Migranal

Migranal®(dihydroergotamine mesylate, USP) Nasal Spray is available (as a clear, colorless to faintly yellowsolution) in 3.5 mL amber glass vials containing 4 mg of dihydroergotamine mesylate, USP.

Migranal® (dihydroergotamine mesylate, USP) 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.

Manufactured by: MiPharm S.p.A, Milan, Italy. Distributed by: Valeant Pharmaceuticals North America, One Enterprise, Aliso Viejo, CA 92656. www.migranal (dihydroergotamine mesylate spray).com. June 2007.

Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is indicated for the acute treatment of migraine headaches with or without aura.

Migranal® (dihydroergotamine mesylate, USP) 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 spray) ® (dihydroergotamine mesylate, USP) Nasal Spray (4 mg/mL) is intended for intranasal use and must not be injected.

In clinical trials, Migranal® (dihydroergotamine mesylate, USP) 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 spray) ® (dihydroergotamine mesylate, USP) Nasal Spray should be administered in each nostril. Fifteen minutes later, an additional one spray (0.5 mg) of Migranal (dihydroergotamine mesylate spray) ® (dihydroergotamine mesylate, USP) Nasal Spray should be administered in each nostril, for a total dosage of four sprays (2.0 mg) of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. Studies have shown no additional benefit from acute doses greater than 2.0 mg for a single migraine administration. The safety of doses greater than 3.0 mg in a 24 hour period and 4.0 mg in a 7 day period has not been established.

Migranal® (dihydroergotamine mesylate, USP) 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, USP) 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, USP) Nasal Spray may increase blood pressure, it should not be given to patients with uncontrolled hypertension.

Migranal® (dihydroergotamine mesylate, USP) 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.

Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should not be administered to patients with hemiplegic or basilar migraine.

In addition to those conditions mentioned above, Migranal® (dihydroergotamine mesylate, USP) 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, USP) Nasal Spray may cause fetal harm when administered to a 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 -1.2 times the exposures in humans receiving the MRDD of 4 mg) or greater. A 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 7 times human exposures at the MRDD) during organogenesis. A 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. A 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.

Migranal® (dihydroergotamine mesylate, USP) 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.

WARNINGS

Migranal® (dihydroergotamine mesylate, USP) 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 CYP3A4 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 Migranal® (dihydroergotamine mesylate, USP) 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

Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should not be used by patients with documented ischemic or vasospastic coronary artery disease. (See CONTRAINDICATIONS) It is strongly recommended that Migranal® dihydroergotamine mesylate, USP) 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, Migranal® (dihydroergotamine mesylate, USP) 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 Migranal (dihydroergotamine mesylate spray) ® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, in these patients with risk factors.

It is recommended that patients who are intermittent long-term users of Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray.

The systematic approach described above is currently recommended as a method to identify patients in whom Migranal (dihydroergotamine mesylate spray) ® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) 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

Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, like other ergot alkaloids, may cause vasospastic reactions other than coronary artery vasospasm. Myocardial and peripheral vascular ischemia have been reported with Migranal® (dihydroergotamine mesylate, USP) Nasal Spray.

Migranal® (dihydroergotamine mesylate, USP) 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, Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray and dihydroergotamine mesylate injection.

Migranal® (dihydroergotamine mesylate, USP) 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 a study evaluating subjects undergoing cardiac catheterization.

Local Irritation

Approximately 30% of patients using Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) 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.

PRECAUTIONS

General

Migranal® (dihydroergotamine mesylate, USP) 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).

Fibrotic Complications: see WARNINGS: Fibrotic Complications

Information for Patients

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, USP) 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, USP) Nasal Spray, should not exceed the dosing guidelines and should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Assessment of the carcinogenic potential of dihydroergotamine mesylate in mice and rats is ongoing.

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

There was no evidence of impairment of fertility in rats given intranasal doses of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray up to 1.6 mg/day (associated with mean plasma dihydroergotamine mesylate exposures [AUC] approximately 9 to 11 times those in humans receiving the MRDD of 4 mg).

Pregnancy

Pregnancy Category X. See CONTRAINDICATIONS.

Nursing Mothers

Ergot drugs are known to inhibit prolactin. It is likely that Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, nursing should not be undertaken with the use of Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray in this population because patients over age 65 were excluded from the controlled clinical trials.

SIDE EFFECTS

During clinical studies and the foreign postmarketing experience with Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) 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.

Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray treated patients and occurred more frequently than in the placebo-group in the migraine placebo-controlled trials

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 Migranal® (dihydroergotamine mesylate, USP) 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 Migranal (dihydroergotamine mesylate spray) ® (dihydroergotamine mesylate, USP) Nasal Spray in placebo-controlled trials and reported an event divided by the total number of patients (n=1796) exposed to Migranal® (dihydroergotamine mesylate, USP) 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. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is not recommended for prolonged daily use. (See DOSAGE AND ADMINISTRATION)

Drug Abuse And Dependence

Currently available data have not demonstrated drug abuse or psychological dependence with dihydroergotamine. However, cases of drug abuse and psychological dependence in patients on other forms of ergot therapy have been reported. Thus, due to the chronicity of vascular headaches, it is imperative that patients be advised not to exceed recommended dosages.

DRUG INTERACTIONS

Vasoconstrictors

Migranal® (dihydroergotamine mesylate, USP) 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 Migranal (dihydroergotamine mesylate spray) ® (dihydroergotamine mesylate, USP) Nasal Spray. Sumatriptan and Migranal (dihydroergotamine mesylate spray) ® (dihydroergotamine mesylate, USP) 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 Migranal (dihydroergotamine mesylate spray) ® (dihydroergotamine mesylate, USP) 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 5HT1 agonists have been co-administered 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, USP) Nasal Spray or D.H.E. 45®.

Oral Contraceptives

The effect of oral contraceptives on the pharmacokinetics of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray has not been studied.

Pregnancy Category X. See CONTRAINDICATIONS.

During clinical studies and the foreign postmarketing experience with Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) 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.

Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray treated patients and occurred more frequently than in the placebo-group in the migraine placebo-controlled trials

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 Migranal® (dihydroergotamine mesylate, USP) 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 Migranal (dihydroergotamine mesylate spray) ® (dihydroergotamine mesylate, USP) Nasal Spray in placebo-controlled trials and reported an event divided by the total number of patients (n=1796) exposed to Migranal® (dihydroergotamine mesylate, USP) 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. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is not recommended for prolonged daily use. (See DOSAGE AND ADMINISTRATION)

Drug Abuse And Dependence

Currently available data have not demonstrated drug abuse or psychological dependence with dihydroergotamine. However, cases of drug abuse and psychological dependence in patients on other forms of ergot therapy have been reported. Thus, due to the chronicity of vascular headaches, it is imperative that patients be advised not to exceed recommended dosages.

To date, there have been no reports of acute overdosage with this drug. Due to the risk of vascular spasm, exceeding the recommended dosages of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is to be avoided. Excessive doses of dihydroergotamine may result in peripheral signs and symptoms of ergotism. Treatment includes discontinuance of the drug, local application of warmth to the affected area, the administration of vasodilators, and nursing care to prevent tissue damage.

In general, the symptoms of an acute Migranal® (dihydroergotamine mesylate, USP) Nasal Spray overdose are similar to those of an ergotamine overdose, although there is less pronounced nausea and vomiting with Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. The symptoms of an ergotamine overdose include the following: numbness, tingling, pain, and cyanosis of the extremities associated with diminished or absent peripheral pulses; respiratory depression; an increase and/or decrease in blood pressure, usually in that order; confusion, delirium, convulsions, and coma; and/or some degree of nausea, vomiting, and abdominal pain.

In laboratory animals, significant lethality occurs when dihydroergotamine is given at I.V. doses of 44 mg/kg in mice, 130 mg/kg in rats, and 37 mg/kg in rabbits.

Up-to-date information about the treatment of overdosage can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Poison Control Centers are listed in the Physicians' Desk Reference® (PDR). *

Absorption

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.

Distribution

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

Metabolism

Four dihydroergotamine mesylate metabolites have been identified in human plasma following oral administration. The major metabolite, 8'-β-hydroxydihydroergotamine, exhibits affinity equivalent to its parent for adrenergic and 5-HT receptors and demonstrates equivalent potency in several venoconstrictor activity models, in vivo and in vitro. The other metabolites, i.e., dihydrolysergic acid, dihydrolysergic amide and a metabolite formed by oxidative opening of the proline ring are of minor importance. Following nasal administration, total metabolites represent only 20%-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.

Excretion

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.