ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. During clinical studies and the foreign postmarketing experience with dihydroergotamine mesylate nasal spray there have been no fatalities due to cardiac events.Serious cardiac events, including some that have been fatal, have occurred following use of the parenteral form of dihydroergotamine mesylate (D.H.E. 45(R) Injection), but are extremely rare. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).Fibrotic complications have been reported in association with long term use of injectable dihydroergotamine mesylate (See WARNINGS: Fibrotic Complications).Incidence in Controlled Clinical TrialsOf the 1,796 patients and subjects treated with dihydroergotamine mesylate nasal spray doses mg or less in U.S. and foreign clinical studies, 26 (1.4%) discontinued because of adverse events. The adverse events associated with discontinuation were, in decreasing order of frequency: rhinitis 13, dizziness 2, facial edema 2, and one each due to cold sweats, accidental trauma, depression, elective surgery, somnolence, allergy, vomiting, hypotension, and paraesthesia.The most commonly reported adverse events associated with the use of dihydroergotaminemesylate nasal spray during placebo-controlled, double-blind studies for the treatment of migraine headache and not reported at an equal incidence by placebo-treated patients were rhinitis, altered sense of taste, application site reactions, dizziness, nausea, and vomiting. The events cited reflect experience gained under closely monitored conditions of clinical trials in highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ.Dihydroergotamine mesylate nasal spray was generally well tolerated. In most instances these events were transient and self-limited and did not result in patient discontinuation from study. The following table summarizes the incidence rates of adverse events reported by at least 1% of patients who received dihydroergotamine mesylate nasal spray for the treatment of migraine headaches during placebo-controlled, double-blind clinical studies and were more frequent than in those patients receiving placebo.Table 3: Adverse events reported by at least 1% of the Dihydroergotamine Mesylate Nasal Spray treated patients and occurred more frequently than in the placebo-group in the migraine placebo-controlled trialsDihydroergotamine Mesylate Nasal SprayN=597PlaceboN=631Respiratory System Rhinitis 26% 7% Pharyngitis 3% 1% Sinusitis 1% 1%Gastrointestinal System Nausea 10% 4% Vomiting 4% 1% Diarrhea 2% <1%Special Senses, Other Altered Sense of Taste 8% 1%Application Site Application Site Reaction 6% 2%Central and Peripheral Nervous System Dizziness 4% 2% Somnolence 3% 2% Paraesthesia 2% 2%Body as Whole, General Hot Flashes 1% <1% Fatigue 1% 1% Asthenia 1% 0%Autonomic Nervous Sys tem Mouth Dry 1% 1%Musculoskeletal System Stiffness 1% <1%Other Adverse Events During Clinical TrialsIn the paragraphs that follow, the frequencies of less commonly reported adverse clinical events are presented. Because the reports include events observed in open and uncontrolled studies, the role of dihydroergotamine mesylate nasal spray in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, etc., limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of patients who used dihydroergotamine mesylate nasal spray in placebo-controlled trials and reported an event divided by the total number of patients (n=1796) exposed to dihydroergotamine mesylate nasal spray. All reported events are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; and rare adverse events are those occurring in fewer than 1/1,000 patients.Skin and Appendages:Infrequent: petechia, pruritus, rash, cold clammy skin; Rare: papular rash, urticaria, herpes simplex.Musculoskeletal:Infrequent: cramps, myalgia, muscular weakness, dystonia; Rare: arthralgia, involuntary muscle contractions, rigidity.Central and Peripheral Nervous System:Infrequent: confusion, tremor, hypoesthesia, vertigo; Rare: speech disorder, hyperkinesia, stupor, abnormal gait, aggravated migraine.Autonomic Nervous System:Infrequent: increased sweating.Special Senses:Infrequent: sense of smell altered, photophobia, conjunctivitis, abnormal lacrimation, abnormal vision, tinnitus, earache; Rare: eye pain.Psychiatric:Infrequent: nervousness, euphoria, insomnia, concentration impaired; Rare: anxiety, anorexia, depression.Gastrointestinal:Infrequent: abdominal pain, dyspepsia, dysphagia, hiccup; Rare: increased salivation, esophagospasm.Cardiovascular:Infrequent: edema, palpitation, tachycardia; Rare: hypotension, peripheral ischemia, angina.Respiratory System:Infrequent: dyspnea, upper respiratory tract infections; Rare: bronchospasm, bronchitis, pleural pain, epistaxis.Urinary System:Infrequent: increased frequency of micturition, cystitis.Reproductive, Female:Rare: pelvic inflammation, vaginitis.Body as Whole -General:Infrequent: feeling cold, malaise, rigors, fever, periorbital edema; Rare: flu-like symptoms, shock, loss of voice, yawning.Application Site:Infrequent: local anesthesia.Post-introduction ReportsVoluntary reports of adverse events temporally associated with dihydroergotamine products used in the management of migraine that have been received since the introduction of the injectable formulation are included in this section save for those already listed above. Because of their source (open and uncontrolled clinical use), whether or not events reported in association with the use of dihydroergotamine are causally related to it cannot be determined. There have been reports of pleural and retroperitoneal fibrosis in patients following prolonged daily use of injectable dihydroergotamine mesylate. Dihydroergotamine mesylate nasal spray is not recommended for prolonged daily use (See DOSAGE AND ADMINISTRATION).To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Mechanism of Action. Dihydroergotamine binds with high affinity to 5-HT1D and 5-HT1D receptors. It also binds with high affinity to serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors, noradrenaline 2A, 2B and receptors, and dopamine D2L and D3 receptors.The therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effect at 5-HT1D receptors. Two current theories have been proposed to explain the efficacy of 5-HT1D receptor agonists in migraine. One theory suggests that activation of 5-HT1D 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-HT1D receptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release. In addition, dihydroergotamine possesses oxytocic properties (See CONTRAINDICATIONS).. Pharmacokinetics. AbsorptionDihydroergotamine 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.DistributionDihydroergotamine mesylate is 93% plasma protein bound. The apparent steady-state volume of distribution is approximately 800 liters.MetabolismFour dihydroergotamine mesylate metabolites have been identified in human plasma following oral administration. The major metabolite, 8--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 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. 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.ExcretionThe 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 terminal half-life of about 10 hours.SubpopulationsNo studies have been conducted on the effect of renal or hepatic impairment, gender, race, or ethnicity on dihydroergotamine pharmacokinetics. Dihydroergotamine mesylate nasal spray is contraindicated in patients with severely impaired hepatic or renal function (See CONTRAINDICATIONS).InteractionsThe pharmacokinetics of dihydroergotamine did not appear to be significantly affected by the concomitant use of local vasoconstrictor (e.g., fenoxazoline).Multiple oral doses of the -adrenoceptor antagonist propranolol, used for migraine prophylaxis, had no significant influence on the Cmax, Tmax or AUC of dihydroergotamine doses up to 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.. Clinical Trials. The efficacy of 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 mean age of 39 years (range 18 to 65 years). Patients treated single moderate to severe migraine headache with single dose of study medication and assessed pain severity over the 24 hours following treatment. Headache response was determined 0.5, 1, 2, and hours after dosing and was defined as reduction in headache severity to mild or no pain. In studies and 2, four-point pain intensity scale was utilized; in studies and 4, five-point scale was used that included both pain response and restoration of function for severe or incapacitating pain, 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 and 4, total dose of mg was compared to placebo. In studies and 2, doses of and mg were evaluated, and showed no advantage of the higher dose for single treatment. In all studies, patients received regimen consisting of 0.5 mg in each nostril, repeated in 15 minutes (and again in another 15 minutes for the mg dose in studies and 2).The percentage of patients achieving headache response hours after treatment was significantly greater in patients receiving mg doses of dihydroergotamine mesylate nasal spray compared to those receiving placebo in of the studies (See Tables & and Figures & 2).Table 1: Studies and 2: Percentage of patients with headache response and hours following single treatment of study medication [Dihydroergotamine Mesylate Nasal Spray or Placebo]N2 hours4 hoursStudy 1Dihydroergotamine Mesylate Nasal Spray10561%+ 70%+ Placebo9823%28%Study 2Dihydroergotamine Mesylate Nasal Spray10347%56% Placebo10233%35% Headache response was defined as reduction in headache severity to mild or no pain.Headache response was based on pain intensity as interpreted by the patient using four-point pain intensity scale. value 0.01+ value 0.001Table 2: Studies and 4: Percentage of patients with headache response and hours following s ingle treatment of study medication [Dihydroergotamine Mesylate Nasal Spray or Placebo]N2 hours4 hoursStudy 3Dihydroergotamine Mesylate Nasal Spray5032%48%+ Placebo5020%22%Study 4Dihydroergotamine Mesylate Nasal Spray4730%47% Placebo5020%30% Headache response was defined as reduction in headache severity to mild or no pain.Headache response was evaluated on five-point scale that included both pain response and restoration of function for severe or incapacitating pain.+ value 0.01Comparisons 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 & 2) provides an estimate of the probability that patient will have responded to single mg dose of dihydroergotamine mesylate nasal spray as function of the time elapsed since initiation of treatment.The figure shows the probability over time of obtaining response following treatment with dihydroergotamine mesylate nasal spray. Headache response was based on pain intensity as interpreted by the patient using four-point pain intensity scale. Patients not achieving response within hours were censored to hours.The figure shows the probability over time of obtaining response following treatment with dihydroergotamine mesylate nasal spray. Headache response was evaluated on five-point scale that confounded pain response and restoration of function for severe or incapacitating pain. Patients not achieving response within hours were censored to hours.For patients with migraine-associated nausea, photophobia, and phonophobia at baseline, there was lower incidence of these symptoms at and hours following administration of 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 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 mg dose of study treatment is summarized in Figure below.Kaplan-Meier plot based on data obtained from all studies with patients not using additional treatments censored to 24 hours. All patients received 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 effect the patients response to 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 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 dihydroergotamine mesylate nasal spray.. figure 1. figure 2. figure 3.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. There have been few reports of serious adverse events associated with the co-administration 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). 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 Prinzmetals variant angina (See WARNINGS). Because dihydroergotamine mesylate nasal spray may increase blood pressure, it should not be given to patients with uncontrolled hypertension. Dihydroergotamine mesylate nasal spray, 5-HT1 agonists (e.g., sumatriptan), ergotamine-containing or ergot-type medications or methysergide should not be used within 24 hours of each other. Dihydroergotamine mesylate nasal spray should not be administered to patients with hemiplegic or basilar migraine.In addition to those conditions mentioned above, 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.Dihydroergotamine mesylate nasal spray may cause fetal harm when administered to pregnant woman. Dihydroergotamine possesses oxytocic properties and, therefore, should not be administered during pregnancy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.There are no adequate studies of dihydroergotamine in human pregnancy, but developmental toxicity has been demonstrated in experimental animals. In embryofetal development studies of dihydroergotamine mesylate nasal spray, intranasal administration to pregnant rats throughout the period of organogenesis resulted in decreased fetal body weights and/or skeletal ossification at doses of 0.16 mg/day (associated with maternal plasma dihydroergotamine exposures [AUC] approximately 0.4 to 1.2 times the exposures in humans receiving the MRDD of mg) or greater. no effect level for embryo-fetal toxicity was not established in rats. Delayed skeletal ossification was also noted in rabbit fetuses following intranasal administration of 3.6 mg/day (maternal exposures approximately times human exposures at the MRDD) during organogenesis. no effect level was seen at 1.2 mg/day (maternal exposures approximately 2.5 times human exposures at the MRDD). When dihydroergotamine mesylate nasal spray was administered intranasally to female rats during pregnancy and lactation, decreased body weights and impaired reproductive function (decreased mating indices) were observed in the offspring at doses of 0.16 mg/day or greater. no effect level was not established. Effects on development occurred at doses below those that produced evidence of significant 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.Dihydroergotamine mesylate nasal spray is contraindicated in patients who have previously shown hypersensitivity to ergot alkaloids.Dihydroergotamine mesylate should not be used by nursing mothers (See PRECAUTIONS).Dihydroergotamine mesylate should not be used with peripheral and central vasoconstrictors because the combination may result in additive or synergistic elevation of blood pressure.

PHARMACOKINETICS SECTION.

Pharmacokinetics. AbsorptionDihydroergotamine 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.DistributionDihydroergotamine mesylate is 93% plasma protein bound. The apparent steady-state volume of distribution is approximately 800 liters.MetabolismFour dihydroergotamine mesylate metabolites have been identified in human plasma following oral administration. The major metabolite, 8--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 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. 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.ExcretionThe 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 terminal half-life of about 10 hours.SubpopulationsNo studies have been conducted on the effect of renal or hepatic impairment, gender, race, or ethnicity on dihydroergotamine pharmacokinetics. Dihydroergotamine mesylate nasal spray is contraindicated in patients with severely impaired hepatic or renal function (See CONTRAINDICATIONS).InteractionsThe pharmacokinetics of dihydroergotamine did not appear to be significantly affected by the concomitant use of local vasoconstrictor (e.g., fenoxazoline).Multiple oral doses of the -adrenoceptor antagonist propranolol, used for migraine prophylaxis, had no significant influence on the Cmax, Tmax or AUC of dihydroergotamine doses up to 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.

PRECAUTIONS SECTION.

PRECAUTIONS. General. 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 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 Raynauds syndrome following the use of any 5-HT agonist are candidates for further evaluation (See WARNINGS).Fibrotic Complications:See WARNINGS: Fibrotic Complications Information for PatientsThe text of patient information sheet is printed at the end of this insert. To assure safe and effective use of 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 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 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 dihydroergotamine mesylate nasal spray, should not exceed the dosing guidelines and should not be used for chronic daily administration (See DOSAGE AND ADMINISTRATION).. Drug Interactions. VasoconstrictorsDihydroergotamine mesylate nasal spray should not be used with peripheral vasoconstrictors because the combination may cause synergistic elevation of blood pressure.SumatriptanSumatriptan has been reported to cause coronary artery vasospasm, and its effect could be additive with dihydroergotamine mesylate nasal spray. Sumatriptan and dihydroergotaminemesylate nasal spray should not be taken within 24 hours of each other (See CONTRAINDICATIONS).Beta BlockersAlthough the results of clinical study did not indicate safety problem associated with the administration of 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.NicotineNicotine may provoke vasoconstriction in some patients, predisposing to greater ischemic response to ergot therapy.CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors)See CONTRAINDICATIONS and WARNINGS.SSRIsWeakness, hyperreflexia, and incoordination have been reported rarely when 5HT1 agonists have been co-administered with SSRIs (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline). There have been no reported cases from spontaneous reports of drug interaction between SSRIs and dihydroergotamine mesylate nasal spray or D.H.E. 45(R).Oral ContraceptivesThe effect of oral contraceptives on the pharmacokinetics of dihydroergotamine mesylatenasal spray has not been studied.. Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisAssessment of the carcinogenic potential of dihydroergotamine mesylate in mice and rats is ongoing.MutagenesisDihydroergotamine mesylate was clastogenic in two in vitro chromosomal aberration assays, the V79Chinese 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.Impairment of FertilityThere was no evidence of impairment of fertility in rats given intranasal doses of dihydroergotamine mesylate nasal spray up to 1.6 mg/day (associated with mean plasma dihydroergotamine mesylate exposures [AUC] approximately to 11 times those in humans receiving the MRDD of mg).. Pregnancy. See CONTRAINDICATIONS.. Nursing Mothers. Ergot drugs are known to inhibit prolactin. It is likely that dihydroergotamine mesylate nasal spray is excreted in human milk, but there are no data on the concentration of dihydroergotamine in human milk. It is known that ergotamine is excreted in breast milk and may cause vomiting, diarrhea, weak pulse, and unstable blood pressure in nursing infants. Because of the potential for these serious adverse events in nursing infants exposed to dihydroergotamine mesylate nasal spray, nursing should not be undertaken with the use of dihydroergotamine mesylate nasal spray (See CONTRAINDICATIONS).. Pediatric Use. Safety and effectiveness in pediatric patients have not been established.. Use in the Elderly. There is no information about the safety and effectiveness of dihydroergotamine mesylate nasal spray in this population because patients over age 65 were excluded from the controlled clinical trials.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information. Information for the PatientDihydroergotamine Mesylate (dye hye droe er got meen mes late) Nasal SprayThe solution used in 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 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 dihydroergotamine mesylate nasal spray. Your pharmacist and/or health care provider can provide more detailed information.Dihydroergotamine mesylate nasal spray has been evaluated in limited number of patients long term (e.g., year or longer).Purpose of your MedicationDihydroergotamine mesylate nasal spray is intended to treat an active migraine headache. Do not try to use it to prevent headache if you have no symptoms. Do not use it to treat common tension headache or headache that is not at all typical of your usual migraine headache. Administration of 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 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 dihydroergotamine mesylate nasal spray if you:Are pregnant or nursing.have any disease affecting your heart, arteries, or circulation.are taking certain anti-HIV medications (protease inhibitors).are taking macrolide antibiotic such as troleandomycin, clarithromycin or erythromycin.Important questions to consider before using dihydroergotamine mesylate nasalsprayPlease answer the following questions before you use your 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 dihydroergotamine mesylate nasal spray.Do you have high blood pressureDo you have chest pain, shortness of breath, heart disease, or have you had any surgery on your heart arteriesDo 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 male over 40)Do you have any problems with blood circulation in your arms or legs, fingers, or toesAre you pregnant Do you think you might be pregnant Are you trying to become pregnant Are you sexually active and not using birth control Are you breast feedingHave you ever had to stop taking this or any other medication because of an allergy or bad reactionAre 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 doctors prescriptionDo you smokeHave you had, or do you have, any disease of the liver or kidneyIs this headache different from your usual migraine attacksAre you using dihydroergotamine mesylate nasal spray or other dihydroergotamine mesylate containing drugs on daily basisAre you taking protease inhibitor for HIV therapyAre you taking macrolide class of antibioticSerious or potentially life-threatening reductions in blood flow to the brain or extremities have been reported rarely due to interactions between 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 DIHYDROERGOTAMINE MESYLATE NASAL SPRAY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA 1088.Side Effects To Watch Out ForIn clinical trials, most migraine patients have used 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 dihydroergotamine mesylate nasal spray. These side effects are temporary and usually do not require you to stop using 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 toesPain, tightness, or discomfort in your chestMuscle pain or cramps in your arms and legsWeakness in your legsTemporary speeding or slowing of your heart rateSwelling or itchingDosing InformationEach vial contains one complete dose of dihydroergotamine mesylate nasal spray, which is spray in each nostril followed in 15 minutes by an additional spray in each nostril, for total of sprays.Studies have shown no benefit from acute doses greater than mg (4 sprays) for single administration. The safety of doses greater than mg in 24 hour period has not been established.The safety of doses greater than mg in 7-day period has not been established.Dihydroergotamine mesylate nasal spray, should not be used for chronic daily administration.Learn what to do in case of an OverdoseIf 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 dihydroergotamine mesylate nasal sprayUse available training materials.Read and follow the instructions in the administration instructions which are provided with the dihydroergotamine mesylate nasal spray package before attempting to use the product.If there are any questions concerning the use of your dihydroergotamine mesylate nasal spray, ask your doctor or pharmacist, or contact Amneal Pharmaceuticals at 1-877-835-5472. Check the contents of the package:8 Nasal Spray Vials8 Nasal SprayersAdministration InstructionsPackage Insert 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 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. Using the sprayer:Remove cap from spray unit. Holding the vial upright, point nasal sprayer away from face and pump times before using. DO NOT PUMP MORE THAN 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 full treatment of dihydroergotamine mesylate nasal spray.)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. After completing these instructions:Carefully dispose of the nasal spray pump with the vial.Important Notes: Once dihydroergotamine mesylate nasal spray vial has been opened, it must be thrown away after hours.Storing dihydroergotamine mesylate nasal spray Keep medication in safe place away from childrenKeep dihydroergotamine mesylate nasal spray away from heat and light.Do not expose dihydroergotamine mesylate nasal spray to temperatures over 77F.Never refrigerate or freeze dihydroergotamine mesylate nasal spray.Do not keep an opened dihydroergotamine mesylate nasal spray vial for more than 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 dihydroergotamine mesylate nasal sprayWhat if need help in using my dihydroergotamine mesylate nasal sprayIf you have any questions or if you need help in opening, putting together, or using dihydroergotamine mesylate nasal spray, speak to your doctor or pharmacist, or contact Amneal Pharmaceuticals at 1-877-835-5472 or visit www.amneal.com.How much medication should use and how oftenEach vial contains one complete dose of dihydroergotamine mesylate nasal spray, which is spray in each nostril, followed by an additional spray in each nostril 15 minutes later for total of sprays. Do not use more than this amount unless instructed to do so by your doctor. Dihydroergotamine mesylate nasal spray is not intended for chronic daily use.Why do have to prime or pump the nasal sprayer times before using Am wasting the medicationYou have to prime the nasal sprayer 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 full dose of dihydroergotamine mesylate nasal spray.Can assemble the medication vial and the nasal sprayer so it is ready before need to use itNo. 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 hours.Can reuse my dihydroergotamine mesylate nasal sprayerNo. After completing the full dose, you must carefully dispose of your dihydroergotamine mesylate nasal sprayer and the opened vial. You should use new unit for your next migraine attack. Each Unit contains new nasal sprayer, and vial of dihydroergotamine mesylate nasal spray medication.Can use dihydroergotamine mesylate nasal spray if have stuffy nose, cold, or allergiesYes. dihydroergotamine mesylate nasal spray can be used if you have stuffy nose, cold, or allergies. However, if you are taking any medications for your cold, or allergies, even those you can buy without doctors prescription, speak with your doctor before using dihydroergotamine mesylate nasal spray.Do need to sniff the medication when spray it in my nostrilNo, you should not sniff because 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 dihydroergotamine mesylate nasal spray, consult your doctor or pharmacist.Trademark of Medical Economics Company, Inc.Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807Rev. 06-2020-00. Are pregnant or nursing.. have any disease affecting your heart, arteries, or circulation.. are taking certain anti-HIV medications (protease inhibitors).. are taking macrolide antibiotic such as troleandomycin, clarithromycin or erythromycin.. 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 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 Are you breast feeding. 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 doctors 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 dihydroergotamine mesylate nasal spray or other dihydroergotamine mesylate containing drugs on daily basis. Are you taking protease inhibitor for HIV therapy. Are you taking macrolide class of antibiotic. 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. Each vial contains one complete dose of dihydroergotamine mesylate nasal spray, which is spray in each nostril followed in 15 minutes by an additional spray in each nostril, for total of sprays.. Studies have shown no benefit from acute doses greater than mg (4 sprays) for single administration. The safety of doses greater than mg in 24 hour period has not been established.. The safety of doses greater than mg in 7-day period has not been established.. Dihydroergotamine mesylate nasal spray, should not be used for chronic daily administration.. Use available training materials.Read and follow the instructions in the administration instructions which are provided with the dihydroergotamine mesylate nasal spray package before attempting to use the product.If there are any questions concerning the use of your dihydroergotamine mesylate nasal spray, ask your doctor or pharmacist, or contact Amneal Pharmaceuticals at 1-877-835-5472. Read and follow the instructions in the administration instructions which are provided with the dihydroergotamine mesylate nasal spray package before attempting to use the product.. If there are any questions concerning the use of your dihydroergotamine mesylate nasal spray, ask your doctor or pharmacist, or contact Amneal Pharmaceuticals at 1-877-835-5472.. Check the contents of the package:8 Nasal Spray Vials8 Nasal SprayersAdministration InstructionsPackage Insert 8 Nasal Spray Vials. Nasal Sprayers. Administration Instructions. Package Insert. 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 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. Lift tab to bend back blue cover. In one piece, completely remove the blue cover and metal seal in 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.. Using the sprayer:Remove cap from spray unit. Holding the vial upright, point nasal sprayer away from face and pump times before using. DO NOT PUMP MORE THAN 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 full treatment of dihydroergotamine mesylate nasal spray.)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. Remove cap from spray unit. Holding the vial upright, point nasal sprayer away from face and pump times before using. DO NOT PUMP MORE THAN 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 full treatment of dihydroergotamine mesylate nasal spray.). 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.. After completing these instructions:. Carefully dispose of the nasal spray pump with the vial.Important Notes: Once dihydroergotamine mesylate nasal spray vial has been opened, it must be thrown away after hours.Storing dihydroergotamine mesylate nasal spray Keep medication in safe place away from children. Keep dihydroergotamine mesylate nasal spray away from heat and light.. Do not expose dihydroergotamine mesylate nasal spray to temperatures over 77F.. Never refrigerate or freeze dihydroergotamine mesylate nasal spray.. Do not keep an opened dihydroergotamine mesylate nasal spray vial for more than hours.. Check the expiration date printed on the vial containing medication. If the expiration date has passed, do not use it.

WARNINGS SECTION.

WARNINGS. Dihydroergotamine mesylate nasal spray should only be used where clear diagnosis of migraine headache has been established. CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the co-administration of dihydroergotamine and potent CYP 3A4 inhibitors, such as protease inhibitors and macrolide antibiotics, resulting in vasospasm that led to cerebral ischemia and/or and ischemia of the extremities. The use of potent CYP 3A4 inhibitors with dihydroergotamine should therefore be avoided (See CONTRAINDICATIONS). Examples of some of the more potent CYP 3A4 inhibitors include: antifungals ketoconazole and itraconazole, the protease inhibitors ritonavir, nelfinavir, and indinavir, and macrolide antibiotics erythromycin, clarithromycin, and troleandomycin. Other less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with dihydroergotamine.Fibrotic ComplicationsThere have been reports of pleural and retroperitoneal fibrosis in patients following prolonged daily use of injectable 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 injectable dihydroergotamine mesylate; however, in those cases, patients also received drugs known to be associated with cardiac valvular fibrosis.Administration of dihydroergotamine mesylate nasal spray, should not exceed the dosing guidelines and should not be used for chronic daily administration (See DOSAGE AND ADMINISTRATION).Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events: Dihydroergotamine mesylate nasal spray should not be used by patients with documented ischemic or vasospastic coronary artery disease (See CONTRAINDICATIONS). It is strongly recommended that dihydroergotamine mesylate nasal spray not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, females who are surgically or physiologically postmenopausal, or males who are over 40 years of age) unless cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patients medical history or electrocardiographic investigations reveal findings indicative of or consistent with coronary artery vasospasm or myocardial ischemia, dihydroergotamine mesylate nasal spray should not be administered (See CONTRAINDICATIONS). For patients with risk factors predictive of CAD who are determined to have satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of dihydroergotamine mesylate nasal spray take place in the setting of physicians office or similar medically staffed and equipped facility unless the patient has previously received dihydroergotamine mesylate. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following dihydroergotamine mesylate nasal spray, in these patients with risk factors. It is recommended that patients who are intermittent long-term users of dihydroergotamine mesylate nasal spray and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use dihydroergotamine mesylate nasal spray. The systematic approach described above is currently recommended as method to identify patients in whom dihydroergotamine mesylate nasal spray may be used to treat migraine headaches with an acceptable margin of cardiovascular safety.Cardiac Events and FatalitiesNo deaths have been reported in patients using dihydroergotamine mesylate nasal spray. However, the potential for adverse cardiac events exists. Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported to have occurred following the administration of dihydroergotamine mesylate injection (e.g., D.H.E. 45(R) Injection). Considering the extent of use of dihydroergotamine mesylate in patients with migraine, the incidence of these events is extremely low.Drug-Associated Cerebrovascular Events and FatalitiesCerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with D.H.E. 45(R) Injection; and some have resulted in fatalities. In number of cases, it appears possible that the cerebrovascular events were primary, the D.H.E. 45(R) Injection having been administered in the incorrect belief that the symptoms experienced were 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).Other Vasospasm Related EventsDihydroergotamine mesylate nasal spray, like other ergot alkaloids, may cause vasospastic reactions other than coronary artery vasospasm. Myocardial and peripheral vascular ischemia have been reported with dihydroergotamine mesylate nasal spray.Dihydroergotamine mesylate nasal spray 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, dihydroergotamine mesylate nasal spray should be discontinued immediately if signs or symptoms of vasoconstriction develop.Increase in Blood PressureSignificant elevation in blood pressure has been reported on rare occasions in patients with and without history of hypertension treated with dihydroergotamine mesylate nasal spray and dihydroergotamine mesylate injection. Dihydroergotamine mesylate nasal spray is contraindicated in patients with uncontrolled hypertension (See CONTRAINDICATIONS).An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5HT1 agonist in study evaluating subjects undergoing cardiac catheterization.Local IrritationApproximately 30% of patients using dihydroergotamine mesylate nasal spray (compared to 9% of placebo patients) have reported irritation in the nose, throat, and/or disturbances in taste. Irritative symptoms include congestion, burning sensation, dryness, paraesthesia, discharge, epistaxis, pain, or soreness. The symptoms were predominantly mild to moderate in severity and transient. In approximately 70% of the above mentioned cases, the symptoms resolved within four hours after dosing with dihydroergotamine mesylate nasal spray. Examinations of the nose and throat in small subset (N 66) of study participants treated for up to 36 months (range to 36 months) did not reveal any clinically noticeable injury. Other than this limited number of patients, the consequences of extended and repeated use of dihydroergotamine mesylate nasal spray on the nasal and/or respiratory mucosa have not been systematically evaluated in patients.Nasal tissue in animals treated with dihydroergotamine mesylate daily at nasal cavity surface area exposures (in mg/mm2) that were equal to or less than those achieved in humans receiving the maximum recommended daily dose of 0.08 mg/kg/day 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.