Dihydroergotamine (Nasal-Systemic )


Dihydroergotamine Mesilate.

Primary: CN105

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).


Antimigraine agent—



Headache, migraine (treatment)—Intranasal dihydroergotamine is indicated to relieve (abort) acute migraine headaches (with or without aura) {01}.

Intranasal dihydroergotamine is not recommended for treatment of basilar artery migraine or hemiplegic migraine {01}.


Physicochemical characteristics:
    Synthetic {01}.
Molecular weight—
    679.8 {01}

Mechanism of action/Effect:

Dihydroergotamine is an ergot derivative that interacts with several neurotransmitter receptors, including alpha-adrenergic, serotonergic (tryptaminergic), and dopaminergic receptors {01}. The dihydroergotamine- induced decreases in the firing of serotonergic (5-hydroxytryptaminergic, 5-HT) neurons may be responsible for relief of migraine headache {01}. Specifically, it is thought that agonist activity at the 5-HT 1D receptor subtype provides relief of acute headache {01}. It has been proposed that constriction of cerebral blood vessels by the ergot derivative (resulting from alpha-adrenergic stimulation as well as from activity at 5-HT receptors) reduces the pulsation in cerebral arteries that may be responsible for the pain of migraine headaches {01}. It has also been proposed that dihydroergotamine may relieve vascular headaches by decreasing the release of pro-inflammatory neuropeptide release {01}.

Other actions/effects:

Dihydroergotamine stimulates uterine smooth muscle {01}.


Following intranasal administration, the bioavailability of dihydroergotamine is 32% {01}. The rate of absorption of intranasal dihydroergotamine demonstrates interpatient variability, which may be dependent on the administration technique {01}.

Protein binding:

Very high (93%) {01}.


Hepatic; extensive {01}. The principal metabolite, 8´-hydroxy-dihydroergotamine, is pharmacologically active {01}. Following intranasal administration of dihydroergotamine, the metabolites represent 20 to 30% of the area under the plasma concentration–time curve (AUC) {01}.


Approximately 10 hours {01}.

    Primarily fecal (biliary) {01}. Following intranasal administration of dihydroergotamine, 2% of the dose is excreted in the urine {01}.

Precautions to Consider


Long-term studies in mice and rabbits are currently being done to evaluate the carcinogenic potential of dihydroergotamine {01}.


Dihydroergotamine demonstrated no mutagenic effects in presence or absence of metabolic activation in the Ames test or the in vitro mammalian Chinese hamster gene mutation assays, or in the rat hepatocyte unscheduled DNA synthesis test assay {01}. There was evidence of clastogenic activity in the V79 Chinese hamster cell assay with metabolic activation and the cultured human peripheral blood lymphocyte in vitro chromosomal aberration assays. However, there was no evidence of clastogenic activity in the in vivo mouse and hamster micronucleus tests {01}.

There was no evidence of impairment of fertility in rats receiving doses of intranasal dihydroergotamine of up to 1.6 mg per kg of body weight (mg/kg) per day (area under the plasma concentration–time curve [AUC] exposure approximately 9 to 11 times the maximum recommended human dose [MRHD]) {01}.

Adequate and well-controlled studies in humans have not been done. However, use during pregnancy is contraindicated because of intranasal dihydroergotamine's oxytocic activity, which may result in fetal harm. Therefore, if intranasal dihydroergotamine should be used by a pregnant woman, or if a woman becomes pregnant during treatment, she should be advised that this medication may harm the fetus.

An embryofetal developmental study during the organogenesis period in pregnant rabbits showed that intranasal dihydroergotamine doses of up to 0.16 mg per day or greater (AUC exposure approximately 0.4 to 1.2 times the exposure in humans receiving the MRHD) resulted in decreased fetal body weight and/or skeletal ossification {01}. In rabbits receiving doses of intranasal dihydroergotamine of up to 3.6 mg per day during the organogenesis period (equivalent to maternal concentration of approximately 7 times the MRHD), a delay in skeletal ossification was observed in the fetuses {01}. However, in rabbits receiving doses of up to 1.2 mg per day (equivalent to maternal concentrations of 2.5 times the MRHD), no delay in ossification was observed {01}. In female rats receiving doses of intranasal dihydroergotamine of up to 0.16 mg per day or greater during pregnancy and lactation, decreased body weights and impaired reproductive function were observed in the offspring {01}. Intranasal dihydroergotamine doses that produced developmental effects in these studies were below those that demonstrated evidence of any maternal toxicity {01}. In addition, the prolonged vasoconstriction of the uterine vessels and/or increased myometrial tone resulted in a reduction in the uteroplacental blood flow, which is presumed to be the cause for dihydroergotamine-induced intrauterine growth retardation {01}.

FDA Pregnancy Category X {01}.


It is expected that intranasal dihydroergotamine would be distributed into human breast milk {01}. However, there is currently no data on the concentration of dihydroergotamine distributed into human breast milk.

Ergot alkaloids are distributed into human breast milk and have the potential to cause adverse effects, such as vomiting, diarrhea, weak pulse, and unstable blood pressure {01}. These medications may also inhibit lactation {01}.

Due to intranasal dihydroergotamine's potential to cause serious adverse effects, use of this medicine is not recommended for nursing mothers {01}.


No information is available on the relationship of age to the effects of intranasal dihydroergotamine in pediatric patients {01}. Safety and efficacy have not been established {01}.


No information is available on the relationship of age to the effects of intranasal dihydroergotamine in geriatric patients {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Antibiotics, macrolide, especially, such as:
Troleandomycin    (these antibiotics may inhibit the metabolism of intranasal dihydroergotamine and increase the risk of vasospasm {01})

Beta-adrenergic blocking agents    (these medications may potentiate vasoconstriction {01})

» Ergot alkaloids, other or
» Vasoconstictors, systemic, other, such as:
Epinephrine, parenteral
Phenylephrine, parenteral     (concurrent use with intranasal dihydroergotamine may result in additive increases of blood pressure {01})

» 5-hydroxytryptamine agonists, such as:
Sumatriptan    (a delay of 24 hours between administration of sumatriptan and intranasal dihydroergotamine is recommended because of the possibility of additive and/or prolonged vasoconstriction {01})

Nicotine    (this medication may potentiate vasoconstriction {01})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problems exist:
» Coronary artery disease, especially:
Angina pectoris
Myocardial infarction, history of
Myocardial ischemia, silent, documented
Prinzmetal's angina
» Other conditions in which coronary vasoconstriction would be detrimental    (intranasal dihydroergotamine may cause coronary vasospasms {01})

» Hepatic function impairment, severe
» Hypertension, severe, uncontrolled    (may be exacerbated {01})

» Renal function impairment, severe
» Vascular surgery
Risk-benefit should be considered when the following medical problems exist
Coronary artery disease, predisposition to    (intranasal dihydroergotamine may cause serious coronary adverse effects; patients in whom coronary artery disease is a possibility on the basis of age or the presence of other risk factors, such as diabetes, hypercholesterolemia, obesity, a strong family history of coronary artery disease, or tobacco smoking, should be evaluated for the presence of cardiovascular disease before intranasal dihydroergotamine is prescribed; even after a satisfactory evaluation, the advisability of administering the patient's first dose under medical supervision should be considered {01})

Hypersensitivity to ergot alkaloids
Hypertension, controlled    (may precipitate an increase in blood pressure {01})

» Sepsis

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Electrocardiogram (ECG)    (monitoring is recommended for long-term intermittent users of intranasal dihydroergotamine {01})

Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent or rare
Cardiovascular effects, including angina pectoris{01}
arrythmias{01} (irregular heartbeat), coronary vasospasm–induced{01} (chest pain), myocardial infarction or ischemia{01} (feeling of heaviness in chest; pain in back, chest, or left arm; shortness of breath or troubled breathing)
peripheral ischemia{01} (itching of skin; numbness and tingling of face, fingers, or toes; pain in arms legs, or lower back, especially pain in calves and/or heels upon exertion; pale, bluish-colored, or cold hands or feet; weak or absent pulses in legs)
upper respiratory tract infection{01} (cough, fever, sneezing, or sore throat)

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Asthenia{01} (unusual tiredness or weakness)
dry mouth{01}
fatigue{01} (unusual feeling of tiredness)
hot flashes{01} (sudden sweatings and feelings of warmth)
irritation in the nose{01} (burning or tingling sensation, dryness, soreness or pain in the nose; runny and/or stuffy nose; unexplained nosebleeds)
increased sweating{01}
muscle stiffness{01}
nausea and/or vomiting{01}
paresthesia{01} (sensation of burning, warmth, heat, numbness, tightness, or tingling)
pharyngitis{01} (sore throat)
sinusitis{01} (runny or stuffy nose; headache)
somnolence (sleepiness)
taste perversion{01} (change in sense of taste)

Note: Irritation in the nose was found to be mild to moderate. In most cases, the symptoms resolved within four hours of the administration of intranasal dihydroergotamine.

Incidence less frequent or rare
Anorexia{01} (decreased appetite)
bronchitis{01} (congestion in chest; cough; difficult and/or painful breathing)
central nervous system (CNS) effects, including anxiety{01}
euphoria{01} (unusual feeling of well being), insomnia{01} (trouble in sleeping), nervousness{01}
cold, clammy skin{01}
dyspepsia{01} (heartburn)
dysphagia{01} (difficulty swallowing)
dyspnea{01} (shortness of breath)
edema{01} (swelling of face, fingers, feet or lower legs)
ear pain{01}
eye problems, including blurred vision{01}
conjunctivitis{01} (red or irritated eyes), eye pain{01}
increased watering of the eyes{01}
hypotension{01} (dizziness or lightheadedness when getting up from a lying or sitting position; sudden fainting)
increased salivation{01} (increased watering of the mouth)
increased yawning{01}
palpitations{01} (pounding heartbeat)
pruritus{01} (itching of the skin)
muscle weakness{01}
petechia{01} (pinpoint red spots on skin)
skin rash{01}
tinnitus{01} (ringing or buzzing in the ears)
stomach pain{01}
tremors{01} (trembling or shaking of hands or feet)

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and/or chronic
hypertension{01} (dizziness; headaches, severe or continuing; increase in blood pressure)
nausea and/or vomiting{01}
numbness, tingling, and/or pain in the legs or arms{01}
respiratory depression{01} (shortness of breath)
stomach pain{01}

Treatment of overdose

Specific treatment:
For peripheral vasospasm: Warmth should be applied to ischemic extremities {01}. If necessary a vasodilator may be administered {01}. Nursing measures designed to prevent tissue damage should be instituted {01}.

Supportive care:
Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation {01}.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Dihydroergotamine (Nasal-Systemic)— .
In providing consultation, consider emphasizing the following» selected information ( = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to ergot alkaloids

Pregnancy—Use of intranasal dihydroergotamine is contraindicated during pregnancy because of its potential oxytocic activity, which may result in fetal harm

Breast-feeding—Use of intranasal dihydroergotamine is not recommended for nursing mothers. Intranasal dihydroergotamine may be distributed into breast milk and cause adverse effects, such as vomiting, diarrhea, weak pulse, unstable blood pressure, seizures in the infant. Also, intranasal dihydroergotamine may inhibit lactation
Other medications, especially 5-hydroxytryptamine agonists and vasoconstrictors
Other medical problems, especially coronary artery disease, or other conditions that may be adversely affected by coronary artery constriction; hypertension, severe, uncontrolled

Proper use of this medication
» Proper administration technique; reading patient directions carefully before use

» Not administering if atypical headache symptoms are present; checking with physician instead

» Administering after onset of headache pain

Additional benefit may be obtained if the patient lies down in a quiet, dark room after administering medication

Using additional doses, if needed, for return of migraine headache after initial relief was obtained, provided that prescribed limits (quantity used and frequency of administration) are not exceeded

Compliance with prophylactic therapy, if prescribed

» Proper dosing

» Proper storage

Precautions while using this medication
Avoiding alcohol, which aggravates headache

Caution when driving or doing anything else requiring alertness because of possible drowsiness, dizziness, lightheadedness, impairment of physical or mental abilities

Side/adverse effects
Signs of potential side effects, especially cardiovascular effects, peripheral ischemia, or upper respiratory tract infection

Nasal Dosage Form


Usual adult dose
Antimigraine agent
Nasal, 0.5 mg (one spray) in each nostril. Followed by another 0.5 mg (one spray) dose in each nostril fifteen minutes later {01}.

Usual adult prescribing limits
Nasal, 3 mg (6 sprays) per day; or 4 mg (8 sprays) per week {01}.

Usual pediatric dose
Safety and efficacy have not been established in patients younger than 18 years of age {01}.

Usual geriatric dose
See Usual adult dose .

Strength(s) usually available

0.5 mg per metered spray (Rx) [Migranal (caffeine) (dextrose) (carbon dioxide)]

Packaging and storage:
Store below 25 ºC (77 ºF).

Developed: 07/08/1998

  1. Migranal package insert (Novartis—US), New 12/97, Rec 5/98.