Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/241
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Dihydroergotamine Mesylate (Injection, Solution)
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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.
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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'��)-, monomethanesulfonate. Its molecular weight is 679.80 and its molecular formula is CHNO���CHOS. 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.
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Mechanism of Action: Dihydroergotamine binds with high affinity to 5-HTand 5-HTreceptors. It also binds with high affinity to serotonin 5-HT, 5-HT, and 5-HTreceptors, noradrenaline��,��and��receptors, and dopamine Dand Dreceptors. The therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effect at 5-HTreceptors. Two current theories have been proposed to explain the efficacy of 5-HTreceptor agonists in migraine. One theory suggests that activation of 5-HTreceptors 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-HTreceptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release. In addition, dihydroergotamine possesses oxytocic properties.<br/>Pharmacokinetics:<br/>Absorption: 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.<br/>Distribution: Dihydroergotamine mesylate is 93% plasma protein bound. The apparent steady-state volume of distribution is approximately 800 liters.<br/>Metabolism: Four dihydroergotamine mesylate metabolites have been identified in human plasma following oral administration. The major metabolite, 8'-��-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.<br/>Excretion: 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.<br/>Subpopulations: 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.<br/>Interactions: 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 . No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known.
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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. Packages of 5: NDC 0574-0850-05Packages of 10: NDC 0574-0850-10 Store at 20 to 25��C (68 to 77��F). Excursions permitted between 15 to 30��C (59 to 86��F) [See USP Controlled Room Temperature]. Do not refrigerate or freeze. To assure constant potency, protect the ampules from light and heat. Use carton to protect contents from light until used. Administer only if clear and colorless.
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WARNING: Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of DIHYDROERGOTAMINE with potent CYP3A4 inhibitors including protease inhibitors and macrolide antibiotics. Because CYP3A4 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.
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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, USP 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, USP overdose are similar to those of an ergotamine overdose, although there is less pronounced nausea and vomiting with Dihydroergotamine Mesylate Injection, USP. 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 Physician's Desk Reference (PDR).
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Dihydroergotamine Mesylate
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Dihydroergotamine Mesylate (Injection, Solution)
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Serious cardiac events, including some that have been fatal, have occurred following use of Dihydroergotamine Mesylate Injection, USP, but are extremely rare. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation. . Fibrotic complications have been reported in association with long term use of injectable dihydroergotamine mesylate .<br/>Post-Introduction Reports: The following events derived from postmarketing experience have been occasionally reported in patients receiving Dihydroergotamine Mesylate Injection, USP: 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, USP is not recommended for prolonged daily use.
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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.
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Dihydroergotamine Mesylate
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