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Migranal

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Migranal

Warnings
Precautions

WARNINGS

Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should only be used where a clear diagnosis of migraine headache has been established.

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 (See CONTRAINDICATIONS). 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 CYP3A4 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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, 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

Migranal® (dihydroergotamine mesylate, USP) Nasal Spray should not be used by patients with documented ischemic or vasospastic coronary artery disease. (See CONTRAINDICATIONS) It is strongly recommended that Migranal® 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, Migranal® (dihydroergotamine mesylate, USP) Nasal Spray 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 Migranal (dihydroergotamine mesylate spray) ® (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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, in these patients with risk factors.

It is recommended that patients who are intermittent long-term users of Migranal® (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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray.

The systematic approach described above is currently recommended as a method to identify patients in whom Migranal (dihydroergotamine mesylate spray) ® (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 Migranal® (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

Migranal® (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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray.

Migranal® (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, Migranal® (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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray and dihydroergotamine mesylate injection.

Migranal® (dihydroergotamine mesylate, USP) Nasal Spray is contraindicated in patients with uncontrolled hypertension. (See CONTRAINDICATIONS)

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 Migranal® (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 Migranal® (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 Migranal® (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/mm²) 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.

PRECAUTIONS

General

Migranal® (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 WARNINGS).

Fibrotic Complications: see WARNINGS: Fibrotic Complications

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 Migranal® (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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, should not exceed the dosing guidelines and should not be used for chronic daily administration (see DOSAGE AND ADMINISTRATION).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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

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.

Impairment of Fertility

There was no evidence of impairment of fertility in rats given intranasal doses of Migranal® (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

Pregnancy Category X. See CONTRAINDICATIONS.

Nursing Mothers

Ergot drugs are known to inhibit prolactin. It is likely that Migranal® (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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray, nursing should not be undertaken with the use of Migranal® (dihydroergotamine mesylate, USP) Nasal Spray. (See CONTRAINDICATIONS)

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 Migranal® (dihydroergotamine mesylate, USP) Nasal Spray in this population because patients over age 65 were excluded from the controlled clinical trials.

Last reviewed on RxList: 5/11/2009
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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