see contraindications and warnings . ssri's weakness, hyperreflexia, and incoordination have been reported rarely when 5-ht 1 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 dihydroergotamine mesylate. oral contraceptives the effect of oral contraceptives on the pharmacokinetics of dihydroergotamine mesylate has not been studied.

it 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. 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, usp, 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 should not be used by patients with documented ischemic or vasospastic coronary artery disease. (see contraindications .) it is strongly recommended that dihydroergotamine mesylate 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 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 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, in those patients with risk factors. it is recommended that patients who are intermittent long-term users of dihydroergotamine mesylate 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. the systematic approach described above is currently recommended as a method to identify patients in whom dihydroergotamine mesylate 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; and some have resulted in fatalities. in a number of cases, it appears possible that the cerebrovascular events were primary, the dihydroergotamine mesylate 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, 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. dihydroergotamine mesylate 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 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 is contraindicated in patients with uncontrolled hypertension. (see contraindications .) an 18% increase in mean pulmonary artery pressure was seen following dosing with another 5-ht 1 agonist in a study evaluating subjects undergoing cardiac catheterization.

orted. a causal relationship has not been established. dihydroergotamine mesylate is not recommended for prolonged daily use. (see dosage and administration .) to report suspected adverse reactions, contact sagent pharmaceuticals, inc. at 1-866-625-1618 or fda at 1-800-fda-1088 or www.fda.gov/medwatch .

see contraindications and warnings . ssri's weakness, hyperreflexia, and incoordination have been reported rarely when 5-ht 1 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 dihydroergotamine mesylate. oral contraceptives the effect of oral contraceptives on the pharmacokinetics of dihydroergotamine mesylate has not been studied.

ytocic properties. (see contraindications .) pharmacokinetics 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. 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% to 30% of plasma auc. 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. 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. subpopulations no studies have been conducted on the effect of renal or hepatic impairment, gender, race, or ethnicity on dihydroergotamine pharmacokinetics. dihydroergotamine mesylate is contraindicated in patients with severely impaired hepatic or renal function (see contraindications .) 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 (see contraindications ). no pharmacokinetic interactions involving other cytochrome p450 isoenzymes are known.

wing nasal administration, total metabolites represent only 20% to 30% of plasma auc. 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. 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. subpopulations no studies have been conducted on the effect of renal or hepatic impairment, gender, race, or ethnicity on dihydroergotamine pharmacokinetics. dihydroergotamine mesylate is contraindicated in patients with severely impaired hepatic or renal function (see contraindications .) 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 (see contraindications ). no pharmacokinetic interactions involving other cytochrome p450 isoenzymes are known.

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).

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