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.

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-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, 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.

7.1 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 (5.2, 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 (SSRI’s) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline). 

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 (5.9)]. 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.

8.2 Lactation

Risk Summary

There are no data on the presence of dihydroergotamine in human milk; however, ergotamine, a related drug, is excreted in human milk. There are reports of vomiting, diarrhea, weak pulse, and unstable blood pressure in breastfed infants exposed to ergotamine. BREKIYA may reduce milk supply because it may decrease prolactin levels.

Because of the potential for reduced milk supply and serious adverse events in the breastfed infant, including diarrhea, vomiting, weak pulse, and unstable blood pressure; advise patients not to breastfeed during treatment with BREKIYA and for 3 days after the last dose. Breast milk supply during this time should be pumped and discarded.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of 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

BREKIYA 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.

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

Absorption

Following BREKIYA administration, the mean maximum plasma concentration was 3.8 ng/mL, and the median time from dosing to maximum plasma concentration was approximately 0.4 hours.

Distribution

Dihydroergotamine mesylate is 93% plasma protein bound. The apparent steady-state volume of distribution is approximately 800 liters.

Elimination

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% to 30% of plasma AUC. 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. The total body clearance is 1.5 L/min which reflects mainly hepatic clearance. Only 6% to 7% of unchanged dihydroergotamine is excreted in the urine after intramuscular injection. The renal clearance (0.1 L/min) is unaffected by the route of dihydroergotamine administration. The decline of plasma dihydroergotamine after intramuscular or intravenous administration is multi-exponential with a terminal half-life of about 9 hours.

Specific Populations

No studies have been conducted on the effect of renal or hepatic impairment, gender, race, or ethnicity on dihydroergotamine pharmacokinetics [see Contraindications (4)].

Drug Interaction Studies

Pharmacokinetic interactions have been reported in patients treated orally with other ergot alkaloids (e.g., increased levels of ergotamine) and macrolide antibiotics, presumably due to inhibition of cytochrome P450 3A metabolism of the alkaloids. 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., 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 (4)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 2-year mouse carcinogenicity study, subcutaneous (SC) administration of dihydroergotamine mesylate (0, 0.5, 1.5 or 5 mg/kg/day) resulted in an increased incidence of fibrosarcoma at the injection sites in males and females at the high dose. The higher dose not associated with an increase in tumors (1.5 mg/kg/day) is approximately 2 times the recommended human dose (RHD) of 3 mg/day SC on a body surface area (mg/m2) basis.

In a 2-year rat carcinogenicity study, intranasal administration of dihydroergotamine mesylate (0, 0.4, 0.8 or 1.6 mg/day for 13 weeks, followed by 0, 0.08, 0.24 or 0.8 mg/day for the remainder of the study) did not result in an increase in tumors.

Mutagenesis

Dihydroergotamine mesylate was negative in an in vitro mutagenicity (Ames) assay and positive in in vitro chromosomal aberration (V79 Chinese hamster cell assay with metabolic activation, and human peripheral blood lymphocyte) assays. Dihydroergotamine was negative in in vivo micronucleus assays in mouse and hamster.

Impairment of Fertility

Intranasal administration of dihydroergotamine to rats at doses up to 1.6 mg/day was not associated with adverse effects on fertility.

16.1 How Supplied

BREKIYA (dihydroergotamine mesylate) injection is a clear, colorless, sterile solution of 1 mg/mL dihydroergotamine mesylate available as:

Caution: 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 [see Contraindications (4) and Warnings and Precautions (5.9)].

16.2 Storage and Handling

Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Do not refrigerate or freeze. Protect from light. Retain in original pack until time of use.

NDC 64896-509-01

BREKIYA® (dihydroergotamine mesylate) injection, 1 mg/mL

Rx only

Autoinjector Label

Amneal Pharmaceuticals LLC

NDC 64896-509-01

BREKIYA® (dihydroergotamine mesylate) injection, 1 mg/mL

Rx only

Pouch

Amneal Pharmaceuticals LLC

NDC 64896-509-02

BREKIYA® (dihydroergotamine mesylate) injection, 1 mg/mL

Rx only

Carton

Amneal Pharmaceuticals LLC