Dihydroergotamine Mesylate

INDICATIONS AND USAGE Dihydroergotamine Mesylate Injection, USP is indicated for the acute treatment of migraine headaches with or without aura and the acute treatment of cluster headache episodes.

DOSAGE AND ADMINISTRATION Dihydroergotamine Mesylate Injection, USP should be administered in a dose of 1 mL intravenously, intramuscularly or subcutaneously. The dose can be repeated, as needed, at 1-hour intervals to a total dose of 3 mL for intramuscular or subcutaneous delivery or 2 mL for intravenous delivery in a 24-hour period. The total weekly dosage should not exceed 6 mL. Dihydroergotamine Mesylate Injection, USP should not be used for chronic daily administration.

CONTRAINDICATIONS There have been a few reports of serious adverse events associated with the coadministration of dihydroergotamine and potent CYP3A4 inhibitors, such as protease inhibitors and macrolide antibiotics, resulting in vasospasm that led to cerebral ischemia and/or ischemia of the extremities. The use of potent CYP3A4 inhibitors (i.e., ritonavir, nelfinavir, indinavir, erythromycin, clarithromycin, troleandomycin, ketoconazole, itraconazole) with dihydroergotamine is, therefore, contraindicated (see WARNINGS, CYP3A4 Inhibitors ). Dihydroergotamine Mesylate Injection, USP should not be given to patients with ischemic heart disease (e.g., angina pectoris, history of myocardial infarction, or documented silent ischemia) or to patients who have clinical symptoms or findings consistent with coronary artery vasospasm including Prinzmetal's variant angina (see WARNINGS ). Because Dihydroergotamine Mesylate Injection, USP may increase blood pressure, it should not be given to patients with uncontrolled hypertension. Dihydroergotamine Mesylate Injection, USP, 5-HT 1 agonists (e.g., sumatriptan), ergotamine-containing or ergot-type medications or methysergide should not be used within 24 hours of each other. Dihydroergotamine Mesylate Injection, USP should not be administered to patients with hemiplegic or basilar migraine. In addition to those conditions mentioned above, Dihydroergotamine Mesylate Injection, USP is also contraindicated in patients with known peripheral arterial disease, sepsis, following vascular surgery and severely impaired hepatic or renal function. Dihydroergotamine Mesylate Injection, USP is contraindicated in patients who have previously shown hypersensitivity to ergot alkaloids. Dihydroergotamine mesylate should not be used with peripheral and central vasoconstrictors because the combination may result in additive or synergistic elevation of blood pressure.

ADVERSE REACTIONS Serious cardiac events, including some that have been fatal, have occurred following use of Dihydroergotamine Mesylate Injection, USP, but are extremely rare. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation (see CONTRAINDICATIONS , WARNINGS , and PRECAUTIONS ). Fibrotic complications have been reported in association with long term use of injectable dihydroergotamine mesylate (see WARNINGS, Fibrotic Complications ). Post-introduction Reports The following events derived from postmarketing experience have been occasionally reported in patients receiving Dihydroergotamine Mesylate Injection, USP: vasospasm, paraesthesia, hypertension, dizziness, anxiety, dyspnea, headache, flushing, diarrhea, rash, increased sweating, and pleural and retroperitoneal fibrosis after long-term use of dihydroergotamine. Extremely rare cases of myocardial infarction and stroke have been reported. A causal relationship has not been established. Dihydroergotamine Mesylate Injection, USP is not recommended for prolonged daily use (see DOSAGE AND ADMINISTRATION ). To report SUSPECTED ADVERSE REACTIONS, contact Provepharm Inc., at 1–833-727-6556 or safety-us@provepharm.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions Vasoconstrictors Dihydroergotamine Mesylate Injection, USP should not be used with peripheral vasoconstrictors because the combination may cause synergistic elevation of blood pressure. Sumatriptan Sumatriptan has been reported to cause coronary artery vasospasm, and its effect could be additive with Dihydroergotamine Mesylate Injection, USP. Sumatriptan and Dihydroergotamine Mesylate Injection, USP should not be taken within 24 hours of each other (see CONTRAINDICATIONS ). Beta Blockers Although the results of a clinical study did not indicate a safety problem associated with the administration of Dihydroergotamine Mesylate Injection, USP to subjects already receiving propranolol, there have been reports that propranolol may potentiate the vasoconstrictive action of ergotamine by blocking the vasodilating property of epinephrine. Nicotine Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy. CYP3A4 Inhibitors (e.g., Macrolide Antibiotics and Protease Inhibitors) (see CONTRAINDICATIONS and WARNINGS ) SSRI's Weakness, hyperreflexia, and incoordination have been reported rarely when 5-HT 1 agonists have been co-administered with SSRI's (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline). There have been no reported cases from spontaneous reports of drug interaction between SSRI's and Dihydroergotamine Mesylate Injection, USP. Oral Contraceptives The effect of oral contraceptives on the pharmacokinetics of Dihydroergotamine Mesylate Injection, USP has not been studied.

Mechanism of Action Dihydroergotamine binds with high affinity to 5-HT 1D α and 5-HT 1D β receptors. It also binds with high affinity to serotonin 5-HT 1A , 5-HT 2A , and 5-HT 2C receptors, noradrenaline α 2A , α 2B and α 1 receptors, and dopamine D 2L and D 3 receptors. The therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effect at 5-HT 1D receptors. Two current theories have been proposed to explain the efficacy of 5-HT 1D receptor agonists in migraine. One theory suggests that activation of 5-HT 1D receptors located on intracranial blood vessels, including those on arteriovenous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine headache. The alternative hypothesis suggests that activation of 5-HT 1D receptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release. In addition, dihydroergotamine possesses oxytocic properties.

DESCRIPTION Dihydroergotamine mesylate is ergotamine hydrogenated in the 9, 10 position as the mesylate salt. Dihydroergotamine mesylate, USP is white to slightly yellowish powder, or off white to faintly red powder. Dihydroergotamine mesylate is known chemically as ergotaman-3 ́,6 ́,18-trione,9,10-dihydro-12 ́-hydroxy-2 ́-methyl-5 ́-(phenylmethyl)-,(5 ́α)-, monomethanesulfonate. Its molecular weight is 679.78 g/mol and its empirical formula is C 33 H 37 N 5 O 5 •CH 4 O 3 S. The chemical structure is: Dihydroergotamine mesylate C 33 H 37 N 5 O 5 ●CH 4 O 3 S Mol. Wt. 679.78 g/mol Dihydroergotamine mesylate injection, USP is a clear, colorless solution supplied in sterile glass ampules for intravenous, intramuscular, or subcutaneous administration. Each mL contains 1 mg Dihydroergotamine Mesylate, USP; Alcohol, USP 6.1% by volume; Glycerin, USP 15% by weight; Water for Injection, USP; Methanesulfonic Acid and/or Sodium Hydroxide for pH adjustment (pH range is 3.4 to 4.9). structural-formula-dihydroergotamine-mesylate

OVERDOSAGE To date, there have been no reports of acute overdosage with this drug. Due to the risk of vascular spasm, exceeding the recommended dosages of Dihydroergotamine Mesylate Injection, USP is to be avoided. Excessive doses of dihydroergotamine may result in peripheral signs and symptoms of ergotism. Treatment includes discontinuance of the drug, local application of warmth to the affected area, the administration of vasodilators, and nursing care to prevent tissue damage. In general, the symptoms of an acute Dihydroergotamine Mesylate Injection, USP overdose are similar to those of an ergotamine overdose, although there is less pronounced nausea and vomiting with Dihydroergotamine Mesylate Injection, USP. The symptoms of an ergotamine overdose include the following: numbness, tingling, pain, and cyanosis of the extremities associated with diminished or absent peripheral pulses; respiratory depression; an increase and/or decrease in blood pressure, usually in that order; confusion, delirium, convulsions, and coma; and/or some degree of nausea, vomiting, and abdominal pain. In laboratory animals, significant lethality occurs when dihydroergotamine is given at I.V. doses of 44 mg/kg in mice, 130 mg/kg in rats, and 37 mg/kg in rabbits. Up-to-date information about the treatment of overdosage can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Poison Control Centers are listed in the Physician's Desk Reference (PDR) * .

HOW SUPPLIED/STORAGE AND HANDLING Dihydroergotamine Mesylate Injection, USP Available as a clear, colorless, sterile solution in single 1 mL sterile ampules containing 1 mg of dihydroergotamine mesylate per mL is available as: Strength Size NDC NUMBER 1 mg/mL 1 mL (Single-Dose ampule) 36000-300-10 (Carton of 10) Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Use carton to protect contents from light until used. Do not refrigerate or freeze. To assure constant potency, protect the ampules from light and heat. Administer only if clear and colorless. Discard unused portion. All trademarks are the property of their respective owner. Manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015 USA Manufactured by: Siegfried Hameln GmbH, Langes Feld 13, Hameln, 31789, Germany (DEU) Rev. 2023-07-14