Migranal

Migranal (dihydroergotamine mesylate spray) ® is ergotamine hydrogenated in the 9,10 position as the mesylate salt. Migranal (dihydroergotamine mesylate spray) ® is known chemically as ergotaman-3', 6', 18-trione, 9,10-dihydro-12'-hydroxy-2'-methyl-5'- (phenylmethyl)-, (5'α)-, monomethanesulfonate. Its molecular weight is 679.80 and its empirical formula is C33H37N5O5•CH4O3S.

The chemical structure is:

C33H37N5O5•CH4O3S       Mol. wt. 679.80

MigranaI® (dihydroergotamine mesylate, USP) Nasal Spray is provided for intranasal administration as a clear, colorless to faintly yellow solution in an amber glass vial containing:

dihydroergotamine mesylate, USP....................................4.0 mg
caffeine, anhydrous, USP.................................................10.0 mg
dextrose, anhydrous, USP ...............................................50.0 mg
carbon dioxide, USP.........................................................qs
purified water, USP..........................................................qs 1.0 mL

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.

• Valeant Pharmaceuticals International

• Valeant Pharmaceuticals North America LLC

• Xcel Pharmaceuticals

• Tell all of your health care providers that you take Migranal. This includes your doctors, nurses, pharmacists, and dentists.
• If you drink grapefruit juice or eat grapefruit often, talk with your doctor.
• This medicine is not meant for regular, daily use. Talk with the doctor.
• Do not use more than what your doctor told you to use. Do not use more often or longer than what you were told. Doing any of these things may raise the chance of very bad side effects.
• Use care if you have risks for heart disease (high blood pressure, high cholesterol, overweight, high blood sugar or diabetes, cigarette smoking, man older than 40 years of age, other family members with early heart disease, woman after change of life). Talk with your doctor.
• Very bad and sometimes deadly side effects like a heartbeat that does not feel normal, heart attack, stroke, and very bad high blood pressure have happened with this medicine. Talk with the doctor.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant. If you are pregnant or you get pregnant while taking Migranal, call your doctor right away.

The efficacy of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray for the acute treatment of migraine headaches was evaluated in four randomized, double blind, placebo controlled studies in the U.S. The patient population for the trials was predominantly female (87%) and Caucasian (95%) with a mean age of 39 years (range 18 to 65 years). Patients treated a single moderate to severe migraine headache with a single dose of study medication and assessed pain severity over the 24 hours following treatment. Headache response was determined 0.5, 1, 2, 3 and 4 hours after dosing and was defined as a reduction in headache severity to mild or no pain. In studies 1 and 2, a four-point pain intensity scale was utilized; in studies 3 and 4, a five-point scale was used that included both pain response and restoration of function for "severe" or "incapacitating" pain, a less clear endpoint. Although rescue medication was allowed in all four studies, patients were instructed not to use them during the four hour observation period. In studies 3 and 4, a total dose of 2 mg was compared to placebo. In studies 1 and 2, doses of 2 and 3 mg were evaluated, and showed no advantage of the higher dose for a single treatment. In all studies, patients received a regimen consisting of 0.5 mg in each nostril, repeated in 15 minutes (and again in another 15 minutes for the 3 mg dose in studies 1 and 2).

The percentage of patients achieving headache response 4 hours after treatment was significantly greater in patients receiving 2 mg doses of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray compared to those receiving placebo in 3 of the 4 studies (see Tables 1 & 2 and Figures 1 & 2).

Comparisons of drug performance based upon results obtained in different clinical trials are never reliable. Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study.

The Kaplan-Meier plots below (Figures 1 & 2) provides an estimate of the probability that a patient will have responded to a single 2 mg dose of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray as a function of the time elapsed since initiation of treatment.

*The figure shows the probability over time of obtaining a response following treatment with Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. Headache response was based on pain intensity as interpreted by the patient using a four-point pain intensity scale. Patients not achieving response within 4 hours were censored to 4 hours.

*The figure shows the probability over time of obtaining a response following treatment with Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. Headache response was evaluated on a five-point scale that confounded pain response and restoration of function for "severe" or "incapacitating" pain. Patients not achieving response within 4 hours were censored to 4 hours.

For patients with migraine-associated nausea, photophobia, and phonophobia at baseline, there was a lower incidence of these symptoms at 2 and 4 hours following administration of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray compared to placebo.

Patients were not allowed to use additional treatments for eight hours prior to study medication dosing and during the four hour observation period following study treatment. Following the 4 hour observation period, patients were allowed to use additional treatments. For all studies, the estimated probability of patients using additional treatments for their migraines over the 24 hours following the single 2 mg dose of study treatment is summarized in Figure 3 below.

* Kaplan-Meier plot based on data obtained from all studies with patients not using additional treatments censored to 24 hours. All patients received a single treatment of study medication for their migraine attack. The plot also includes patients who had no response to the initial dose.

Neither age nor sex appear to effect the patient's response to Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. While patients with menstrual migraine, migraine with aura, and migraine without aura by medical history were included in the clinical evaluation of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, patients were not required to report the specific type of migraine treated with study medication. Thus, neither the effect of menses on migraine nor the presence or the absence of aura were assessed. The racial distribution of patients was insufficient to determine the effect of race on the efficacy of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray.

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.

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.

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, 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)

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).1

Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is available (as a clear, colorless to faintly yellow solution) 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.