TRUDHESA (dihydroergotamine mesylate)

TRUDHESA (dihydroergotamine mesylate) nasal spray

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TRUDHESA TM (dihydroergotamine mesylate) nasal spray

TRUDHESA (dihydroergotamine mesylate) nasal spray is a single-dose, drug-device combination product containing a dihydroergotamine mesylate drug constituent and a nasal spray device constituent.

The chemical name for dihydroergotamine mesylate is ergotaman-3′, 6′, 18-trione, 9,10-dihydro­12′-hydroxy-2′-methyl-5′- (phenylmethyl)-, (5’α)-,monomethanesulfonate.

Its molecular weight is 679.78, and its molecular formula is C33H37N5O5•CH4O3S.

INDICATIONS AND USAGE

TRUDHESA is indicated for the acute treatment of migraine with or without aura in adults.

Limitations of Use

  • TRUDHESA is not indicated for the preventive treatment of migraine.
  • TRUDHESA is not indicated for the management of hemiplegic or basilar migraine.

Dosage and administration

The recommended dose of TRUDHESA is 1.45 mg administered as two metered sprays into the nose (one spray of 0.725 mg into each nostril). The dose may be repeated, if needed, a minimum of 1 hour after the first dose.

Do not use more than 2 doses of TRUDHESA within a 24-hour period or 3 doses within a 7-day period.

Assessment Prior to First Dose

Prior to initiation of TRUDHESA, a cardiovascular evaluation is recommended. For patients with risk factors predictive of coronary artery disease who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of TRUDHESA take place in the setting of an equipped healthcare facility.

Important Administration Instructions

  • TRUDHESA is for nasal administration only and must not be injected.
  • TRUDHESA must be assembled prior to use.
  • Use or discard TRUDHESA within 8 hours once the vial has been opened or the product has been assembled.
  • Prime the assembled TRUDHESA before initial use by releasing 4 sprays.
  • Use TRUDHESA immediately after priming.
  • Discard TRUDHESA immediately after use.
  • Open and prepare a new TRUDHESA if an additional dose is needed.

CONTRAINDICATIONS

TRUDHESA is contraindicated in patients:

  • with concomitant use of strong CYP3A4 inhibitors, such as protease inhibitors (e.g., ritonavir, nelfinavir, or indinavir), macrolide antibiotics (e.g., erythromycin or clarithromycin), and antifungals (ketoconazole or itraconazole)
  • with ischemic heart disease (angina pectoris, history of myocardial infarction, or documented silent ischemia) or patients who have clinical symptoms or findings consistent with coronary artery vasospasm, including Prinzmetal’s variant angina
  • with uncontrolled hypertension
  • with peripheral arterial disease
  • with sepsis
  • following vascular surgery
  • with severe hepatic impairment
  • with severe renal impairment
  • with known hypersensitivity to ergot alkaloids
  • with recent use (i.e., within 24 hours) of other 5-HT 1 agonists (e.g., sumatriptan) or ergotamine-containing or ergot-type medications
  • with concomitant use of peripheral and central vasoconstrictors because the combination may result in additive or synergistic elevation of blood pressure

WARNINGS AND PRECAUTIONS

  • Myocardial Ischemia and/or Infarction, Other Cardiac Adverse Reactions, and Fatalities: In patients with risk factors, consider 1 st dose administration under medical supervision with electrocardiogram.
  • Cerebrovascular Adverse Reactions and Fatalities: Cerebral hemorrhage, subarachnoid hemorrhage and stroke have been reported; discontinue TRUDHESA if suspected.
  • Other Vasospasm Related Adverse Reactions: TRUDHESA may cause vasospasm or elevation in blood pressure. Discontinue if signs or symptoms of vasoconstriction develop.
  • Medication Overuse Headache: Detoxification may be necessary.
  • Preterm Labor: Advise pregnant women of the risk.
  • Fibrotic Complications: Pleural and retroperitoneal fibrosis have been reported following prolonged daily use of dihydroergotamine mesylate.
  • Administration of TRUDHESA should not exceed the dosing guidelines or be used for chronic daily administration.
  • Local Irritation: If severe local irritation occurs for no other attributable reasons, suspend TRUDHESA until resolution.

DRUG INTERACTIONS

CYP3A4 Inhibitors: There have been rare reports of serious adverse events in connection with the coadministration of intravenous administration of dihydroergotamine and strong CYP3A4 inhibitors, such as protease inhibitors (e.g., ritonavir, nelfinavir, indinavir), macrolide antibiotics (e.g., erythromycin, clarithromycin), and antifungals (e.g., ketoconazole, itraconazole), resulting in vasospasm that led to cerebral ischemia and/or ischemia of the extremities. The use of strong CYP3A4 inhibitors with dihydroergotamine is contraindicated.

Administer moderate CYP3A4 inhibitors (e.g., saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, clotrimazole) with caution.

Triptans: Triptans (serotonin [5-HT] 1B/1D receptor agonists) have been reported to cause coronary artery vasospasm, and its effect could be additive with TRUDHESA. Therefore, triptans and TRUDHESA should not be taken within 24 hours of each other.

Beta Blockers: There have been reports that propranolol may potentiate the vasoconstrictive action of ergotamine by blocking the vasodilating property of epinephrine.

Vasoconstrictors: TRUDHESA is contraindicated for use with peripheral and central vasoconstrictors because the combination may cause synergistic elevation of blood pressure

Nicotine: Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy

Selective Serotonin Reuptake Inhibitors: Weakness, hyperreflexia, and incoordination have been reported rarely when 5-HT 1 agonists have been coadministered with selective serotonin reuptake inhibitors (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline).

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USE IN SPECIFIC POPULATIONS

Pregnancy: Available data from published literature indicate an increased risk of preterm delivery with TRUDHESA use during pregnancy. Avoid use of TRUDHESA during pregnancy. Data collected over decades have shown no increased risk of major birth defects or miscarriage with use of dihydroergotamine mesylate during pregnancy.

Lactation: There are no data on the presence of dihydroergotamine in human milk; however, ergotamine, a related drug, is present in human milk. There are reports of diarrhea, vomiting, weak pulse, and unstable blood pressure in breastfed infants exposed to ergotamine. TRUDHESA may reduce milk supply because it may decrease prolactin levels. Because of the potential for reduced milk supply and serious adverse events in the breastfed infant, including diarrhea, vomiting, weak pulse, and unstable blood pressure, advise patients not to breastfeed during treatment with TRUDHESA and for 3 days after the last dose. Breast milk supply during this time should be pumped and discarded.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Clinical studies of TRUDHESA and other dihydroergotamine mesylate products did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

DRUG ABUSE AND DEPENDENCE

Controlled Substance: TRUDHESA contains dihydroergotamine (as the mesylate salt), which is not a controlled substance.

Abuse: Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Currently available data have not demonstrated drug abuse with dihydroergotamine. However, cases of drug abuse in patients on other forms of ergot therapy have been reported.

Dependence: Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Currently available data have not demonstrated physical or psychological dependence with dihydroergotamine. However, cases of psychological dependence in patients on other forms of ergot therapy have been reported.

OVERDOSAGE

Excessive doses of dihydroergotamine may result in peripheral signs and symptoms of ergotism. In general, the symptoms of an acute TRUDHESA overdose are similar to those of an ergotamine overdose, although there may be less pronounced nausea and vomiting with TRUDHESA. 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, dihydroergotamine was lethal when given at intravenous doses of 44 mg/kg in mice, 130 mg/kg in rats, and 37 mg/kg in rabbits.

Treatment

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. Up-to-date information about the treatment of overdosage can often be obtained from a certified Regional Poison Control Center.

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