D.H.E. 45 Drug Interactions: What to Avoid and What to Tell Your Doctor

D.H.E. 45 (dihydroergotamine mesylate) has several important drug interactions — including some that are potentially life-threatening. Because DHE works through vasoconstriction and interacts with the liver enzyme CYP3A4, certain medications can dramatically increase its effects to dangerous levels. Always give your doctor and pharmacist a complete list of every medication, supplement, and herbal product you take before using DHE.

Boxed Warning: CYP3A4 Inhibitors (Contraindicated)

D.H.E. 45 carries a Boxed Warning — the FDA's highest-level safety alert — regarding coadministration with strong CYP3A4 inhibitors. These drugs block the liver enzyme that breaks down DHE, causing DHE blood levels to rise dangerously. The result can be severe vasospasm leading to cerebral ischemia and/or ischemia of the extremities — which can be life-threatening or cause permanent tissue damage.

These combinations are CONTRAINDICATED — meaning do not use:

Macrolide antibiotics: Erythromycin, clarithromycin (Biaxin), troleandomycin

HIV protease inhibitors: Ritonavir (Norvir), nelfinavir, indinavir, saquinavir

Azole antifungals: Ketoconazole, itraconazole

If you have been prescribed any of these medications, do not use D.H.E. 45 until your prescriber confirms it is safe. Contact your doctor immediately.

Use With Caution: Less Potent CYP3A4 Inhibitors

These drugs inhibit CYP3A4 less potently but should still be used with caution alongside DHE. Your doctor should evaluate the risk-benefit ratio:

Fluconazole (Diflucan) — common antifungal; less potent CYP3A4 inhibitor

Clotrimazole — topical antifungal; minimal systemic absorption, but systemic forms warrant caution

Fluoxetine (Prozac) and fluvoxamine (Luvox) — SSRI antidepressants

Nefazodone — antidepressant

Zileuton (Zyflo) — asthma medication (5-lipoxygenase inhibitor)

Grapefruit juice — contains furanocoumarins that inhibit intestinal CYP3A4

Triptans — Do Not Combine Within 24 Hours

D.H.E. 45 and triptans (sumatriptan, zolmitriptan, rizatriptan, eletriptan, almotriptan, etc.) both cause vasoconstriction. Using them together or within 24 hours of each other creates additive vasoconstriction that can lead to coronary artery spasm, peripheral ischemia, or stroke.

Do not take a triptan within 24 hours of using DHE.

Do not take DHE within 24 hours of using a triptan.

Other Ergotamine-Type Drugs

Do not use D.H.E. 45 within 24 hours of any other ergotamine-containing medication, including:

Ergotamine tartrate (Ergomar)

Ergotamine with caffeine (Cafergot)

Methysergide (Sansert)

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Peripheral and Central Vasoconstrictors

Combining D.H.E. 45 with peripheral or central vasoconstrictors creates a risk of synergistic, dangerous blood pressure elevation. This category includes:

Pseudoephedrine, phenylephrine (common cold/decongestant medications)

Cocaine (vasoconstrictor, never combine with DHE)

Epinephrine (adrenaline) — inform all healthcare providers you use DHE

SSRIs and SNRIs (Serotonin-Related Risk)

There have been rare reports of weakness, hyperreflexia, and incoordination when 5-HT1 agonists (like DHE) were used alongside SSRIs (selective serotonin reuptake inhibitors) such as fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine. These symptoms may indicate early serotonin syndrome. If you experience unexpected muscle weakness or twitching after taking DHE alongside your antidepressant, contact your doctor.

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Beta-Blockers

Beta-blockers (propranolol, metoprolol, atenolol) used for migraine prevention or blood pressure control can increase the risk of peripheral ischemia when combined with DHE. The alpha-vasoconstrictive effects of DHE may be enhanced when beta-blockade prevents compensatory vasodilation. This combination requires careful medical supervision.

What to Tell Your Doctor and Pharmacist

Before starting D.H.E. 45, tell every prescriber and pharmacist:

All antibiotics, antifungals, and antiretrovirals you take or have been recently prescribed.

Any triptans you are prescribed or use (even occasionally).

All antidepressants, especially SSRIs and SNRIs.

All blood pressure or cardiac medications.

All herbal supplements — especially St. John's Wort (which affects CYP enzymes).

For information on D.H.E. 45 side effects, see our D.H.E. 45 side effects guide. For a complete overview, see what is D.H.E. 45.