: Additional potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Avoid use in the elderly due to the vasoconstrictive properties and cardiovascular adverse effects associated with ergot alkaloids.

Dosage form specific issues:

• Rectal suppositories: Solitary rectal or anal ulcers have occurred rarely when suppositories are used in higher than recommended doses or with continual use of recommended doses for prolonged periods of time. After discontinuation, spontaneous healing occurs within 4 to 8 weeks.

Other warnings/precautions:

• Appropriate use: Do not use for prolonged daily administration; serious adverse effects are associated with long-term continuous use. Use caution and remain within recommended dosage limits.

• Medication-overuse headache/Withdrawal: Discontinuation even after limited use may result in withdrawal symptoms (ie, rebound headache, nausea, vomiting).

Monitoring Parameters

BUN, serum creatinine, liver function tests at baseline, signs of peripheral ischemia (eg, vasospasm, digit coldness, and pallor), numbness, muscle pains, extremity weakness, chest pain, tachycardia or bradycardia, hypersensitivity reactions.

Pregnancy Risk Factor

X

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination. Ergotamine and caffeine both cross the placenta and may cause prolonged constriction of the uterine vessels and/or increased myometrial tone leading to reduced placental blood flow. Use is contraindicated in pregnant women.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea or vomiting. Have patient report immediately to prescriber angina, bradycardia, tachycardia, abnormal heartbeat, edema, severe dizziness, passing out, severe headache, vision changes, muscle weakness, muscle pain, change in color of hands or feet from pale to blue or red, burning or numbness of hands or feet, rectal sores, rectal pain, or wounds on fingers or toes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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