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.

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.

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-HT1 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-HT1 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 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.

6.1 Clinical Trials Experience

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 studies described below were conducted with dihydroergotamine mesylate nasal spray; adverse reactions with ATZUMI nasal powder are expected to be similar to adverse reactions with dihydroergotamine mesylate nasal spray.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of dihydroergotamine. 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 [see Warnings and Precautions (5.2)].

7.1 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, 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 ATZUMI is contraindicated [see Contraindications (4)]. Administer moderate CYP3A4 inhibitors with caution.

7.2 Triptans

Triptans (serotonin [5-HT] 1B/1D receptor agonists) have been reported to cause coronary artery vasospasm, and its effects could be additive with ATZUMI. Therefore, triptans and ATZUMI should not be taken within 24 hours of each other [see Contraindications (4)].

7.3 Beta Blockers

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

7.4 Vasoconstrictors

ATZUMI 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)].

7.5 Nicotine

Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy [see Warnings and Precautions (5.2, 5.4)].

7.6 Selective Serotonin Reuptake Inhibitors

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

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of ATZUMI have not been established in pediatric patients.

8.5 Geriatric Use

Clinical studies of ATZUMI and other dihydroergotamine 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.

9.1 Controlled Substance

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

9.2 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.

9.3 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.

10.1 Symptoms

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

10.2 Treatment

Treatment of an overdose of ATZUMI should consist of discontinuation of the drug, general supportive measures including monitoring of vital signs, and observation of the clinical status of the patient for at least 24 hours, or while symptoms or signs persist. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

12.1 Mechanism of Action

Dihydroergotamine binds with high affinity to 5-HT1Dα and 5-HT1Dβ receptors.

The therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effects at 5-HT1D receptors.

12.2 Pharmacodynamics

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

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

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16.1 How Supplied

ATZUMI (dihydroergotamine) nasal powder is supplied in a single-dose nasal device with white powder containing 5.2 mg of dihydroergotamine. ATZUMI is available in a carton of 8 nasal devices each individually packaged in a protective foil pouch (NDC 76978-101-08).

16.2 Storage and Handling

Store ATZUMI 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).

Store ATZUMI in its protective foil pouch until ready to use.

Serious and/or Life-Threatening Reactions with Coadministration of CYP3A4 Inhibitors

Inform patients that serious and/or life-threatening peripheral ischemia (cerebral ischemia and/or ischemia of the extremities) has been associated with the coadministration of dihydroergotamine and strong CYP3A4 inhibitors, such as macrolide antibiotics and protease inhibitors [see Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7.1)].

Myocardial Ischemia and/or Infarction, Other Cardiac Events, Cerebrovascular Events, and Fatalities

Inform patients of the risk for serious cardiac, cerebrovascular, and other vasospasm related events. Advise patients to notify their healthcare provider if they develop any risk factors or symptoms while taking ATZUMI. Inform patients that nicotine may provoke vasoconstriction predisposing to a greater ischemic response [see Warnings and Precautions (5.2, 5.3, 5.4)].

Increase in Blood Pressure

Inform patients of the risk for significant elevation in blood pressure [see Warnings and Precautions (5.5)].

Medication Overuse Headache

Inform patients that use of drugs to treat migraine attacks for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [see Warnings and Precautions (5.6)].

Local Irritation

Advise patients to notify their healthcare provider if they have bothersome local irritation [see Warning and Precautions (5.9)].

Drug Interactions

Advise patients to inform their healthcare providers if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions [see Drug Interactions (7)].

Pregnancy

Advise patients of the risk for preterm birth. Advise women to inform their healthcare provider if they are pregnant or intend to become pregnant [see Warnings and Precautions (5.7), Use in Specific Populations (8.1)].

Lactation

Advise patients not to breastfeed during treatment with ATZUMI [see Use In Specific Populations (8.2)].

Administration Instructions

Instruct patients not to squeeze ATZUMI before inserting it into the nostril because priming is not required. Inform patients that they will need to squeeze the air pump on the ATZUMI device three separate times into one nostril to give a dose. Instruct the patient to squeeze while inhaling, release to allow the air pump to expand back to its original shape, then repeat two more times [see Instructions for Use]. Tell patients to use fast, complete, pulse-like squeezes to deliver their dose. [see Dosage and Administration (2.3)].