دهیدرو ارگاتامین مسیلات
Dihydroergotamine Mesylate Spray (Migranal)
دهیدرو ارگاتامین مسیلات

نام ژنریک

Dihydroergotamine Mesylate

شکل دارویی

موارد و مقدار مصرف


جلوگيري يا رفع سردردهاي عروقي، ‌از جمله ميگرن و سردردهاي خوشه اي.


بزرگسالان: يك ميلي گرم به صورت تزريق عضلاني يا وريدي. اين مقدار مصرف در فواصل يك ساعته تكرار شده، تا مقدار تام سه ميلي گرم تزريق عضلاني مي شود. مقدار تام تزريق وريدي نبايد از دو ميلي گرم تجاوز كند. حداكثر مقدار مصرف شش ميلي گرم در هفته است.


مكانيسم اثر


اثر تنگ كننده عروق: دي هيدروارگوتامين با تحريك گيرنده هاي آلفا ـ‌ آدرنرژيك موجب تنگي عروق محيطي مي شود (اگر تونيسيته عروق پايين باشد). با اين وجود، اين دارو موجب انبساط عروق با تونيسيته بالا مي شود.


مقادير زياد اين دارو گيرنده هاي آلفا ـ‌ آدرنرژيك را به طور رقابتي مسدود مي كند.


دي هيدروارگوتامين با مقادير مصرف درماني از برداشت مجدد نوراپينفرين جلوگيري كرده، ‌فعاليت تنگ كننده عروق آن را افزايش مي دهد. همچنين، اين دارو يك آنتاگونيست ضعيف سروتونين بوده و افزايش ميزان تجمع پلاكتي ناشي از سروتونين را كاهش مي دهد.


در درمان سردردهاي عروقي، دي هيدروارگوتامين احتمالاً به طور مستقيم موجب تنگ شدن شاخه هاي شريان كاروتيد منبسط شده و در همان حال دامنه نبض را كاهش مي دهد كه ظاهراً به دليل اثرات كاتكول آمين و سروتونين اين دارو است.


اثر اين دارو بر روي فشار خون غير قابل پيش بيني و معمولاً بسيار كم است. اثر تنگ كننده عروق اين دارو بر روي وريدها و ونولها بارزتر از شريانها و آرتريولها است.

موارد مصرف

فارماكوكينتيك


جذب: به طور ناقص و نامنظم از دستگاه گوارش جذب مي شود. زمان شروع اثر دارو احتمالاً بستگي به آن دارد كه دارو با چه فاصله اي از شروع سردرد مصرف شده است. زمان شروع اثر دارو، بعد از تزريق عضلاني، طي 30-15، و بعد از تزريق وريدي طي چند دقيقه حاصل مي شود. اثر دارو، بعد از تزريق عضلاني، ‌تا 4-3 ساعت دوام دارد.


پخش: حدود 90 درصد به پروتئين پلاسما پيوند مي يابد.


متابوليسم: احتمالاً به طور گسترده در كبد متابوليزه مي شود (در عبور اول كبدي به مقدار زيادي متابوليزه مي شود).


دفع: حدود 10 درصد دارو طي 72 ساعت به صورت متابوليت از طريق ادرار و باقيمانده دارو با ترشح صفراوي از طريق مدفوع دفع مي شود. نيم عمر 9 الي 10 ساعت است.

موارد منع مصرف

عوارض جانبي


قلبي ـ ‌عروقي: براديكاردي يا تاكيكاردي گذرا، ‌اسپاسم شديد عروقي، بي حسي، گزگز انگشتان دست و پا، ‌درد و ناراحتي سردل ، افزايش فشار شرياني، ادم موضعي.


دستگاه گوارش : تهوع ، استفراغ.


ساير عوارض: خارش، ضعف ساق پا، سرگيجه، درد عضلاني اندامها.


توجه: در صورت بروز اسپاسم عروقي يا حساسيت مفرط، بايد مصرف دارو قطع شود.


مسموميت و درمان


تظاهرات باليني: نشانه هاي مسموميت با ارگوت، ‌از جمله ايسكمي محيطي، پاراستزي، ‌سردرد، تهوع و استفراغ.


درمان: بيمار بايد به مدت طولاني و به دقت تحت نظر باشد. اقدامات لازم براي حمايت دستگاه تنفس مي‌ بايست به عمل آيد، و تشنجات را در صورت لزوم درمان كرد ‌و در صورت بروز اسپاسم عروقي، قسمتهاي ايسكميك اندامها را بايد گرم گردد (از گرماي مستقيم خودداري شود). در صورت لزوم مي توان داروهاي گشادكننده عروق (نيتروپروسايد، پرازوسين يا تولازولين) مصرف كرد.

موارد قابل توجه

-

مکانیزم اثر

فارماكوكینتیك

تداخل دارويي


در صورت مصرف همزمان با داروهاي كاهنده فشار خون، ممكن است اثرات كاهنده فشارخون اين داروها خنثي شود.


داروهاي مهاركننده CYP 450 (ضد قارچهاي آزولي ، ماكروليدها و مهاركنندههاي پروتئاز) ممكن است باعث وازواسپاسم و ايسكمي شديد محيطي و مركزي شوند. از مصرف همزمان اجتناب نماييد.


تنگ کننده هاي محيطي عروق ممکن است اثرات افزايش فشار يکديگر را افزايش دهند. از مصرف همزمان اجتناب نماييد.


پروپرانولول و ساير بتابلاکرها مي‌ توانند با مهار اثرات گشادکنندگي گيرنده بتا 2 باعث انقباض شديد عروق محيطي و سردي اندام ‌هاي انتهايي شود . بيمار را مانيتور نماييد.


داروهاي SSRI ممکن است باعث هايپررفلکسي، ضعف و عدم همکاري شوند. بيمار را مانيتور نماييد.


سوماتريپتان با اين دارو ممکن است اثرات تجمعي داشته باشند و باعث وازواسپاسم در عروق کرونري شوند. از مصرف همزمان اجتناب کنيد.


نيکوتين مي تواند باعث تشديد وازواسپاسم در برخي از بيماران شود. در طي مصرف دارو از استعمال دخانيات خودداري شود.

سایر اطلاعات

طبقه‌‌بندي درماني: ضد سردرد.


طبقه‌بندي مصرف در بارداري: رده X


اشكال دارويي:


Tablet: 1.5, 2.5 mg


Injection: 1 mg/ml


ملاحظات اختصاصي


علاوه بر ملاحظات مربوط به تمامي آلكالوئيدهاي ارگوت، رعايت موارد زير نيز توصيه مي شود:


1- مؤثرترين زمان مصرف دي هيدروارگوتامين هنگام بروز اولين علائم ميگرن، ‌يا بلافاصله بعد از شروع سردرد است.


2- در صورت بروز اسپاسم شديد عروقي، اندامها بايد گرم نگهداشته شوند و اقدامات حمايتي براي جلوگيري از آسيب بافتي بايد به عمل آيد. در صورت لزوم، بايد داروهاي گشاد كننده عروق (نيتروپروسايد، ‌پرازوسين، يا تولازولين) تجويز شود.


3- آمپولهاي حاوي دارو بايد از گرما و نور دور نگه داشته شود. در صورت تغيير رنگ دارو از مصرف آن خودداري شود.


4- اين دارو فقط براي مصرف كوتاه مدت تجويز مي شود. از تجويز مقادير زياد دارو بايد خودداري شود.


5- در صورت قطع مصرف دارو ممكن است سردرد واجهشي ارگوتاميني يا افزايش دفعات يا طول مدت سردردها بروز كند.


6- اين دارو براي درمان كمي فشار خون وضعيتي استفاده شده است.


7- مصرف همزمان با داروي مهاركننده CYP3A4 ممنوع است.


نكات قابل توصيه به بيمار


1- بعد از مصرف دارو، در يك اتاق آرام و تاريك دراز بكشيد.


2- در صورت بروز احساس بي حسي يا گزگز انگشتان دست و پا، يا تاولهاي قرمز يا بنفش بر روي دستها يا پاها، فوراً به پزشك اطلاع دهيد.


3- از مصرف الكل خودداري كنيد، زيرا ممكن است سردرد را تشديد كند.


4- كشيدن سيگار ممكن است عوارض جانبي دي هيدروارگوتامين را افزايش دهد. از كشيدن سيگار طي مصرف دارو خودداري كنيد.


5- طي مصرف اين دارو‌، از قرار گرفتن در هواي بسيار سرد خودداري كنيد. سرما ممكن است عوارض جانبي را افزايش دهد.


6- هرگونه بيماري يا عفونت را به پزشك اطلاع دهيد ، زيرا ممكن است حساسيت به واكنشهاي دارويي را افزايش دهد.


مصرف در سالمندان: مصرف اين دارو در افراد سالخورده بايد با احتياط همراه باشد، ‌زيرا اين بيماران نسبت به واكنشهاي دارويي حساس تر هستند.


مصرف در شيردهي: شيردهي طي درمان با دي هيدروارگوتامين توصيه نمي شود.


مصرف در بارداري: اين دارو اثرات اكسيتوسيك دارد. قبل از آغاز مصرف از عدم بارداري مطمئن شويد و خانمهاي در سن باروري را از تبعات دارو بر روي جنين آگاه سازيد.

Dihydroergotamine Mesylate Spray (Migranal)

MIGRANAL
(dihydroergotamine mesylate) Spray

WARNING

Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of DIHYDROERGOTAMINE with potent CYP 3A4 inhibitors including protease inhibitors and macrolide antibiotics. Because CYP 3A4 inhibition elevates the serum levels of DIHYDROERGOTAMINE, the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities is increased. Hence, concomitant use of these medications is contraindicated. (See also CONTRAINDICATIONS and WARNINGS section)

DRUG DESCRIPTION

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:

 MIGRANAL (dihydroergotamine mesylate) Structural Formula Illustration

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

What are the possible side effects of dihydroergotamine nasal (Migranal)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using dihydroergotamine and call your doctor at once if you have a serious side effect such as:

  • fast or slow heart rate;
  • chest pain or heavy feeling, pain spreading to the arm or shoulder, and nausea, sweating, or general ill feeling;
  • sudden numbness or weakness, sudden headache, confusion, or problems with vision, speech, or balance;
  • muscle pain in your arms or legs,...

Read All Potential Side Effects and See Pictures of Migranal »

Last reviewed on RxList: 5/11/2009
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

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.

DOSAGE AND ADMINISTRATION

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).

HOW SUPPLIED

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.

Last reviewed on RxList: 5/11/2009
This monograph has been modified to include the generic and brand name in many instances.

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

    Migranal®
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 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.

Read the Migranal (dihydroergotamine mesylate spray) Side Effects Center for a complete guide to possible side effects »

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.

Last reviewed on RxList: 5/11/2009
This monograph has been modified to include the generic and brand name in many instances.

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.

Last reviewed on RxList: 5/11/2009
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

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). *

CONTRAINDICATIONS

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.

Last reviewed on RxList: 5/11/2009
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Mechanism of Action

Dihydroergotamine binds with high affinity to 5-HT1Dα and 5-HT1Dβ receptors. It also binds with high affinity to serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors, noradrenaline α2A, α2B and α1 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

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.

Subpopulations

No studies have been conducted on the effect of renal or hepatic impairment, gender, race, or ethnicity on dihydroergotamine pharmacokinetics. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is contraindicated in patients with severely impaired hepatic or renal function. (See CONTRAINDICATIONS)

Interactions

The pharmacokinetics of dihydroergotamine did not appear to be significantly affected by the concomitant use of a local vasoconstrictor (e.g., fenoxazoline).

Multiple oral doses of the b-adrenoceptor antagonist propranolol, used for migraine prophylaxis, had no significant influence on the Cmax, Tmax or AUC of dihydroergotamine doses up to 4 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 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).

Table 1: Studies 1 and 2: Percentage of patients with headache responsea 2 and 4 hours following a single treatment of study medication [Migranal® (dihydroergotamine mesylate, USP) Nasal Spray or Placebo]

    N 2 hours 4 hours
Study 1 Migranal® 105 61% ** 70% **
Placebo 98 23% 28%
Study 2 Migranal® 103 47% 56% *
Placebo 102 33% 35%
aHeadache response was defined as a reduction in headache severity to mild or no pain. Headache response was based on pain intensity as interpreted by the patient using a four-point pain intensity scale.
*p value < 0.01
**p value < 0.01

Table 2: Studies 3 and 4: Percentage of patients with headache responsea 2 and 4 hours following a single treatment of study medication [Migranal® (dihydroergotamine mesylate, USP) Nasal Spray or Placebo]

    N 2 hours 4 hours
Study 3 Migranal® 50 32% 48% *
Placebo 50 20% 22%
Study 4 Migranal® 47 30% 47%
Placebo 50 20% 30%
a Headache response was defined as a reduction in headache severity to mild or no pain. Headache response was evaluated on a fivepoint scale that included both pain response and restoration of function for “severe” or “incapacitating” pain.
*p value < 0.01

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.

Figure 1 - Estimated Probability of a Patient Responding During the Four Hours Following a Single 2 mg Dose of Migranal (dihydroergotamine mesylate spray) ® (dihydroergotamine mesylate, USP) Nasal Spray as a function of the time elapsed since initiation of treatment*

 Estimated Probability of a Patient Response - Illustration

*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.

Figure 2 - Estimated Probability of a Patient Responding to Migranal® (dihydroergotamine mesylate, USP) Nasal Spray During the Four Hours Following Dosing*

 Estimated Probability of a Patient Response - Illustration 2

*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.

Figure 3 - Estimated Probability of a Patient Using Additional Treatments for Migraine Over the 24 Hours Following Either Migranal (dihydroergotamine mesylate spray) ® (dihydroergotamine mesylate, USP) Nasal Spray 2mg (or placebo)*

Estimated Probability of a Patient Using Additional Treatments for Migraine - Illustration

*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 spray) ® (dihydroergotamine mesylate, USP) Nasal Spray.

Last reviewed on RxList: 5/11/2009
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

Migranal®
(dihydroergotamine mesylate, USP) Nasal Spray.

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

Please read this information carefully before using your Migranal® (dihydroergotamine mesylate, USP) Nasal Spray for the first time. Keep this information handy for future reference. This leaflet does not contain all of the information on Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. Your pharmacist and/or health care provider can provide more detailed information.

Migranal® (dihydroergotamine mesylate, USP) Nasal Spray has been evaluated in a limited number of patients long term (e.g., 1 year or longer).

Purpose of your Medication

Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is intended to treat an active migraine headache. Do not try to use it to prevent a headache if you have no symptoms. Do not use it to treat common tension headache or a headache that is not at all typical of your usual migraine headache. Administration of Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray if you:

Important questions to consider before using Migranal® (dihydroergotamine mesylate, USP) Nasal Spray

Please answer the following questions before you use your Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray.

  • 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 a 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 a doctor's 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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray or other dihydroergotamine mesylate containing drugs on a daily basis?
  • Are you taking a protease inhibitor for HIV therapy?
  • Are you taking a macrolide class of antibiotic?

Serious or potentially life-threatening reductions in blood flow to the brain or extremities have been reported rarely due to interactions between Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) NASAL SPRAY.

Side Effects To Watch Out For

In clinical trials, most migraine patients have used Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. These side effects are temporary and usually do not require you to stop using Migranal (dihydroergotamine mesylate spray) ® (dihydroergotamine mesylate, USP) 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 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

Dosing Information

  • Each vial contains one complete dose of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, which is 1 spray in each nostril followed in 15 minutes by an additional spray in each nostril, for a total of 4 sprays.
  • Studies have shown no benefit from acute doses greater than 2.0 mg (4 sprays) for a single administration. The safety of doses greater than 3.0 mg in a 24 hour period has not been established.
  • The safety of doses greater than 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.

Learn what to do in case of an Overdose

If 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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray

  1. Use available training materials.
    • Read and follow the instructions in the administration instructions which are provided with the Migranal® (dihydroergotamine mesylate, USP) Nasal Spray package before attempting to use the product.
    • If there are any questions concerning the use of your Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, ask your doctor or pharmacist, or call the Migranal® (dihydroergotamine mesylate, USP) Nasal Spray Information Line at 1-888-MY-RELIEF (1-888-697-3543) for training in the use of the spray.
  2. Check the contents of the package:
    • 6 Nasal Spray Vials
    • 6 Nasal Sprayers
    • Administration Instructions
    • Package Insert
  3. 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 a 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.
  4. Using the sprayer:
    • Remove cap from spray unit. Holding the vial upright, point nasal sprayer away from face and pump 4 times before using. DO NOT PUMP MORE THAN 4 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 a full treatment of MIGRANAL (dihydroergotamine mesylate 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.
  5. After completing these instructions:
    • Carefully dispose of the nasal spray pump with the vial.
Important Notes:
  • Once a Migranal® (dihydroergotamine mesylate, USP) Nasal Spray vial has been opened, it must be thrown away after 8 hours. Storing Migranal® (dihydroergotamine mesylate, USP) Nasal Spray
  • Keep medication in a safe place away from children
  • Keep Migranal® (dihydroergotamine mesylate, USP) Nasal Spray away from heat and light.
  • Do not expose Migranal® (dihydroergotamine mesylate, USP) Nasal Spray to temperatures over 77°F.
  • Never refrigerate or freeze Migranal® (dihydroergotamine mesylate, USP) Nasal Spray.
  • Do not keep an opened Migranal® (dihydroergotamine mesylate, USP) Nasal Spray vial for more than 8 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 Migranal®(dihydroergotamine mesylate, USP) Nasal Spray

What if I need help in using my Migranal® (dihydroergotamine mesylate, USP) Nasal Spray?

If you have any questions or if you need help in opening, putting together, or using Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, speak to your doctor or pharmacist, or call the Migranal® (dihydroergotamine mesylate, USP) Nasal Spray Information Line at 1-888-MY-RELIEF (1-888-697-3543) or visit www.migranal (dihydroergotamine mesylate spray) .com.

How much medication should I use and how often?

Each vial contains one complete dose of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, which is 1 spray in each nostril, followed by an additional spray in each nostril 15 minutes later for a total of 4 sprays. Do not use more than this amount unless instructed to do so by your doctor. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is not intended for chronic daily use.

Why do I have to prime or pump the Nasal Sprayer 4 times before using? Am I wasting the medication?

You have to prime the Nasal Sprayer 4 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 a full dose of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray.

Can I assemble the medication vial and the Nasal Sprayer so it is ready before I need to use it?

No. 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 8 hours.

Can I reuse my Migranal (dihydroergotamine mesylate spray) ® (dihydroergotamine mesylate, USP) Nasal Sprayer?

No. After completing the full dose, you must carefully dispose of your Migranal® (dihydroergotamine mesylate, USP) Nasal Sprayer and the opened vial. You should use a new unit for your next migraine attack. Each Unit contains a new Nasal Sprayer, and a vial of Migranal (dihydroergotamine mesylate spray) ® (dihydroergotamine mesylate, USP) Nasal Spray medication.

Can I use Migranal® (dihydroergotamine mesylate, USP) Nasal Spray if I have a stuffy nose, cold, or allergies?

Yes. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray can be used if you have a stuffy nose, cold, or allergies. However, if you are taking any medications for your cold, or allergies, even those you can buy without a doctor's prescription, speak with your doctor before using Migranal® (dihydroergotamine mesylate, USP) Nasal Spray.

Do I need to sniff the medication when I spray it in my nostril?

No, you should not sniff because Migranal® (dihydroergotamine mesylate, USP) 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 Migranal (dihydroergotamine mesylate spray) ® (dihydroergotamine mesylate, USP) Nasal Spray, consult your doctor or pharmacist.

Last reviewed on RxList: 5/11/2009
This monograph has been modified to include the generic and brand name in many instances.

>

PATIENT INFORMATION

Migranal®
(dihydroergotamine mesylate, USP) Nasal Spray.

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

Please read this information carefully before using your Migranal® (dihydroergotamine mesylate, USP) Nasal Spray for the first time. Keep this information handy for future reference. This leaflet does not contain all of the information on Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. Your pharmacist and/or health care provider can provide more detailed information.

Migranal® (dihydroergotamine mesylate, USP) Nasal Spray has been evaluated in a limited number of patients long term (e.g., 1 year or longer).

Purpose of your Medication

Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is intended to treat an active migraine headache. Do not try to use it to prevent a headache if you have no symptoms. Do not use it to treat common tension headache or a headache that is not at all typical of your usual migraine headache. Administration of Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray if you:

Important questions to consider before using Migranal® (dihydroergotamine mesylate, USP) Nasal Spray

Please answer the following questions before you use your Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray.

  • 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 a 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 a doctor's 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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray or other dihydroergotamine mesylate containing drugs on a daily basis?
  • Are you taking a protease inhibitor for HIV therapy?
  • Are you taking a macrolide class of antibiotic?

Serious or potentially life-threatening reductions in blood flow to the brain or extremities have been reported rarely due to interactions between Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) NASAL SPRAY.

Side Effects To Watch Out For

In clinical trials, most migraine patients have used Migranal® (dihydroergotamine mesylate, USP) 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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. These side effects are temporary and usually do not require you to stop using Migranal (dihydroergotamine mesylate spray) ® (dihydroergotamine mesylate, USP) 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 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

Dosing Information

  • Each vial contains one complete dose of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, which is 1 spray in each nostril followed in 15 minutes by an additional spray in each nostril, for a total of 4 sprays.
  • Studies have shown no benefit from acute doses greater than 2.0 mg (4 sprays) for a single administration. The safety of doses greater than 3.0 mg in a 24 hour period has not been established.
  • The safety of doses greater than 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.

Learn what to do in case of an Overdose

If 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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray

  1. Use available training materials.
    • Read and follow the instructions in the administration instructions which are provided with the Migranal® (dihydroergotamine mesylate, USP) Nasal Spray package before attempting to use the product.
    • If there are any questions concerning the use of your Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, ask your doctor or pharmacist, or call the Migranal® (dihydroergotamine mesylate, USP) Nasal Spray Information Line at 1-888-MY-RELIEF (1-888-697-3543) for training in the use of the spray.
  2. Check the contents of the package:
    • 6 Nasal Spray Vials
    • 6 Nasal Sprayers
    • Administration Instructions
    • Package Insert
  3. 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 a 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.
  4. Using the sprayer:
    • Remove cap from spray unit. Holding the vial upright, point nasal sprayer away from face and pump 4 times before using. DO NOT PUMP MORE THAN 4 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 a full treatment of MIGRANAL (dihydroergotamine mesylate 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.
  5. After completing these instructions:
    • Carefully dispose of the nasal spray pump with the vial.
Important Notes:
  • Once a Migranal® (dihydroergotamine mesylate, USP) Nasal Spray vial has been opened, it must be thrown away after 8 hours. Storing Migranal® (dihydroergotamine mesylate, USP) Nasal Spray
  • Keep medication in a safe place away from children
  • Keep Migranal® (dihydroergotamine mesylate, USP) Nasal Spray away from heat and light.
  • Do not expose Migranal® (dihydroergotamine mesylate, USP) Nasal Spray to temperatures over 77°F.
  • Never refrigerate or freeze Migranal® (dihydroergotamine mesylate, USP) Nasal Spray.
  • Do not keep an opened Migranal® (dihydroergotamine mesylate, USP) Nasal Spray vial for more than 8 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 Migranal®(dihydroergotamine mesylate, USP) Nasal Spray

What if I need help in using my Migranal® (dihydroergotamine mesylate, USP) Nasal Spray?

If you have any questions or if you need help in opening, putting together, or using Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, speak to your doctor or pharmacist, or call the Migranal® (dihydroergotamine mesylate, USP) Nasal Spray Information Line at 1-888-MY-RELIEF (1-888-697-3543) or visit www.migranal (dihydroergotamine mesylate spray) .com.

How much medication should I use and how often?

Each vial contains one complete dose of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, which is 1 spray in each nostril, followed by an additional spray in each nostril 15 minutes later for a total of 4 sprays. Do not use more than this amount unless instructed to do so by your doctor. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is not intended for chronic daily use.

Why do I have to prime or pump the Nasal Sprayer 4 times before using? Am I wasting the medication?

You have to prime the Nasal Sprayer 4 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 a full dose of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray.

Can I assemble the medication vial and the Nasal Sprayer so it is ready before I need to use it?

No. 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 8 hours.

Can I reuse my Migranal (dihydroergotamine mesylate spray) ® (dihydroergotamine mesylate, USP) Nasal Sprayer?

No. After completing the full dose, you must carefully dispose of your Migranal® (dihydroergotamine mesylate, USP) Nasal Sprayer and the opened vial. You should use a new unit for your next migraine attack. Each Unit contains a new Nasal Sprayer, and a vial of Migranal (dihydroergotamine mesylate spray) ® (dihydroergotamine mesylate, USP) Nasal Spray medication.

Can I use Migranal® (dihydroergotamine mesylate, USP) Nasal Spray if I have a stuffy nose, cold, or allergies?

Yes. Migranal® (dihydroergotamine mesylate, USP) Nasal Spray can be used if you have a stuffy nose, cold, or allergies. However, if you are taking any medications for your cold, or allergies, even those you can buy without a doctor's prescription, speak with your doctor before using Migranal® (dihydroergotamine mesylate, USP) Nasal Spray.

Do I need to sniff the medication when I spray it in my nostril?

No, you should not sniff because Migranal® (dihydroergotamine mesylate, USP) 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 Migranal (dihydroergotamine mesylate spray) ® (dihydroergotamine mesylate, USP) Nasal Spray, consult your doctor or pharmacist.

Last reviewed on RxList: 5/11/2009
This monograph has been modified to include the generic and brand name in many instances.

MIGRANAL
(dihydroergotamine mesylate) Spray

WARNING

Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of DIHYDROERGOTAMINE with potent CYP 3A4 inhibitors including protease inhibitors and macrolide antibiotics. Because CYP 3A4 inhibition elevates the serum levels of DIHYDROERGOTAMINE, the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities is increased. Hence, concomitant use of these medications is contraindicated. (See also CONTRAINDICATIONS and WARNINGS section)

DRUG DESCRIPTION

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:

 MIGRANAL (dihydroergotamine mesylate) Structural Formula Illustration

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

Last reviewed on RxList: 5/11/2009
This monograph has been modified to include the generic and brand name in many instances.

MIGRANAL
(dihydroergotamine mesylate) Spray

WARNING

Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of DIHYDROERGOTAMINE with potent CYP 3A4 inhibitors including protease inhibitors and macrolide antibiotics. Because CYP 3A4 inhibition elevates the serum levels of DIHYDROERGOTAMINE, the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities is increased. Hence, concomitant use of these medications is contraindicated. (See also CONTRAINDICATIONS and WARNINGS section)

DRUG DESCRIPTION

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:

 MIGRANAL (dihydroergotamine mesylate) Structural Formula Illustration

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

Last reviewed on RxList: 5/11/2009
This monograph has been modified to include the generic and brand name in many instances.

MIGRANAL
(dihydroergotamine mesylate) Spray

WARNING

Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of DIHYDROERGOTAMINE with potent CYP 3A4 inhibitors including protease inhibitors and macrolide antibiotics. Because CYP 3A4 inhibition elevates the serum levels of DIHYDROERGOTAMINE, the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities is increased. Hence, concomitant use of these medications is contraindicated. (See also CONTRAINDICATIONS and WARNINGS section)

DRUG DESCRIPTION

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:

 MIGRANAL (dihydroergotamine mesylate) Structural Formula Illustration

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

Last reviewed on RxList: 5/11/2009
This monograph has been modified to include the generic and brand name in many instances.

Migranal Patient Information Including Side Effects

Brand Names: Migranal

Generic Name: dihydroergotamine (nasal) (Pronunciation: dye HYE droe er GOT a meen)

What is dihydroergotamine nasal (Migranal)?

Dihydroergotamine is in a group of drugs called ergot alkaloids (ER-got AL-ka-loids). It works by narrowing the blood vessels around the brain.

Dihydroergotamine nasal is used to a treat migraine headache attack.

This medication will only treat a migraine headache that has already begun. It will not prevent headaches or reduce the number of attacks.

Dihydroergotamine nasal should not be used to treat common tension headaches or any headache that seems to be different from your usual migraine headaches.

Dihydroergotamine nasal may also be used for other purposes not listed in this medication guide.

What are the possible side effects of dihydroergotamine nasal (Migranal)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using dihydroergotamine and call your doctor at once if you have a serious side effect such as:

  • fast or slow heart rate;
  • chest pain or heavy feeling, pain spreading to the arm or shoulder, and nausea, sweating, or general ill feeling;
  • sudden numbness or weakness, sudden headache, confusion, or problems with vision, speech, or balance;
  • muscle pain in your arms or legs, leg weakness;
  • numbness or tingling and a pale or blue-colored appearance in your fingers or toes;
  • swelling or itching in any part of your body;
  • stomach cramps, diarrhea that may be bloody;
  • cough with stabbing chest pain and trouble breathing; or
  • dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, confusion, chest pain, shortness of breath, uneven heartbeats, seizure).

Less serious side effects may include:

  • pain, soreness, burning, tingling, or dryness in your nose or throat;
  • runny or stuffy nose, nosebleeds;
  • changes in your sense of taste;
  • headache, dizziness, drowsiness;
  • feeling anxious or depressed;
  • cold sweats; or
  • nausea, vomiting.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Migranal (dihydroergotamine mesylate spray) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about dihydroergotamine nasal (Migranal)?

This medication can harm an unborn baby or a nursing baby. Do not use dihydroergotamine nasal if you are pregnant or breast-feeding.

Do not use this medication if you are allergic to dihydroergotamine or other ergot medicines, or if you have a history of heart disease, angina (chest pain), blood circulation problems, history of a heart attack or stroke, coronary artery disease, uncontrolled high blood pressure, severe liver or kidney disease, a serious infection, if you have recently had heart or blood vessel surgery.

Using certain medications together with dihydroergotamine can cause severe decreases in blood flow and lead to dangerous side effects. Tell your doctor about all other medications you are using, especially antibiotics, antidepressants, heart or blood pressure medications, or medicines to treat HIV or AIDS.

Also tell your doctor about all of your medical conditions, especially breathing problems, high blood pressure, ischemic bowel disease, liver or kidney disease, or risk factors for coronary artery disease (such as diabetes, menopause, smoking, being overweight, having high blood pressure or high cholesterol, having a family history of coronary artery disease, being older than 40 and a man, or being a woman who has had a hysterectomy).

Side Effects Centers

Migranal Patient Information including How Should I Take

What should I discuss with my healthcare provider before using dihydroergotamine nasal (Migranal)?

Do not use this medication if you are allergic to dihydroergotamine or other ergot medicine such as ergotamine (Ergomar, Ergostat, Cafergot, Ercaf, Wigraine), ergonovine (Ergotrate), methylergonovine (Methergine), or methysergide (Sansert).

Do not use dihydroergotamine nasal if you are pregnant or breast-feeding, or if you have:

  • a history of heart disease, angina (chest pain), blood circulation problems, coronary artery disease (hardening of the arteries), or history of a heart attack or stroke;
  • uncontrolled high blood pressure;
  • severe liver or kidney disease;
  • a serious infection called sepsis; or
  • if you have recently had heart or blood vessel surgery (such as bypass surgery).

Using certain medications together with dihydroergotamine can cause even greater decreases in blood flow than dihydroergotamine used alone. A severe decrease in blood flow to the brain and other parts of the body can lead to dangerous side effects. Do not use dihydroergotamine if you are also using any of the following medications:

  • conivaptan (Vaprisol);
  • diclofenac (Arthrotec, Cataflam, Voltaren, Flector Patch, Solareze);
  • imatinib (Gleevec);
  • isoniazid (for treating tuberculosis);
  • an antibiotic such as clarithromycin (Biaxin), dalfopristin/quinupristin (Synercid), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin), telithromycin (Ketek), or troleandomycin (Tao);
  • an antifungal medication such as clotrimazole (Mycelex Troche), itraconazole (Sporanox), ketoconazole (Nizoral), or voriconazole (Vfend);
  • an antidepressant such as nefazodone;
  • heart or blood pressure medication such as diltiazem (Cardizem, Dilacor, Tiazac), nicardipine (Cardene), quinidine (Quinaglute, Quinidex, Quin-Release), or verapamil (Calan, Covera, Isoptin, Verelan); or
  • HIV/AIDS medicine such as amprenavir (Agenerase), atazanavir (Reyataz), delavirdine (Rescriptor), fosamprenavir (Lexiva), indinavir (Crixivan), nelfinavir (Viracept), saquinavir (Invirase, Fortovase), or ritonavir (Norvir).

If you have certain conditions, you may need a dose adjustment or special tests to safely use this medication. Before using dihydroergotamine, tell your doctor if you have:

  • breathing problems;
  • high blood pressure;
  • ischemic bowel disease;
  • liver disease;
  • kidney disease; or
  • coronary artery disease (or risk factors that include diabetes, menopause, smoking, being overweight, having high blood pressure or high cholesterol, having a family history of coronary artery disease, being older than 40 and a man, or being a woman who has had a hysterectomy).

FDA pregnancy category X. This medication can cause birth defects. Do not use dihydroergotamine if you are pregnant. Tell your doctor right away if you become pregnant during treatment. Use an effective form of birth control while you are using this medication.

Dihydroergotamine passes into breast milk and may be harmful to a nursing infant. Dihydroergotamine may also decrease milk production. Do not use dihydroergotamine if you are breast-feeding a baby.

How should I use dihydroergotamine nasal (Migranal)?

Use this medication exactly as prescribed by your doctor. Never use more than your prescribed dose of dihydroergotamine nasal. Follow the directions on your prescription label. Tell your doctor if the medicine seems to stop working as well in treating your migraine attacks. Dihydroergotamine is not for daily use.

Dihydroergotamine nasal spray is absorbed quickly through your nasal passages and is for use only in the nose. The nasal spray liquid should not be injected into the body.

Your doctor may want to give your first dose of dihydroergotamine nasal in a hospital or clinic setting to quickly treat any serious side effects that occur.

Dihydroergotamine nasal comes in a bottle (vial) with a nasal sprayer attachment. Do not open the vial and attach the sprayer until you are ready to use the medication. A new vial and sprayer should be used for each new headache episode.

Before using the medication, prime the nasal spray by pumping exactly 4 sprays into the air.

Use the first dose of dihydroergotamine as soon as you notice headache symptoms, or after an attack has already begun. Use one spray in each nostril, and after 15 minutes use a second spray in each nostril, for a total of 4 sprays.

Do not tilt your head back while you are using the nasal spray, and do not sniff through your nose during use or just after use. Throw away the vial and sprayer after you finish using it to treat one headache episode, or no longer than 8 hours after opening the vial.

If you still have migraine symptoms after using a total of 4 sprays, call your doctor before using any more. Do not use more than 6 total sprays of dihydroergotamine nasal in any 24-hour period. Do not use more than 8 total sprays of this medication over a period of 7 days.

If you use dihydroergotamine nasal long-term, your doctor may want to check your heart function periodically using an electrocardiograph or ECG (sometimes called an EKG), a machine that measures electrical activity of the heart. This will help your doctor determine if it is still safe for you to use this medication. Do not miss any scheduled visits to your doctor.

Do not give this medication to anyone else, even if they have the same headache symptoms you have. Dihydroergotamine can be dangerous if it is used to treat headache in a person who has not been diagnosed by a doctor as having true migraine headaches.

Store dihydroergotamine nasal at room temperature away from moisture and heat. Do not refrigerate or freeze the nasal spray. Do not use any stored dihydroergotamine if the expiration date on the label has passed.

Side Effects Centers

Migranal Patient Information including If I Miss a Dose

What happens if I miss a dose (Migranal)?

Since dihydroergotamine is used on an as-needed basis, you are not likely to miss a dose.

What happens if I overdose (Migranal)?

Seek emergency medical attention if you think you have used too much of this medicine. An overdose of dihydroergotamine can be fatal.

Overdose can cause stomach pain, nausea, vomiting, confusion, weak or shallow breathing, numbness and tingling or pain in your hands or feet, blue-colored fingers or toes, fainting, and seizure (convulsions).

What should I avoid while using dihydroergotamine nasal (Migranal)?

  • another ergot medicine such as ergotamine (Ergomar, Ergostat, Cafergot, Ercaf, Wigraine), ergonovine (Ergotrate), methylergonovine (Methergine), or methysergide (Sansert); or
  • almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), sumatriptan (Imitrex), rizatriptan (Maxalt, Maxalt-MLT), or zolmitriptan (Zomig).

Grapefruit and grapefruit juice may interact with dihydroergotamine nasal and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor. Do not increase or decrease the amount of grapefruit products in your diet without first talking to your doctor.

What other drugs will affect dihydroergotamine nasal (Migranal)?

Many drugs can interact with dihydroergotamine. Below is just a partial list. Talk with your doctor before using dihydroergotamine nasal if you are also taking:

  • zileuton (Zyflo);
  • cold or allergy medications;
  • nicotine (Nicoderm, Nicorette);
  • diet pills, stimulants, or medication to treat ADHD (such as Ritalin or Adderall);
  • an antidepressant such as fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), nefazodone (Serzone), paroxetine (Paxil), sertraline (Zoloft), and others; or
  • heart or blood pressure medication such as atenolol (Tenormin), carvedilol (Coreg), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal, InnoPran), sotalol (Betapace), and others.

This list is not complete and there may be other drugs that can interact with dihydroergotamine. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

Where can I get more information?

Your pharmacist can provide more information about dihydroergotamine nasal.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 2.03. Revision date: 12/15/2010.

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