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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

Efficacy in migraine is attributed to the activation of 5-HT1D receptors located on intracranial blood vessels resulting in vasoconstriction and/or activation of 5-HT1D receptors on sensory nerve endings of the trigeminal system resulting in the inhibition of pro-inflammatory neuropeptide release. Dihydroergotamine binds with high affinity to serotonin 5-HT1Dα, 5-HT1Dβ, 5-HT1A, 5-HT2A, and 5-HT2C receptors, noradrenaline α2A, α2B and α1 receptors, and dopamine D2L and D3 receptors. Dihydroergotamine also possesses oxytocic properties.

Distribution

Vd: ~800 L

Metabolism

Extensively hepatic (one active metabolite, 8'-β-hydroxydihydroergotamine)

Excretion

Primarily feces; urine (6% to 7% as unchanged drug)

Time to Peak

Serum: IM: 24 minutes; IV: 1 to 2 minutes; Intranasal: 30 to 60 minutes (Saper 2006); SubQ 15 to 45 minutes (Schran 1985)

Half-Life Elimination

~9 to 10 hours

Protein Binding

93%

Use: Labeled Indications

Cluster headaches (injection): Acute treatment of cluster headaches.

Migraines (intranasal; injection): Acute treatment of migraine headaches with or without aura; not intended for the prophylactic therapy of migraine or for the management of hemiplegic or basilar migraine.

Off Label Uses

Orthostatic hypotension

Data for a limited number of patients suggest that dihydroergotamine may be beneficial for the treatment of orthostatic hypotension [Conte 1976], [Jennings 1979], [Said 1987], [Thulesius 1986] Additional data may be necessary to further define the role of dihydroergotamine in this condition.

Pelvic congestion with pain

Data from one small (n=12), single-blind, crossover trial suggested that intravenous dihydroergotamine when administered during an acute attack reduces pelvic congestion on venography thereby reducing pelvic pain [Reginald 1987]. Additional data may be necessary to further define the role of dihydroergotamine in this condition. Optimal dosing has not been established nor has the optimal treatment for this condition been established.

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 angina; hemiplegic or basilar migraine; peripheral vascular disease; sepsis; severe hepatic or renal dysfunction; following vascular surgery; avoid use within 24 hours of 5-hydroxytryptamine-1 (5HT1) receptor agonists (triptans), other serotonin agonists, or ergot-like agents; concurrent use of peripheral and central vasoconstrictors; concurrent use of potent inhibitors of CYP3A4 (includes protease inhibitors, azole antifungals, and some macrolide antibiotics); pregnancy, breastfeeding

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 into each nostril; repeat after 15 minutes for a total of 4 sprays (2 mg). Note: Studies have shown no additional benefit from acute doses greater than 2 mg for a single migraine administration. Safety of doses greater than 6 sprays (3 mg) in a 24-hour period or 8 sprays (4 mg) in a week have not been established. Do not use for chronic daily administration.

Intractable migraine (status migrainosus; >72 hours): IV: Note: Some clinicians use modified versions of this protocol with additional adjunctive medications and/or alternate antiemetic agents.

Raskin protocol (off-label dosing): Initial: 0.5 mg (following premedication with metoclopramide); subsequent dosing is titrated (range: 0.2 to 1 mg) every 8 hours for up to 7 days (most patients will be headache-free within 3 days); administer with or without metoclopramide based on response and tolerance (Ford 1997; Raskin 1986; Raskin 1990)

Ford protocol (off-label dosing): Following premedication with metoclopramide; 3 mg in 1,000 mL normal saline at 42 mL/hr for up to 7 days (most patients will be headache-free within 3 days). If nausea persists, reduce the rate to 21 to 30 mL/hour. Metoclopramide may be used for nausea and benztropine for akathisia or other extrapyramidal symptoms (Ford 1997).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling.

Severe impairment: Use is contraindicated.

Dosing: Hepatic Impairment

Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Severe impairment: Use is contraindicated.

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.

IV:

Ford protocol: Administer as a continuous infusion; refer to indication-specific infusion rates in dosing for detailed recommendations (Ford 1997)

Raskin protocol: Administer slowly over 2 to 3 minutes (Raskin 1986; Raskin 1990)

Storage

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

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, 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

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

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

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 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: May cause vasospastic reactions associated with symptoms of muscle pains, numbness, coldness, pallor, and cyanosis of the digits; myocardial and peripheral vascular ischemia have been reported. In patients with compromised circulation, persistent vasospasm may result in gangrene or death. Evaluate patients who experience signs or symptoms suggestive of angina following administration for the presence of CAD or a predisposition to variant angina before receiving additional doses. Similarly, evaluate patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud syndrome. Significant hypertension has been reported (rarely) in patient with and without a history of hypertension. Adverse cardiac events, including acute myocardial infarction, life-threatening disturbance of cardiac rhythm, and death have been rarely reported.

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

• 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: [US 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.

Dosage form specific issues:

• 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), severe headache, angina, tachycardia, burning or numbness feeling, severe dizziness, passing out, vision changes, wounds on fingers or toes, muscle pain, muscle weakness, muscle cramps, severe nose irritiation, 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 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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