Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/115
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Dihydroergotamine Mesylate (Injection)
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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 beused for chronic daily administration. Parenteral drug products should be inspected visually for particulate matter and discoloration, whenever solution and container permit.
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Dihydroergotamine mesylate is ergotamine hydrogenated in the 9, 10 position as the mesylate salt. Dihydroergotamine mesylate is known chemically as dihydroergotamine monomethanesulfonate. Its molecular weight is 679.78 and its molecular formula is CHNO���CHOS. Its structural formula is: Dihydroergotamine Mesylate Injection is a sterile, clear, colorless solution in sterile vials for IV, IM, or subcutaneous administration. Each mL contains dihydroergotamine mesylate USP 1 mg, alcohol 6% (v/v), glycerin 153.6 mg, and water for injection, qs. Methanesulfonic acid and/or sodium hydroxide added to adjust pH to a range of 3.4 to 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% to 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% to 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 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 ergtomine) 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, crythromycin), and in patients treated with dihydroergotamine and protease inhibitors (e.g. ritonavir), presumably due to inhibition of cytochrome P450 3A metabolism of ergotamine . No pharmacokinectic interactions involving other cytochrome P450 isoenzymes are known.
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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. Dihydroergotamine mesylate injection 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. Because dihydroergotamine mesylate injection may increase blood pressure, it should not be given to patients with uncontrolled hypertension. Dihydroergotamine mesylate injection, 5-HTagonists (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 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 embryo-fetal 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 to 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. Dihydroergotamine mesylate injection is contraindicated in patients who have previously shown hypersensitivity to ergot alkaloids. Dihydroergotamine mesylate should not be used by nursing mothers. Dihydroergotamine mesylate should not be used with peripheral and central vasoconstrictors because the combination may result in additive or synergistic elevation of blood pressure.
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Dihydroergotamine Mesylate Injection USP is available as a clear, colorless, sterile solution in single 1 mL sterile vials; each mL containing 1 mg of dihydroergotamine mesylate, in cartons of 10 (NDC 55390-013-10). Store at 20��to 25��C (68��to 77��F). See USP controlled room temperature, in light-resistant containers. Do not refrigerate or freeze. To assure constant potency, protect the vials from light and heat. 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 CYP 3A4 inhibitors including protease inhibitors and macrolide antibiotics. Because CYP 3A4 inhibition elevates the serum levels of DIHYDROERGOTAMINE, the risk for vasospasm leadingto cerebral ischemia and/or ischemia of the extremities is increased. Hence, concomitant use of these medications is contraindicated.
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General: Dihydroergotamine mesylate injection 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.<br/>Fibrotic Complications: See WARNINGS: Fibrotic Complications.<br/>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 dihydroergotamine mesylate injection, the information and instructions provided in the patient information sheet should be discussed with patients. 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 dihydroergotamine mesylate injection should not exceed the dosing guidelines and should not be used for chronic daily administration<br/>Drug Interactions:<br/>Vasoconstrictors: Dihydroergotamine mesylate injection should not be used with peripheral vasoconstrictors because the combination may cause synergistic elevation of blood pressure.<br/>Sumatriptan: Sumatriptan has been reported to cause coronary artery vasospasm, and its effect could be additive with dihydroergotamine mesylate injection. Sumatriptan and dihydroergotamine mesylate injection should not be taken within 24 hours of each other.<br/>Beta Blockers: Although the results of a clinical study did not indicate a safety problem associated with the administration of dihydroergotamine mesylate injection 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.<br/>Nicotine: Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy.<br/>CYP 3A4 Inhibitors: (e.g. Macrolide Antibiotics and Protease Inhibitors) See CONTRAINDICATIONS and WARNINGS.<br/>SSRI's: Weakness, hyperreflexia, and incoordination have been reported rarely when 5-HTagonists 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 dihydroergotamine mesylate injection.<br/>Oral Contraceptives: The effect of oral contraceptives on the pharmacokinetics of dihydroergotamine mesylate injection has not been studied.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: Assessment of the carcinogenic potential of dihydroergotamine mesylate in mice and rats is ongoing.<br/>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.<br/>Impairment of Fertility: Impairment of fertility was not evaluated for dihydroergotamine mesylate injection. There was no evidence of impairment of fertility in rats given intranasal doses of Migranal' 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).<br/>Pregnancy:<br/>Teratogenic Effects; Pregnancy Category X: See CONTRAINDICATIONS.<br/>Nursing Mothers: Ergot drugs are known to inhibit prolactin. It is likely that dihydroergotamine mesylate injection 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 dihydroergotamine mesylate injection nursing should not be undertaken with the use of dihydroergotamine mesylate injection.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
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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 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 IV 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)
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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. Fibrotic complications have been reported in association with long term use of injectabledihydroergotamine mesylate<br/>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.
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Dihydroergotamine mesylate injection should only be used where a clear diagnosis of migraine headache has been established.<br/>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 ischemia of the extremities. The use of potent CYP 3A4 inhibitors with dihydroergotamine should therefore be avoided Examples of some of the more potent CYP 3A4 inhibitors include: anti-fungals 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 CYP 3A4 of other agents being considered for concomitant use with dihydroergotamine.<br/>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<br/>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. 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. 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 begiven 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.<br/>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.<br/>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).<br/>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.<br/>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. An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5-HTagonist in a study evaluating subjects undergoing cardiac catheterization.
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Dihydroergotamine mesylate injection 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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