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Dihydroergotamine

Class: Non-selective alpha-Adrenergic Blocking Agents
- Ergot Alkaloids
VA Class: CN105
CAS Number: 6190-39-2
Brands: D.H.E. 45, Migranal

Medically reviewed by Drugs.com on Mar 22, 2022. Written by ASHP.

Warning

  • Possible serious and/or life-threatening cerebral and/or peripheral ischemia when administered concomitantly with potent CYP3A4 inhibitors (see Interactions); concomitant use contraindicated.

Introduction

Ergot alkaloid.

Uses for Dihydroergotamine

Vascular Headaches

Acute treatment of migraine attacks (with or without aura) or cluster headaches.

One of several preferred initial therapies in moderate to severe migraines or mild to moderate migraines that respond poorly to NSAIAs.

IV treatment of intractable migraines (e.g., status migrainosus); usually used in combination with IV antiemetic.

Not recommended for management of hemiplegic or basilar migraine or for prophylaxis or chronic daily management of migraine.

Other Uses

Used in combination with low-dose heparin therapy for prevention of postoperative DVT and pulmonary embolism; generally has been replaced by other more effective therapies (e.g., low molecular weight heparin alone, warfarin).

Dihydroergotamine Dosage and Administration

General

    Vascular Headaches
  • Administer as soon as possible after onset of first symptoms of vascular headache.

  • After administering the initial dose, patient should lie down and relax in a quiet, darkened room.

Administration

Administer by IM, IV, or sub-Q injection or by nasal inhalation using a spray pump.

Administer by nasal inhalation or by IM, sub-Q, or direct IV injection for the acute treatment of migraine; if self-administration by parenteral route is desired, sub-Q injection generally is preferred because of ease of administration.

Administer by IM, sub-Q, or direct IV injection for the acute treatment of cluster headaches; sub-Q injection generally is preferred for self-administration because of ease of administration.

Administer by direct IV injection or continuous IV infusion for the acute treatment of intractable migraines in an inpatient setting.

Dihydroergotamine preparations are not recommended for prolonged daily use.

Intranasal Administration

Nasal solution intended for topical intranasal use only, and must not be injected.

Prior to initial use, assemble and fully prime the spray pump (i.e., spray 4 times). Consult the manufacturer’s patient instructions for information on assembly, priming, and use of the nasal spray pump.

Spray once in each nostril; wait 15 minutes and spray once again in each nostril. Do not tilt head back or inhale through nose while administering the drug.

Discard nasal spray applicator (with any remaining drug in opened ampul) 8 hours after assembly.

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

To minimize adverse local effects, some clinicians suggest flushing the IV line or port with 10–20 mL of sodium chloride 0.45 or 0.9% prior to administering the drug. Do not mix with buffers (e.g., sodium bicarbonate, sodium acetate) to minimize local adverse effects (see Compatibility under Stability).

Dilution

For continuous IV infusion, add 3 mg of dihydroergotamine mesylate in 1 L of sodium chloride 0.9%, resulting in a final concentration of 3 mcg/mL.

Rate of Administration

May administer undiluted by direct IV injection over 1–2 minutes.

Has been administered by continuous IV infusion as a 3-mcg/mL solution at a rate of 126 mcg (42 mL) per hour.

Sub-Q Administration

Administer sub-Q into the middle of thigh after aspiration (to guard against accidental intravascular injection).

To minimize adverse local effects, some clinicians suggest diluting usual sub-Q dose (1 mg) with 1 mL of sodium chloride 0.9%. Do not mix with buffers (e.g., sodium bicarbonate, sodium acetate) to minimize local adverse effects (see Compatibility under Stability).

Dosage

Available as dihydroergotamine mesylate; dosage expressed in terms of the salt.

Adults

Vascular Headaches
Migraine
Intranasal

0.5 mg (1 spray) in each nostril (1 mg total) initially; repeat 15 minutes later for a total dose of 2 mg. Higher dosages provide no additional benefit.

IV

1 mg by direct IV injection initially, followed by 1 mg at 1-hour intervals until the attack has abated or a total of 2 mg has been given in a 24-hour period.

Alternatively, 3 mg has been administered by continuous IV infusion over 24 hours for the treatment of intractable migraines.

IM

1 mg initially, followed by 1 mg at 1-hour intervals until the attack has abated or a total of 3 mg has been given in a 24-hour period.

Sub-Q

1 mg initially, followed by 1 mg at 1-hour intervals until the attack has abated or a total of 3 mg has been given in a 24-hour period.

Cluster Headaches
IV

1 mg initially, followed by 1 mg at 1-hour intervals until the attack has abated or a total of 2 mg has been given in a 24-hour period.

IM

1 mg initially, followed by 1 mg at 1-hour intervals until the attack has abated or a total of 3 mg has been given in a 24-hour period.

Sub-Q

1 mg initially, followed by 1 mg at 1-hour intervals until the attack has abated or a total of 3 mg has been given in a 24-hour period.

Prescribing Limits

Adults

Vascular Headaches
Intranasal

Safety of >3 mg in any 24-hour period and >4 mg in any 7-day period has not been established.

IV

Maximum 2 mg in any 24-hour period.

Maximum total weekly dosage: 6 mg.

IM

Maximum 3 mg in any 24-hour period.

Maximum total weekly dosage: 6 mg.

Sub-Q

Maximum 3 mg in any 24-hour period.

Maximum total weekly dosage: 6 mg.

Cautions for Dihydroergotamine

Contraindications

  • Known or suspected pregnancy and in nursing women.

  • Concomitant therapy with peripheral or central vasoconstrictors or potent CYP3A4 inhibitors; recent (i.e., 24 hours) therapy with a 5-HT1 receptor agonist (e.g., sumatriptan) or an ergot alkaloid (e.g., ergotamine, methysergide). (See Interactions.)

  • Known or suspected ischemic heart disease (e.g., angina pectoris, history of myocardial infarction, documented silent ischemia) or coronary artery vasospasm (e.g., Prinzmetal variant angina).

  • Known peripheral arterial disease, uncontrolled hypertension, or following vascular surgery.

  • Severe hepatic or renal impairment.

  • Sepsis.

  • Basilar or hemiplegic migraine.

  • Known hypersensitivity to ergot alkaloids.

Warnings/Precautions

Warnings

Use only in patients in whom a clear diagnosis of migraine has been established.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; developmental toxicity observed in animals. Possesses oxytocic properties.

If used during pregnancy, or if pregnancy occurs during therapy, apprise the patient of the potential hazard to the fetus.

Fibrosis

Retroperitoneal and pleuropulmonary fibrosis reported following long-term daily use. Possible fibrotic thickening of cardiac valves with continuous, long-term administration.

Do not administer on a chronic daily basis.

Cardiac Effects

Possible myocardial ischemia and/or infarction, coronary vasospasm, life-threatening cardiac rhythm disturbance, and death. (See Contraindications.)

Use not recommended in patients in whom unrecognized CAD is likely (e.g., postmenopausal women, men >40 years of age, patients with risk factors such as hypertension, hypercholesterolemia, obesity, diabetes mellitus, smoking, or family history of CAD) unless there is satisfactory evidence from a prior cardiovascular evaluation that the patient does not have CAD, ischemic heart disease, or other underlying cardiovascular disease.

Administer initial dose to patients with risk factors for CAD who have completed satisfactory cardiovascular evaluation under medical supervision (e.g., in clinician’s office, possibly followed by ECG) unless patient previously received the drug.

Periodic cardiovascular evaluation recommended in patients with risk factors for CAD if receiving intermittent long-term therapy.

Patients with symptoms suggestive of angina after receiving dihydroergotamine should be evaluated for presence of CAD or predisposition to Prinzmetal variant angina before receiving additional doses.

Cerebrovascular Events

Possible cerebral or subarachnoid hemorrhage, stroke, and other cerebrovascular events, sometimes fatal.

Risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack) may be increased in patients with migraine.

Other Cardiovascular or Vasospastic Effects

Peripheral vascular ischemia and colonic ischemia reported. Further evaluation recommended if signs or symptoms suggestive of decreased arterial flow (e.g., manifestations of ischemic bowel syndrome or Raynaud’s phenomenon) occur following administration.

Substantial increases in BP reported rarely in patients with or without history of hypertension. (See Contraindications.)

Increases in mean pulmonary artery pressure observed following administration of another 5-HT1 receptor agonist to patients with suspected CAD who were undergoing cardiac catheterization.

Ergotism

Potential for ergotism, manifested by intense arterial vasoconstriction, producing signs and symptoms of peripheral vascular ischemia; if left untreated, can progress to gangrene. Do not exceed recommended dosages.

If signs and symptoms of impaired circulation occur, immediately discontinue therapy.

Local Effects of Intranasal Administration

Nasal or throat irritation reported frequently following intranasal administration (see Common Adverse Effects under Cautions). Effects of long-term, repeated administration on nasal and respiratory mucosa have not been systematically evaluated to date; however, nasal and throat examinations performed in a limited number of patients revealed no evidence of mucosal injury following repeated administration over periods up to 36 months.

Specific Populations

Pregnancy

Category X. (See Fetal/Neonatal Morbidity and Mortality and also see Contraindications, under Cautions.)

Lactation

Not known whether dihydroergotamine is distributed into milk; however, ergotamine is distributed into milk and may cause vomiting, diarrhea, weak pulse, and unstable BP in nursing infants. Dihydroergotamine is contraindicated in nursing women.

Inhibits prolactin.

Pediatric Use

Safety and efficacy not established in children.

Geriatric Use

Insufficient experience with intranasal dihydroergotamine in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

Hepatic Impairment

Contraindicated in patients with severe hepatic impairment.

Renal Impairment

Contraindicated in patients with severe renal impairment.

Common Adverse Effects

With parenteral dihydroergotamine, vasospasm, paresthesia, hypertension, dizziness, anxiety, dyspnea, headache, flushing, diarrhea, rash, increased sweating.

With intranasal dihydroergotamine, mild-to-moderate nasal or throat irritation (e.g., congestion, burning sensation, dryness, paresthesia, discharge, epistaxis, pain, soreness), taste disturbances, rhinitis, application site reactions, dizziness, nausea, vomiting.

Interactions for Dihydroergotamine

Extensively metabolized, principally by CYP3A4. Inhibits CYP3A.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased serum dihydroergotamine concentrations); potentially fatal cerebral ischemia and/or ischemia of the extremities possible. Concomitant use with potent CYP3A4 inhibitors contraindicated.

Less-potent CYP3A4 inhibitors: Similar effects not reported to date; however, consider possibility of serious toxicity during concomitant use.

Specific Drugs and Foods

Drug or Food

Interaction

Comment

Antidepressants, SSRIs (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline)

Weakness, hyperreflexia, and/or incoordination reported rarely with other 5-HT1 receptor agonists

Potential decrease in dihydroergotamine metabolism

Use with caution

Antifungals, azole (e.g., fluconazole, itraconazole, ketoconazole)

Potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole): Inhibition of dihydroergotamine metabolism and increased risk of potentially fatal cerebral ischemia and/or ischemia of the extremities

Less potent CYP3A4 inhibitors (e.g., fluconazole): Potential decrease in dihydroergotamine metabolism

Concomitant use of potent CYP3A4 inhibitors contraindicated

Use less potent CYP3A4 inhibitors with caution

Clotrimazole

Potential decrease in dihydroergotamine metabolism

Use with caution

Ergot alkaloids (e.g., ergotamine, methysergide)

Potential for excessive vasoconstriction

Use within 24 hours contraindicated

Grapefruit juice

Potential decrease in dihydroergotamine metabolism

Use with caution

HIV protease inhibitors (e.g., ritonavir, nelfinavir, indinavir, saquinavir)

Potent CYP3A4 inhibitors (e.g., ritonavir, nelfinavir, indinavir): Inhibition of dihydroergotamine metabolism and increased risk of potentially fatal cerebral ischemia and/or ischemia of the extremities

Less potent CYP3A4 inhibitors (e.g., saquinavir): Potential decrease in dihydroergotamine metabolism

Concomitant use of potent CYP3a4 inhibitors contraindicated

Use less potent CYP3A4 inhibitors with caution

Macrolide antibiotics (e.g., erythromycin, clarithromycin, troleandomycin)

Inhibition of dihydroergotamine metabolism; increased risk of potentially fatal cerebral ischemia and/or ischemia of the extremities

Concomitant use contraindicated

Nefazodone

Potential decrease in dihydroergotamine metabolism

Use with caution

Nicotine

Possible vasoconstriction and increased ischemic response

Use with caution

Propranolol

Potentiation of dihydroergotamine's vasoconstrictive action

Use with caution

Serotonin (5-HT1) receptor agonists (e.g., sumatriptan)

Additive vasoconstrictor effects

Use within 24 hours contraindicated

Vasoconstrictors, peripheral or central

Additive increases in BP

Concomitant use contraindicated

Zileuton

Potential decrease in dihydroergotamine metabolism

Use with caution

Dihydroergotamine Pharmacokinetics

Absorption

Bioavailability

Following oral administration, bioavailability is <1% because of first-pass metabolism.

Following intranasal administration, mean bioavailability is 32% relative to parenteral administration.

Absolute bioavailability for sub-Q and IM routes has not been determined, however, no difference was observed in bioavailability from IM and sub-Q doses.

Onset

Intranasal: About 30 minutes.

IM: 15–30 minutes.

IV: Variable, usually <5 minutes.

Duration

Intranasal: At least 4 hours.

Sub-Q or IV: Approximately 8 hours.

Distribution

Plasma Protein Binding

93%.

Elimination

Metabolism

Extensively metabolized in the liver to several metabolites; principal metabolite is pharmacologically active.

Metabolized by CYP3A4.

Elimination Route

Eliminated principally in feces (via bile) as metabolites; <10% of a dose is excreted in urine.

Half-life

Following intranasal administration: Biphasic; terminal half-life is approximately 10 hours.

Following IM or IV administration: Multi-exponential; terminal half-life is approximately 9 hours.

Stability

Storage

Intranasal

Solution

<25°C; do not refrigerate or freeze.

Parenteral

Injection

<25°C; do not refrigerate or freeze. Protect from light and heat.

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Stable at pH 3.6–4.8. Increased degradation observed at pH <3.6; decreasing solubility occurs at pH >4.8.

Solution Compatibilityc

Compatible

Dextrose 5% in water

Sodium chloride 0.9%

Actions

  • A serotonin (5-hydroxytryptamine; 5-HT) type 1D receptor agonist. May ameliorate migraine through selective constriction of certain intracranial blood vessels, inhibition of neuropeptide release, and reduced transmission in trigeminal pathway.

  • Has greater α-adrenergic blocking activity but less vasoconstrictor activity than ergotamine.

  • Possesses oxytocic properties.

Advice to Patients

  • Risk of MI or other vasospastic effects; importance of informing clinicians if persistent paresthesia or chest, muscle, or abdominal pain occurs.

  • Risk of ergotism; importance of informing clinicians if intermittent claudication; muscle pain; or numbness, coldness, and pallor of the digits occur.

  • Importance of taking dihydroergotamine exactly as prescribed.

  • Importance of providing patient a copy of manufacturer’s patient information.

  • If patient is to administer parenteral dihydroergotamine, provide careful instructions on proper administration methods, including aseptic technique.

  • For patients using dihydroergotamine nasal spray, provide careful instruction on pump assembly, priming, and administration.

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Dihydroergotamine Mesylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Intranasal

Solution

0.5 mg/metered spray (4 mg/mL)

Migranal Nasal Spray (with anhydrous caffeine 10 mg/mL; available in ampul with a nasal spray applicator)

Xcel

Parenteral

Injection

1 mg/mL

D.H.E. 45 (with alcohol 6.1% and glycerin 15%)

Xcel

AHFS DI Essentials™. © Copyright 2022, Selected Revisions April 1, 2010. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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