DailyMed Label: Migranal

DailyMed Label: Migranal

2022

DailyMed Prescription

Migranal

dihydroergotamine mesylate

Bausch Health US, LLC

NDC: 0187-0245

NDC: 0187-0245

NDC: 0187-0245

MIGRANAL is ergotamine hydrogenated in the 9,10 position as the mesylate salt. MIGRANAL is known chemically as ergotaman-3’, 6’, 18-trione, 9,10-dihydro-12’-hydroxy-2’-methyl-5’- (phenylmethyl)-, (5’α)-, monomethane-sulfonate. Its molecular weight is 679.78 and its empirical formula is C 33 H 37 N 5 O 5 •CH 4 O 3 S. The chemical structure is: MIGRANAL (dihydroergotamine mesylate) Nasal Spray is provided for intranasal administration as a clear, colorless to light yellow aqueous solution in an amber glass vial containing:   dihydroergotamine mesylate ………4 mg   caffeine, anhydrous ……..10 mg   dextrose, anhydrous ……..50 mg   carbon dioxide ………….qs   purified water.. ……..qs 1 mL Each milliliter contains   Dihydroergotamine mesylate …………4 mg (equivalent to 3.43 mg dihydroergotamine) chemical structure

MIGRANAL (dihydroergotamine mesylate) Nasal Spray is indicated for the acute treatment of migraine headaches with or without aura. MIGRANAL (dihydroergotamine mesylate) Nasal Spray is not intended for the prophylactic therapy of migraine or for the management of hemiplegic or basilar migraine.

The solution used in MIGRANAL (dihydroergotamine mesylate) Nasal Spray (4 mg/mL) is intended for intranasal use and must not be injected. In clinical trials, MIGRANAL (dihydroergotamine mesylate) Nasal Spray has been effective for the acute treatment of migraine headaches with or without aura. One spray (0.5 mg) of MIGRANAL (dihydroergotamine mesylate) Nasal Spray should be administered in each nostril. Fifteen minutes later, an additional one spray (0.5 mg) of MIGRANAL (dihydroergotamine mesylate) Nasal Spray should be administered in each nostril, for a total dosage of four sprays (2 mg) of MIGRANAL (dihydroergotamine mesylate) Nasal Spray. Studies have shown no additional benefit from acute doses greater than 2 mg for a single migraine administration. The safety of doses greater than 3 mg in a 24-hour period and 4 mg in a 7-day period has not been established. MIGRANAL (dihydroergotamine mesylate) Nasal Spray, should not be used for chronic daily administration. Prior to administration, the pump must be primed (i.e., squeeze 4 times) before use (see administration instructions). Once the nasal spray applicator has been prepared, it should be discarded (with any remaining drug in opened vial) after 8 hours. Prior to administration, the pump must be primed (i.e., squeeze 4 times) before use (see administration instructions). Once the nasal spray applicator has been prepared, it should be discarded (with any remaining drug in opened vial after 8 hours).

There have been a few reports of serious adverse events associated with the coadministration of dihydroergotamine and potent CYP 3A4 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 CYP 3A4 inhibitors (ritonavir, nelfinavir, indinavir, erythromycin, clarithromycin, troleandomycin, ketoconazole, itraconazole) with dihydroergotamine is, therefore contraindicated ( see WARNINGS, CYP 3A4 Inhibitors ). MIGRANAL (dihydroergotamine mesylate) Nasal Spray should not be given to patients with ischemic heart disease (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 MIGRANAL (dihydroergotamine mesylate) Nasal Spray may increase blood pressure, it should not be given to patients with uncontrolled hypertension. MIGRANAL (dihydroergotamine mesylate) Nasal Spray, 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. MIGRANAL (dihydroergotamine mesylate) Nasal Spray should not be administered to patients with hemiplegic or basilar migraine. In addition to those conditions mentioned above, MIGRANAL (dihydroergotamine mesylate) Nasal Spray is also contraindicated in patients with known peripheral arterial disease, sepsis, following vascular surgery, and severely impaired hepatic or renal function. MIGRANAL (dihydroergotamine mesylate) Nasal Spray 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.

MIGRANAL (dihydroergotamine mesylate) Nasal Spray may cause coronary artery vasospasm; patients who experience signs or symptoms suggestive of angina following its administration should, therefore, be evaluated for the presence of CAD or a predisposition to variant angina before receiving additional doses. Similarly, 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 are candidates for further evaluation ( see WARNINGS ). see WARNINGS, Fibrotic Complications The text of a patient information sheet is printed at the end of this insert. To assure safe and effective use of MIGRANAL (dihydroergotamine mesylate) Nasal Spray, the information and instructions provided in the patient information sheet should be discussed with patients. Once the nasal spray applicator has been prepared, it should be discarded (with any remaining drug) after 8 hours. Patients should be advised to report to the physician immediately any of the following: numbness or tingling in the fingers and toes, muscle pain in the arms and legs, weakness in the legs, pain in the chest, temporary speeding or slowing of the heart rate, swelling, or itching. Prior to the initial use of the product by a patient, the prescriber should take steps to ensure that the patient understands how to use the product as provided (see Patient Information Sheet and product packaging). Administration of MIGRANAL (dihydroergotamine mesylate) Nasal Spray, should not exceed the dosing guidelines and should not be used for chronic daily administration ( see DOSAGE AND ADMINISTRATION ). MIGRANAL (dihydroergotamine mesylate) Nasal Spray should not be used with peripheral vasoconstrictors because the combination may cause synergistic elevation of blood pressure. Sumatriptan has been reported to cause coronary artery vasospasm, and its effect could be additive with MIGRANAL (dihydroergotamine mesylate) Nasal Spray. Sumatriptan and MIGRANAL (dihydroergotamine mesylate) Nasal Spray should not be taken within 24 hours of each other ( see CONTRAINDICATIONS ) . Although the results of a clinical study did not indicate a safety problem associated with the administration of MIGRANAL (dihydroergotamine mesylate) Nasal Spray to subjects already receiving propranolol, there have been reports that propranolol may potentiate the vasoconstrictive action of ergotamine by blocking the vasodilating property of epinephrine. Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy. See CONTRAINDICATIONS and WARNINGS. Weakness, hyperreflexia, and incoordination have been reported rarely when 5HT 1 agonists have been coadministered with SSRI’s (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline). There have been no reported cases from spontaneous reports of drug interaction between SSRI’s and MIGRANAL (dihydroergotamine mesylate) Nasal Spray or D.H.E. 45. The effect of oral contraceptives on the pharmacokinetics of MIGRANAL (dihydroergotamine mesylate) Nasal Spray has not been studied. In a 2-year mouse carcinogenicity study, subcutaneous 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. 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. Dihydroergotamine mesylate was clastogenic in two in vitro chromosomal aberration assays, the V79 Chinese hamster cell assay with metabolic activation and the cultured human peripheral blood lymphocyte assay. There was no evidence of mutagenic potential when dihydroergotamine mesylate was tested in the presence or absence of metabolic activation in two gene mutation assays (the Ames test and the in vitro mammalian Chinese hamster V79/HGPRT assay) and in an assay for DNA damage (the rat hepatocyte unscheduled DNA synthesis test). Dihydroergotamine was not clastogenic in the in vivo mouse and hamster micronucleus tests. Intranasal administration of dihydroergotamine to rats at doses up to 1.6 mg/day was not associated with adverse effects on fertility. Risk Summary Available data from published literature indicate an increased risk of preterm delivery with MIGRANAL use during pregnancy. Avoid use of MIGRANAL during pregnancy ( see WARNINGS ). 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 intranasal 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. 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 and greater. A no-effect level for adverse effects on embryofetal development 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 development 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 effects on pre- and postnatal development 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. There are no data on the presence of dihydroergotamine in human milk; however, ergotamine, a related drug, is present in human milk. There are reports of diarrhea, vomiting, weak pulse, and unstable blood pressure in breastfed infants exposed to ergotamine. MIGRANAL 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 MIGRANAL and for 3 days after the last dose. Breast milk supply during this time should be pumped and discarded. Safety and effectiveness in pediatric patients have not been established. There is no information about the safety and effectiveness of MIGRANAL (dihydroergotamine mesylate) Nasal Spray in this population because patients over age 65 were excluded from the controlled clinical trials.

MIGRANAL (dihydroergotamine mesylate) Nasal Spray should not be used with peripheral vasoconstrictors because the combination may cause synergistic elevation of blood pressure. Sumatriptan has been reported to cause coronary artery vasospasm, and its effect could be additive with MIGRANAL (dihydroergotamine mesylate) Nasal Spray. Sumatriptan and MIGRANAL (dihydroergotamine mesylate) Nasal Spray should not be taken within 24 hours of each other ( see CONTRAINDICATIONS ) . Although the results of a clinical study did not indicate a safety problem associated with the administration of MIGRANAL (dihydroergotamine mesylate) Nasal Spray to subjects already receiving propranolol, there have been reports that propranolol may potentiate the vasoconstrictive action of ergotamine by blocking the vasodilating property of epinephrine. Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy. See CONTRAINDICATIONS and WARNINGS. Weakness, hyperreflexia, and incoordination have been reported rarely when 5HT 1 agonists have been coadministered with SSRI’s (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline). There have been no reported cases from spontaneous reports of drug interaction between SSRI’s and MIGRANAL (dihydroergotamine mesylate) Nasal Spray or D.H.E. 45. The effect of oral contraceptives on the pharmacokinetics of MIGRANAL (dihydroergotamine mesylate) Nasal Spray has not been studied.

MIGRANAL (dihydroergotamine mesylate) Nasal Spray is available (as a clear, colorless to light yellow aqueous solution) in 3.5 mL amber glass vials containing 4 mg of dihydroergotamine mesylate. MIGRANAL (dihydroergotamine mesylate) Nasal Spray is provided as a package of 8 units, administration instruction sheet, and one package insert. Each unit consists of one vial and one sprayer (NDC 0187-0245-03). Store below 25°C (77°F). Do not refrigerate or freeze. * Trademark of PDR Network, LLC Distributed by: Bausch Health US, LLC Bridgewater, NJ 08807 USA Manufactured by: Mipharm, S.p.A. Milano, Italy www.migranal.com MIGRANAL is a trademark of Bausch Health Companies Inc. or its affiliates. All other product/brand names and/or logos are trademarks of the respective owners. © 2022 Bausch Health Companies Inc. or its affiliates Rev. 09/2022 9603503

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. 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. Dihydroergotamine mesylate is 93% plasma protein bound. The apparent steady-state volume of distribution is approximately 800 liters. 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. 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. No studies have been conducted on the effect of renal or hepatic impairment, gender, race, or ethnicity on dihydroergotamine pharmacokinetics. MIGRANAL (dihydroergotamine mesylate) Nasal Spray is contraindicated in patients with severely impaired hepatic or renal function ( see CONTRAINDICATIONS ). 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 Cmax, Tmax 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.

The efficacy of MIGRANAL (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 MIGRANAL (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 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. 2 and 4 Hours Following a Single Treatment of Study Medication [MIGRANAL (Dihydroergotamine Mesylate) Nasal Spray or Placebo] N 2 hours 4 hours Study 1 MIGRANAL 105 61% p value < 0.001 70% Placebo 98 23% 28% Study 2 MIGRANAL 103 47% 56% p value < 0.01 Placebo 102 33% 35% Table 2: Studies 3 and 4: Percentage of Patients with Headache Response 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. 2 and 4 Hours Following a Single Treatment of Study Medication [MIGRANAL (Dihydroergotamine Mesylate) Nasal Spray or Placebo] N 2 hours 4 hours Study 3 MIGRANAL 50 32% 48% p value < 0.01 Placebo 50 20% 22% Study 4 MIGRANAL 47 30% 47% Placebo 50 20% 30% 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 MIGRANAL (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 MIGRANAL (dihydroergotamine mesylate) Nasal Spray. Headache response was based on pain intensity as interpreted by the patient using a four-point pain intensity scale. Patients not achieving response within 4 hours were censored to 4 hours. *The figure shows the probability over time of obtaining a response following treatment with MIGRANAL (dihydroergotamine mesylate) Nasal Spray. Headache response was evaluated on a five-point scale that confounded pain response and restoration of function for "severe" or "incapacitating" pain. Patients not achieving response within 4 hours were censored to 4 hours. For patients with migraine-associated nausea, photophobia, and phonophobia at baseline, there was a lower incidence of these symptoms at 2 and 4 hours following administration of MIGRANAL (dihydroergotamine mesylate) Nasal Spray compared to placebo. Patients were not allowed to use additional treatments for eight hours prior to study medication dosing and during the four-hour observation period following study treatment. Following the 4-hour observation period, patients were allowed to use additional treatments. For all studies, the estimated probability of patients using additional treatments for their migraines over the 24 hours following the single 2 mg dose of study treatment is summarized in Figure 3 below.   *Kaplan-Meier plot based on data obtained from all studies with patients not using additional treatments censored to 24 hours. All patients received a single treatment of study medication for their migraine attack. The plot also includes patients who had no response to the initial dose. Neither age nor sex appear to affect the patient’s response to MIGRANAL (dihydroergotamine mesylate) Nasal Spray. While patients with menstrual migraine, migraine with aura, and migraine without aura by medical history were included in the clinical evaluation of MIGRANAL (dihydroergotamine mesylate) Nasal Spray, patients were not required to report the specific type of migraine treated with study medication. Thus, neither the effect of menses on migraine nor the presence or the absence of aura were assessed. The racial distribution of patients was insufficient to determine the effect of race on the efficacy of MIGRANAL (dihydroergotamine mesylate) Nasal Spray. figure1.jpg figure2.jpg figure3.jpg

Information for the Patient MIGRANAL ® (dihydroergotamine mesylate) Nasal Spray. The solution used in MIGRANAL (dihydroergotamine mesylate) Nasal Spray (4 mg/mL) is intended for intranasal use and must not be injected. Please read this information carefully before using your MIGRANAL (dihydroergotamine mesylate) Nasal Spray for the first time. Keep this information handy for future reference. This leaflet does not contain all of the information on MIGRANAL (dihydroergotamine mesylate) Nasal Spray. Your pharmacist and/or health care provider can provide more detailed information. MIGRANAL (dihydroergotamine mesylate) Nasal Spray has been evaluated in a limited number of patients long term (e.g., 1 year or longer). Purpose of your Medication MIGRANAL (dihydroergotamine mesylate) Nasal Spray is intended to treat an active migraine headache. Do not try to use it to prevent a headache if you have no symptoms. Do not use it to treat common tension headache or a headache that is not at all typical of your usual migraine headache. Administration of MIGRANAL (dihydroergotamine mesylate) Nasal Spray, should not exceed the dosing guidelines and should not be used for chronic daily administration. There have been reports of fibrosis (stiffening) in the lung or kidney areas in patients following prolonged daily use of injectable dihydroergotamine mesylate. Rarely, prolonged daily use of other ergot alkaloid drugs (the class of drugs to which MIGRANAL (dihydroergotamine mesylate) Nasal Spray belongs) has been associated with heart valvular fibrosis. Rare cases have also been reported in association with the use of injectable dihydroergotamine mesylate; however, in those cases, patients also received drugs known to be associated with heart valvular fibrosis. Do not use MIGRANAL (dihydroergotamine mesylate) Nasal Spray if you: • have any disease affecting your heart, arteries, or circulation. • are taking certain anti-HIV medications (protease inhibitors). • are taking a macrolide antibiotic such as troleandomycin, clarithromycin or erythromycin. Important questions to consider before using MIGRANAL (dihydroergotamine mesylate) Nasal Spray Please answer the following questions before you use your MIGRANAL (dihydroergotamine mesylate) Nasal Spray. If you answer YES to any of these questions or are unsure of the answer, you should talk to your doctor before using MIGRANAL (dihydroergotamine mesylate) Nasal Spray. • Do you have high blood pressure? • Do you have chest pain, shortness of breath, heart disease, or have you had any surgery on your heart arteries? • Do you have risk factors for heart disease (such as high blood pressure, high cholesterol, obesity, diabetes, smoking, strong family history of heart disease, or are you postmenopausal or a male over 40)? • Do you have any problems with blood circulation in your arms or legs, fingers, or toes? • Are you pregnant? Do you think you might be pregnant? Are you trying to become pregnant? Are you sexually active and not using birth control? o MIGRANAL may cause preterm labor. MIGRANAL should be avoided during pregnancy. Talk to your healthcare provider right away if you are pregnant or want to become pregnant. • Are you breastfeeding? o MIGRANAL may reduce breast milk supply and pass into your breast milk. MIGRANAL may be harmful to your baby. Do not breastfeed your baby while taking MIGRANAL and for 3 days after you use MIGRANAL. Talk with your healthcare provider about the best way to feed your baby if you take MIGRANAL. • Have you ever had to stop taking this or any other medication because of an allergy or bad reaction? • Are you taking any other migraine medications, erythromycin or other antibiotics, or medications for blood pressure prescribed by your doctor, or other medicines obtained from your drugstore without a doctor’s prescription? • Do you smoke? • Have you had, or do you have, any disease of the liver or kidney? • Is this headache different from your usual migraine attacks? • Are you using MIGRANAL (dihydroergotamine mesylate) Nasal Spray or other dihydroergotamine mesylate containing drugs on a daily basis? • Are you taking a protease inhibitor for HIV therapy? • Are you taking a macrolide class of antibiotic? Serious or potentially life-threatening reductions in blood flow to the brain or extremities have been reported rarely due to interactions between MIGRANAL (dihydroergotamine mesylate) Nasal Spray and protease inhibitors or macrolide antibiotics. REMEMBER TO TELL YOUR DOCTOR IF YOU HAVE ANSWERED YES TO ANY OF THESE QUESTIONS BEFORE YOU USE MIGRANAL (dihydroergotamine mesylate) NASAL SPRAY. Side Effects To Watch Out For In clinical trials, most migraine patients have used MIGRANAL (dihydroergotamine mesylate) Nasal Spray without serious side effects. You may experience some nasal congestion or irritation, altered sense of taste, sore throat, nausea, vomiting, dizziness, and fatigue after using MIGRANAL (dihydroergotamine mesylate) Nasal Spray. These side effects are temporary and usually do not require you to stop using MIGRANAL (dihydroergotamine mesylate) Nasal Spray. Although the following reactions rarely occur, they can be serious and should be reported to your physician immediately: • Numbness or tingling in your fingers and toes • Pain, tightness, or discomfort in your chest • Muscle pain or cramps in your arms and legs • Weakness in your legs • Temporary speeding or slowing of your heart rate • Swelling or itching Dosing Information • Each vial contains one complete dose of MIGRANAL (dihydroergotamine mesylate) Nasal Spray, which is 1 spray in each nostril followed in 15 minutes by an additional spray in each nostril, for a total of 4 sprays. • Studies have shown no benefit from acute doses greater than 2 mg (4 sprays) for a single administration. The safety of doses greater than 3 mg in a 24 hour period has not been established. • The safety of doses greater than 4 mg in a 7-day period has not been established. • MIGRANAL (dihydroergotamine mesylate) Nasal Spray, should not be used for chronic daily administration. Learn what to do in case of an Overdose If you have used more medication than you have been instructed, contact your doctor, hospital emergency department, or nearest poison control center immediately. How to use the MIGRANAL (dihydroergotamine mesylate) Nasal Spray 1. Use available training materials. • Read and follow the instructions in the administration instructions which are provided with the MIGRANAL (dihydroergotamine mesylate) Nasal Spray package before attempting to use the product. • If there are any questions concerning the use of your MIGRANAL (dihydroergotamine mesylate) Nasal Spray, ask your doctor or pharmacist, or contact Bausch Health US, LLC at 1-800-321-4576. 2. Check the contents of the package: • 8 Nasal Spray Vials • 8 Nasal Sprayers • Administration Instructions • Package Insert 3. Assemble the sprayer: Assemble your nasal sprayer only when you are ready to use it. • Lift tab to bend back blue cover. In one piece, completely remove the blue cover and metal seal in a circular motion. Keeping the vial upright, remove rubber stopper. Set vial aside. • Remove plastic cover from the bottom of pump unit. Insert spray pump into vial and turn clockwise until securely fastened. 4. Using the sprayer: • Remove cap from spray unit. Holding the vial upright, point nasal sprayer away from face and pump 4 times before using. DO NOT PUMP MORE THAN 4 TIMES. (Although some medication will spray out, there is enough medication in each vial to allow you to prepare your nasal spray pump properly and still receive a full treatment of MIGRANAL.) • Spray once into each nostril. Do not tilt head back or sniff through your nose while spraying or immediately after. Wait 15 minutes. Spray once again into each nostril. 5. After completing these instructions: • Carefully dispose of the nasal spray pump with the vial. Important Notes: • Once a MIGRANAL (dihydroergotamine mesylate) Nasal Spray vial has been opened, it must be thrown away after 8 hours. Storing MIGRANAL (dihydroergotamine mesylate) Nasal Spray • Keep medication in a safe place away from children • Keep MIGRANAL (dihydroergotamine mesylate) Nasal Spray away from heat and light. • Do not expose MIGRANAL (dihydroergotamine mesylate) Nasal Spray to temperatures over 77°F. • Never refrigerate or freeze MIGRANAL (dihydroergotamine mesylate) Nasal Spray. • Do not keep an opened MIGRANAL (dihydroergotamine mesylate) Nasal Spray vial for more than 8 hours.   Check the expiration date printed on the vial containing medication. If the expiration date has passed, do not use it. Answers to patients’ questions about MIGRANAL (dihydroergotamine mesylate) Nasal Spray What if I need help in using my MIGRANAL (dihydroergotamine mesylate) Nasal Spray? If you have any questions or if you need help in opening, putting together, or using MIGRANAL (dihydroergotamine mesylate) Nasal Spray, speak to your doctor or pharmacist, or contact Bausch Health US, LLC at 1-800-321-4576 or visit www.migranal.com. How much medication should I use and how often? Each vial contains one complete dose of MIGRANAL (dihydroergotamine mesylate) Nasal Spray, which is 1 spray in each nostril, followed by an additional spray in each nostril 15 minutes later for a total of 4 sprays. Do not use more than this amount unless instructed to do so by your doctor. MIGRANAL (dihydroergotamine mesylate) Nasal Spray is not intended for chronic daily use. Why do I have to prime or pump the Nasal Sprayer 4 times before using? Am I wasting the medication? You have to prime the Nasal Sprayer 4 times to make sure that you get the proper amount of medication when you use it. Although you will see some medication spray out, there is still enough medication in each vial to allow you to prepare your sprayer properly and still receive a full dose of MIGRANAL (dihydroergotamine mesylate) Nasal Spray. Can I assemble the medication vial and the Nasal Sprayer so it is ready before I need to use it? No. The brown (amber) glass vial containing your medication must remain unopened until you are ready to use it. It may not be fully effective if opened and not used within 8 hours. Can I reuse my MIGRANAL (dihydroergotamine mesylate) Nasal Sprayer? No. After completing the full dose, you must carefully dispose of your MIGRANAL (dihydroergotamine mesylate) Nasal Sprayer and the opened vial. You should use a new unit for your next migraine attack. Each Unit contains a new Nasal Sprayer, and a vial of MIGRANAL (dihydroergotamine mesylate) Nasal Spray medication. Can I use MIGRANAL (dihydroergotamine mesylate) Nasal Spray if I have a stuffy nose, cold, or allergies? Yes. MIGRANAL (dihydroergotamine mesylate) Nasal Spray can be used if you have a stuffy nose, cold, or allergies. However, if you are taking any medications for your cold, or allergies, even those you can buy without a doctor’s prescription, speak with your doctor before using MIGRANAL (dihydroergotamine mesylate) Nasal Spray. Do I need to sniff the medication when I spray it in my nostril? No, you should not sniff because MIGRANAL (dihydroergotamine mesylate) Nasal Spray should remain in the nose so that it can be absorbed into the bloodstream through the lining of the nose. If you have any other unanswered questions about MIGRANAL (dihydroergotamine mesylate) Nasal Spray, consult your doctor or pharmacist. Distributed by: Bausch Health US, LLC Bridgewater, NJ 08807 USA Manufactured by: Mipharm, S.p.A. Milano, Italy MIGRANAL is a trademark of Bausch Health Companies Inc. or its affiliates. All other product/brand names and/or logos are trademarks of the respective owners. © 2022 Bausch Health Companies Inc. or its affiliates www.migranal.com Rev. 09/2022 9603503

NDC 0187-0245-03 Rx only MIGRANAL ® (dihydroergotamine mesylate) NASAL SPRAY This Kit Contains: • 8 MIGRANAL Vials • 8 MIGRANAL Nasal Sprayers • Administration Instructions • Package Insert   FOR NASAL USE ONLY NOT FOR INJECTION 4 mg/mL (1 mL/Vial) 9605502 carton.jpg