Pharmacology Update
Dihydroergotamine Mesylate Nasal Spray
By William T. Elliott, MD, and James Chan, PharmD
Dihydroergotamine is now available as a nasal spray for the treatment of migraine headache. Novartis received FDA approval in December for its product, which is marketed under the name of Migranal.
Dihydroergotamine is an agonist of various 5HT (serotonin) receptor subtypes. Its therapeutic effect is attributed to agonist effect at 5HT1D receptors.1 Dihydroergotamine has been used for migraine headaches for over 50 years-primarily by parenteral routes (IV, IM, SQ) or as a rectal suppository. Dihydroergotamine has a long duration of action and as a nasal spray has the advantage of ease of administration.
This is the second 5HT (serotonin) receptor agonist nasal spray to be approved by the FDA for the treatment of migraine, the other being sumatriptan (Imitrex).
Indications
Dihydroergotamine nasal spray is indicated for the acute treatment of migraine headaches with or without aura. It is not indicated for the management of hemiplegia or basilar migraine.
Potential Advantages
The nasal formulation provides a more convenient and less painful route of delivery of dihydroergotamine. Compared to sumatriptan, dihydroergotamine has a much longer elimination half life-10 hours vs. two hours.1,2 The risk of headache recurrence within 24 hours appears to be low at only 15%,3 compared to the risk of recurrence for various forms of sumatriptan ranging from 33% to 47%.4 An unpublished study comparing sumatriptan nasal spray 20 mg and dihydroergotamine (1 mg with an optional 1 mg compared to the recommended 1 mg and 1 mg in 15 minutes) showed a recurrence rate of 23% for sumatriptan and 13% for dihydroergotamine.6 Rebound headache appears to occur rarely.5
Potential Disadvantages
Common side effects compared to placebo include local irritation in nose and throat (30% vs 9%), rhinitis (26% vs 7%), nausea (10% vs 4%), and altered sense of taste (8% vs 1%). Local irritation generally resolved within four hours after dosing.1
Dihydroergotamine nasal spray is contraindicated during pregnancy. The vasocontrictive effects of dihydroergotamine may be enhanced when used in combination with beta blockers, nicotine, or macrolide antibiotics (e.g., erythromycin).1 The nasal spray is not as user friendly as Imitrex, as it requires breaking an ampule and assembling the nasal sprayer.
Dosing Information
Migranal is supplied as 4 mg/mL unit dose ampules for nasal administration. The standard dose is one spray (0.5 mg) in each nostril and repeated in 15 minutes for a total dose of 2 mg. The pump must be primed (i.e., squeezed 4 times) before use. After the ampule as been opened, the unused portion should be discarded after eight hours. Migranal is supplied in individual kits, each containing four unit dose trays, a patient instruction book, one assembly case, and one patient information sheet. Each tray contains one ampule, a nasal spray applicator, and a breaker cap on the ampule.
Comments
The nasal spray provides a more convenient way of delivering dihydroergotamine. Clinical trials demonstrated superior efficacy over placebo.1,7,8 The onset of action is somewhat unclear, as some studies reported significant efficacy 1-2 hours after treatment while others did not. The percent of patients with headache response at two hours ranges from 47% to 61% and from 56% to 70% at four hours. Numerically, the responses seemed lower than those reported for sumatriptan nasal spray. However, no comparative trials have been published. Dihydroergotamine appears to have a lower headache recurrence rate. Results for an unpublished trial comparing subcutaneous sumatriptan and dihydroergotamine indicated headache recurrence 24 hours after treatment of 45% vs. 18%.5
Clinical Implications
Dihydroergotamine nasal spray offers another effective agent for the treatment of acute migraine headache that can be self-administered by the patient. It generally shares similar contraindications and warnings with sumatriptan, although only dihydroergotamine is contraindicated in pregnant women. These drugs should not be use in patients with ischemic heart disease, uncontrolled hypertension, or those who have clinical signs and symptoms consistent with coronary artery vasospasm, including Prinzmetal variant angina. Dihydroergotamine is less selective than sumatriptan in terms of affinity for 5HT receptors. While sumatriptan binds mainly to 5HT1D, dihydroergotamine binds to other 5HT1 and 5HT2, alpha adrenergic, and dopaminergic receptors. Whether these differences in receptor binding activity translate into any clear clinical advantage of one drug over the other remains to be established.
The costs of intranasal dihydroergotamine and intranasal sumatriptan are comparable.