BREKIYA

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

2 DOSAGE AND ADMINISTRATION For subcutaneous injection only. ( 2.1 ) Recommended dosage is 1 mg administered subcutaneously as a single 1 mL autoinjector. ( 2.1 ) Do not exceed 3 mg (3 doses) in a 24-hour period. ( 2.1 ) Do not exceed 6 mg (6 doses) in a week. ( 2.1 ) Prior to initiation, a cardiovascular evaluation is recommended. ( 2.2 ) 2.1 Recommended Dosage BREKIYA autoinjector is for subcutaneous injection only. The recommended dose of BREKIYA is 1 mg administered subcutaneously via a single 1 mL autoinjector. The dose may be repeated, as needed, at 1-hour intervals to a total maximum of 3 mg (3 doses) in a 24-hour period. Do not exceed 6 mg (6 doses) total in a week. 2.2 Assessment Prior to First Dose Prior to initiation of BREKIYA, a cardiovascular evaluation is recommended [see Warnings and Precautions (5.3) ] . 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 BREKIYA take place in the setting of an equipped healthcare facility. 2.3 Important Administration Instructions See the “Instructions for Use” for detailed steps for administering the subcutaneous injection using the autoinjector. Preparation BREKIYA is a prefilled, single-dose disposable autoinjector intended to be given subcutaneously into the skin of the middle thigh. Rotate injection sites. Choose an injection site at least 2 inches away from the last injection site. Do not inject into moles, scars, birthmarks, or areas where the skin is tender, bruised, red, or hard. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Carefully examine the liquid medication for discoloration, cloudiness, floating flakes or particles. Administer only if clear and colorless. Administration Remove the red needle cap by pulling it straight off. Position the autoinjector straight onto the cleaned injection site with the white safety guard resting on the skin. Push the autoinjector down and press and release the gray activation button to start the injection. A “click” will sound when the injection starts. The autoinjector takes approximately 10 seconds to deliver the dose; when the viewing window is fully blocked (completely blue), the full dose has been administered.

4 CONTRAINDICATIONS BREKIYA is contraindicated in patients: with concomitant use of strong CYP3A4 inhibitors [see Warnings and Precautions (5.1) and Drug Interactions (7.1) ] with ischemic heart disease (e.g., 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 dihydroergotamine, ergot alkaloids, latex, or any of the ingredients in BREKIYA [see Warnings and Precautions (5.9) ] with recent use (i.e., within 24 hours) of other 5-HT 1 agonists, 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) ] Concomitant use of strong CYP3A4 inhibitors ( 4 ) Ischemic heart disease or coronary artery vasospasm ( 4 ) Uncontrolled hypertension, peripheral arterial diseases, sepsis, following vascular surgery, or severe hepatic or renal impairment ( 4 ) Concomitant use of other 5-HT 1 agonists or ergotamine-containing or ergot-type medications within 24 hours ( 4 ) Hypersensitivity to dihydroergotamine, ergot alkaloids, latex, or any of the ingredients in BREKIYA (4) Concomitant use with peripheral and central vasoconstrictors ( 4 )

5 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 an electrocardiogram. ( 5.2 ) Cerebrovascular Adverse Reactions and Fatalities: Cerebrovascular hemorrhage, subarachnoid hemorrhage, and stroke have been reported; discontinue BREKIYA if suspected. ( 5.3 ) Other Vasospasm Related Adverse Reactions: BREKIYA 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. Do not exceed the BREKIYA dosing guidelines or use for chronic daily administration. ( 5.8 ) 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 and strong CYP3A4 inhibitors. Because CYP3A4 inhibition elevates the serum levels of dihydroergotamine, the risk for vasospasm leading to cerebral ischemia and/or and ischemia of the extremities is increased. Hence, concomitant use of BREKIYA 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 BREKIYA 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 BREKIYA, 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, BREKIYA 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 BREKIYA 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 BREKIYA, 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 events exists with BREKIYA 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 BREKIYA if a cerebrovascular event is suspected. 5.4 Other Vasospasm Related Adverse Reactions BREKIYA, 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 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. BREKIYA 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 BREKIYA, 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 mesylate. BREKIYA 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, BREKIYA may cause preterm labor. Avoid use of BREKIYA 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 BREKIYA 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 BREKIYA should not exceed the dosing guidelines and should not be used for chronic daily administration [see Dosage and Administration (2.1) ]. 5.9 Hypersensitivity The rigid needle shield of the BREKIYA autoinjector contains a needle cover (located inside the cap) that contains dry natural rubber, which is made from latex. BREKIYA is contraindicated in patients who have previously shown hypersensitivity to ergot alkaloids or latex.

7 DRUG INTERACTIONS 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 ) 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 BREKIYA 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 effect could be additive with BREKIYA. Therefore, triptans and BREKIYA 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 BREKIYA 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 (5.4) ] . 7.6 Selective Serotonin Reuptake Inhibitors Weakness, hyperreflexia, and incoordination have been reported rarely when 5-HT 1 agonists have been co-administered with selective serotonin reuptake inhibitors (SSRI’s) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline).

6 ADVERSE REACTIONS 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 Cardiac Adverse Reactions, 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) ] Hypersensitivity [see Warnings and Precautions (5.9) ] The following adverse reactions associated with the use of dihydroergotamine were identified in clinical studies or postmarketing reports. 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 the drug exposure. Serious cardiac events, including some that have been fatal, have occurred following use of dihydroergotamine. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation [see Contraindications (4) and Warnings and Precautions (5.2) ]. Fibrotic complications have been reported in association with long term use of injectable dihydroergotamine mesylate [see Warnings and Precautions (5.8) ]. Vasospasm, paresthesia, hypertension, dizziness, anxiety, dyspnea, headache, flushing, diarrhea, rash, increased sweating, and pleural and retroperitoneal fibrosis occurred 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 , 5.3 )]. Serious cardiac events (including fatal) that have been reported with dihydroergotamine mesylate injection use include coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, ventricular fibrillation. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

8.1 Pregnancy Risk Summary Available data from published literature indicate an increased risk of preterm delivery with dihydroergotamine, the active moiety in BREKIYA, use during pregnancy. Avoid use of BREKIYA during pregnancy [see Warnings and Precautions (5.7) ] . Data collected over decades have shown no increased risk of major birth defects or miscarriage with the use of dihydroergotamine mesylate during pregnancy . In animal reproduction studies, adverse effects on development were observed following administration of dihydroergotamine mesylate during pregnancy (decreased fetal body weight and/or skeletal ossification) in rats and rabbits or during pregnancy and lactation in rats (decreased body weight and impaired reproductive function in the offspring) at doses that were not associated with maternal toxicity (see Data). The estimated rate of major birth defects (2.2% to 2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy. Data Animal Data Intranasal administration of dihydroergotamine mesylate to pregnant rats throughout the period of organogenesis resulted in decreased fetal body weight and/or skeletal ossification at doses of 0.16 mg/day or greater. A no-effect level for adverse effects on embryofetal toxicity was not identified in rats. Intranasal administration of dihydroergotamine mesylate to pregnant rabbits throughout organogenesis resulted in decreased skeletal ossification at 3.6 mg/day. The no-effect dose for adverse effects on embryofetal toxicity in rabbits was 1.2 mg/day. Intranasal administration of dihydroergotamine mesylate to female rats throughout pregnancy and lactation resulted in decreased body weight and impaired reproductive function (decreased mating indices) in the offspring at doses of 0.16 mg/day or greater. A no-effect dose for adverse developmental effects in rats was not established. Effects on offspring development occurred at doses below those that produced evidence of maternal toxicity in these studies. Dihydroergotamine-induced intrauterine growth retardation has been attributed to reduced uteroplacental blood flow resulting from prolonged vasoconstriction of the uterine vessels and/or increased myometrial tone.