Possible serious and/or life-threatening cerebral and/or peripheral ischemia when administered concomitantly with potent CYP3A4 inhibitors (see Interactions); concomitant use contraindicated.
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in combination with low-dose heparin therapy for prevention of postoperative DVT and pulmonary embolism; generally has been replaced by other more effective therapies (e.g., low molecular weight heparin alone, warfarin).
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.
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).
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
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).
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.
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.
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
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
Potential decrease in dihydroergotamine metabolism
Use with caution
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.
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.
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 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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