Brekiya Drug Information

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. 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.

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.

Assessment

Prior to First Dose Prior to initiation of BREKIYA, a cardiovascular evaluation is recommended . 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.

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.

The following clinically significant adverse reactions are described elsewhere in the labeling: Peripheral Ischemia Following Coadministration with Strong CYP3A4 Inhibitors Myocardial Ischemia and/or Infarction, Other Cardiac Adverse Reactions, and Fatalities Cerebrovascular Adverse Reactions and Fatalities Other Vasospasm Related Adverse Reactions Increase in Blood Pressure Medication Overuse Headache Preterm Labor Fibrotic Complications Hypersensitivity 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. Fibrotic complications have been reported in association with long term use of injectable dihydroergotamine mesylate. 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. 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. 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

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. The use of strong CYP3A4 inhibitors with BREKIYA is contraindicated. Administer moderate CYP3A4 inhibitors with caution.

Triptans Triptans (serotonin. 7.3 Beta Blockers

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

Vasoconstrictors

BREKIYA is contraindicated for use with peripheral and central vasoconstrictors because the combination may cause synergistic elevation of blood pressure.

Nicotine Nicotine may provoke vasoconstriction in some patients, predisposing to a greater

ischemic response to ergot therapy .

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).

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 . 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.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

is contraindicated in patients: with concomitant use of strong CYP3A4 inhibitors 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 with uncontrolled hypertension 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 with recent use (i.e., within 24 hours) of other 5-HT 1 agonists, ergotamine-containing or ergot-type medications with concomitant use of peripheral and central vasoconstrictors because the combination may result in additive or synergistic elevation of blood pressure Concomitant use of strong CYP3A4 inhibitors Ischemic heart disease or coronary artery vasospasm Uncontrolled hypertension, peripheral arterial diseases, sepsis, following vascular surgery, or severe hepatic or renal impairment Concomitant use of other 5-HT 1 agonists or ergotamine-containing or ergot-type medications within 24 hours Hypersensitivity to dihydroergotamine, ergot alkaloids, latex, or any of the ingredients in BREKIYA Concomitant use with peripheral and central vasoconstrictors

Symptoms Excessive doses of dihydroergotamine may result in peripheral signs and symptoms of ergotism. In general, the symptoms of an acute BREKIYA overdose may be similar to those of an ergotamine overdose, although there may be less pronounced nausea and vomiting with BREKIYA. 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 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. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.