Dihydroergotamine Mesylate Injection, USP is ergotamine hydrogenated in the 9, 10 position as the mesylate salt. Dihydroergotamine Mesylate Injection, USP  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

Dihydroergotamine mesylate

C33H37N5O5•CH4O3S            Mol. wt. 679.80

Dihydroergotamine Mesylate Injection, USP is a clear, colorless solution supplied in sterile ampules for intravenous, intramuscular, or subcutaneous administration. Each mL contains 1 mg Dihydroergotamine Mesylate, USP; Alcohol, USP 6.1% by volume; Glycerin, USP 15% by weight; Water for Injection, USP; Methanesulfonic Acid and/or Sodium Hydroxide for pH adjustment (pH range is 3.4 to 4.9).

Dihydroergotamine Mesylate Injection, USP is indicated for the acute treatment of migraine headaches with or without aura and the acute treatment of cluster headache episodes.

There have been a few reports of serious adverse events associated with the coadministration of dihydroergotamine and potent CYP3A4 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 CYP3A4 inhibitors (i.e., ritonavir, nelfinavir, indinavir, erythromycin, clarithromycin, troleandomycin, ketoconazole, itraconazole) with dihydroergotamine is, therefore contraindicated (See WARNINGS, CYP3A4  Inhibitors).

Dihydroergotamine mesylate injection should not be given to patients with ischemic heart disease (e.g., angina pectoris, history of myocardial infarction, or documented silent ischemia) or to patients who have clinical symptoms or findings consistent with coronary artery vasospasm including Prinzmetal's variant angina. (See WARNINGS).

Because dihydroergotamine mesylate injection may increase blood pressure, it should not be given to patients with uncontrolled hypertension.

Dihydroergotamine mesylate injection, 5-HT1 agonists (e.g., sumatriptan), ergotamine-containing or ergot-type medications or methysergide should not be used within 24 hours of each other.

Dihydroergotamine mesylate injection should not be administered to patients with hemiplegic or basilar migraine.

In addition to those conditions mentioned above, dihydroergotamine mesylate injection is also contraindicated in patients with known peripheral arterial disease, sepsis, following vascular surgery and severely impaired hepatic or renal function.

Dihydroergotamine mesylate injection is contraindicated in patients who have previously shown hypersensitivity to ergot alkaloids.

Dihydroergotamine mesylate should not be used with peripheral and central vasoconstrictors because the combination may result in additive or synergistic elevation of blood pressure.

Dihydroergotamine mesylate injection should only be used where a clear diagnosis of migraine headache has been established.

CYP3A4 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 CYP3A4 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 CYP3A4 inhibitors with dihydroergotamine should therefore be avoided (see CONTRAINDICATIONS). Examples of some of the more potent CYP3A4 inhibitors include: antifungals ketoconazole and itraconazole, the protease inhibitors ritonavir, nelfinavir, and indinavir, and macrolide antibiotics erythromycin, clarithromycin, and troleandomycin. Other less potent CYP3A4 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 Dihydroergotamine Mesylate Injection, should not exceed the dosing guidelines and should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION).

Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events

Dihydroergotamine mesylate injection should not be used by patients with documented ischemic or vasospastic coronary artery disease. (See CONTRAINDICATIONS). It is strongly recommended that dihydroergotamine mesylate injection not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, females who are surgically or physiologically postmenopausal, or males who are over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient's medical history or electrocardiographic investigations reveal findings indicative of or consistent with coronary artery vasospasm or myocardial ischemia, dihydroergotamine mesylate injection should not be administered. (See CONTRAINDICATIONS).

For patients with risk factors predictive of CAD who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of dihydroergotamine mesylate injection take place in the setting of a physician's office or similar medically staffed and equipped facility unless the patient has previously received dihydroergotamine mesylate. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following dihydroergotamine mesylate injection, in those patients with risk factors.

It is recommended that patients who are intermittent long-term users of dihydroergotamine mesylate injection and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use dihydroergotamine mesylate injection .

The systematic approach described above is currently recommended as a method to identify patients in whom dihydroergotamine mesylate injection may be used to treat migraine headaches with an acceptable margin of cardiovascular safety.

Cardiac Events and Fatalities

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. 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 dihydroergotamine mesylate injection; and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the dihydroergotamine mesylate injection having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack).

Other Vasospasm Related Events

Dihydroergotamine mesylate injection, like other ergot alkaloids, may cause vasospastic reactions other than coronary artery vasospasm. Myocardial, peripheral vascular, and colonic ischemia have been reported with dihydroergotamine mesylate injection.

Dihydroergotamine mesylate injection associated vasospastic phenomena may also cause muscle pains, numbness, coldness, pallor, and cyanosis of the digits. In patients with compromised circulation, persistent vasospasm may result in gangrene or death. Dihydroergotamine mesylate injection should be discontinued immediately if signs or symptoms of vasoconstriction develop.

Increase In Blood Pressure

Significant elevation in blood pressure has been reported on rare occasions in patients with and without a history of hypertension treated with dihydroergotamine mesylate injection. Dihydroergotamine mesylate injection is contraindicated in patients with uncontrolled hypertension. (See CONTRAINDICATIONS).

An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5-HT1 agonist in a study evaluating subjects undergoing cardiac catheterization.

Medication Overuse Headache

Overuse of acute migraine drugs (e.g., ergotamines, triptans, opioids, or a combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (i.e., medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients including withdrawal of the overused drugs and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.

Preterm Labor

Based on the mechanism of action of dihydroergotamine and findings from the published literature, Dihydroergotamine Mesylate Injection may cause preterm labor. Avoid use of Dihydroergotamine Mesylate Injection during pregnancy (see PRECAUTIONS).

Serious cardiac events, including some that have been fatal, have occurred following use of dihydroergotamine mesylate 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).

Post-introduction Reports

The following events derived from postmarketing experience have been occasionally reported in patients receiving dihydroergotamine mesylate injection: vasospasm, paraesthesia, hypertension, dizziness, anxiety, dyspnea, headache, flushing, diarrhea, rash, increased sweating, and pleural and retroperitoneal fibrosis after long-term use of dihydroergotamine. Extremely rare cases of myocardial infarction and stroke have been reported. A causal relationship has not been established.

Dihydroergotamine mesylate injection is not recommended for prolonged daily use. (See DOSAGE AND ADMINISTRATION).

To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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

To date, there have been no reports of acute overdosage with this drug. Due to the risk of vascular spasm, exceeding the recommended dosages of dihydroergotamine mesylate injection 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 dihydroergotamine mesylate injection overdose are similar to those of an ergotamine overdose, although there is less pronounced nausea and vomiting with dihydroergotamine mesylate injection. 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 (PDR).*

Dihydroergotamine Mesylate Injection should be administered in a dose of 1 mL intravenously, intramuscularly or subcutaneously. The dose can be repeated, as needed, at 1 hour intervals to a total dose of 3 mL for intramuscular or subcutaneous delivery or 2 mL for intravenous delivery in a 24 hour period. The total weekly dosage should not exceed 6 mL. Dihydroergotamine Mesylate Injection, should not be used for chronic daily administration.

Dihydroergotamine Mesylate Injection, USP

Available as a clear, colorless, sterile solution in single 1 mL sterile ampules containing 1 mg of dihydroergotamine mesylate per mL, in packages of 10 (NDC 0143-9273-10). Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15° to 30ºC (59º to 86ºF) [See USP Controlled Room Temperature]. Use carton to protect contents from light until used.

Do not refrigerate or freeze. To assure constant potency, protect the ampules from light and heat. Administer only if clear and colorless.

Information for the Patient

Dihydroergotamine Mesylate Injection, USP

Before self-injecting Dihydroergotamine Mesylate Injection, USP by subcutaneous administration, you will need to obtain professional instruction on how to properly administer your medication. Below are some of the steps you should follow carefully. Read this leaflet completely before using this medication.

This leaflet does not contain all of the information on Dihydroergotamine Mesylate Injection, USP. Your pharmacist and/or health care provider can provide more detailed information.

Purpose of your Medication

Dihydroergotamine Mesylate Injection, USP 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 Dihydroergotamine Mesylate Injection, USP 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 Dihydroergotamine Mesylate Injection, USP 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 Dihydroergotamine Mesylate Injection, USP if you:

• have any disease affecting your heart, arteries, or circulation.
• are taking certain anti-HIV medications (protease inhibitors).
• are taking a macrolide antibiotic such as troleandomycin, clarithromycin or erythromycin.

Important questions to consider before using

Dihydroergotamine Mesylate Injection, USP

Please answer the following questions before you use your Dihydroergotamine Mesylate Injection, USP.

If you answer YES to any of these questions or are unsure of the answer, you should talk to your doctor before using Dihydroergotamine Mesylate Injection, USP.

• 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 you are 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?
  • Dihydroergotamine Mesylate Injection, USP may cause preterm labor. Dihydroergotamine Mesylate Injection, USP should be avoided during pregnancy. Talk to your healthcare provider right away if you are pregnant or want to become pregnant.
• Are you breastfeeding?
  • Dihydroergotamine Mesylate Injection, USP may reduce breast milk supply and pass into your breast milk. Dihydroergotamine Mesylate Injection, USP may be harmful to your baby. Do not breastfeed your baby while taking
  • Dihydroergotamine Mesylate Injection, USP and for 3 days after you use Dihydroergotamine Mesylate Injection, USP. Talk with your healthcare provider about the best way to feed your baby if you take Dihydroergotamine Mesylate Injection, USP.
• 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 Dihydroergotamine Mesylate Injection, USP 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 Dihydroergotamine Mesylate Injection, USP and protease inhibitors or macrolide antibiotics.

REMEMBER TO TELL YOUR DOCTOR IF YOU HAVE ANSWERED "YES" TO ANY OF THESE QUESTIONS BEFORE YOU USE Dihydroergotamine Mesylate Injection, USP

Side Effects To Watch Out For

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.

Dosage

Your doctor will have told you what dose to use for each migraine attack. Should you get another migraine attack in the same day as the attack you treated, you must not treat it with Dihydroergotamine Mesylate Injection, USP unless at least 6 hours have elapsed since your last injection. No more than 6 mL of Dihydroergotamine Mesylate Injection, USP should be injected during a one-week period. Dihydroergotamine Mesylate Injection, USP is not intended to be used on a prolonged daily basis.

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 Dihydroergotamine Mesylate Injection, USP

1. Use available training materials.

• Read and follow the instructions in the patient instruction booklet which is provided with the Dihydroergotamine Mesylate Injection, USP package before attempting to use the product.
• If there are any questions concerning the use of your Dihydroergotamine Mesylate Injection, USP, ask your Doctor or pharmacist.

2. Preparing for the Injection

• Carefully examine the ampule (glass vial) of Dihydroergotamine Mesylate Injection, USP for any cracks or breaks, and the liquid for discoloration, cloudiness, or particles. If any of these defects are present, use a new ampule, make certain it is intact, and return the defective ampule to your doctor or pharmacy. Once you open an ampule, if it is not used within an hour, it should be thrown away.

3. Locating an Injection Site

• Administer your subcutaneous injection in the middle of your thigh, well above the knee.

4. Drawing the Medication into the Syringe

   A. Wash your hands thoroughly with soap and water.

   B. Check the dose of your medication.

   C. Look to see if there is any liquid at the top of the ampule. If there is, gently flick the ampule with your finger to get all the liquid into the bottom portion of the ampule.

   D. Hold the bottom of the ampule in one hand. Clean the ampule neck with an alcohol wipe using the other hand. To break, place the alcohol wipe around the neck of the ampule and break it open by pressing your thumb against the neck of the ampule.

   E. Tilt the ampule down at a 45º angle. Insert the needle into the solution in the ampule.

   F. Draw up the medication by pulling back the plunger slowly and steadily until you reach your dose.

   G. Check the syringe for air bubbles. Hold it with the needle pointing upward. If there are air bubbles, tap your finger against the barrel of the syringe to get the bubbles to the top. Slowly and carefully push the plunger up so that the bubbles are pushed out through the needle and you see a drop of medication.

   H. When there are no air bubbles, check the dose of the medication. If the dose is incorrect, repeat steps E, F, G and H until you draw up the right dose.

5. Preparing the Injection Site

• With a new alcohol wipe, clean the selected injection site thoroughly with a firm, circular motion from inside to outside. Wait for the injection site to dry before injecting.

6. Administering the Injection

• Hold the syringe/needle in your right hand.
• With your left hand, firmly grasp about a 1-inch fold of skin at the injection site.
• Push the needle shaft, bevel side up, all the way into the fold of skin at a 45º to 90º angle, then release the fold of skin.
• While holding the syringe with your left hand, use your right hand to draw back slightly on the plunger.
• If you do not see any blood coming back into the syringe, inject the medication by pushing down on the plunger. If you do see blood in the syringe, that means the needle has penetrated a vein. If this happens, pull the needle/syringe out of the skin slightly and draw back on the plunger again. If no blood is seen this time, inject the medication.
• Use your right hand to pull the needle out of your skin quickly at the same angle you injected it. Immediately press the alcohol wipe on the injection site and rub.

Check the expiration date printed on the ampule containing medication. If the expiration date has passed, do not use it.

Answers to Patients' Questions About Dihydroergotamine Mesylate Injection, USP

What if I need help in using my Dihydroergotamine Mesylate Injection, USP?

If you have any questions or if you need help in opening, putting together, or using Dihydroergotamine Mesylate Injection, USP, speak to your doctor or pharmacist.

How much medication should I use and how often?

Your doctor will have told you what dose to use for each migraine attack. Should you get another migraine attack in the same day as the attack you treated, you must not treat it with Dihydroergotamine Mesylate Injection, USP unless at least 6 hours have elapsed since your last injection. No more than 6 mL of Dihydroergotamine Mesylate Injection, USP should be injected during a one-week period. Do not use more than this amount unless instructed to do so by your doctor. Dihydroergotamine Mesylate Injection, USP is not intended for chronic daily use.

If you have any other unanswered questions about Dihydroergotamine Mesylate Injection, USP, consult your doctor or pharmacist.

*Trademark of PDR Network, LLC

Manufactured by:

Hikma Farmacêutica (Portugal), S.A.

Estrada do Rio da Mó 8, 8A e 8B – Fervença          

2705-906 Terrugem – Sintra, Portugal

Distributed by:

Hikma Pharmaceuticals USA Inc.

Berkeley Heights, NJ 07922

Revised: May 2022

PIN482-WES/3

NDC 0143-9273-01   Rx only

Dihydroergotamine

Mesylate Injection, USP

1 mg/mL

For IV, IM or SC use

1 mL Single Dose Ampule

NDC 0143-9273-10   Rx only

Dihydroergotamine

Mesylate Injection, USP

1 mg/mL

(1 mL ampule)

For Intravenous, Intramuscular or Subcutaneous use

10 x 1 mL Single Dose Ampules