Dihydroergotamine Mesylate

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Overview

What is Dihydroergotamine Mesylate?

Dihydroergotamine mesylate, USP is ergotamine hydrogenated in the 9,10 position as the mesylate salt. Dihydroergotamine mesylate, USP 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 CHNO•CHOS.

The chemical structure is:

Dihydroergotamine Mesylate, USP Nasal Spray is provided for intranasal administration as a clear, colorless to faintly yellow solution in an amber glass vial containing:

What does Dihydroergotamine Mesylate look like?

What are the available doses of Dihydroergotamine Mesylate?

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What should I talk to my health care provider before I take Dihydroergotamine Mesylate?

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How should I use Dihydroergotamine Mesylate?

Dihydroergotamine Mesylate, USP Nasal Spray is indicated for the acute treatment of migraine headaches with or without aura.

Dihydroergotamine Mesylate, USP Nasal Spray is not intended for the prophylactic therapy of migraine or for the management of hemiplegic or basilar migraine.

The solution used in Dihydroergotamine Mesylate, USP Nasal Spray (4 mg/mL) is intended for intranasal use and must not be injected.

In clinical trials, Dihydroergotamine Mesylate, USP Nasal Spray has been effective for the acute treatment of migraine headaches with or without aura. One spray (0.5 mg) of Dihydroergotamine Mesylate, USP Nasal Spray should be administered in each nostril. Fifteen minutes later, an additional one spray (0.5 mg) of Dihydroergotamine Mesylate, USP Nasal Spray should be administered in each nostril, for a total dosage of four sprays (2.0 mg) of Dihydroergotamine Mesylate, USP Nasal Spray. Studies have shown no additional benefit from acute doses greater than 2.0 mg for a single migraine administration. The safety of doses greater than 3.0 mg in a 24 hour period and 4.0 mg in a 7 day period has not been established.

Dihydroergotamine Mesylate, USP Nasal Spray, should not be used for chronic daily administration.

Prior to administration, the pump must be primed (i.e., squeeze 4 times) before use. (See administration instructions).

Once the nasal spray applicator has been prepared, it should be discarded (with any remaining drug in opened vial) after 8 hours.

What interacts with Dihydroergotamine Mesylate?

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 (See ).

Dihydroergotamine Mesylate, USP Nasal Spray 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. (See )

Because Dihydroergotamine Mesylate, USP Nasal Spray may increase blood pressure, it should not be given to patients with uncontrolled hypertension.

Dihydroergotamine Mesylate, USP Nasal Spray, 5-HT1 agonists (e.g., sumatriptan), ergotamine-containing or ergot-type medications or methysergide should not be used within 24 hours of each other.

Dihydroergotamine Mesylate, USP Nasal Spray should not be administered to patients with hemiplegic or basilar migraine.

In addition to those conditions mentioned above, Dihydroergotamine Mesylate, USP Nasal Spray is also contraindicated in patients with known peripheral arterial disease, sepsis, following vascular surgery, and severely impaired hepatic or renal function.

Dihydroergotamine Mesylate, USP Nasal Spray 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, USP 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 -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, USP 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, USP Nasal Spray is contraindicated in patients who have previously shown hypersensitivity to ergot alkaloids.

Dihydroergotamine mesylate should not be used by nursing mothers. (See )

Dihydroergotamine mesylate should not be used with peripheral and central vasoconstrictors because the combination may result in additive or synergistic elevation of blood pressure.

What are the warnings of Dihydroergotamine Mesylate?

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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 and 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: antifungals 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.

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, USP Nasal Spray, should not exceed the dosing guidelines and should not be used for chronic daily administration (see ).

Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events:

Dihydroergotamine Mesylate, USP Nasal Spray should not be used by patients with documented ischemic or vasospastic coronary artery disease. It is strongly recommended that Dihydroergotamine Mesylate, USP Nasal Spray 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, USP Nasal Spray 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, USP Nasal Spray 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, USP Nasal Spray, in these patients with risk factors.

It is recommended that patients who are intermittent long-term users of Dihydroergotamine Mesylate, USP Nasal Spray 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, USP Nasal Spray.

The systematic approach described above is currently recommended as a method to identify patients in whom Dihydroergotamine Mesylate, USP Nasal Spray may be used to treat migraine headaches with an acceptable margin of cardiovascular safety.

Cardiac Events and Fatalities

No deaths have been reported in patients using Dihydroergotamine Mesylate, USP Nasal Spray. However, 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 (e.g., D.H.E. 45 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 D.H.E. 45 Injection; 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 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).

Other Vasospasm Related Events

Dihydroergotamine Mesylate, USP Nasal Spray, like other ergot alkaloids, may cause vasospastic reactions other than coronary artery vasospasm. Myocardial and peripheral vascular ischemia have been reported with Dihydroergotamine Mesylate, USP Nasal Spray.

Dihydroergotamine Mesylate, USP Nasal Spray 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, USP Nasal Spray 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, USP Nasal Spray and dihydroergotamine mesylate injection. Dihydroergotamine Mesylate, USP Nasal Spray is contraindicated in patients with uncontrolled hypertension.

An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5HT1 agonist in a study evaluating subjects undergoing cardiac catheterization.

Local Irritation

Approximately 30% of patients using Dihydroergotamine Mesylate, USP Nasal Spray (compared to 9% of placebo patients) have reported irritation in the nose, throat, and/or disturbances in taste. Irritative symptoms include congestion, burning sensation, dryness, paraesthesia, discharge, epistaxis, pain, or soreness. The symptoms were predominantly mild to moderate in severity and transient. In approximately 70% of the above mentioned cases, the symptoms resolved within four hours after dosing with Dihydroergotamine Mesylate, USP Nasal Spray. Examinations of the nose and throat in a small subset (N = 66) of study participants treated for up to 36 months (range 1-36 months) did not reveal any clinically noticeable injury. Other than this limited number of patients, the consequences of extended and repeated use of Dihydroergotamine Mesylate, USP Nasal Spray on the nasal and/or respiratory mucosa have not been systematically evaluated in patients.

Nasal tissue in animals treated with dihydroergotamine mesylate daily at nasal cavity surface area exposures (in mg/mm) that were equal to or less than those achieved in humans receiving the maximum recommended daily dose of 0.08 mg/kg/day showed mild mucosal irritation characterized by mucous cell and transitional cell hyperplasia and squamous cell metaplasia. Changes in rat nasal mucosa at 64 weeks were less severe than at 13 weeks. Local effects on respiratory tissue after chronic intranasal dosing in animals have not been evaluated.

What are the precautions of Dihydroergotamine Mesylate?

General

Dihydroergotamine Mesylate, USP Nasal Spray 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. (See ).

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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, USP Nasal Spray, the information and instructions provided in the patient information sheet should be discussed with patients.

Once the nasal spray applicator has been prepared, it should be discarded (with any remaining drug) after 8 hours.

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, USP Nasal Spray, should not exceed the dosing guidelines and should not be used for chronic daily administration (see ).

Drug Interactions

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Dihydroergotamine Mesylate, USP Nasal Spray should not be used with peripheral vasoconstrictors because the combination may cause synergistic elevation of blood pressure.

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Sumatriptan has been reported to cause coronary artery vasospasm, and its effect could be additive with Dihydroergotamine Mesylate, USP Nasal Spray. Sumatriptan and Dihydroergotamine Mesylate, USP Nasal Spray should not be taken within 24 hours of each other.

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Although the results of a clinical study did not indicate a safety problem associated with the administration of Dihydroergotamine Mesylate, USP Nasal Spray 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.

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Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy.

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Weakness, hyperreflexia, and incoordination have been reported rarely when 5HT agonists have been coadministered 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, USP Nasal Spray or D.H.E. 45.

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The effect of oral contraceptives on the pharmacokinetics of Dihydroergotamine Mesylate, USP Nasal Spray has not been studied.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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Assessment of the carcinogenic potential of dihydroergotamine mesylate in mice and rats is ongoing.

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Dihydroergotamine mesylate was clastogenic in two 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 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 mouse and hamster micronucleus tests.

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There was no evidence of impairment of fertility in rats given intranasal doses of Dihydroergotamine Mesylate, USP 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).

Pregnancy

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Nursing Mothers

Ergot drugs are known to inhibit prolactin. It is likely that Dihydroergotamine Mesylate, USP Nasal Spray 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, USP Nasal Spray, nursing should not be undertaken with the use of Dihydroergotamine Mesylate, USP Nasal Spray.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Use in the Elderly

There is no information about the safety and effectiveness of Dihydroergotamine Mesylate, USP Nasal Spray in this population because patients over age 65 were excluded from the controlled clinical trials.

What are the side effects of Dihydroergotamine Mesylate?

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. (See , , and .). Fibrotic complications have been reported in association with long term use of injectable dihydroergotamine mesylate ().

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. ( )

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp at 1-877-233-2001 or FDA at 1-800-FDA-1088 or

What should I look out for while using Dihydroergotamine Mesylate?

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 (See ).

Dihydroergotamine Mesylate, USP Nasal Spray 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. (See )

Because Dihydroergotamine Mesylate, USP Nasal Spray may increase blood pressure, it should not be given to patients with uncontrolled hypertension.

Dihydroergotamine Mesylate, USP Nasal Spray, 5-HT1 agonists (e.g., sumatriptan), ergotamine-containing or ergot-type medications or methysergide should not be used within 24 hours of each other.

Dihydroergotamine Mesylate, USP Nasal Spray should not be administered to patients with hemiplegic or basilar migraine.

In addition to those conditions mentioned above, Dihydroergotamine Mesylate, USP Nasal Spray is also contraindicated in patients with known peripheral arterial disease, sepsis, following vascular surgery, and severely impaired hepatic or renal function.

Dihydroergotamine Mesylate, USP Nasal Spray 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, USP 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 -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, USP 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, USP Nasal Spray is contraindicated in patients who have previously shown hypersensitivity to ergot alkaloids.

Dihydroergotamine mesylate should not be used by nursing mothers. (See )

Dihydroergotamine mesylate should not be used with peripheral and central vasoconstrictors because the combination may result in additive or synergistic elevation of blood pressure.

Dihydroergotamine Mesylate, USP Nasal Spray should only be used where a clear diagnosis of migraine headache has been established.

What might happen if I take too much Dihydroergotamine Mesylate?

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, USP Nasal Spray 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, USP Nasal Spray overdose are similar to those of an ergotamine overdose, although there is less pronounced nausea and vomiting with Dihydroergotamine Mesylate, USP Nasal Spray. 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 Physicians' Desk Reference (PDR).

How should I store and handle Dihydroergotamine Mesylate?

Dihydroergotamine Mesylate, USP Nasal Spray is available (as a clear, colorless to faintly yellow solution) in 3.5 mL amber glass vials containing 4 mg of dihydroergotamine mesylate, USP. Dihydroergotamine Mesylate, USP Nasal Spray is provided as a package of 8 units, administration instruction sheet, and one package insert. Each unit consists of one vial and one sprayer. (NDC 68682-357-10)

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Clinical Information

Chemical Structure

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Clinical Pharmacology

Dihydroergotamine binds with high affinity to 5-HT and 5-HT receptors. It also binds with high affinity to serotonin 5-HT, 5-HT, and 5-HT receptors, noradrenaline α, α and α1 receptors, and dopamine D and D receptors.

The therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effect at 5-HT receptors. Two current theories have been proposed to explain the efficacy of 5-HT receptor agonists in migraine. One theory suggests that activation of 5-HT 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-HT receptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release. In addition, dihydroergotamine possesses oxytocic properties.

Non-Clinical Toxicology

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 (See ).

Dihydroergotamine Mesylate, USP Nasal Spray 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. (See )

Because Dihydroergotamine Mesylate, USP Nasal Spray may increase blood pressure, it should not be given to patients with uncontrolled hypertension.

Dihydroergotamine Mesylate, USP Nasal Spray, 5-HT1 agonists (e.g., sumatriptan), ergotamine-containing or ergot-type medications or methysergide should not be used within 24 hours of each other.

Dihydroergotamine Mesylate, USP Nasal Spray should not be administered to patients with hemiplegic or basilar migraine.

In addition to those conditions mentioned above, Dihydroergotamine Mesylate, USP Nasal Spray is also contraindicated in patients with known peripheral arterial disease, sepsis, following vascular surgery, and severely impaired hepatic or renal function.

Dihydroergotamine Mesylate, USP Nasal Spray 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, USP 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 -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, USP 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, USP Nasal Spray is contraindicated in patients who have previously shown hypersensitivity to ergot alkaloids.

Dihydroergotamine mesylate should not be used by nursing mothers. (See )

Dihydroergotamine mesylate should not be used with peripheral and central vasoconstrictors because the combination may result in additive or synergistic elevation of blood pressure.

Dihydroergotamine Mesylate, USP Nasal Spray should only be used where a clear diagnosis of migraine headache has been established.

Dihydroergotamine Mesylate, USP Nasal Spray 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. (See ).

During clinical studies and the foreign postmarketing experience with Dihydroergotamine Mesylate, USP Nasal Spray there have been no fatalities due to cardiac events.

Serious cardiac events, including some that have been fatal, have occurred following use of the parenteral form of dihydroergotamine mesylate (D.H.E. 45 Injection), but are extremely rare. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation. (See , , and ).

Fibrotic complications have been reported in association with long term use of injectable dihydroergotamine mesylate (see ).

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Professional

Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

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