DIHYDROERGOTAMINE MESYLATE

Dihydroergotamine mesylate is ergotamine hydrogenated in the 9,10 position as the mesylate salt. Dihydroergotamine mesylate 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: 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) image description

Dihydroergotamine mesylate nasal spray is indicated for the acute treatment of migraine headaches with or without aura. 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 dihydroergotamine mesylate nasal spray (4 mg/mL) is intended for intranasal use and must not be injected. In clinical trials, dihydroergotamine mesylate nasal spray has been effective for the acute treatment of migraine headaches with or without aura. One spray (0.5 mg) of dihydroergotamine mesylate nasal spray should be administered in each nostril. Fifteen minutes later, an additional one spray (0.5 mg) of dihydroergotamine mesylate nasal spray should be administered in each nostril, for a total dosage of four sprays (2 mg) of 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. 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 ) . 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 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 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.

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 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 Trials Of the 1,796 patients and subjects treated with dihydroergotamine mesylate nasal spray doses 2 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 dihydroergotamine mesylate 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 a 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 a 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 Reactions 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 Trials Dihydroergotamine mesylate N=597 Placebo N=631 Respiratory 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 a Whole, General Hot Flashes 1% <1% Fatigue 1% 1% Asthenia 1% 0% Autonomic Nervous System Mouth Dry 1% 1% Musculoskeletal System Stiffness 1% <1% Other Adverse Events During Clinical Trials In 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 a 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 Reports Voluntary 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 Trifluent Pharma Ltd, at 1-210-944-6920 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Vasoconstrictors Dihydroergotamine mesylate Nasal Spray should not be used with peripheral vasoconstrictors because the combination may cause synergistic elevation of blood pressure. Sumatriptan Sumatriptan has been reported to cause coronary artery vasospasm, and its effect could be additive with dihydroergotamine mesylate nasal spray. Sumatriptan and dihydroergotamine mesylate nasal spray should not be taken within 24 hours of each other. (See CONTRAINDICATIONS ) Beta Blockers Although the results of a clinical study did not indicate a 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. Nicotine Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy. CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) See CONTRAINDICATIONS and WARNINGS . SSRI's 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 dihydroergotamine mesylate nasal spray or D.H.E. 45. Oral Contraceptives The effect of oral contraceptives on the pharmacokinetics of dihydroergotamine mesylate nasal spray has not been studied. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis 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. Mutagenesis 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. 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. Pregnancy Risk Summary Available data from published literature indicate an increased risk of preterm delivery with dihydroergotamine mesylate use during pregnancy. Avoid use of dihydroergotamine mesylate nasal spray 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. Nursing Mothers 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. Dihydroergotamine mesylate 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 dihydroergotamine mesylate nasal spray and for 3 days after the last dose. Breast milk supply during this time should be pumped and discarded. 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.