D.H.E. 45- dihydroergotamine mesylate injection, solution
Bausch Health US, LLC
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 (see CONTRAINDICATIONS and WARNINGS).
D.H.E. 45 is ergotamine hydrogenated in the 9, 10 position as the mesylate salt. D.H.E. 45 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 C33 H37 N5 O5 •CH4 O3 S.
The chemical structure is:
C33 H37 N5 O5 •CH4 O3 S Mol. Wt. 679.80
D.H.E. 45 (dihydroergotamine mesylate) Injection, USP is a clear, colorless solution supplied in sterile ampuls 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 binds with high affinity to 5-HT1D α and 5-HT1D β 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 arteriovenous 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).
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% to 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% 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.
No studies have been conducted on the effect of renal or hepatic impairment, gender, race, or ethnicity on dihydroergotamine pharmacokinetics. D.H.E. 45 (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 P4503A metabolism of the alkaloids by troleandomycin. Dihydroergotamine has also been shown to be an inhibitor of cytochrome P4503A 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 P4503A metabolism of ergotamine (see CONTRAINDICATIONS). No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known.
D.H.E. 45 (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).
D.H.E. 45 (dihydroergotamine mesylate) Injection, USP 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 D.H.E. 45 (dihydroergotamine mesylate) Injection, USP may increase blood pressure, it should not be given to patients with uncontrolled hypertension.
D.H.E. 45 (dihydroergotamine mesylate) Injection, USP, 5-HT1 agonists (e.g., sumatriptan), ergotamine-containing or ergot-type medications or methysergide should not be used within 24 hours of each other.
D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should not be administered to patients with hemiplegic or basilar migraine.
In addition to those conditions mentioned above, D.H.E. 45 (dihydroergotamine mesylate) Injection, USP is also contraindicated in patients with known peripheral arterial disease, sepsis, following vascular surgery and severely impaired hepatic or renal function.
D.H.E. 45 (dihydroergotamine mesylate) Injection, USP 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 embryofetal 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 embryofetal 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.
D.H.E. 45 (dihydroergotamine mesylate) Injection, USP is contraindicated in patients who have previously shown hypersensitivity to ergot alkaloids.
Dihydroergotamine mesylate should not be used by nursing mothers (see PRECAUTIONS).
Dihydroergotamine mesylate should not be used with peripheral and central vasoconstrictors because the combination may result in additive or synergistic elevation of blood pressure.
D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should only be used where a clear diagnosis of migraine headache has been established.
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 and 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.
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 D.H.E. 45 (dihydroergotamine mesylate) Injection, USP, should not exceed the dosing guidelines and should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION).
D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should not be used by patients with documented ischemic or vasospastic coronary artery disease (see CONTRAINDICATIONS). It is strongly recommended that D.H.E. 45 (dihydroergotamine mesylate) Injection, USP 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, D.H.E. 45 (dihydroergotamine mesylate) Injection, USP 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 D.H.E. 45 (dihydroergotamine mesylate)
Injection, USP 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 D.H.E. 45 (dihydroergotamine mesylate) Injection, USP in those patients with risk factors.
It is recommended that patients who are intermittent long-term users of D.H.E. 45 (dihydroergotamine mesylate) Injection, USP and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use D.H.E. 45 (dihydroergotamine mesylate) Injection, USP.
The systematic approach described above is currently recommended as a method to identify patients in whom D.H.E. 45 (dihydroergotamine mesylate) Injection, USP may be used to treat migraine headaches with an acceptable margin of cardiovascular safety.
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.
Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with D.H.E. 45 (dihydroergotamine mesylate) Injection, USP; and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the D.H.E. 45 (dihydroergotamine mesylate) Injection, USP 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).
D.H.E. 45 (dihydroergotamine mesylate) Injection, USP, like other ergot alkaloids, may cause vasospastic reactions other than coronary artery vasospasm. Myocardial, peripheral vascular, and colonic ischemia have been reported with D.H.E. 45 (dihydroergotamine mesylate) Injection, USP.
D.H.E. 45 (dihydroergotamine mesylate) Injection, USP 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. D.H.E. 45 (dihydroergotamine mesylate) Injection, USP should be discontinued immediately if signs or symptoms of vasoconstriction develop.
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