INDICATIONS AND USAGE 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.

WARNINGS Dihydroergotamine mesylate nasal spray should only be used where a 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 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 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 Complications There 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 a 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 patient's 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 a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of dihydroergotamine mesylate nasal spray take place in the setting of a physician's 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 a 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 Fatalities No 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 ® 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 Fatalities Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with D.H.E.

45 ® Injection; and some have resulted in fatalities.

In a number of cases, it appears possible that the cerebrovascular events were primary, the D.H.E.

45 ® Injection having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not.

It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack).

Other Vasospasm Related Events Dihydroergotamine 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 Pressure Significant elevation in blood pressure has been reported on rare occasions in patients with and without a history of hypertension treated with dihydroergotamine mesylate 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 5HT 1 agonist in a study evaluating subjects undergoing cardiac catheterization.

Local Irritation Approximately 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 a small subset (N = 66) of study participants treated for up to 36 months (range 1-36 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.

Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamines, triptans, opioids, or a combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (i.e., medication overuse headache).

Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks.

Detoxification of patients including withdrawal of the overused drugs and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.

Preterm Labor Based on the mechanism of action of dihydroergotamine and findings from the published literature, dihydroergotamine mesylate nasal spray may cause preterm labor.

Avoid use of dihydroergotamine mesylate nasal spray during pregnancy ( see PRECAUTIONS ).

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 ® 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 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 Trials Dihydroergotamine Mesylate Nasal Spray 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 Somerset Therapeutics, LLC at 1-800-417-9175 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.