By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

The FDA has approved a new intranasal formulation of dihydroergotamine mesylate (INP104) for the acute treatment of migraine headaches. This formulation uses a proprietary precision olfactory delivery (POD) technology developed by Impel NeuroPharma. Dihydroergotamine mesylate (DHE) has been available as a nasal spray (Migranal) since 1997. INP104 is distributed as Trudhesa.


DHE nasal spray can be prescribed to treat migraine in adults with or without aura.1


The recommended dose is 1.45 mg (0.725 mg into each nostril).1 The dose may be repeated, if needed, a minimum of one hour after the first dose. Do not use more than two doses within a 24-hour period or three doses within seven days. INP104 is available as four single-dose units (each containing 4 mg of DHE) and one nasal spray device.


POD delivers DHE to the upper nasal cavity and may prevent or reduce drug dripping out of the nose or into the nasopharynx, thereby improving systemic availability.2 INP104 showed comparable bioavailability with intravenous DHE and shorter time to reach peak plasma levels and four times higher plasma levels than Migranal.2


INP104 shares the same contraindications and warning as other DHE formulations (e.g., peripheral ischemia following coadministration with strong CYP3A4 inhibitors, patients with cardiovascular risk factors).


The efficacy of INP104 is based on the relative bioavailability compared to DHE nasal spray (Migranal) in healthy subjects. INP104 was evaluated in a Phase III, open-label study of subjects with mainly moderate to severe headache pain who self-administered INP104 with self-recognized migraine attacks.3 INP104 used for 24 weeks (up to 52 weeks) showed acceptable safety and tolerability. Nasal endoscopic examination did not show clinically significant changes in nasal mucosa or olfactory function abnormalities. About two-thirds of subjects self-reported pain relief at two hours after their first dose and close to half experienced pain relief at one hour. For those who were pain free, recurrence was 7.1% and 14.3% at 24 hours and 48 hours, respectively.


Migraine headache is a common disorder characterized by recurrent attacks.4 It is more prevalent in women than men (18% to 26% vs. 6% to 9%). When possible, preventive therapy should be considered to reduce the number, severity, and duration of attacks. 

For acute treatment, acetaminophen and nonsteroidal anti-inflammatory drugs are considered first-line solutions for mild to moderate attacks. Triptans are considered first-line treatment for moderate to severe attacks and best taken early in an attack. Patients may respond to certain triptans, not others, and some do not respond.

DHE has less receptor specificity than triptans but slower dissociation from the receptors and is considered second-line therapy for moderate to severe migraine attacks. It can be given early or late during an attack. INP104 provides an improved formulation with a better delivery device, enhancing bioavailability. The cost for INP104 is $850 for four units. Migranal is $3,427 for eight units; a generic version is $440 for eight units.


  1. Impel NeuroPharma, Inc. Trudhesa prescribing information. September 2021.
  2. Shrewsbury SB, Jeleva M, Satterly KH, et al. STOP 101: A phase 1, randomized, open-label, comparative bioavailability study of INP104, dihydroergotamine mesylate (DHE) administered intranasally by a I123 precision olfactory delivery (POD ®) device, in healthy adult subjects. Headache 2019;59:394-409.
  3. Smith TR, Winner P, Aurora SK, et al. STOP 301: A phase 3, open-label study of safety, tolerability, and exploratory efficacy of INP104, precision olfactory delivery (POD ®) of dihydroergotamine mesylate, over 24/52 weeks in acute treatment of migraine attacks in adult patients. Headache 2021;61:1214-1226.
  4. Mayans L, Walling A. Acute migraine headache: Treatment strategies. Am Fam Physician 2018;97:243-251.