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Dihydroergotamine

Pronunciation

(dye hye droe er GOT a meen)

Index Terms

  • DHE
  • Dihydroergotamine Mesylate

Dosage Forms

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

Solution, Injection, as mesylate:

D.H.E. 45: 1 mg/mL (1 mL)

Generic: 1 mg/mL (1 mL)

Solution, Nasal, as mesylate:

Migranal: 4 mg/mL (1 mL)

Generic: 4 mg/mL (1 mL)

Brand Names: U.S.

  • D.H.E. 45
  • Migranal

Pharmacologic Category

  • Antimigraine Agent
  • Ergot Derivative

Pharmacology

Ergot alkaloid alpha-adrenergic blocker directly stimulates vascular smooth muscle to vasoconstrict peripheral and cerebral vessels; also has effects on serotonin receptors

Distribution

Vd: ~800 L

Metabolism

Extensively hepatic (one active metabolite)

Excretion

Primarily feces; urine (6% to 7% as unchanged drug); Clearance: 1.5 mL/minute

Onset of Action

IM: 15-30 minutes

Time to Peak

Serum: IM: 24 minutes; IV: 1-2 minutes; Intranasal: 30-60 minutes; SubQ 15-45 minutes

Duration of Action

IM: 3-4 hours

Half-Life Elimination

~9-10 hours

Protein Binding

93%

Use: Labeled Indications

Treatment of migraine headache with or without aura; injection also indicated for treatment of cluster headaches

Use: Unlabeled

Adjunct for DVT prophylaxis for hip surgery, for orthostatic hypotension, xerostomia secondary to antidepressant use, and pelvic congestion with pain

Contraindications

Hypersensitivity to dihydroergotamine or any component of the formulation; uncontrolled hypertension, ischemic heart disease, angina pectoris, history of MI, silent ischemia, or coronary artery vasospasm including Prinzmetal's angina; hemiplegic or basilar migraine; peripheral vascular disease; sepsis; severe hepatic or renal dysfunction; following vascular surgery; avoid use within 24 hours of sumatriptan, zolmitriptan, other serotonin agonists, or ergot-like agents; avoid during or within 2 weeks of discontinuing MAO inhibitors; concurrent use of peripheral and central vasoconstrictors; ergot alkaloids are contraindicated with potent inhibitors of CYP3A4 (includes protease inhibitors, azole antifungals, and some macrolide antibiotics); pregnancy, breast-feeding

Dosing: Adult

Migraine, cluster headache:

IM, SubQ: 1 mg at first sign of headache; repeat hourly to a maximum dose of 3 mg/day; maximum dose: 6 mg/week

IV: 1 mg at first sign of headache; repeat hourly up to a maximum dose of 2 mg/day; maximum dose: 6 mg/week

Intranasal: 1 spray (0.5 mg) of nasal spray should be administered into each nostril; if needed, repeat after 15 minutes, up to a total of 4 sprays (2 mg). Note: Do not exceed 6 sprays (3 mg) in a 24-hour period and no more than 8 sprays (4 mg) in a week.

Intractable migraine (status migrainosus; >72 hours): IV: Raskin protocol (off-label dosing): Initial test dose: 0.5 mg (following premedication with metoclopramide); subsequent dosing is titrated (range: 0.2-1 mg) every 8 hours for 2-3 days and administered with or without metoclopramide based on response and tolerance (Raskin, 1986; Raskin, 1990). Note: Some clinicians use modified versions of this protocol, with additional adjunctive medications and/or alternate antiemetic agents.

Dosing: Geriatric

Refer to adult dosing. Patients >65 years of age were not included in controlled clinical studies.

Dosing: Renal Impairment

Contraindicated in severe renal impairment

Dosing: Hepatic Impairment

Dosage reductions are probably necessary but specific guidelines are not available; contraindicated in severe hepatic dysfunction.

Administration

Intranasal: Prior to administration of nasal spray, the nasal spray applicator must be primed (pumped 4 times); in order to let the drug be absorbed through the skin in the nose, patients should not inhale deeply through the nose while spraying or immediately after spraying; for best results, treatment should be initiated at the first symptom or sign of an attack; however, nasal spray can be used at any stage of a migraine attack.

IM, SubQ: May administer by intramuscular or subcutaneous injection.

IV: Administer slowly over 2-3 minutes (Raskin protocol)

Storage

Injection: Store below 25°C (77°F); do not refrigerate or freeze; protect from heat. Protect from light.

Nasal spray: Prior to use, store below 25°C (77°F); do not refrigerate or freeze. Once spray applicator has been prepared, use within 8 hours; discard any unused solution.

Drug Interactions

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 or rasagiline 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 Dihydroergotamine. Management: Avoid dihydroergotamine 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

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

Posaconazole: May increase the serum concentration of Dihydroergotamine. 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

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

Serotonin 5-HT1D Receptor Agonists: May enhance the vasoconstricting effect of Ergot Derivatives. Ergot Derivatives may enhance the vasoconstricting effect of Serotonin 5-HT1D Receptor Agonists. 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 CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

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

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

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

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

Adverse Reactions

>10%: Nasal spray: Respiratory: Rhinitis (26%)

1% to 10%: Nasal spray:

Central nervous system: Taste disorder (8%), dizziness (4%), drowsiness (3%)

Endocrine & metabolic: Hot flash (1%)

Gastrointestinal: Nausea (10%), vomiting (4%), diarrhea (2%)

Local: Application site reaction (6%)

Neuromuscular & skeletal: Stiffness (1%), weakness (1%)

Respiratory: Pharyngitis (3%)

<1% (Limited to important or life-threatening): Injection and nasal spray: Abdominal pain, anxiety, cerebral hemorrhage, cerebrovascular accident, coronary artery vasospasm, diaphoresis, diarrhea, dizziness, dyspnea, edema, fibrothorax (prolonged use), flushing, headache, hyperkinesia, hypertension, ischemic heart disease, muscle cramps, myalgia, myasthenia, myocardial infarction, palpitations, paresthesia, peripheral cyanosis, peripheral ischemia, retroperitoneal fibrosis (prolonged use), skin rash, subarachnoid hemorrhage, tremor, valvular sclerosis (associated with ergot alkaloids), ventricular fibrillation, ventricular tachycardia (transient)

ALERT: U.S. Boxed Warning

Concurrent drug therapy:

Serious and life-threatening peripheral ischemia have been associated with the coadministration of dihydroergotamine with potent CYP3A4 inhibitors including protease inhibitors and macrolide antibiotics. Because CYP3A4 inhibition elevates the serum levels of dihydroergotamine, the risk for vasospasm leading to cerebral ischemia and 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 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 decreased cerebral blood flow, ECG changes, and hypertension; sustained vasoconstriction may also lead to ischemic colitis, intermittent claudication, aggravation of angina, or precipitation of MI. Do not use is any patient at risk or predisposed to vascular effects of ergot alkaloids.

• Cerebrovascular events: Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have also occurred (in some cases resulted in fatalities) following use of the injection.

• 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 use.

Disease-related concerns:

• Cardiovascular disease: Do not give to patients with risk factors for CAD until a cardiovascular evaluation has been performed; if evaluation is satisfactory, the healthcare provider should administer the first dose and cardiovascular status should be periodically evaluated.

Concurrent drug therapy issues:

• CYP3A4 inhibitors: [U.S. Boxed Warning]: Ergot alkaloids are contraindicated with potent inhibitors of CYP3A4 (includes protease inhibitors, azole antifungals, and some macrolide antibiotics); concomitant use associated with an increased risk of vasospasm leading to cerebral ischemia and/or ischemia of the extremities.

Special populations:

• Elderly: Use with extreme caution or avoid use in the elderly; due to vasoconstrictive properties and cardiovascular adverse effects associated with ergot alkaloids.

Dosage form specific issues:

• Migranal® Nasal Spray: Local irritation to nose and throat (usually transient and mild-moderate in severity) can occur; long-term consequences on nasal or respiratory mucosa have not been extensively evaluated.

Pregnancy Risk Factor

X

Pregnancy Considerations

Dihydroergotamine is oxytocic and should not be used during pregnancy.

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, vomiting, rhinitis, pharyngitis, change in taste, nosebleed, or rhinorrhea. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), angina, tachycardia, burning or numbness feeling, severe dizziness, passing out, muscle pain, weakness, muscle cramps, abnormal heartbeat, change in color of hands or feet from pale to blue or red, sensation of cold, bradycardia, edema, or severe abdominal pain (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 healthcare 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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