Dihydroergotamine (Monograph)

Brand names: D.H.E. 45, Migranal
Drug class: Non-selective alpha-Adrenergic Blocking Agents
- Ergot Alkaloids
VA class: CN105
CAS number: 6190-39-2

Medically reviewed by Drugs.com on Mar 22, 2024. Written by ASHP.

Introduction

Ergot alkaloid.¹³⁶

Uses for Dihydroergotamine

Vascular Headaches

Acute treatment of migraine attacks (with or without aura) or cluster headaches.^{129 139}

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

IV treatment of intractable migraines^{† [off-label]} (e.g., status migrainosus^{† [off-label]}); usually used in combination with IV antiemetic.^{c e f}

Not recommended for management of hemiplegic or basilar migraine or for prophylaxis or chronic daily management of migraine.^{129 139}

Other Uses

Used in combination with low-dose heparin therapy for prevention of postoperative DVT and pulmonary embolism;^{10 11 28 101 102 103 104 105 106 107 108 109 110 115 116 117 118 119} generally has been replaced by other more effective therapies (e.g., low molecular weight heparin alone, warfarin).^{142 143}

Related/similar drugs

Ubrelvy, acetaminophen, prednisone, ibuprofen, amitriptyline, naproxen, diclofenac

Dihydroergotamine Dosage and Administration

General

Vascular Headaches

• Administer as soon as possible after onset of first symptoms of vascular headache.^a

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

Administration

Administer by IM, IV, or sub-Q injection or by nasal inhalation using a spray pump.^{129 139}

Administer by nasal inhalation or by IM, sub-Q, or direct IV injection for the acute treatment of migraine;^{129 139} if self-administration by parenteral route is desired, sub-Q injection generally is preferred because of ease of administration.¹³⁹

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.¹³⁹

Administer by direct IV injection or continuous IV infusion^{† [off-label]} for the acute treatment of intractable migraines in an inpatient setting.^{c e f}

Dihydroergotamine preparations are not recommended for prolonged daily use.^{129 136 139}

Intranasal Administration

Nasal solution intended for topical intranasal use only, and must not be injected.^{129 136}

Prior to initial use, assemble and fully prime the spray pump (i.e., spray 4 times).^{129 136} Consult the manufacturer’s patient instructions for information on assembly, priming, and use of the nasal spray pump.¹²⁹

Spray once in each nostril; wait 15 minutes and spray once again in each nostril.^{129 b} Do not tilt head back or inhale through nose while administering the drug.^{129 b}

Discard nasal spray applicator (with any remaining drug in opened ampul) 8 hours after assembly.¹²⁹

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.^c Do not mix with buffers (e.g., sodium bicarbonate, sodium acetate) to minimize local adverse effects (see Compatibility under Stability).^c

Dilution

For continuous IV infusion^{† [off-label]}, add 3 mg of dihydroergotamine mesylate in 1 L of sodium chloride 0.9%, resulting in a final concentration of 3 mcg/mL.^{c f}

Rate of Administration

May administer undiluted by direct IV injection over 1–2 minutes.^{c d}

Has been administered by continuous IV infusion^{† [off-label]} as a 3-mcg/mL solution at a rate of 126 mcg (42 mL) per hour.^{c f}

Sub-Q Administration

Administer sub-Q into the middle of thigh after aspiration (to guard against accidental intravascular injection).¹³⁹

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

Dosage

Available as dihydroergotamine mesylate; dosage expressed in terms of the salt.^{129 139}

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.^{129 136} Higher dosages provide no additional benefit.¹²⁹

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.¹³⁹

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

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.¹³⁹

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.¹³⁹

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.¹³⁹

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.¹³⁹

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.¹³⁹

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.¹²⁹

IV

Maximum 2 mg in any 24-hour period.¹³⁹

Maximum total weekly dosage: 6 mg.¹³⁹

IM

Maximum 3 mg in any 24-hour period.¹³⁹

Maximum total weekly dosage: 6 mg.¹³⁹

Sub-Q

Maximum 3 mg in any 24-hour period.¹³⁹

Maximum total weekly dosage: 6 mg.¹³⁹

Cautions for Dihydroergotamine

Contraindications

• Known or suspected pregnancy and in nursing women.^{129 139}

• 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).^{129 139} (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).^{129 139}

• Known peripheral arterial disease, uncontrolled hypertension, or following vascular surgery.^{129 139}

• Severe hepatic or renal impairment.^{129 139}

• Sepsis.^{129 139}

• Basilar or hemiplegic migraine.^{129 139}

• Known hypersensitivity to ergot alkaloids.^{129 139}

Warnings/Precautions

Warnings

Use only in patients in whom a clear diagnosis of migraine has been established.^{129 139}

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; developmental toxicity observed in animals.^{129 139} Possesses oxytocic properties.^{129 139}

If used during pregnancy, or if pregnancy occurs during therapy, apprise the patient of the potential hazard to the fetus.^{129 139}

Fibrosis

Retroperitoneal and pleuropulmonary fibrosis reported following long-term daily use.^{129 139} Possible fibrotic thickening of cardiac valves with continuous, long-term administration.^{129 139}

Do not administer on a chronic daily basis.^{129 139}

Cardiac Effects

Possible myocardial ischemia and/or infarction, coronary vasospasm, life-threatening cardiac rhythm disturbance, and death.^{129 139} (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.^{129 139}

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.^{129 139}

Periodic cardiovascular evaluation recommended in patients with risk factors for CAD if receiving intermittent long-term therapy.^{129 139}

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.^{129 139}

Cerebrovascular Events

Possible cerebral or subarachnoid hemorrhage, stroke, and other cerebrovascular events, sometimes fatal.^{129 139}

Risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack) may be increased in patients with migraine.^{129 139}

Other Cardiovascular or Vasospastic Effects

Peripheral vascular ischemia and colonic ischemia reported.^{129 139} 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.^{129 139}

Substantial increases in BP reported rarely in patients with or without history of hypertension.^{129 139} (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.^{129 139}

Ergotism

Potential for ergotism, manifested by intense arterial vasoconstriction, producing signs and symptoms of peripheral vascular ischemia; if left untreated, can progress to gangrene.^{129 139} Do not exceed recommended dosages.^{129 139}

If signs and symptoms of impaired circulation occur, immediately discontinue therapy.^{129 139}

Local Effects of Intranasal Administration

Nasal or throat irritation reported frequently following intranasal administration (see Common Adverse Effects under Cautions).¹²⁹ 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.¹²⁹

Specific Populations

Pregnancy

Category X.^{129 139} (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.^{129 139} Dihydroergotamine is contraindicated in nursing women.^{129 139}

Inhibits prolactin.^{129 139}

Pediatric Use

Safety and efficacy not established in children.^{129 139}

Geriatric Use

Insufficient experience with intranasal dihydroergotamine in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.¹²⁹

Hepatic Impairment

Contraindicated in patients with severe hepatic impairment.^{129 139}

Renal Impairment

Contraindicated in patients with severe renal impairment.^{129 139}

Common Adverse Effects

With parenteral dihydroergotamine, vasospasm,¹³⁹ paresthesia,¹³⁹ hypertension,¹³⁹ dizziness,¹³⁹ anxiety,¹³⁹ dyspnea,¹³⁹ headache,¹³⁹ flushing,¹³⁹ diarrhea,¹³⁹ rash,¹³⁹ increased sweating.¹³⁹

With intranasal dihydroergotamine, mild-to-moderate nasal or throat irritation (e.g., congestion, burning sensation, dryness, paresthesia, discharge, epistaxis, pain, soreness),¹²⁹ taste disturbances,¹²⁹ rhinitis,¹²⁹ application site reactions,¹²⁹ dizziness,¹²⁹ nausea,¹²⁹ vomiting.¹²⁹

Drug Interactions

Extensively metabolized, principally by CYP3A4.^{129 139} Inhibits CYP3A.^{129 139}

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.^{129 139} Concomitant use with potent CYP3A4 inhibitors contraindicated.^{129 139}

Less-potent CYP3A4 inhibitors: Similar effects not reported to date; however, consider possibility of serious toxicity during concomitant use.^{129 139}

Specific Drugs and Foods

Dihydroergotamine Pharmacokinetics

Absorption

Bioavailability

Following oral administration, bioavailability is <1% because of first-pass metabolism.^{d 129}

Following intranasal administration, mean bioavailability is 32% relative to parenteral administration.¹²⁹

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.¹³⁹

Onset

Intranasal: About 30 minutes.^b

IM: 15–30 minutes.^d

IV: Variable, usually <5 minutes.^d

Duration

Intranasal: At least 4 hours.^b

Sub-Q or IV: Approximately 8 hours.^d

Distribution

Plasma Protein Binding

93%.^{129 139}

Elimination

Metabolism

Extensively metabolized in the liver to several metabolites; principal metabolite is pharmacologically active.^{129 139}

Metabolized by CYP3A4.^{129 139}

Elimination Route

Eliminated principally in feces (via bile) as metabolites; <10% of a dose is excreted in urine.^{129 139 d}

Half-life

Following intranasal administration: Biphasic; terminal half-life is approximately 10 hours.¹²⁹

Following IM or IV administration: Multi-exponential; terminal half-life is approximately 9 hours.¹³⁹

Stability

Storage

Intranasal

Solution

<25°C; do not refrigerate or freeze.¹²⁹

Parenteral

Injection

<25°C; do not refrigerate or freeze.¹³⁹ Protect from light and heat.¹³⁹

Compatibility

Parenteral

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

Solution Compatibilityc

Actions

• A serotonin (5-hydroxytryptamine; 5-HT) type 1D receptor agonist.^{129 139} May ameliorate migraine through selective constriction of certain intracranial blood vessels, inhibition of neuropeptide release, and reduced transmission in trigeminal pathway.^{129 139}

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

• Possesses oxytocic properties.^{129 139}

Advice to Patients

• Risk of MI or other vasospastic effects; importance of informing clinicians if persistent paresthesia or chest, muscle, or abdominal pain occurs.^{129 139}

• Risk of ergotism; importance of informing clinicians if intermittent claudication; muscle pain; or numbness, coldness, and pallor of the digits occur.^{129 139}

• Importance of taking dihydroergotamine exactly as prescribed.^{129 139}

• Importance of providing patient a copy of manufacturer’s patient information.^{129 139}

• If patient is to administer parenteral dihydroergotamine, provide careful instructions on proper administration methods, including aseptic technique.¹³⁹

• For patients using dihydroergotamine nasal spray, provide careful instruction on pump assembly, priming, and administration.¹²⁹

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^{129 139}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.^{129 139}

• Importance of informing patients of other important precautionary information.^{129 139} (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.

Frequently asked questions

• What are the new drugs for the treatment of migraines?

Medical Disclaimer