These Highlights Do Not Include All The Information Needed To Use Trudhesa Safely And Effectively. See Full Prescribing Information For Trudhesa.

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.

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.

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)].

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

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 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.

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-dihydro-12'-hydroxy-2'-methyl-5'- (phenylmethyl)-, (5'α)-, monomethanesulfonate. Its molecular weight is 679.78, and its molecular formula is C₃₃H₃₇N₅O₅∙CH₄O₃S.

The chemical structure is:

The drug constituent is a dihydroergotamine mesylate solution. Each milliliter (mL) of solution contains dihydroergotamine mesylate 4.0 mg (equivalent to 3.43 mg dihydroergotamine), and the following inactive ingredients: caffeine (10.0 mg), carbon dioxide (q.s.), dextrose (50.0 mg), and water (q.s. to 1.0 mL).

TRUDHESA nasal spray, after assembly and priming, delivers 0.725 mg dihydroergotamine mesylate per spray. A total dose of 1.45 mg of dihydroergotamine mesylate is delivered in 2 sprays. The nasal spray device contains hydrofluoroalkane-134a (HFA) propellant.

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.

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.

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)].

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

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.

The efficacy of TRUDHESA is based on the relative bioavailability of TRUDHESA nasal spray compared to dihydroergotamine mesylate nasal spray in healthy subjects.

The clinical studies described below were conducted using dihydroergotamine mesylate nasal spray.

The efficacy of dihydroergotamine mesylate nasal spray for the acute treatment of migraine headaches was evaluated in four randomized, double-blind, placebo controlled studies in the U.S. The patient population for the trials was predominantly female (87%) and Caucasian (95%) with a mean age of 39 years (range 18 to 65 years). Patients treated a single moderate to severe migraine headache with a single dose of study medication and assessed pain severity over the 24 hours following treatment. Headache response was determined 0.5, 1, 2, 3 and 4 hours after dosing and was defined as a reduction in headache severity to mild or no pain. In studies 1 and 2, a four-point pain intensity scale was utilized; in studies 3 and 4, a five-point scale was used to record pain response. Although rescue medication was allowed in all four studies, patients were instructed not to use them during the four hour observation period. In studies 3 and 4, a total dose of 2 mg was compared to placebo. In studies 1 and 2, doses of 2 and 3 mg were evaluated, and showed no advantage of the higher dose for a single treatment. In all studies, patients received a regimen consisting of 0.5 mg in each nostril, repeated in 15 minutes (and again in another 15 minutes for the 3 mg dose in studies 1 and 2).

The percentage of patients achieving headache response 4 hours after treatment was significantly greater in patients receiving 2 mg doses of dihydroergotamine mesylate nasal spray compared to those receiving placebo in 3 of the 4 studies (see Table 2 and Table 3 and Figure 1 and Figure 2).

The Kaplan-Meier plots below (Figure 1 and Figure 2) provides an estimate of the probability that a patient will have responded to a single 2 mg dose of dihydroergotamine mesylate nasal spray as a function of the time elapsed since initiation of treatment.

For patients with migraine-associated nausea, photophobia, and phonophobia at baseline, there was a lower incidence of these symptoms at 2 and 4 hours following administration of dihydroergotamine mesylate nasal spray compared to placebo.

Patients were not allowed to use additional treatments for 8 hours prior to study medication dosing and during the 4-hour observation period following study treatment. Following the 4-hour observation period, patients were allowed to use additional treatments. For all studies, the estimated probability of patients using additional treatments for their migraines over the 24 hours following the single 2 mg dose of study treatment is summarized in Figure 3 below.

Neither age nor sex appear to affect the patient's response to dihydroergotamine mesylate nasal spray. The racial distribution of patients was insufficient to determine the effect of race on the efficacy of dihydroergotamine mesylate nasal spray.

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) [see Warnings and Precautions (5.1) and Drug Interactions (7.1)]
• 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 [see Warnings and Precautions (5.4)]
• with uncontrolled hypertension [see Warnings and Precautions (5.5)]
• 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-HT₁ agonists (e.g., sumatriptan) or ergotamine-containing or ergot-type medications [see Drug Interactions (7.2)]
• with concomitant use of peripheral and central vasoconstrictors because the combination may result in additive or synergistic elevation of blood pressure [see Warnings and Precautions (5.5)]

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Peripheral Ischemia Following Coadministration with Strong CYP3A4 Inhibitors [see Boxed Warning and Warnings and Precautions (5.1)]
• Myocardial Ischemia and/or Infarction, Other Adverse Cardiac Events, and Fatalities [see Warnings and Precautions (5.2)]
• Cerebrovascular Adverse Reactions and Fatalities [see Warnings and Precautions (5.3)]
• Other Vasospasm Related Adverse Reactions [see Warnings and Precautions (5.4)]
• Increase in Blood Pressure [see Warnings and Precautions (5.5)]
• Medication Overuse Headache [see Warnings and Precautions (5.6)]
• Preterm Labor [see Warnings and Precautions (5.7)]
• Fibrotic Complications [see Warnings and Precautions (5.8)]
• Local Irritation [see Warnings and Precautions (5.9)]

Beta Blockers/Nicotine: May potentiate/provoke vasoconstriction (7.3, 7.5)

Selective Serotonin Reuptake Inhibitors: Weakness, hyperreflexia, and incoordination may occur with coadministration. (7.6)

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.

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)].

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)].

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.

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.

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

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.

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

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.

• 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. (2.2, 5.2)
• Cerebrovascular Adverse Reactions and Fatalities: Cerebral hemorrhage, subarachnoid hemorrhage and stroke have been reported; discontinue TRUDHESA if suspected. (5.3)
• Other Vasospasm Related Adverse Reactions: TRUDHESA may cause vasospasm or elevation in blood pressure. Discontinue if signs or symptoms of vasoconstriction develop. (5.4, 5.5)
• Medication Overuse Headache: Detoxification may be necessary. (5.6)
• Preterm Labor: Advise pregnant women of the risk. (5.7, 8.1)
• 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. (5.8)
• Local Irritation: If severe local irritation occurs for no other attributable reasons, suspend TRUDHESA until resolution. (5.9)

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)].

• The recommended dose of TRUDHESA is 1.45 mg (administered as one metered spray of 0.725 mg into each nostril). (2.1)
• The dose may be repeated, if needed, a minimum of 1 hour after the first dose. Do not use more than 2 doses within a 24-hour period or 3 doses within 7 days. (2.1)
• Prior to initiation, a cardiovascular evaluation is recommended. (2.2)
• TRUDHESA is for nasal administration only. (2.3)
• Assemble and prime (i.e., pumped 4 times) before use. (2.3)
• Use TRUDHESA immediately after priming and then discard. (2.3)

TRUDHESA (dihydroergotamine mesylate) nasal spray is a single-dose, drug-device combination product containing a vial of dihydroergotamine mesylate with a clear and colorless to faintly yellow solution and an intranasal delivery device. Each spray delivers 0.725 mg of dihydroergotamine mesylate.

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)].

• Pregnancy: Based on animal data, may cause fetal harm (8.1)
• Lactation: Advise not to use during breastfeeding. (8.2)

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-HT₁ agonist in a study evaluating subjects undergoing cardiac catheterization.

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.

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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

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.

Weakness, hyperreflexia, and incoordination have been reported rarely when 5-HT₁ agonists have been coadministered with selective serotonin reuptake inhibitors (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline).

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.

Trudhesa™

(dihydroergotamine mesylate) nasal spray

0.725 mg per spray

Recommended Dosage: See Prescribing Information

Contains: 4 Nasal Spray Devices, 4 Trudhesa Vials,

Instructions for Use and Prescribing Information

NOT FOR INDIVIDUAL SALE

Contents are disposable; discard used nasal spray device

and vial after use. For nasal use only.

RX ONLY

622338

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.

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)].

Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of dihydroergotamine with strong CYP3A4 inhibitors. 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), Warnings and Precautions (5.1), 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.

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.

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.

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)].

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

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 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.

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-dihydro-12'-hydroxy-2'-methyl-5'- (phenylmethyl)-, (5'α)-, monomethanesulfonate. Its molecular weight is 679.78, and its molecular formula is C₃₃H₃₇N₅O₅∙CH₄O₃S.

The chemical structure is:

The drug constituent is a dihydroergotamine mesylate solution. Each milliliter (mL) of solution contains dihydroergotamine mesylate 4.0 mg (equivalent to 3.43 mg dihydroergotamine), and the following inactive ingredients: caffeine (10.0 mg), carbon dioxide (q.s.), dextrose (50.0 mg), and water (q.s. to 1.0 mL).

TRUDHESA nasal spray, after assembly and priming, delivers 0.725 mg dihydroergotamine mesylate per spray. A total dose of 1.45 mg of dihydroergotamine mesylate is delivered in 2 sprays. The nasal spray device contains hydrofluoroalkane-134a (HFA) propellant.

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.

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.

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)].

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

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.

The efficacy of TRUDHESA is based on the relative bioavailability of TRUDHESA nasal spray compared to dihydroergotamine mesylate nasal spray in healthy subjects.

The clinical studies described below were conducted using dihydroergotamine mesylate nasal spray.

The efficacy of dihydroergotamine mesylate nasal spray for the acute treatment of migraine headaches was evaluated in four randomized, double-blind, placebo controlled studies in the U.S. The patient population for the trials was predominantly female (87%) and Caucasian (95%) with a mean age of 39 years (range 18 to 65 years). Patients treated a single moderate to severe migraine headache with a single dose of study medication and assessed pain severity over the 24 hours following treatment. Headache response was determined 0.5, 1, 2, 3 and 4 hours after dosing and was defined as a reduction in headache severity to mild or no pain. In studies 1 and 2, a four-point pain intensity scale was utilized; in studies 3 and 4, a five-point scale was used to record pain response. Although rescue medication was allowed in all four studies, patients were instructed not to use them during the four hour observation period. In studies 3 and 4, a total dose of 2 mg was compared to placebo. In studies 1 and 2, doses of 2 and 3 mg were evaluated, and showed no advantage of the higher dose for a single treatment. In all studies, patients received a regimen consisting of 0.5 mg in each nostril, repeated in 15 minutes (and again in another 15 minutes for the 3 mg dose in studies 1 and 2).

The percentage of patients achieving headache response 4 hours after treatment was significantly greater in patients receiving 2 mg doses of dihydroergotamine mesylate nasal spray compared to those receiving placebo in 3 of the 4 studies (see Table 2 and Table 3 and Figure 1 and Figure 2).

The Kaplan-Meier plots below (Figure 1 and Figure 2) provides an estimate of the probability that a patient will have responded to a single 2 mg dose of dihydroergotamine mesylate nasal spray as a function of the time elapsed since initiation of treatment.

For patients with migraine-associated nausea, photophobia, and phonophobia at baseline, there was a lower incidence of these symptoms at 2 and 4 hours following administration of dihydroergotamine mesylate nasal spray compared to placebo.

Patients were not allowed to use additional treatments for 8 hours prior to study medication dosing and during the 4-hour observation period following study treatment. Following the 4-hour observation period, patients were allowed to use additional treatments. For all studies, the estimated probability of patients using additional treatments for their migraines over the 24 hours following the single 2 mg dose of study treatment is summarized in Figure 3 below.

Neither age nor sex appear to affect the patient's response to dihydroergotamine mesylate nasal spray. The racial distribution of patients was insufficient to determine the effect of race on the efficacy of dihydroergotamine mesylate nasal spray.

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) [see Warnings and Precautions (5.1) and Drug Interactions (7.1)]
• 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 [see Warnings and Precautions (5.4)]
• with uncontrolled hypertension [see Warnings and Precautions (5.5)]
• 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-HT₁ agonists (e.g., sumatriptan) or ergotamine-containing or ergot-type medications [see Drug Interactions (7.2)]
• with concomitant use of peripheral and central vasoconstrictors because the combination may result in additive or synergistic elevation of blood pressure [see Warnings and Precautions (5.5)]

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Peripheral Ischemia Following Coadministration with Strong CYP3A4 Inhibitors [see Boxed Warning and Warnings and Precautions (5.1)]
• Myocardial Ischemia and/or Infarction, Other Adverse Cardiac Events, and Fatalities [see Warnings and Precautions (5.2)]
• Cerebrovascular Adverse Reactions and Fatalities [see Warnings and Precautions (5.3)]
• Other Vasospasm Related Adverse Reactions [see Warnings and Precautions (5.4)]
• Increase in Blood Pressure [see Warnings and Precautions (5.5)]
• Medication Overuse Headache [see Warnings and Precautions (5.6)]
• Preterm Labor [see Warnings and Precautions (5.7)]
• Fibrotic Complications [see Warnings and Precautions (5.8)]
• Local Irritation [see Warnings and Precautions (5.9)]

Beta Blockers/Nicotine: May potentiate/provoke vasoconstriction (7.3, 7.5)

Selective Serotonin Reuptake Inhibitors: Weakness, hyperreflexia, and incoordination may occur with coadministration. (7.6)

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.

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)].

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)].

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.

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.

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

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.

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

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.

• 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. (2.2, 5.2)
• Cerebrovascular Adverse Reactions and Fatalities: Cerebral hemorrhage, subarachnoid hemorrhage and stroke have been reported; discontinue TRUDHESA if suspected. (5.3)
• Other Vasospasm Related Adverse Reactions: TRUDHESA may cause vasospasm or elevation in blood pressure. Discontinue if signs or symptoms of vasoconstriction develop. (5.4, 5.5)
• Medication Overuse Headache: Detoxification may be necessary. (5.6)
• Preterm Labor: Advise pregnant women of the risk. (5.7, 8.1)
• 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. (5.8)
• Local Irritation: If severe local irritation occurs for no other attributable reasons, suspend TRUDHESA until resolution. (5.9)

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)].

• The recommended dose of TRUDHESA is 1.45 mg (administered as one metered spray of 0.725 mg into each nostril). (2.1)
• The dose may be repeated, if needed, a minimum of 1 hour after the first dose. Do not use more than 2 doses within a 24-hour period or 3 doses within 7 days. (2.1)
• Prior to initiation, a cardiovascular evaluation is recommended. (2.2)
• TRUDHESA is for nasal administration only. (2.3)
• Assemble and prime (i.e., pumped 4 times) before use. (2.3)
• Use TRUDHESA immediately after priming and then discard. (2.3)

TRUDHESA (dihydroergotamine mesylate) nasal spray is a single-dose, drug-device combination product containing a vial of dihydroergotamine mesylate with a clear and colorless to faintly yellow solution and an intranasal delivery device. Each spray delivers 0.725 mg of dihydroergotamine mesylate.

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)].

• Pregnancy: Based on animal data, may cause fetal harm (8.1)
• Lactation: Advise not to use during breastfeeding. (8.2)

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-HT₁ agonist in a study evaluating subjects undergoing cardiac catheterization.

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.

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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

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.

Weakness, hyperreflexia, and incoordination have been reported rarely when 5-HT₁ agonists have been coadministered with selective serotonin reuptake inhibitors (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline).

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.

Trudhesa™

(dihydroergotamine mesylate) nasal spray

0.725 mg per spray

Recommended Dosage: See Prescribing Information

Contains: 4 Nasal Spray Devices, 4 Trudhesa Vials,

Instructions for Use and Prescribing Information

NOT FOR INDIVIDUAL SALE

Contents are disposable; discard used nasal spray device

and vial after use. For nasal use only.

RX ONLY

622338

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.

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)].

Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of dihydroergotamine with strong CYP3A4 inhibitors. 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), Warnings and Precautions (5.1), 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.