VA Class:CN105

AHFS Class:

• Non-selective alpha-Adrenergic Blocking Agents 12:16.04.04

Generic Name(s):

• Dihydroergotamine Mesylate

Dihydroergotamine is a semisynthetic ergot alkaloid that is structurally and pharmacologically related to ergotamine.136

Vascular Headaches

Parenteral and intranasal dihydroergotamine mesylate preparations are used for the acute management of attacks of migraine with or without aura in adults.129,139 Some experts state that therapy with dihydroergotamine administered by IM or subcutaneous injection or by intranasal inhalation may be considered in patients with moderate to severe migraine headache or when an adequate trial of nonsteroidal anti-inflammatory agents (NSAIAs) or non-opiate analgesics (including fixed-combination preparations such as acetaminophen, aspirin, and caffeine) has failed to provide adequate relief during previous migraine attacks.141 IV dihydroergotamine, given in conjunction with an antiemetic, is an appropriate choice for treatment of severe migraine.141 Some clinicians state, however, that IV dihydroergotamine should be reserved for patients who do not respond to any other drug therapy, including 5-HT₁ selective receptor agonists.145 (For further information on management and classification of migraine headache, see Vascular Headaches: General Principles in Migraine Therapy, under Uses in Sumatriptan 28:32.28.) Parenteral dihydroergotamine mesylate also is used in the management of cluster headaches.139 The onset of action of dihydroergotamine mesylate following IV, IM, or intranasal administration of the drug occurs within a few, 15-30, or 30 minutes, respectively.

Because dihydroergotamine rarely can cause potentially serious or life-threatening adverse effects (see Warnings under Cautions: Warnings/Precautions), the drug should be used only in patients in whom a clear diagnosis of migraine has been established.129,139 The manufacturer states that the drug should not be used for the management of common tension headaches, headaches with atypical symptoms, or hemiplegic or basilar migraine.129,136,139 In addition, dihydroergotamine should not be used for the prophylaxis of migraine headache.129,136,139

Other Uses

Dihydroergotamine has been used with some success when administered in combination with low-dose heparin therapy for prevention of postoperative deep-vein thrombosis and pulmonary embolism in patients undergoing major abdominal, pelvic, thoracic, or hip-replacement surgery.10,11,28,101,102,103,104,105,106,107,108,109,110,115,116,117,118,119 However, other therapies (e.g., low molecular weight heparin alone, warfarin) have been shown to be more effective than combined use of dihydroergotamine and low-dose unfractionated heparin for this indication in certain patient populations (e.g., those undergoing hip-replacement or hip-fracture surgery), and such therapies generally have supplanted the combined use of dihydroegotamine and low-dose unfractionated heparin.142,143 A fixed-combination preparation containing dihydroergotamine mesylate and heparin sodium has been withdrawn from the market in some countries, including the US, because of several cases of vasospasm (e.g., arterial vasospasm, ischemia, ergotism) associated with its use.142,143,144 For additional information on the prevention of postoperative deep-vein thrombosis and pulmonary embolism, see Venous Thrombosis and Pulmonary Embolism: Prophylaxis, in Uses in Heparin 20:12.04.16.

Administration

Dihydroergotamine mesylate is administered by IM, IV, or subcutaneous injection or by nasal inhalation using a spray pump.129,139 To be most effective in the management of vascular headache, the drug should be administered as soon as possible after the first symptoms are evident (i.e., during the prodromal phase if there is one or at the beginning of an attack). The amount of drug required and the speed and degree of relief are thought to be directly related to the promptness with which the drug is started. However, patients should be cautioned against exceeding dosing guidelines and be advised that parenteral and intranasal dihydroergotamine mesylate preparations are not intended for prolonged daily use.129,139 After the initial dose is administered, the patient should lie down and relax in a quiet, darkened room.

Dihydroergotamine mesylate nasal solution is intended for topical intranasal use only, and must not be injected.129,136 The nasal solution spray pump containing dihydroergotamine mesylate should be assembled according to the manufacturer's instructions.129 Prior to initial use, the spray pump should be fully primed.129,136 The patient instructions provided by the manufacturer should be consulted for use of the nasal spray pump.129

Dosage

Vascular Headaches

Parenteral Dosage

For the acute management of migraine headaches, the usual adult IM or subcutaneous dose of dihydroergotamine mesylate is 1 mg initially, followed by 1 mg at 1-hour intervals until the attack has abated or until a total of 3 mg has been given in a 24-hour period.139 If a more rapid response is desired, dihydroergotamine mesylate may be administered IV. The total IV dose should not exceed 2 mg in a 24-hour period.139 The total weekly IM, subcutaneous, or IV dosage should not exceed 6 mg.139

Intranasal Dosage

For the acute management of migrane headaches, the usual adult intranasal dose of dihydroergotamine mesylate is 0.5 mg (1 spray) administered in each nostril (1 mg total) initially, followed by 1 mg (1 spray [0.5 mg] in each nostril) 15 minutes later for a total dose of 2 mg.129,136 Intranasal dihydroergotamine mesylate doses exceeding 2 mg for a single migraine episode do not appear to provide additional therapeutic benefit.129,136 In addition, safety of intranasal dihydroergotamine mesylate dosages exceeding 3 mg daily or 4 mg weekly has not been established.129,136 Intranasal dihydroergotamine mesylate is not recommended for prolonged daily use.136

Contraindications

Known or suspected ischemic heart disease (e.g., angina pectoris, history of myocardial infarction, documented silent ischemia), coronary artery vasospasm (e.g., Prinzmetal's variant angina), uncontrolled hypertension, peripheral arterial disease, sepsis, severe renal or hepatic impairment, or following vascular surgery.129,139

Basilar or hemiplegic migraine.129,139

Concomitant therapy with peripheral and central vasoconstrictors or potent inhibitors of the cytochrome P-450 (CYP) 3A4 isoenzyme or 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 Drug Interactions.)

Known or suspected pregnancy and in nursing women.129,139

Known hypersensitivity to ergot alkaloids.129,139

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; dihydroergotamine possesses oxytocic properties, and adverse effects on embryofetal development (e.g., decreased fetal body weight, decreased or delayed skeletal ossification) have been demonstrated in animals.129,139 No adequate and well-controlled studies in humans.129,139 Patients who become pregnant while taking this drug should be apprised of the potential hazard to the fetus.129,139

Fibrotic Complications

Pleural and retroperitoneal fibrosis have occurred in patients following prolonged daily use of parenteral dihydroergotamine mesylate.129,139 Cardiac valvular fibrosis has occurred rarely in patients receiving parenteral dihydroergotamine.129,139 The manufacturer states that dihydroergotamine mesylate should not be used for prolonged daily administration and dosages of the drug should not exceed those recommended by the manufacturer. (See Dosage and Administration: Dosage.)129,139

Cardiac Effects

Risk of myocardial ischemia and/or infarction, coronary vasospasm, life-threatening cardiac rhythm disturbance, and death associated with use of dihydroergotamine.129,139 Dihydroergotamine should not be used in patients with known ischemic or vasospastic heart disease.129,139 (See Cautions: Contraindications.)Use not recommended in patients in whom unrecognized coronary artery disease is likely (e.g., postmenopausal women, men older than 40 years of age, patients with risk factors such as hypertension, hypercholesterolemia, obesity, diabetes mellitus, smoking, or family history of coronary artery disease) unless a prior cardiovascular evaluation provides satisfactory evidence that the patient does not have coronary artery disease, ischemic heart disease, or other clinically important underlying cardiovascular disease.129,139 For patients with risk factors for coronary artery disease who nevertheless have completed a satisfactory cardiovascular evaluation, the manufacturer strongly recommends that administration of an initial dose of dihydroergotamine take place under medical supervision (e.g., in the clinician's office, possibly followed by an ECG) unless such patients have previously received the drug.129,139 Periodic cardiovascular evaluation is recommended for patients with risk factors for coronary artery disease who are receiving intermittent long-term therapy with dihydroergotamine. 129,139

Other Cardiovascular Effects

Substantial increases in systemic blood pressure have been reported rarely in patients with or without a history of hypertension receiving dihydroergotamine.129,139 Use in patients with uncontrolled hypertension is contraindicated.129,139

Peripheral vascular ischemia and colonic ischemia have been reported in patients receiving dihydroergotamine.129,139 Vasospastic phenomena associated with the drug may result in muscle pain, numbness, coldness, pallor, and cyanosis of the digits.129,139 Because persistent vasospasm may result in gangrene or death in patients with compromised circulation, dihydroergotamine should be discontinued immediately if signs or symptoms of vasoconstriction develop.129,139

Cerebrovascular Events

Cerebral or subarachnoid hemorrhage, stroke, and other cerebrovascular events, some of which resulted in death, have occurred in patients treated with parenteral dihydroergotamine.129,139 In a number of patients, it appears that dihydroergotamine might have been used to treat symptoms thought to be a consequence of migraine, but actually related to a cerebrovascular event.129,139 Patients with a history of migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack).129,139

General Precautions

Patients experiencing signs or symptoms suggestive of angina after receiving dihydroergotamine should be evaluated for the presence of coronary artery disease or predisposition to Prinzmetal's variant angina before receiving additional doses of the drug.129,139 Similarly, patients experiencing signs or symptoms suggestive of decreased arterial flow (e.g., manifestations of ischemic bowel syndrome or Raynaud's phenomenon) following the use of any 5-HT receptor agonist should be further evaluated.129,139

Specific Populations

Pregnancy

Category X.129,139 (See Users Guide.) (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings and also Contraindications, in Cautions.)

Lactation

Ergot alkaloids inhibit prolactin secretion, and it is likely that dihydroergotamine is distributed into milk.129,139 Nursing should not be undertaken in women receiving dihydroergotamine. 129,139 (See Cautions: Contraindications.)

Pediatric Use

Safety and efficacy of dihydroergotamine not established in children.129,139

Geriatric Use

Experience with intranasal dihydroergotamine in those 65 years of age and older is insufficient to determine whether they respond differently than younger adults.129

Renal Impairment

Contraindicated in patients with severe renal impairment.129,139 The effect of renal impairment on the pharmacokinetics of dihydroergotamine has not been evaluated in controlled studies.129,139

Hepatic Impairment

Contraindicated in patients with severe hepatic impairment.129,139 The effect of hepatic impairment on the pharmacokinetics of dihydroergotamine has not been evaluated in controlled studies. 129,139

Common Adverse Effects

Vasospasm,139 paresthesia,139 hypertension,139 dizziness,139 anxiety,139 dyspnea,139 headache,139 flushing,139 diarrhea,139 rash,139 increased sweating,139 and pleural and retroperitoneal fibrosis139 after long-term use of the drug have been reported in patients receiving parenteral dihydroergotamine during postmarketing surveillance.139

Mild-to-moderate nasal or throat irritation (e.g., congestion, burning sensation, dryness, paresthesia, discharge, epistaxis, pain, soreness) and/or taste disturbances have occurred in 30% of patients receiving intranasal dihydroergotamine in clinical studies.129 Adverse effects occurring in 4-26% of patients receiving intranasal dihydroergotamine and at an incidence greater than with placebo include rhinitis,129 application site reactions,129 dizziness,129 nausea,129 and vomiting.129

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacologic and pharmacokinetic interaction (serious vasospastic effects secondary to increased plasma concentrations of dihydroergotamine) with inhibitors of cytochrome P-450 (CYP) 3A4 isoenzyme. 129,139 Serious and/or life-threatening peripheral ischemia has been reported in patients receiving dihydroergotamine concomitantly with potent CYP3A4 inhibitors such as protease inhibitors and macrolide antibiotics.129,139 Concomitant use with such agents is contraindicated.129,139 Caution is advised if dihydroergotamine is used concurrently with less potent CYP3A4 inhibitors (e.g., saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, clotrimazole).129 Clinicians should consider the effects on CYP3A4 of other agents being considered for concomitant use with dihydroergotamine.129,139

Peripheral Vasconstrictors

Potential pharmacologic interaction (additive increases in blood pressure).129,139 Concomitant use of dihydroergotamine with these agents is contraindicated.129,139

Sumatriptan

Potential pharmacologic interaction (additive vasospastic effects).129,139 Use within 24 hours of dihydroergotamine is contraindicated.129,139

Beta-Adrenergic Blocking Agents

Potential pharmacologic interaction.129,139 There have been reports that propranolol may potentiate the vasoconstrictive action of ergotamine by blocking the vasodilating property of epinephrine.129,139

Nicotine

Potential pharmacologic interaction.129,139 Nicotine may provoke vasoconstriction in some patients, predisposing them to a greater ischemic response to ergot alkaloid therapy.129,139

Selective Serotonin-Reuptake Inhibitors

Potential pharmacologic interaction (weakness, hyperreflexia, incoordination) reported rarely when 5-HT₁ receptor agonists were used concomitantly with selective serotonin-reuptake inhibitors (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline); no such interactions have been reported thus far between dihydroergotamine and selective serotonin-reuptake inhibitors.129,139

Oral Contraceptives

The effect of oral contraceptives on the pharmacokinetics of dihydroergotamine has not been studied.129,139

Pharmacokinetics

Absorption

Bioavailability

Following oral administration, bioavailability is <1% because of first-pass metabolism.147,129

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.146

IM: 15-30 minutes.147

IV: Variable, usually <5 minutes.147

Duration

Intranasal: At least 4 hours.146

Sub-Q or IV: Approximately 8 hours.147

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.129,139,147

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

Description

Dihydroergotamine is a semisynthetic ergot alkaloid that is structurally and pharmacologically related to ergotamine.136 The mechanism of action of dihydroergotamine in the acute management of migraine headaches generally is attributed to the agonist effect at serotonin (5-hydroxytryptamine; 5-HT) type 1D receptors.129,139 Some clinicians suggest that activation of 5-HT_1D receptors located on intracranial blood vessels, including those on arteriovenous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine headache.129,139 Alternatively, other clinicians have suggested that activation of 5-HT_1D receptors on sensory nerve endings of the trigeminal system results in the inhibition of proinflammatory neuropeptide release.129,139 Dihydroergotamine also exhibits oxytocic activity.129,139

Advice to Patients

Importance of immediately informing a clinician of numbness or tingling in the fingers and toes, muscle pain in the arms and legs, weakness in the legs, pain in the chest, temporary speeding or slowing of the heart rate, swelling, or itching.129,139

Importance of adhering to prescribed directions for use (including an understanding of proper storage, preparation, and administration techniques) and of not exceeding the recommended dosage or dosing frequency.129,139

Importance of informing clinician of existing or contemplated concomitant therapy, including prescription (see Drug Interactions) and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease).129,139 Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed.129,139

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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