Get your patient on Trudhesa (Dihydroergotamine Mesylate)

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.

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.

Prior to initiation of TRUDHESA, a cardiovascular evaluation is recommended [see Warnings and Precautions (5.2) ] . 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.

TRUDHESA is for nasal administration only and must not be injected.

TRUDHESA must be assembled prior to use (see Instructions for 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.

Safety and effectiveness in pediatric patients have not been established.

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.

Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of dihydroergotamine with strong CYP3A4 inhibitors, including protease inhibitors, macrolide antibiotics, and antifungals. Because CYP3A4 inhibition elevates the serum levels of dihydroergotamine, the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities is increased. Hence, concomitant use of TRUDHESA with strong CYP3A4 inhibitors is contraindicated [see Contraindications (4) and Drug Interactions (7.1) ] .

The potential for adverse cardiac adverse reactions exists with TRUDHESA treatment. Serious adverse cardiac events, including some that have been fatal, have occurred following use of dihydroergotamine mesylate. These events have included acute myocardial infarction, life-threatening disturbances of cardiac rhythm (e.g., ventricular tachycardia and ventricular fibrillation), coronary artery vasospasm, and transient myocardial ischemia.

Prior to initiation of TRUDHESA, a cardiovascular evaluation is recommended to determine if the patient is free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. If, during the cardiovascular evaluation, the patient's medical history (including risk factors), or electrocardiographic investigation, findings are consistent with coronary artery vasospasm or myocardial ischemia, TRUDHESA should not be administered [see Contraindications (4) ] .

For patients with risk factors predictive of coronary artery disease (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of coronary artery disease, females who are surgically or physiologically postmenopausal, or males who are over 40 years of age) 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, unless the patient has previously received dihydroergotamine mesylate. During the interval immediately following the first use of TRUDHESA, an electrocardiogram is recommended in those patients with risk factors because ischemia can occur in the absence of clinical symptoms.

The potential for adverse cerebrovascular adverse reactions exists with TRUDHESA treatment. Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with dihydroergotamine mesylate; and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the dihydroergotamine mesylate having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack). Discontinue TRUDHESA if a cerebrovascular event is suspected.

TRUDHESA, like other ergot alkaloids, may cause vasospastic reactions other than coronary artery vasospasm. Myocardial, peripheral vascular, and colonic ischemia have been reported with dihydroergotamine mesylate.

Dihydroergotamine mesylate associated vasospastic phenomena may also cause muscle pains, numbness, coldness, pallor, and cyanosis of the digits. In patients with compromised circulation, persistent vasospasm may result in gangrene or death. TRUDHESA should be discontinued immediately if signs or symptoms of vasoconstriction develop.

Patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud's syndrome, following the use of any 5-HT agonist, including TRUDHESA, should be evaluated by a healthcare provider.

Significant elevation in blood pressure has been reported on rare occasions in patients with and without a history of hypertension treated with dihydroergotamine mesylate. TRUDHESA is contraindicated in patients with uncontrolled hypertension [see Contraindications (4) ] .

An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5-HT ₁ agonist in a study evaluating subjects undergoing cardiac catheterization.

Overuse of acute migraine drugs (e.g., ergotamines, triptans, opioids, or a combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (i.e., medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients including withdrawal of the overused drugs and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.

Based on the mechanism of action of dihydroergotamine and findings from the published literature, TRUDHESA may cause preterm labor. Avoid use of TRUDHESA during pregnancy [see Use in Specific Populations (8.1) ].

The potential for fibrotic complications exists with TRUDHESA treatment. There have been reports of pleural and retroperitoneal fibrosis in patients following prolonged daily use of dihydroergotamine mesylate. Rarely, prolonged daily use of other ergot alkaloid drugs has been associated with cardiac valvular fibrosis. Rare cases have also been reported in association with the use of dihydroergotamine mesylate; however, in those cases, patients also received drugs known to be associated with cardiac valvular fibrosis.

Administration of TRUDHESA should not exceed the dosing guidelines and should not be used for chronic daily administration [see Dosage and Administration (2.1) ].

Local irritative symptoms were reported in 52% of patients treated with at least one dose of TRUDHESA in an open-labeled trial, which allowed repeated use of TRUDHESA over 6 to 12 months. The most common local irritative symptoms (at least 1% of patients) were nasopharyngitis (21%), rhinitis (19%), nasal discomfort (7%), product taste abnormal/dysgeusia (6%), sinusitis (5%), sinus discomfort (4%), olfactory test abnormal [defined based on a change in score at a prespecified threshold on the University of Pennsylvania Smell Identification Test (UPSIT)] (4%), epistaxis (3%), pharyngitis (3%), nasal mucosal disorder (2%), change in smell (1%), ear discomfort (1%), and rhinorrhea (1%). If a severe local irritation event occurs for no other attributable reasons, TRUDHESA should be temporarily suspended until the event resolves. If the event does not resolve, or it recurs with re-challenge, TRUDHESA should be discontinued permanently. Administration of TRUDHESA should not exceed the dosing guidelines and should not be used for chronic daily administration [see Dosage and Administration (2.1) ] .

Nasal tissue in animals treated with dihydroergotamine mesylate daily showed mild mucosal irritation characterized by mucous cell and transitional cell hyperplasia and squamous cell metaplasia. Changes in rat nasal mucosa at 64 weeks were less severe than at 13 weeks. Local effects on respiratory tissue after chronic intranasal dosing in animals have not been evaluated.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following adverse reactions have been identified during postapproval use of dihydroergotamine mesylate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Vasospasm, paresthesia, hypertension, dizziness, anxiety, dyspnea, headache, flushing, diarrhea, rash, increased sweating, and pleural and retroperitoneal fibrosis after long-term use of dihydroergotamine. Cases of myocardial infarction and stroke have been reported following the use of dihydroergotamine mesylate [see Warnings and Precautions (5.2) ] .

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 [see Warnings and Precautions (5.1) ] . The use of strong CYP3A4 inhibitors with dihydroergotamine is contraindicated [see Contraindications (4) ] . Administer moderate CYP3A4 inhibitors (e.g., saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, clotrimazole) with caution.

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 [see Contraindications (4) ] .

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

TRUDHESA is contraindicated for use with peripheral and central vasoconstrictors because the combination may cause synergistic elevation of blood pressure [see Warnings and Precautions (5.5) ] .

Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy [see Warnings and Precautions (5.1 , 5.5) ] .

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).

Dihydroergotamine binds with high affinity to 5-HT _1Dα and 5-HT _1Dβ receptors. The therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effects at 5-HT _1D receptors.

Significant elevation in blood pressure has been reported in patients with and without a history of hypertension [see Warnings and Precautions (5.5) ].

Dihydroergotamine possesses oxytocic properties [see Warnings and Precautions (5.7) ] .

TRUDHESA (dihydroergotamine mesylate) nasal spray (0.725 mg per spray) is supplied as a package of 4 single-dose units (NDC 77530-725-04). Each single-dose unit contains:

• One amber glass vial (NDC 77530-725-01) containing 4 mg dihydroergotamine mesylate in a 1 mL clear and colorless to faintly yellow solution. The stopper is not made with natural rubber latex.
• One nasal spray device.

Store TRUDHESA at controlled room temperature, 20°C to 25°C (68°F to 77°F), with excursions allowed between 15°C to 30°C (59°F to 86°F). Do not refrigerate or freeze.