Dihydroergotamine injection

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, swelling or itching in any part of your body;

• chest 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;

• leg weakness, muscle pain in your arms or legs;

• numbness, tingling, and a pale or blue-colored appearance in your fingers or toes;

• 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).

Less serious side effects may include:

• headache, dizziness, feeling anxious;

• diarrhea;

• sweating, mild skin rash, redness or tingly feeling under your skin.

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.

• Most of the time, dihydroergotamine injection will be given in a hospital or doctor's office. If stored at home, follow how to store as you were told by the doctor.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Dihydroergotamine Mesylate is ergotamine hydrogenated in the 9, 10 position as the mesylate salt. Dihydroergotamine Mesylate 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 molecular formula is C33H37N5O5•CH4O3S.

The chemical structure is:

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 - 4.9.

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

Absolute bioavailability for the subcutaneous and intramuscular route have not been determined, however, no difference was observed in dihydroergotamine bioavailability from intramuscular and subcutaneous doses. Dihydroergotamine mesylate is poorly bioavailable following oral administration.

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

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. Quantitative pharmacokinetic characterization of the four metabolites has not been performed.

The major excretory route of dihydroergotamine is via the bile in the feces. The total body clearance is 1.5 L/min which reflects mainly hepatic clearance. Only 6%-7% of unchanged dihydroergotamine is excreted in the urine after intramuscular injection. The renal clearance (0.1 L/min) is unaffected by the route of dihydroergotamine administration. The decline of plasma dihydroergotamine after intramuscular or intravenous administration is multi-exponential with a terminal half-life of about 9 hours.

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

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.

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.

Dihydroergotamine Mesylate Injection, USP 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 is used to treat migraine headaches and cluster headaches. It is not recommended for migraines that affect only one side of the brain (hemiplegic migraine) or the base of the brain/neck area (basilar migraine), or to prevent migraines from occurring.

Dihydroergotamine is an ergot medication that helps narrow widened blood vessels in the head, thereby reducing the throbbing effects of these headaches.

How to use Dihydroergotamine MESYLATE Ampul

Read the Patient Information Leaflet provided by your pharmacist before you start using dihydroergotamine and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Inject this medication into a vein, into a muscle, or under the skin as directed by your doctor. Dosage is based on your medical condition and response to treatment. Usually, this medication should be used only as needed. It is not meant for long-term daily use. This medication works best if it is taken as the first signs of the headache occur. If you wait until the headache has worsened, the medication may not work as well.

If your headache returns or you have no relief from the first dose, you may repeat the dose 1 hour after the first dose, but only if instructed to do so by your doctor.

If this medication is given into a muscle or under the skin, a third dose may be given 1 hour after the second dose if needed. Do not use more than 3 milliliters in 24 hours or 6 milliliters in a week.

If this medication is given into a vein, do not use more than 2 milliliters in 24 hours or 6 milliliters in a week.

If you are giving this medication to yourself at home, learn all preparation and usage instructions from your health care professional. The solution is normally clear and colorless. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid. Learn how to store and discard medical supplies safely.

Other "ergot" drugs (e.g., ergotamine, methysergide), or "triptan-type" drugs (e.g., sumatriptan) should not be used within 24 hours of this drug.

If you are using drugs for migraine attacks on 10 or more days each month, the drugs may actually make your headaches worse (medication overuse headache). Do not use medications more often or for longer than directed. Tell your doctor if you need to use this medication more often, or if the medication is not working as well, or if your headaches get worse.

See also Warning and How to Use sections.

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include: bronchodilators/decongestants/stimulants (such as epinephrine, pseudoephedrine, methylphenidate, amphetamine).

If you also take "triptan" migraine drugs (e.g., sumatriptan, rizatriptan), you will need to separate your "triptan" dose from your dose of this medication to reduce the risk of serious side effects. Ask your doctor how long you should wait between your doses of these drugs.

Some products have ingredients that could raise your heart rate or blood pressure. Tell your pharmacist what products you are using, and ask how to use them safely (especially cough-and-cold products, diet aids, or other migraine medications).

Use in patients with severe renal dysfunction is contraindicated.

Data not available