Dihydroergotamine

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) [contains alcohol, usp]

Generic: 1 mg/mL (1 mL)

Solution, Nasal, as mesylate:

Migranal: 4 mg/mL (1 mL)

Generic: 4 mg/mL (1 mL)

Pharmacology

Mechanism of Action

Efficacy in migraine is attributed to the activation of 5-HT_1D receptors located on intracranial blood vessels resulting in vasoconstriction and/or activation of 5-HT_1D 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-HT_1Dα, 5-HT_1Dβ, 5-HT_1A, 5-HT_2A, and 5-HT_2C receptors, noradrenaline α_2A, α_2B and α₁ receptors, and dopamine D_2L and D₃ receptors. Dihydroergotamine also possesses oxytocic properties.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: ~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.

Use: Off Label

Medication-overuse headache or intractable migraine headache (status migrainosus)c

Data from nonblinded, nonrandomized descriptive and observational trials suggest that dihydroergotamine may be beneficial for the treatment of medication-overuse headache or intractable migraine headache Ford 1997, Raskin 1986, Silberstein 1990, Silberstein 1992.

Orthostatic hypotensionc

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 painc

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

Dosage and Administration

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.

Medication-overuse headache or iintractable migraine headache (status migrainosus) (alternative agent) (off-label use): Note: Use in inpatient setting for medication-overuse headache when patients are unlikely to be successful with discontinuing the overused medication along with rescue therapy and preventive therapy (Garza 2019). Premedicate with metoclopramide for nausea; during therapy, administer metoclopramide as needed for nausea, diphenoxylate with atropine as needed for diarrhea, and benztropine as needed for akathisia or dystonic reactions (Ford 1997; Raskin 1990). Some clinicians use modified versions of these protocols with additional adjunctive medications and/or alternate antiemetic agents.

Repetitive dosing regimen (Raskin protocol): IV: Initial: 0.5 mg; subsequent dosing is titrated based on response and tolerability (range: 0.2 to 1 mg) every 8 hours for up to 7 days (most patients will be headache-free within 3 days). If headache persists without nausea following initial dose, a second dose of 0.5 mg may be given in one hour (Ford 1997; Raskin 1986; Raskin 1990).

Continuous dosing regimen (Ford protocol): IV: 3 mg in 1,000 mL NS at 42 mL/hour for up to 7 days (most patients will be headache-free within 3 days). If significant nausea persists, reduce the rate to 21 to 30 mL/hour (Ford 1997).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Migraine, intractable (>72 hours) (status migrainosus): Limited data available; optimal dose not established:

IV: Premedicate with antiemetic (metoclopramide or prochlorperazine have been used)

Low-dose regimen: Note: Improvement usually seen after 5 doses; some experts recommend administering 1 additional dose after headache subsides. If no improvement noted after 5 doses, discontinue therapy (Linder 1994; O'Brien 2010).

Children 6 to <10 years: 0.1 mg/dose every 6 hours; continue therapy until headache-free up to a maximum of 8 doses per episode (Linder 1994).

Children 10 to 12 years: 0.15 mg/dose every 6 hours; continue therapy until headache-free up to a maximum of 8 doses per episode.

Adolescents ≤16 years: 0.2 mg/dose every 6 hours; continue therapy until headache-free up to a maximum of 8 doses per episode.

High-dose regimen: Note: Improvement usually seen after 5 doses; some experts recommend administering 1 additional dose after headache subsides. If no improvement after 5 doses, discontinue therapy. Some experts recommend using an initial test dose (half of the appropriate dose for age and weight); if test dose tolerated, remainder of dose administered 30 minutes later (Kabbouche 2009).

Children 6 to 9 years or Children ≥10 years who weigh <25 kg: 0.5 mg/dose every 8 hours; if improvement noted, continue therapy until headache-free up to a maximum of 15 doses per episode (Kabbouche 2009; Kabbouche 2015; Kacperski 2016; O'Brien 2010).

Children ≥10 years weighing >25 kg and Adolescents: 1 mg/dose every 8 hours; if improvement noted, continue therapy until headache-free up to a maximum of 15 doses per episode (Kabbouche 2009; Kabbouche 2015; Kacperski 2016; O'Brien 2010).

Intranasal: Limited data available: Adolescents: 1 spray (0.5 mg) into each nostril (total dose: 1 mg) (Kliegman 2016); adult data suggests that dose should be repeated after 15 minutes for a total of 4 sprays (2 mg); maximum daily dose: 6 sprays (3 mg)/24-hour period; Note: Do not exceed 8 sprays (4 mg)/week.

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:

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

Repetitive dosing regimen (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

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

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

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

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

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

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

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

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

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

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

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

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

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

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

Nefazodone: Ergot Derivatives may enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase the serum concentration of Ergot Derivatives. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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 (High risk with Inhibitors). 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

Serotonergic Agents (High Risk): Ergot Derivatives may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: Nefazodone. Monitor therapy

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

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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

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%, postmarketing, and/or case reports (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)

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

Pregnancy Risk Factor

X

Pregnancy Considerations

Dihydroergotamine is oxytocic and should not be used during pregnancy.

Patient Education

What is this drug used for?

• It is used to treat migraine headaches.
• It is used to treat cluster headaches.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Nausea
• Vomiting
• Nose irritation
• Sore throat
• Change in taste
• Nosebleed
• Runny nose
• Stuffy nose
• Nasal burning
• Dry nose

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Severe cerebrovascular disease like change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or vision changes
• Severe headache
• Chest pain
• Fast heartbeat
• Dizziness
• Passing out
• Vision changes
• Wounds on fingers or toes
• Muscle pain
• Muscle weakness
• Muscle cramps
• Abnormal heartbeat
• Change in color of hands or feet from pale to blue or red
• Sensation of cold in extremities
• Numbness, pain, or tingling in extremities
• Slow heartbeat
• Swelling
• Swelling in the arms or legs
• Shortness of breath
• Excessive weight gain
• Severe abdominal pain
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.