Dihydroergotamine Mesylate

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

• 
  

  Possible serious and/or life-threatening cerebral and/or peripheral ischemia when administered concomitantly with potent CYP3A4 inhibitors (see Interactions); concomitant use contraindicated.^{129 139}

  
  

Introduction

Ergot alkaloid.¹³⁶

Uses for Dihydroergotamine Mesylate

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† (e.g., status migrainosus†); 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DVT and pulmonary embolism;^{10 11 28 101 102 103 104 105 106 107 108 109 110 115 116 117 118 119} generally has been replaced by other more effective therapies (e.g., low molecular weight heparin alone, warfarin).^{142 143}

Dihydroergotamine Mesylate 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† 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†, 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† 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 Mesylate

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}

  
  


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  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

Interactions for Dihydroergotamine Mesylate

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

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 agonists129 139 Potential decrease in dihydroergotamine metabolism129 139	Use with caution129 139
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 extremities129 139 Less potent CYP3A4 inhibitors (e.g., fluconazole): Potential decrease in dihydroergotamine metabolism129 139	Concomitant use of potent CYP3A4 inhibitors contraindicated129 139 Use less potent CYP3A4 inhibitors with caution129 139
Clotrimazole	Potential decrease in dihydroergotamine metabolism129 139	Use with caution129 139
Ergot alkaloids (e.g., ergotamine, methysergide)	Potential for excessive vasoconstriction129 139	Use within 24 hours contraindicated129 139
Grapefruit juice	Potential decrease in dihydroergotamine metabolism129 139	Use with caution129 139
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 extremities129 139 Less potent CYP3A4 inhibitors (e.g., saquinavir): Potential decrease in dihydroergotamine metabolism129 139	Concomitant use of potent CYP3a4 inhibitors contraindicated129 139 Use less potent CYP3A4 inhibitors with caution129 139
Macrolide antibiotics (e.g., erythromycin, clarithromycin, troleandomycin)	Inhibition of dihydroergotamine metabolism; increased risk of potentially fatal cerebral ischemia and/or ischemia of the extremities129 139	Concomitant use contraindicated129 139
Nefazodone	Potential decrease in dihydroergotamine metabolism129 139	Use with caution129 139
Nicotine	Possible vasoconstriction and increased ischemic response129 139	Use with caution129 139
Propranolol	Potentiation of dihydroergotamine’s vasoconstrictive action129 139	Use with caution129 139
Serotonin (5-HT1) receptor agonists (e.g., sumatriptan)	Additive vasoconstrictor effects129 139	Use within 24 hours contraindicated129 139
Vasoconstrictors, peripheral or central	Additive increases in BP129 139	Concomitant use contraindicated129 139
Zileuton	Potential decrease in dihydroergotamine metabolism129 139	Use with caution129 139

Dihydroergotamine Mesylate 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

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

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 Compatibility^c

Compatible
Dextrose 5% in water
Sodium chloride 0.9%

ActionsActions

• 
  

  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}

  
  


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  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.

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 04/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

D.H.E. 45 1MG/ML Solution (VALEANT): 5/$623.05 or 15/$1825.62

Dihydroergotamine Mesylate 1MG/ML Solution (PADDOCK): 1/$32.99 or 3/$89.97

Migranal 4MG/ML Solution (VALEANT): 6/$523.2 or 18/$1463.02

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions April 01, 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

Only references cited for selected revisions after 1984 are available electronically.

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11. Sagar S, Nairn D, Stamatakis JD et al. Efficacy of low-dose heparin in prevention of extensive deep-vein thrombosis in patients undergoing total-hip replacement. Lancet. 1976; 1:1151-4. [IDIS 61691] [PubMed 58199]

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102. Multicenter Trial Committee. Prophylactic efficacy of low-dose dihydroergotamine and heparin in postoperative deep venous thrombosis following intra-abdominal operations. J Vasc Surg. 1984; 1:608-16. [PubMed 6389909]

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114. Ulrich J, Jessen B, Siggaard-Andersen J. Comparative effects of dihydroergotamine and hydergin on the blood flow, capillary filtration rate and the capacitance vessels in the human calf studied by plethysmography. Angiology. 1973; 24:657-63. [PubMed 4202983]

115. Barone JA, Raia JJ, Levy DB. Combination dihydroergotamine mesylate and heparin sodium with lidocaine HCl: pharmacokinetics, mechanism of action, clinical efficacy, and adverse effects. Pharmacotherapy. 1986; 6(4 Part 2):3-11S.

116. Kakkar VV, Fok PJ, Murray WJG et al. Heparin and dihydroergotamine prophylaxis against thrombo-embolism after hip arthroplasty. J Bone Joint Surg (Br Vol). 1985; 67:538-42.

117. Multicenter Trial Committee. Prophylactic efficacy of low-dose dihydroergotamine and heparin in postoperative deep venous thrombosis following intra-abdominal operations. J Vasc Surg. 1984; 1:608-16. [PubMed 6389909]

118. Comerota AJ, White JV. The use of dihydroergotamine and heparin in the prophylaxis of deep venous thrombosis. Chest. 1986; 89(Suppl):389-95S. [IDIS 215373] [PubMed 3512187]

119. Gent M, Roberts RS. A meta-analysis of the studies of dihydroergotamine plus heparin in the prophylaxis of deep vein thrombosis. Chest. 1986; 89(Suppl):396-400S.

120. Muler-Schweinitzer E. What is known about the action of dihydroergotamine on the vasculature in man? Int J Clin Pharmacol Ther Toxicol. 1984; 22:677-82.

121. Kilroy RA, Aull LD, Ellis LM. Vascular spasm during heparin—dihydroergotamine prophylaxis. Clin Pharm. 1987; 6:575-7. [IDIS 231610] [PubMed 3691005]

122. van den Berg E, Walterbusch G, Gotzen L et al. Ergotism leading to threatened limb amputation or to death in two patients given heparin-dihydroergotamine prophylaxis. Lancet. 1982; 1:955-6. [IDIS 149396] [PubMed 6122783]

123. van den Berg E, Rumpf KD, Frolich H et al. Vascular spasm during thromboembolism prophylaxis with heparin-dihydroergotamine. Lancet. 1982; 2:268-9. [IDIS 154649] [PubMed 6124691]

124. Krupp P, Majer M. Ergotism and heparin-dihydroergotamine prophylaxis. Lancet. 1982; 1:1302. [IDIS 151180] [PubMed 6123037]

125. Gatterer R. Ergotism as complication of thromboembolic prophylaxis with heparin and dihydroergotamine. Lancet. 1986; 2:638-9. [IDIS 221205] [PubMed 2875358]

126. Cunningham M, de Torrente A, Ekoe JM et al. Vascular spasm and gangrene during heparin-dihydroergotamine prophylaxis. Br J Surg. 1984; 71:829-31. [PubMed 6498453]

127. Rem JA, Gratzl O, Follath F et al. Akuter Myokardinfarkt unter “Low-dose-Heparin-Dihydroergotamin”: Folge eines Koronararterienspasmus? (German; with English abstract.) Schweiz Med Wochenschr. 1986; 116:1814-6.

128. Monreal M, Foz M, Ubierna MT et al. Skin and muscle necrosis during heparin-dihydroergotamine prophylaxis. Lancet. 1984; 2:820. [IDIS 191098] [PubMed 6148565]

129. Novartis Pharmaceuticals. Migranal(dihydroergotamine mesylate) nasal spray prescribing information. East Hanover, NJ; Undated.

130. Ziegler D, Ford R, Kriegler J et al. Dihydroergotamine nasal spray for the acute treatment of migraine. Neurology. 1994; 44:

131. Humbert H, Cabiac MD, Dubray C et al. Human pharmacokinetics of dihydroergotamine administed by nasal spray. Clin Pharmacol Ther. 1996; 60: 265-75. [IDIS 464771] [PubMed 8841149]

132. Gallagher RM, DiSerio F et al. Dihydroergotamine nasal spray in the acute treatment of migraine headache. Clin Pharmacol Ther. 1993; 53: 225.

133. Massiou H. Dihydroergotamine nasal spray in prevention and treatment of migraine attacks: two controlled trials versus placebo. Cephalgia. 1987 (suppl. 6): 440-1.

134. Dihydroergotamine Nasal Spray Multicenter Investigators. Efficacy, safety, and tolerability of dihydroergotamine nasal spray as monotherapy in the treatment of acute migraine. Headache. 1995; 35:177-84. [PubMed 7775172]

135. Gallagher RM. Acute treatment of migraine with dihydroergotamine nasal spray. Arch Neurol. 1996; 53:1285-91. [PubMed 8970458]

136. Novartis. Product information form for American hospital formulary service: Migranal(dihydroergotamine mesylate) nasal spray. East Hanover, NJ; 1997 Sept 26.

137. Pryse-Phillips WEM, Dodick DW, Edmeads JG et al. Guidelines for the diagnosis and management of migraine in clinical practice. CMAJ. 1997; 156:1273. [IDIS 384971] [PubMed 9145054]

138. Danish Neurological Society and the Danish Headache Society. Guidelines for the management of headache. Cephalgia. 1998; 18:9-22.

139. Novartis. D.H.E. 45 (dihydroergotamine mesylate) injection prescribing information. East Hanover, NJ; Undated.

140. Redfield MM, Nicholson WJ, Edwards WD. Valve disease associated with ergot alkaloid use: echocardiographic and pathologic correlations. Ann Intern Med. 1992; 117:50-52. [IDIS 298556] [PubMed 1596047]

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