1 ML dihydroergotamine mesylate 1 MG/ML Auto-Injector

INDICATIONS AND USAGE ATZUMI is indicated for the acute treatment of migraine with or without aura in adults. ATZUMI is an ergotamine derivative indicated for the acute treatment of migraine with or without aura in adults. ( 1 ) Limitations of Use ATZUMI is not indicated for the preventive treatment of migraine or for the management of hemiplegic migraine or migraine with brainstem aura. ( 1 ) Limitations of Use ATZUMI is not indicated for the preventive treatment of migraine. ATZUMI is not indicated for the management of hemiplegic migraine or migraine with brainstem aura.

DOSAGE AND ADMINISTRATION ATZUMI is for nasal administration only. ( 2.1 ) The recommended dose of ATZUMI is 5.2 mg, the contents of one nasal device, administered into one nostril. ( 2.1 ) To administer a dose, the white air pump of the ATZUMI device must be squeezed three separate times into one nostril. ( 2.1 ) The dose may be repeated, if needed, a minimum of 1 hour after the first dose. The maximum dose in a 24-hour period is 10.4 mg (two doses of ATZUMI 5.2 mg). ( 2.1 ) The safety of taking more than 4 doses within a 7-day period or 12 doses within a 30-day period has not been established. ( 2.1 ) Prior to initiation, a cardiovascular evaluation is recommended. ( 2.2 ) 2.1 Dosing Information ATZUMI is for nasal administration only. The recommended dose of ATZUMI is 5.2 mg (the contents of one nasal device) and is administered as a powdered medicine into one nostril [see Dosage and Administration (2.3) ]. The dose may be repeated, if needed, a minimum of 1 hour after the first dose. The maximum dose in a 24-hour period is 10.4 mg (two doses of ATZUMI 5.2 mg). The safety of taking more than 4 doses in a 7-day period or 12 doses within a 30-day period has not been established. 2.2 Assessment Prior to First Dose Prior to initiation of ATZUMI, 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 ATZUMI take place in the setting of an equipped healthcare facility. 2.3 Administration Instructions Priming is not required. To administer a dose of ATZUMI, remove the round blue tab from the blue nozzle, and insert the blue nozzle into one nostril. Squeeze the white air pump 3 separate times into 1 nostril while inhaling. Allow the white air pump to expand back to its original shape between squeezes [see Instructions for Use ]. Fast, complete, pulse-like squeezes are needed to deliver the complete dose. Do not squeeze slowly, partially or with any hesitation.

WARNINGS AND PRECAUTIONS Myocardial Ischemia and/or Infarction, Other Cardiac Adverse Reactions, and Fatalities: In patients with risk factors predictive of coronary artery disease, consider first dose administration under medical supervision with electrocardiogram. ( 5.2 ) Cerebrovascular Adverse Reactions and Fatalities: Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have been reported; discontinue ATZUMI if suspected. ( 5.3 ) Other Vasospasm Related Adverse Reactions: ATZUMI 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. Administration of ATZUMI 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 reason, suspend ATZUMI until resolution. ( 5.9 ) 5.1 Peripheral Ischemia Following Coadministration with Strong CYP3A4 Inhibitors 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 ATZUMI with strong CYP3A4 inhibitors is contraindicated [see Contraindications (4) and Drug Interactions (7.1) ] . 5.2 Myocardial Ischemia and/or Infarction, Other Cardiac Adverse Reactions, and Fatalities The potential for cardiac adverse reactions exists with ATZUMI treatment. Serious adverse cardiac events, including some that have been fatal, have occurred following use of dihydroergotamine. 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 ATZUMI, 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, ATZUMI 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 ATZUMI take place in the setting of an equipped healthcare facility, unless the patient has previously received dihydroergotamine. During the interval immediately following the first use of ATZUMI, an electrocardiogram is recommended in those patients with risk factors because ischemia can occur in the absence of clinical symptoms. 5.3 Cerebrovascular Adverse Reactions and Fatalities The potential for adverse cerebrovascular adverse reactions exists with ATZUMI treatment. Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with dihydroergotamine; and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the dihydroergotamine 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 ATZUMI if a cerebrovascular event is suspected. 5.4 Other Vasospasm Related Adverse Reactions ATZUMI, like other ergot alkaloids, may cause vasospastic reactions other than coronary artery vasospasm. Myocardial, peripheral vascular, and colonic ischemia have been reported with dihydroergotamine. Dihydroergotamine 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. ATZUMI 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 1 agonist, including ATZUMI, should be evaluated by a healthcare provider. 5.5 Increase in Blood Pressure Significant elevation in blood pressure has been reported on rare occasions in patients with and without a history of hypertension treated with dihydroergotamine. ATZUMI 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. 5.6 Medication Overuse Headache 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. 5.7 Preterm Labor Based on the mechanism of action of dihydroergotamine and findings from the published literature, ATZUMI may cause preterm labor. Avoid use of ATZUMI during pregnancy [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.2) ] . 5.8 Fibrotic Complications The potential for fibrotic complications exists with ATZUMI treatment. There have been reports of pleural and retroperitoneal fibrosis in patients following prolonged daily use of dihydroergotamine . 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; however, in those cases, patients also received drugs known to be associated with cardiac valvular fibrosis. Administration of ATZUMI should not exceed the dosing guidelines and should not be used for chronic daily administration [see Dosage and Administration (2.1) ] . 5.9 Local Irritation Local irritative symptoms were reported in 29% of patients treated with at least one dose of ATZUMI in an open-labeled trial, which allowed repeated use of ATZUMI up to 12 months. The common local irritative symptoms (at least 1% of patients) were nasal discomfort (11%), altered taste (8%), nasal congestion (5%), nasopharyngitis (5%), rhinorrhea (4%), cough (3%), nasal pain (3%), epistaxis (2%), sneezing (2%), nasal pruritus (1%), and increased lacrimation (1%). If a severe local irritation event occurs for no other attributable reasons, avoid further use of ATZUMI until the event resolves. Monitor patients for severe recurrent local irritation. 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 mucos

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.

CLINICAL PHARMACOLOGY Mechanism of Action Dihydroergotamine binds with high affinity to 5-HT 1Dα and 5-HT 1Dβ 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 arterio-venous 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. Pharmacokinetics Absorption Dihydroergotamine mesylate is poorly bioavailable following oral administration. Following intranasal administration, however, the mean bioavailability of dihydroergotamine mesylate is 32% relative to the injectable administration. Absorption is variable, probably reflecting both intersubject differences of absorption and the technique used for self-administration. Distribution Dihydroergotamine mesylate is 93% plasma protein bound. The apparent steady-state volume of distribution is approximately 800 liters. Metabolism Four dihydroergotamine mesylate metabolites have been identified in human plasma following oral administration. The major metabolite, 8'-β-hydroxydihydroergotamine, exhibits affinity equivalent to its parent for adrenergic and 5-HT receptors and demonstrates equivalent potency in several venoconstrictor activity models, in vivo and in vitro. The other metabolites, i.e., dihydrolysergic acid, dihydrolysergic amide and a metabolite formed by oxidative opening of the proline ring are of minor importance. Following nasal administration, total metabolites represent only 20%-30% of plasma AUC. The systemic clearance of dihydroergotamine mesylate following I.V. and I.M. administration is 1.5 L/min. Quantitative pharmacokinetic characterization of the four metabolites has not been performed. Excretion The major excretory route of dihydroergotamine is via the bile in the feces. After intranasal administration the urinary recovery of parent drug amounts to about 2% of the administered dose compared to 6% after I.M. administration. The total body clearance is 1.5 L/min which reflects mainly hepatic clearance. The renal clearance (0.1 L/min) is unaffected by the route of dihydroergotamine administration. The decline of plasma dihydroergotamine is biphasic with a terminal half-life of about 10 hours. Subpopulations No studies have been conducted on the effect of renal or hepatic impairment, gender, race, or ethnicity on dihydroergotamine pharmacokinetics. Dihydroergotamine mesylate nasal spray is contraindicated in patients with severely impaired hepatic or renal function. (See CONTRAINDICATIONS ) Interactions The pharmacokinetics of dihydroergotamine did not appear to be significantly affected by the concomitant use of a local vasoconstrictor (e.g., fenoxazoline). Multiple oral doses of the β-adrenoceptor antagonist propranolol, used for migraine prophylaxis, had no significant influence on the C max , T max or AUC of dihydroergotamine doses up to 4 mg. Pharmacokinetic interactions have been reported in patients treated orally with other ergot alkaloids (e.g., increased levels of ergotamine) and macrolide antibiotics, principally troleandomycin, presumably due to inhibition of cytochrome P450 3A metabolism of the alkaloids by troleandomycin. Dihydroergotamine has also been shown to be an inhibitor of cytochrome P450 3A catalyzed reactions and rare reports of ergotism have been obtained from patients treated with dihydroergotamine and macrolide antibiotics (e.g., troleandomycin, clarithromycin, erythromycin), and in patients treated with dihydroergotamine and protease inhibitors (e.g. ritonavir), presumably due to inhibition of cytochrome P450 3A metabolism of ergotamine (See CONTRAINDICATIONS ) . No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Clinical Trials 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 that included both pain response and restoration of function for "severe" or "incapacitating" pain, a less clear endpoint. 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 Tables 1 & 2 and Figures 1 & 2). Table 1: Studies 1 and 2: Percentage of Patients with Headache Response a 2 and 4 Hours Following a Single Treatment of Study Medication [Dihydroergotamine mesylate Nasal Spray or Placebo] N 2 hours 4 hours Study 1 DHE 105 61% ** 70%** Placebo 98 23% 28% Study 2 DHE 103 47% 56%* Placebo 102 33% 35% a Headache response was defined as a reduction in headache severity to mild or no pain. Headache response was based on pain intensity as interpreted by the patient using a four-point pain intensity scale. *p value < 0.01 **p value < 0.001 Table 2: Studies 3 and 4: Percentage of Patients with Headache Response a 2 and 4 Hours Following a Single Treatment of Study Medication [Dihydroergotamine mesylate Nasal Spray or Placebo] N 2 hours 4 hours Study 3 DHE 50 32% 48%* Placebo 50 20% 22% Study 4 DHE 47 30% 47% Placebo 50 20% 30% a Headache response was defined as a reduction in headache severity to mild or no pain. Headache response was evaluated on a five-point scale that included both pain response and restoration of function for "severe" or "incapacitating" pain. *p value < 0.01 Comparisons of drug performance based upon results obtained in different clinical trials are never reliable. Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study. The Kaplan-Meier plots below (Figures 1 & 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. *The figure shows the probability over time of obtaining a response following treatment with dihydroergotamine mesyl